CALIFORNIA TUMOR TISSUE REGISTRY

PULMONARY PATHOLOGY

117TH SEMI-ANNUAL CANCER SEMINAR

Case Histories

MODERATOR: Thomas V. Colby, M.D. Mayo Clinic Scottsdale ' Scottsdale, Arizona

December 5, 2004 Hyatt Regency Hotel, Embarcadero Center San Francisco, California 8:30a.m.- 4:30 p.m. Case Histories Pulmonary Palhology

CASE#l (A.CC. #29893) There are two cases on the slide. Case lA. A 78-year-old man had an 11 x 8 x 7 em tumor removed by lobectomy. Much of the mass looked like consolidated lung tissue. Metastases to peribronchial lymph nodes were identified. Case lB. A 64-year-old man presented with consolidation of the left lower lobe. Cytology was considered suspicious for malignancy and a left lower lobectomy was performed. Grossly there was extensive consolidation.

CASE #2 (ACC. #29874/18459/19179) There are two cases on the slide. Case 2A. A 58-year-old man was found to have an abnormal chest x-ray after evaluation for I~ months of cough. He was a former smoker, having quit 30 years earlier. He had a previous diagnosis of systemic blastomycosis. Radiologic studies revealed an 8.0 em diameter, cavila!y right upper lobe mass. Lobectomy was performed after prior biopsies. Metastases were found in one of s.even peribronchial lymph nodes. Case 2B (Comoosite from CTTRAcc. #18459 & 19179). (Ace# I 8459. Contributed by Avrum Jacobson, M.D.; Los .Angeles, CA) A 43-year-old Caucasian male presented with complaints of a persistent cough accompanied by mild lettchest pain. X-rays revealed an infiltrate in the left lower lobe, which partially resolved with a course o( antibiotics. Approximately one month later, there was a similar episode that was acCompanied by shortness of breath. Repeat x•rays showed that the infilttate in the left lower lobe persisted. Physical examination was otherwise unremarkable. Broncboscopic exan:iination revealed an obstruction of the left mainstem bronchus, at the junction of the upper and lower lobe orifices. During thoracotomy, a mass was noted in the superior segment of the !.eft lower lobe. The entire left lung was resected. The specimen consisted of a resected entire left lung. The pleural surface was gflly and relatively smooth, except over a small area that appeared somewhat tan and approximated an undedying tumor. A tumor mass measuring approximately 4.0 em in diameter arose in the hilar area and extended into the superior portioa of the lower lobe. In one foeus, the tumor appeared to extend into the left mainstem bronchus and appeared as a polypoid mass in the lumen of the left mainstem bronchus. Sectioning revealed a .gritty, firm gray mass. Several satellite nodules measuring up to I .0 em in diameter were noted in sqrrounding lung parenchyma. Lymph nOdes did not appear to be involved with tumor. The rumor extended to the pleura, but did not appear to pass through the pleura. (Ace# 19.179. Contributed by Milton L. Bassis, M.D.; San Francisco) A 68-year-old female stated that spots with calcium deposits were found in her lungs on radiologic examination at age 51. She now presents with a new radiologic le~ion m the right lung which was not present four months ago. There was no history of weight loss or hemoptysis. The patient had smoked two packs·of cigarettes per day for forty years. Chest x-ray sl!owed a mass in the right lower lobe which had progressively increased in size over a period of several months. During surgery, a golf ball-sized tumor was found beneath the pleura, close to a major fissure and .hilum of the

2 CITR 11.,.. Semi-Annual Cancer Seminar Case Histories Pulmonary Pathology right lower lobe. After the mass was shelled out from the lower lobe, a right lower lobectomy was performed. The tumor measured 3.0 em in its greatest dimension and bad a whitish-pink appearance. The external surface was irregular with linear reddish markings. The separately received right lower lobe did not contain any residual tumor.

CASE #3 (ACC. #29892)

A 38-year-old woman had carried a clinical diagnosis of sarcoidosis. She had been known to have cystic changes in the left lower lobe for some period of time and when this showed some radiologic change with consolidation of the adjacent parenchyma, a left lower lobectomy was eventually performed.

CASE #4 (ACC. #29896)

A 27-year-old woman was seen one week prior to death for cough. Her wbjte count was elevated and she was started on antibiotics and her condition apparently improved. She was found dead at home after having told a friend that she was hot and had pain in both ears. The patient had a bot tub in the basement of her home. The lungs weighed 1550 grams combined.

CASE #5 (ACC. #29875/14390) There are two cases on the slide.

Case SA (Ace. #29875). A 10-month old boy presented with shortness of breath and was found to have two cystic masses involving the lingula and left upper lobe. These were resected.; one measured 7.0 x 6.5 x 4.5 em and the other 9.0 x 6.0 x 3.5 em. The lesions were muJtiloculated without masses or nodules. Case 58 (Ace 14390). For several weeks prior to admission, a 4-year-old Caucasian male had been experiencing episodes of coughing which were -occasionally productive of frothy white sputUm in small amounts. Approximately one week before admission, there was an episode of possible dyspnea and. difficulty in catching his breath. Admission x-ray revealed a tension pneumothorax in the right, with large blebs in the right tower lobe. Despite the insertion of chest tubes, the pneumothorax persisted, with alternating recurrence and resolution. During surgery, a large cystic lesion containing debris and blood clot was found to arise from the inferior aspect of the interfissural plane ofthe right middle lobe, which was on an approximately I x 2 em pedicle. Markedly thickened pleura was removed from the right lower lobe. The specimen consisted of a pyramidal, 6.5 x 6.0 x 5.5 em multilobulated cystic fleshy mass. The walls of the cysts were smooth, although lobulated, and the cysts contained generally clear fluid which was focally inspissated. The fleshy portions were pink-tan, soft, focally honeycombed, and focally hemorrhagic. (Contributed by Seth Haber, M.D., Santa Clara, CA)

ClTR 111"' Semi·Annual Cancer Seminar 3 Case Histories Pulmonary Pathology

CASE #6 (ACC. #30081)

A 63 year old woman had a history of asthma and chronic cough. She presented with an elevated white. count (11,300) and eosinophilia (6.6%). She bad a mass in the right loweF lobe and underwent lobectomy. Grossly there was a consolidated region in the lobe measuring 9x8x7 em. This was yeUowish gray in appearance and was not grossly suspicious for carcinoma. Mucus plugs were noted in the large airways. Areas of bronchiectasis were noted.

CASE #7 (ACC. #29883)

A 49-year-old man presented with P.rogressive interstitial lung disease and restriction on pulmonary func~on testing. He ultimately underwent orthotopic lung transplantation and the sections are from the explanted lung tissue. (Case courtesy of R. Sobonya, Tucson, AZ)

CASE #8 (ACC. #29884)

A 40-year-old woman with cougb was found to have a left lower lobe mass that involveil the pleura and extended around the aorta.. Pneumonectomy was performed because of the extent of lung involvement although some residual mass was left around the lower thoracic aorta. The patient had a prior history of "uterine sarcoma" three years earlier.

CASE #9 (ACC. #29887) There are two cases on the slide. Case 9A. A 72-year..old asymptomatic man was found to have a nodule radiologically. This was eventually resected. Grossly the mass appeared to be centered on the pleura. Case 9B. A 79-year-old man was initially thought to have a parapneumonic pleural effusion. When this did notiCsolve be underwent thoracotomy and decortication.

CASE #10 (ACC. #29886)

A 43-year-old woman presented with pleuritic chest pain and was found to have a pleural-based mass with associated pleural thickening. Following biopsy she underwent left pleuropneumonectomy.

CASE #11 (ACC. #29885)

A 53-year-old woman had a large lung mass .resected by pneumonectomy. The mass was 14.0 x 8.5 x 5.0 em with satellite nodules in the surroUiilding lung tissue. She received chemotherapy.

4 CITR 117., Semi-Annual Cancer Seminar Case Histories Pulmonary Pathology

CASE #12 (Att. #29895)

A 72-year-old man presented with three months of fever, cough, and bilateral lower lobe infiltrates. He had extensive travel history and mycobacterial and fungal infections were considered. Cultures grew Haemophilus injluenzae.

CASE #13 (Ace. #29889)

An 80-year-old man was having preoperative evaluation for a large squamous carcinoma of the head and neck. He was found to have multiple pulmonary nodules and following a nondiagnostic needle biopsy one of the pulmonary nodules was resected.

CASE #14 (Ace. #29890) Due to paucity of material for two of the cases, the distributed slides each include three cases. The larger fragm.ent on each slide represents autopsy tissue from Case 14A. The smaller fragments represent either Case 14B or 14C. Case 14A. A 60-year-old woman was severely anemic due to a myelodysplastic syndrome which bad been characterized as refractory anemia with excess blasts. She required transfusion of two units of blood every two weeks. She bad a history of COPD and smoking. She was admitted to her final hospitaUzation with fever, increasing shortness of breath and pleural effusions. Sbe developed increasing leukocytosis (without frank leukemia), respiratory failure· and died ten days after admission. Autopsy confirmed infiltrates of immature cells in the lung, pleura, liver, spleen, peritoneum, lymph nodes, soft tissues, and multiple other sites. Case 14B. An adult woman presented with shortness of breath and pulmonary infiltrates. A clinical diagnosis could not be made and a surgical lung biopsy was performed. Case l4C. A 40-year-old man presented with symptoms of anemia and ultimately was found to have a "packed" marrow with 3-5% blasts. The main considerations were acute and chronic myelomonocytic leukemia. Adequate aspirates could not be obtained to evaluate. He also had a history of increasing shortness of breath for four months and this resulted in surgical lung biopsy.

CASE #15 (Att. #29873121388) There are two cases on the sUde. Case 15A (Ace. #29873). A 53-year-old woman underwent resection of what were described as "multiple pulmonary blebs." Tissue containing blebs and bullae up to 15.0 em in diameter were resected. The patient had had a prior hysterectomy for a " large leiomyoma." Case 15B (Ace 21388). For four to six months prior to admission, this 62-year-old Caucasian female experienced episodes of shortness of breath, which was brought on by mild activity while walking in her kitchen. She also noted a weight gain of 25-30 pounds. Routine chest x-ray revealed two suspicious areas in the left lung field, in addition to pleural effusion. The patient had undergone a hysterectomy fourteen years previously for uterine fibroids. Physical

CITR 117"' Semi-Annual Cancez- Seminar 5 Ca.o;e Histories PulmonAry Pathology examination revealed decreased breath sounds in the lower halfof the right chest, and rhonchi in the left lung, along with mles. The specimen consisted of a pinkish-red piece of focaUy anthracotic lung tissue weighing 19 grams and measuring 6.0 x 3.5 x 3.0 em. Half of the specimen consisted of a hard mass which, when sectioned, measured 3.0 em in maximum dimension. The cut surface of the mass was pinkish-white and had a fibrous consistency. The cut surface protruded above the rest of the specimen, and had an interlacing ropy appearance. (Contributed by Theodore Tsuyuki, M.D.; La Habra, CA.)

CASE #16 (Ace. #19888)

A 72-year-old woman presented with shortness of breath and was found to have multiple nodular infiltrates radiologicaUy. She had a history of amiodarone therapy for atrial arrhythmias. Several of the nodular lesions were removed for histologic diagnosis.

6 C1TR 111"' Semi-Annual Cancer Seminar CALIFORNIA TUMOR TISSUE REGISTRY

117™ SEMI·ANNUA~ CANCER SEMINAR

PULMONARY PATHOLOGY

PRELECTOR: Thomas V. Colby, M.D.

Mayo Clinic Scottsdale Scottsdale. Arizona

December 5, 2004 Hyatt Regency Hotel, Embarcadero Center San Francisco, California 8:30 a.m. - 4:30 p.m. 117nt CTTR SEMI-ANNUAL CANCER SEMINAR: PULMONARY PATHOLOGY TABLE OF CONTENTS CARCINOMA OF THE LUNG- WHO CLASSIFICATION page 3 Case 1 HISTOLOGICALLY UNUSUAL ADENOCARCINOMAS page 4 Case 2 SARCOMATOID CARCINOMAS OF THE LUNG page 8 Case 3 MUCINOUS CARCINOMA page 13 IMAGES (CASES 1-3) pages 21-23 ACUTE LUNG INJURY & GRANULOMATOUS INTERSTITIAL PNEUMONIA$

case 4 D I ~~¥~~~~~~':~E~M~~; SUPERIMPOSED ON A GRANULOMATOUS page 25 IMAGES (CASES 4, 5) page 35 BLASTOMAS OF THE LUNG AND CYSTIC LUNG LESIONS IN CHILDREN Case 5 PLEUROPULMONARY BLASTOMAS page 37 EOSINOPHILIC LUNG DISEASE MUCOID IMPACTION WITH BRONCHOCENTRIC GRANULOMATOSIS AND Case 6 EOSINOPHILIC PNEUMONIA CONSISTENT WITH ALLERGIC page 42 BRONCHOPULMONARY ASPERGILLOSIS IMAGES (CASE 6) page 51 FIBROSING INTERSTITIAL PNEUMONIA$, PSEUDOTUMORS, AND HISTIOCYTIC PROLIFERATIONS Case 7 ERDHEIM·CHESTER DISEASE WITH PULMONARY INVOLVEMENT page 53 Case 8 ROSAI·DORFMAN DISEASE page 59 IMAGES (CASES 7, 8) page 65 PLEURAL TUMORS Case 9A LOCALIZED EPITHELIOID' MESOTHELIOMA OF 11HE PLEURA. page 67 Case 9B SARCOMATOlD MESOTHELIOMA OF THE PLEURA. page 67 Case 10 PLEURAL EPITHELIOID HEMANGIOENDOTHELIOMA page 74 IMAGES (CASES 9A, 9B, 10) pages 79-81 VASCULAR TUMORS OF THE LUNG AND PLEURA Case 11 PULMONARY ARTERY SARCOMA page 83 IMAGES (CASES 11, 12) page 93 AIRWAY DISEASE

Case 12 BR~~':~T~~~~~~~~~ AND CHRONIC CELLULAR BRONCHIOLITIS AND page 95

LYMPHORETICULAR LESIONS OF THE LUNG Case 13 PRIMARY PULMONARY HODGKIN LYMPHOMA page 102 14A. ACUTE MYELOGENOUS LEUKEMIA Case 14 14B. ACUTE MYELOGENOUS LEUKEMIA page 110 14C. MYELOMONOCYTIC LEUKEMIA IMAGES (CASES 13, 14) page113 PULMONARY METASTASES Case 15 BENIGN METASTASIZING LEIOMYOMA page 115 IMAGES (CASES 15, 16) page 123 DRUG REACTIONS

Case 16 NO~~~~~~~:~~~~~~~~~~~~~~~~~ATED page 125 Contacting tha CTTR page 131 I. Carcinoma of the Lung WHO classification of preinvasive lesions and carcinomas: Preinvasive lesions Squamous dysplasia Carcinoma in situ Atypical adenomatous hyperplasia (AAH) Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) Malignant Squamous cell carcinoma Y ariants: Papillary, clear cell, small cell, basaloid Small cell carcinoma Combined small cell carcinoma· Adenocarcinoma Acinar Papillary Bronchioloalveolar carcinoma (BAC) Non-mucinous Mucinous Mixed mucinous and non-mucinous or indeterminate cell type Solid adenocarcinoma with mucin Adenocarcinoma with mixed subtypes (the most common) Variants: Fetal adenocarcinoma, mucinous ("colloid'1 adenocarcinoma, mucinous cystadenocarcinoma, signet-ring adenocarcinoma, clear-cell adenocarcinoma Large cell carcinoma Variants: Large cell neuroendocrine carcinoma (combined LCNEC), basaloid carcinoma, lymphoepithelioma-like carcinoma, clear cell carcinoma, large cell carcinoma with rhabdoid phenotype Adenosquamous carcinoma Sarcomatoid carcinoma Pleomorphic carcinoma Spindle cell carcinoma Giant cell carcinoma Carcinosarcoma Pulmonary blastoma Carcinoid tumour Typical carcinoid Atypical carcinoid Carcinomas of salivary-gland type Mucoepidermoid carcinoma Adenoid cystic carcinoma Others Unclassified carcinoma

ClTR 111• Cancer Seminar Pulmonary Pathology 3 CASE 1:

Clinical History: [There are two cases on the slide.]

Case lA (CTTR Ace. # 29893) A 78-year-old man had an 11 x 8 x 7 em tumor, removed by lobectomy. Much of the mass looked like consolidated lung tissue. Metastases to peribronchial lymph nodes were identified.

Key histologic features: Recognizable cohesive poorly differentiated adenocarcinoma in some areas away from the large zones of tumor cell discohesion with airspace filling.

Case l B

Key histologic features: Careful detail to the cytologic features of the cells flooding tlie airspaces; some signet ring forms and cells showing cytologic atypia are identified. Mucin- producing epithelial cells confirmed with histochemical and immunohistochemical stains. ·

Approach to Diagnosis

Both patients presented with mass lesions and a neoplasm should lead the differential even though the microscopy suggests an alveolar filling process such as D1P. An unusual histology for lung cancer should lead one to consider metastases which may be excluded with appropriate immunohistochemical stains, clinical, and radiologic findings.

Diagnoses: Histologically unusual adenocarcinomas.

Follow-up: Not available.

Discussion

The WHO classification is far from perfect but it offers a framework for classification that allows us all to speak the same language. It is oriente<;! to pathologists and the histologic patterns oflung tumors that they encounter.

One of the most distinctive features of lung carcinoma, particularly adenocarcinoma, is histologic heterogeneity and this is actually useful in differential diagnosis since most metastases tend to "breed true", in that they look like the primary tumors and they are generally similar from field to field. When separating primary lung C!lfCinoma from metastatic carcinoma there are a number of strategies: clinical and radiologic presentation, review of the histology of prior tumor(s), and comparison with the lung lesion and immunohistochemistry. Immunohistochemistry is often (but not always) helpful in recognizing primary lung carcinomas

4 Pulmonary Pathology CfTR II 7"' Cancer Seminar and distinguishing them from metastases. Useful immunohistochemical stains are continually evolving. The positive TTF-1 is good support for lung (or thyroid) primary but a negative stain, particularly in a poorly differentiated tumor does not exclude such a possibility. Similarly there are stains that strongly favor origin from another site such as CDX2 for gastrointestinal tract, thyroglobulin for thyroid, PSA for prostate, etc.

Lung cancers exhibit many unusual patterns, two of which are illustrated in the tumors presented. Some of the unusual patterns are:

1. Signet ring change in lung adenocarcinomas - in any such case one should consider a gastrointestinal primary but is a pattern that may be encountered in lung carcinoma. 2. Mucinous cystic tumors simulating mucoid impaction, including mucinous cystadenoma (very rare), and coi.Joid carcinoma/mucinous cystadenocarcinoma. Case I B is an example. 3. Well-differentiated adenocarcinoma with fibrosis and inflammation mimicking honeycomb change and inflammatory lung disease. 4. Highly discohesive tumors mimicking an alveolar filling process such as DIP ("malignant DIP"). Case lA is an example. 5. Sarcomatoid change (see case 2).

Case 18 would qualify in the category of mucinOl!S or colloid carcinoma of the lung.

The WHO International Histologic Classification of Tumors defines mucinous (colloid) adenocarcinomas as a distinctive subset of lung adenocarcinoma that resemble the similarly named counterpart in the gastrointestinal tract. Colloid adenocarcinomas are distinguished from standard lung adenocarcinomas by the presence of tumor cells floating in copious or surrounding mucin. In contrast to mucinous bronchiolo-alveolar carcinoma, colloid carcinomas lend to present as mass lesions rather than as lobar consolidation.

Colloid carcinoma of the·tung is among the group of mucin-rich tumors that has also been called mucinous cystic tumors; three categories have been described:

Mucinous cystadenomas are described as localized tumors with massive pooling of mucus, comprising a unilocular cyst with a wall encompassing the entire lesion. The lining epithelium is tall, columnar goblet cells with absent or minimal cytologic atypia. Invasive carcinoma and peripheral lipidic spread of tumor cells along alveolar walls is lacking. These are very rare.

Pulmonarv mucinous cystic tumors of borderline malignancy are partially encapsulated lesions with massive mucin production, few neoplastic cells, focal epithelial papillae, stratification and cytologic atypia, and focal dissection of mucus into the surrounding parenchyma where there is an associated inflammatory infiltrate. I am not convinced of tbe usefulness of this category.

Colloid (mucinous) carcinomas (also known as cystadenocarcinomas) show massive mucus accumulation with mucin and scant numbers of neoplastic columnar mucinous cells extending into surrounding lung parenchyma, often in a lipidic fashion. The neoplastic cells may be seen

CITR 1171b Cancer Seminar Pulmonary Pathology s floating in the mucin, and cytologically the cells show variable mild atypia. Focal areas of invasive adenocllfcinoma (with desmoplastic stroma:) may be identified.

Moran believes all mucinous cystic tumors should be considered low-grade carcinomas in view of their potential to metastasize, and I agree. Complete but conservative surgical excision of the tumor and long-term follow-up appearS to be the most appropriate treatment. Moran and coworkers identified the following features in 19 colloid carcinomas of the lung:

• Males more commonly affected than females • Mean age: 57 years (range 33-81 years) • All tumors were incidental radiologic findings • Size: 0.5 to 10 em • Gross: Poorly defined mass or mucoid consolidation • Microscopic features: Mucin greatly overshadowing neoplastic cells, some of which may be floating in the mucus and which show cytologic variation from field to field. Focal stromal invasion may be present. • Follow-up: 11 of 19 alive at 2 to 192 months.

Rossi et al. have recently described 13 primary mucinous carcinomas of the lung. These represented 0.24% of theii lung cancers. The clinical features were similar to those studied by Moran et al. Two of the 13 cases were composed entirely of signet ring tumor cells, similar to Case lB. The remaining II were the goblet cell type. Both patients with signet ring cancers died, where.as all 11 with goblet cell type carcinomas were alive. These authors did a battery of immunostains and there were also immunohistochemical differences between the two types of colloid carcinoma as shown below. The staining patterns for carcinomas in the differential ate also included below.

6 Pulmonary Pathology CTTR I 17"' Cancer Seminaz ImmufUJhistochemical features ofMC, m-BAC, and metastatic mucinous colorectal (MCRA) and gastric (MGA) adenocarcinoma *

Goblet cell·type MC Signet-ring cell-type JlfC m·BAC MCRA•

TTF· I +I· + ·I+

CDX·2 + + ·I+

CK7 +I· + + +I·

CK20 + + + ·I+

MUC2 + + ·I +

MUC5AC + + ·I+ + SP.A ·I+ +I · ·I+

Abbreviations: MC, mucinous carcinoma of the lung; m-BAC, mucinous bronchtoloalveolar carcinoma; MCRA. mucinous colorectal adenocarcinoma; MCA. mudnous gastric aden ocarcinoma; Ck7. cytokeratin 7; Ck20, cytokeratln 20; SP·A. surfactant apoproteln A.

•Modified from Rossi et al. Interestingly the mucinous variant SAC shows features distinct from that of the goblet cell type of colloid carcinoma ln addition to the gross and histologic differences there are also immunohistochemical differences as noted in the table above.

The diagnosis of colloid carcinoma can often be suspected grossly on the basis of a mucinous mass lesion. The key histologic fmdings are mucinous flooding of airspaces (and its presence: alone should alert one to search for neoplastic epithelium) and the identification of uniform, well differentiation mucinous cells that are similar one to the next and lack cilia. In some cases, moderate cytologic atypia, nuclear stratification, and mito1ic figures may be present.

Although well-differentiated mucinous epithelium lining alveolar spaces is nearly always indicative of a malignancy, similar epithelium may rarely be seen in congenital cystic adenomatoid malformations, lung cysts, and ~ part of pulmonary hamartomas.

References for Case 1 Colby TV, Koss M, Travis WD. Tumors ofthe lower respiratory tract (AHP fascicle, series #3). American Registry of Pathology, Washington, DC, 1995. Dixon AY, era!. Pulmonary mucinous cystic tumor. A case report with !he review of!he literature. Am J Surg Parholl993;7:722-728. Groeme-Cook F, Mark EJ. Pulmonary mucinous cystic tumors of borderline malignancy. Hum Parhol 1991 ;22:185-190. Higashiyama M, et a!. Cystic mucinous adenocarcinoma of !he lung. Chest 1992; I 01 :763-765. Krage! PJ. Mucinous cystadenoma of !he lung. Arch Parhol Lab Med 1990;114:1053-1056. Moran CA, et al. Mucinous (so-called colloid) carcinoma of!he lung. Mod Parhol1992;5:634-638. Moran CA. Mucin-rich tumors of the lung. Adv Anal Parhol 1995;2:299-305. Rossi 0, Murer B, Cavazza A, et al. Primary mucinous (so-called colloid) carcinoma ofrhe lung. A clinicopathologic and inununoWstochemical study with special reference to CDX-2 homiobox gene and MUC-2 expression. Am J Surg Pathol 2004; 28: 442-452 .. Roux EJ, er al. Mucinous cystadenoma of the lung. Cancer 199S;76: 1540-IS44. Tsuta K, lshii G. Yoh K, Nitadori J, Hasebe T, Nisbiwaki Y, Endoh Y, Kodama T, Nagai K, and Ochiai A. Primary lung carcinoma with signet-ring cell carcinoma components. Am J. Swg Palhol2004;28:868-874.

CASE 2

Clinical History: [There are two cases on the slide]

Case 2A CCTIR Ace. #29874) A 58-year-old man was found to have an abnormal chest x-ray after evaluation for I* months of cough. He was a former smoker, having quit 30 years earlier. He had a previous diagnosis of systemic blastomycosis. Radiologic studies revealed and .8.0 em diameter, cavitary right upper lobe mass. Lobectomy was performed after prior biopsies. Metastases were found in one of seven peribronchial lymph nodes.

Key histologic features: Some foci that are frankly carcinomatous are identifiable in addition to the spindle cell regions that might suggest a sarcoma; cytologically all the nuclei are more epithelial in appearance than mesenchymal.

8 Pulmonary Pathalogy CTTR 117*' Cancer Seminar Case 28 (Composite from CITR Ace.# 18459 & 19179) (Ace # 18459. Contnouted by A vrum Jacobson, M.D.; Los Angeles, CA) A 43-year-old Caucasian male presented with complaints of a persistent cough accompanied by mild left chest pain. X-rays revealed an infiltrate in the left lower lobe, which partially resolved with a course of antibiotics. Approximately one month later, there was a similar episode that was accompanied by shortness of breath. Repeat x-rays showed that the infiEtrate in the left lower lobe persisted. Physical examination was otherwise unremarkable. Bronchoscopic examination revealed an obstruction of the left mainstem bronchus, at the junction of the upper and lower lobe orifices. During thoracotomy, a mass was noted in the superior segment of the left lower lobe. The entire left lung was resected.

The specimen consisted of a re~ected entire left lung. The pleural surface was gray and relatively smooth, except over a small area that appeared somewhat tan and approximated an underlying tumor. A tumor mass measuring approximately 4.0 em in diameter arose in the hilar area and extended into the superior portion of the lower lobe. In one focus, the tumor appeared to extend into the left mainstem bronchus and appeared as a polypoid mass in the lumen of the left mainstem bronchus. Sectioning revealed a gritty, firm gray mass. Several satellite nodules measuring up to 1.0 em in diameter were noted in surrounding lung parenchyma. Lymph nodes did not appear to be involved with tumor. The tumor extended to the pleura, but did not appear to pass through the pleura.

(Ace # 19179. Contributed by Milton L. Bassis, M.D.; San Francisco) A 68-year-old female stated that spots with calcium deposits were found in her lungs on radiologic examination at age 51. She now presents with a new radiologic lesion in the right lung which was not present four months ago. There was no history of weight loss or hemoptysis. The patient had smoked two packs of cigarettes per day for forty years. Chest x-ray showed a mass in the right lower lobe which had progressively increased in size over a period of several months. During surgery, a golf ball-sized tumor was found beneath the pleura, close to a major fissure and hilum of the right lower lobe. After the mass was shelled out from the lower lobe, a right lower lobectomy was performed.

The tumor measured 3.0 em in its greatest dimension and had a whitish-pink appearance. The external surface was irregular with linear reddish markings. The separately received right lower lobe did not contain any residual tumor.

Key histologic features: Cytologically malignant mesenchymal and epithelial (squamous) components readily recognizable. Primitive malignant mesenchymal tissue.

Diagnosis: Sarcomatoid carcinomas of the lung (2B ==carcinosarcoma).

Follow-up: The patient illustrated in 28 died of an intracerebral hemorrhage one year after resection and at autopsy had metastasis to the right lung and multiple mediastinal lymph nodes.

CITR 111"' Cancer Seminar Pulmtmary Patl!ology 9 Discussion

Do sarcomas of the lung exist? One only need look at the literature on sarcomas ,of the lung to see that: there was a flurry of activity in the 1970's and 1980's and relatively few series since then. I suspect a number of those "sarcomas'' are now recognized as-sarcomatoid carcinomaS, Be that as it may, virtually all patterns of soft tissue sar:coma encountered in the soft tissue have been reported in the lung, Recently it has been shown that monophasic svnovial sarcoma (with its characteristic chromosomal translocation) is a form of sarcoma that may be encountered in the lung.

Lung cancer heterogeneity represents a fortnidable barrier to histologic classification of lung neoplasms. While the majority of ·cases fall into the classic four categories of squamous carcinoma, adenocarcinoma, large cell carcinoma, and small cell carcinoma,, there is an appreciable percentage (- 5%) that show divergent differentiation and make classification difficult In the current WHO classification, most of these fall into the sarcomatoid carcinoma category, as shown above. This group of tumors commonly includes a component ofij>indle cells but spindle cells ;1lso may be identified in many other malignant tumors in the lung.

The longstanding Armed Forces Institute of Pathology (AFlP) approach to carcinomas with pleomorphic, sarcomatoid or sarcomatous elements' places the majority into the separate categories of pleomorphic carcinoma and carcinosarcoma. The alternative view suggests these tumors should be considered sarcomatoid carcinomas and this latter view reflects the current approach in the WHO classification and in a variety of organ systems in which carcinomas with spindled elements that resemble a sarcoma are considered to be derived from epithelial cells (ilnd thus "sarcomatoid" carcinomas).

Pleomomhic carcinoma encompasses cases of lung carcinoma that show an exaggerated degree­ of histologic heterogeneity, particularly spindle and/or giant cell foci. This is a useful umbrella concept in carcinoma of the lung, particularly since cases in this category tend to show a.varie(y of histologic patterns and in any one case, one may encounter spindle cell foci, giant cell foci, and more typical, squamous, adeno- or large cell carcinoma. Pure giant cell and pure spindle cell carcinomas are very

Carcinosarcoma is defmed as a malignant tumor with a mixture of carcinoma and sarcoma containing differentiated mesenchymal elements such as cartilage, bone and skeletal muscle. In comparing the AFlP series of carcinosarcoma with the AFlP series of pleomorphic carcinoma, there was no difference in size of tumors, stage at presentation, loca~ion in the lung, or overall survivaL A significantly greater portion of patients with carcinosarcoma had squamous cell or adenosquamous differentiation, whereas pleomorphic carcinomas had a significantly greater frequency of adenocarcinoma and large cell carcinoma. It is suggested that these are different entities with similar behavior, but it seems to .me that conclusion is begging the issue.

10 Pulmonary Parhology CfTR 11 7'" Cancer Seminat Wick .has favored sarcomatoid carcinoma as an encompassing concept, and has proposed the following (somewhat cumbersome) groupings: • Homologous biphasic sarcomatoid carcinoma (formerly called spindle cell carcinomas) • Heterologous biphasic sarcomatoid carcinoma (carcinosarcoma by other classifications) • Monophasic sarcomatoid carcinoma (epithelial differentiation only recognized immunoliistochemically or ultrastructurally) • Special variants: Pulmonary blastoma (including pulmonary endodermal tumor resembling fetal lung or well-differentiated adenocarcinoma simulating fetal lung being a close cousin) Pseudoangiosarcomatous carcinoma Inilammatory sarcomatoid carcinoma

The current WHO classification recognizes the umbrella concept of sarcomatoid carcinoma but then emphasizes the variety of histologic patterns that are included in this category.

Regardiess of the conceptual approach favored. epithelial features need to be proven in this group of tumors either by finding foci with typical epithelial differentiation in routine hematoxylin and eosin sections or confirmation of epithelial differentiation immunohistochemically (with "epithelial" markers) or ultrastructurally. The possibility that one l!iight encounter a tumor in this category in which epithelial differentiation cannot be demonstrated is discussed below.

The spindle cell component in sarcomatoid carcinoma has distinctive ·cytologic features. The cells tend to be larger, fatter, and plumper than typical sarcoma cells, and the nuclei are often larger, rounder, and have more prominent nucleoli. They may merge with polygonal cell foci which resemble conventional large cell carcinoma of the lung. Interestingly, fine needle aspirations from such tumors are usually interpreted as large cell carcinomas.

Sarcomatoid carcinomas also show distinctive histologic features including invasion of large ·vessels, interstitial in alveolar walls surrounding small acinar structures of metaplastic alveolar lining ce1ls, pseudoangiosarcomatous growth, central necrosis and inflammation resembling an abscess/organizing pneumonia, spindled and inflammatory foci resembling inflammatory pseudotumor, rounded necrotic nodules resembling necrotizing granulomas, and cellular dyscohesion and inflammation reminiscent of that seen in inflammatory malignant fibrous histiocytoma and Hodgkin's disease (as well as classic giant cell carcinoma of the lung). In large masses, it may take extensive sampling to identifY foci ofrecognizable epithelial differentiation.

Given the histologic changes described above, sarcomatoid carcinomas may be misinterpreted as: Interstitial fibrosis Abscess with surrounding Organizing pneumonia organizing pneumonia Plasma celi granuloma/ Thromboembolic disease inflammatory myofibroblastic tumor Sarcomas of various types Hodgkin's disease

C1TR 117°' Cancer Seminar Pulmonary Pathology II Many cases are interpreted as inflammatory fibroblastic lesions or abscesses, despite a clinical history suspicious for carcinoma of the lung.

Sarcomatoid carcinomas have a worse prognosis than other non-small cell lung cancers in some series but not all. These tumors should be managed as non-small cell lung cancers.

For tumors that lack a really recognizable epithelial component on hematoxylin and eosin stains, a diagnosis of sarcomatoid carcinoma has traditionally· rested on demonstration of epithelial differentiation immunohistochemically or ultrastructurally. Practically speaking, this can be accomplished in most cases with immunohistochemistry although one does encounter the occasional case that shows the distinctive cytologic features descn"bed above but which lacks identifiable epithelial differentiation at least in the regions sampled. Immunoreactivity for epithelial markers may be only focal and that focus may not have been sampled. In addition, it is known that large cell carcinomas (as readily recognized in hematoxylili and eosin reactions) may lack immunohistochemical ot ultrastructural features of epithelial differentiation in 10-15% of cases. Thus one could encounter a sarcomatoid carcinoma in which epithelial differentiation ~was not readily apparent in the tissue examined.

Key Features of Sarcomatoid Carcinomas

• Associated inflammation and fibrosis (inflammatory sarcomatoid carcinoma). • Vascular invasion (sometimes with infarction). • Interstitial growth. • Histologic he,terogeneity (emphasizing the role ofthe sampling). • Immunohistochemical demonstration of epithelial differentiation may be focal. • Preoperative cytologic preparations may be more recognizable as carcinomatous

References for Case 2 Chang YL,Lee YC, Shih JY, Wu CT. Pulmonary plcomowhis (spindle) cell carci.noma: peduliar clinicopathologic manifestations different ftomordinary non-small cell carcinoma. Lung Cancer 200 I ;34.:91-97. Colby TV, Koss MN, Travis WD. Tumors ofthe respiratory tract In; Atlas ofTumor Pathology. Third series, fascicle 13·, AFIP, Washington DC, 1995. Dacic S, Finkelstein SO, .Sasatomi E, Swalslcy PA, Yousem SA. Molecular pathogenesis of pulmonary carcinosarcoma as.determined by microdisseCtion-based allelotyping. Am J Surg Pathol 2002;26;51 0-516. Fishback N, Travis WD, Moran C, Guinee DG, McCanhy W, Koss M. Pleomorphic (spindle/giant cell) carcinoma of t!te lung; A clinicopathologic studY of78 cases. Cancer 73;~936-2945, 1994. Holst VA, Finkelstein S, Colby TV, Myers JL, Yousem SA. p53 and K-ras mutational ge:notyping in pulmonary carcinosarcoma, spindle cell carcinoma, and pulmonary blastoma; implications for histogenesis. Am J Surg Patho1l997;21:801-811. Humphrey R, Scroggs M, Roggli V. Shelburne J. Pulmonary carcinomas with a sarcomatoid element: An immunocytochemical and ultrastructural analysis. Hum Pathol 1988;19;155-165. Koss MN, Hochholzer L, Frommelt RA. Garcinosarcom:\5 of the lung. A clinicopathologic study of 66 patients. Am J Surg Pathol 1999;23 : 1514-1526. Nakajima M, Kasai T, Hashimoto H, Iwata Y, Manabe H. Sarcomatoid carcinoma ofthe lung. Cancer 1999;86;~08-616. Nappi 0 , Glasner SD, Swanson PE, Wick MR. Biphasic and monophasic sarcomatoi.d carcinomas of the lung. Am J C1in Pathol 1994; I 02:331-340.

12 Pulmonary Pathology CTTR 117"' Cancer Seminar Nishida K, Kobayashi Y, Ishikawa Y"Satoh Y, Okumura S, Nishimura H, Nakagawa K, Nakamura K, Koike M, Tsuchiya E. Sarcomatoid adenocarcinoma of the lung: clinicopathoiogical, immunohistochemical and molecular analyses. Anticancer Res 2002;22:3477-3483 Pelosi G, Scarpa A, Manzotti M, Veronesi G, Spaggiari L, Fraggetta F, Nappi 0 , Benini E, Pasini F, Antonello D, Iannucci A, Maisonneuve P, Viale G. K-ras gene mutational analysis supports a monoclonal origin ofbiphasic pleomorphic carcinoma of the lung. Mod Pathol2004;17:538-546. Pelosi G, Fraggetta F, Nappi 0, Pastorino U, Maisonneuve P, Pasini F, Iannucci A, Colli P, Musavinasab HS, De Manzoni G, Terzi A,. Viale G. Pleomorphic carcinomas of the lung show a selective distribution ofgene products involved in cell differentiaiton, cell cycle control, tumor growth, and tumor cell motility: a clinicopathologic and immunohistochemical study of31 cases. Am J. Surg Pathol 2003;27: 1203-1215. Rainosek DE, Ro JY, Ordonez NG, Kulaga AD, Ayala AG. Sarcomatoid carcinoma of the lung; A case with atypical carcinoid and rhabdomyosarcomatous components. Am J Clio Pathol 1994; I 02:360-364. R~ JY, Chen JL, Lee JS, et al. Sarcomatoid carcinoma of the lung. Immunohistochemical and ultrastructural studies of 14 cases. Cancer 1992;69:376-386. Roggli VL, Vollmer RT, Greenberg SO, McGavran MH, Spjut HJ, Yesne:r R. Lung cancer heterogeneity: a blinded and randomized study of I 00 consecutive case&. Hum Pathol 1985; 16:569-579. .Rossi G, Cavazza, Sturm N, Migaldi M, Facciolongo N, Longo L, Maiorana A, Brambilla E. Pulmonacy carcinomas with·pleomorphic, sarcomatoid, or sarcomatous elements: a clinicopathologic and immuilohistochemical study of75 c;ases. Am J Surg Patl:lol2003;27:311 -324. 'Tamboli P, Toprani TH, Amin MB, RoJS, Ordonez NG, Ayala AG, Ro JY. Carcinoma ofthe lung with rhabdoid features. Hum Pathol2004;.35:-13. Thompson t., Chang B, Barsky SH. Monoclonal origins of malignant mixed tumors (carcinosarcomas). Evidence for a divergent histogenesis. Am J Surg Patholl996;20: 277-285. Travis WD, Brambilla.E, Harris CC, Mul ler-Herm~link HK Ed: World Health Organization Classification of Tumours, Pathology and Genetics: TumourS ofthe Lung, Pleura, Thymus and Heart, !ARC, Lyon (in press). Travis WD, Colby TV, Corrin B, Shimosato Y, and Brambilla E. Histological Typing of Lung and Pleural Tumors. 3,. Edition, Springer, 1999. Wick MR. Ritter JH, Nappi 0. lnfla.mmatocy sarcomatoid carcinoma oftbe lung. Rum Patholl995;26:1014-1021. Wick MR. Ritter JH, Humphrey PA. Sarcomatoid caricnomas of the lung. A clinicopathologic review. Am J Clin Pathol 1997;108:40-53.

CASE3

Cllnical History: (CTTR Ace. # 29892): A 38-year-old woman .had carried a clinical diagnosis of sarcoidosis. She had been known to have cystic changes in the left lower lobe for some period of time and when this showed some radiologic change with consolidation of the adjacent parenchyma, a left lower lobectomy was eventually performed. \ Key histologic features: Confirmation of the cyst as identified radiologically; mucinous BAC evidence (not ·in all blocks) involving lung tissue at the periphery of the cyst; mucinous epithelium in the cyst wall; associated granulomas characteristic of sarcoidosis.

Diagnoses: (1) Mucinous bronchioloalveolar carcinoma complicating cystic lung disease. (2) Sarcoidosis.

Follow-up: Not available.

CITR 111ob Cancer Seminar Pulmonary Pathology 13 Approach to Case 3

Identification of and recognition of the pre-existing cyst(s); knowledge of preoperative radiologic findings useful to know that a cyst should be sought.

Histologic evaluation of the consolidated region identified radiologically around the cyst.

Identification of granulomatous inflammation confirming prior diagnosis of sarcoidosis. Assess histologic features (necrosis, distribution, associated findings). A significant finding or an incidental fmding?

Discussion This case raises a number of issues for discussion.

l. The distinction of intrapulmonary bronchogenic cyst from congenital cystic adenomatoid malformation (CCAM). 2. Malignancy arising in association with lung cysts and CCAMs- these include carcinomas, sarcomas, as well as the distinction of a type 4 CCAM from purely cystic pleuropulmonary blastoma. 3. The significance of well-differentiated mucinous epithelium lining alveolar walls.

The distinction between intrapulmonary bronchogenic cysts from predominantly cystic CCAM is not well defined. CCAM represents a malformation and in most cases one can identify abnormal lung tissue, usually bronchioles, whereas intrapulmonary cysts, including bronchogenic cysts, comprise only the cyst (or cysts) without accompanying recognizable malformed lung tissue. This distinction is probably easier to conceptualize than to make practically in some cases. Interestingly, most of the reports of intrapulmonary bronchogenic cysts are in adults whereas most CCAMs are recognized in children and one might wonder 'if CCAMs could change over time and ultimately be recognizable only as a cyst in older individuals.

The most interesting aspect of this case is the development of malignancy in association with cystic lung disease. IThere are two main groups of lesions described: Carcinoma, usually BAC, developing in patients with lung cysts or patients that have (or have had) CCAMs, and reports of sarcomatous or blastomatous transformation of cystic lung disease (see Case 5).

There have been a number of case reports of malignant transformation of lung cysts and the development of carcinoma in patients with a history of a CCAM. In a recent review from the Brompton Hospital, MacSweeney et al. studied 28 CCAMs, 5 had accompanying microscopic foci of BAC and two others showed mucous cell hyperplasia. Two additional cases had foci of atypical adenomatous hyperplasia in the adjacent lung parenchyma. There are reports of-young adults with radiologically documented cystic lung disease who have developed BAC in the adjacent parenchyma and ·the seminar case represents such an example. These cases have led some to consider that the mucinous epithelium that lines lung cysts and that may be a finding in

14 Pulmonary Pathology CTTR 117"' Cancer Seminar CCAM (primarily type I) has malignant potential. This view is not universally accepted. However, the finding of mucous cell hyperplasia in two cases of MacSweeney et al. and the histologic similarity between the lining epithelium of the cyst and the mucinous cells comprising lhe BAC in the seminar ease (and others from the literature) might favor the malignant potential of this epithelium.

There are also reports of sarcomas complicating cystic lung disease. With the description of pleuropulmonary blastoma it has become apparent that most of those cases represented pleuropulmonary blastomas with a cystic component misinterpreted as a cyst or CCAM. This is discussed with Case 1#5.

The original classification of CCAM included types I, 2, and 3. Recently that classification has been extended to include 5 types (type 0 - type 4). The differences between these types are summarized in the following table which ls taken from the report by MacSweeney et al.

ClTR I 17"' Cancer Seminar Pulmonary Pathology IS ( The extended classification of congenital cystic adenomatoid malformations

Proportional Type Gross Appearance Microscopy Other features Incidence 0 1-3% Solid. The lungs are small and firm Bronchial-type airways that have cartilage, smooth Neonates throughout. muscle and glands are separated by abundant Other malformatiQns mesenchymal tissue Poor prolli!osis I 60-700/o Large cysts (up to !Ocm) The cysts are lined by pseudostratified Presentation may be late Ciliated cells that are often interspersed Resectable with rows ofmucous cells Good prognosis Rare cases show carcinomatous change 2 10-15% Sponge-like. composed of multiple The cysts resemble dilated bronchioles Neonates small cysts (up to 2cm) and solid pale Separated by l).Onnal alveoli Other malformations tumour-like tissue Striated muscle in 5% Poor prognosis 3 .5% Solid There is an excess of brOnchiolar structures separated Neonates by air spaces that are small, have a cuboidal lining Poor prognosis and resemble late fetal lung 4 15% Large cysts (up to lOcm) The cysts are lined by a flattened epitbeliwn resting Neonates and infant~ upon loose mesenchymal tissue Good prolli!osis Type 4 CCAMs are thought by Stocker to be malformati.ons of the distal lung tissue and as such there arc.large cysts with thin septa lined by flattened epithelium resembling alveolar lining cells. These are difficull to distinguish from cystic pleuropulmonary blastomas which have only a focal interstitial malignant mesenchymal component (see Case 5). MacSweeney et al. concluded that in some cases there is sufficient ovedap that the distinction between these two entities may not lle possible on bisto\ogy alone. They noted that the presence of stromal hyperceUularity, even if focal, in a suspected type 4 CCAM should raise the possibility of a cystic pleuropulmonary blastoma. One of their cases of type 4 CCAM proved at follow-up (at the time of a recurrence) to be a. pleuropulmonary blastoma.

References for Case 3 de Perrot M, Pache JC, Spiliopoulos· A. Carcinoma arising in congenital lung cysts. Thorac Cardiovasc Surg 2001;49:184-5 Granata C, Gambini C, Balducci T et at. Bronchioloalveolar carcinoma arising in congenital cystic adenomatoid malformation in a child: a case report and review on malignancies originating in congeni1al cystic adenomatoid malfor:mation. Pediatr Pulmonol 1998;25:62-6 KaSiovsky RA, Purdy S, Dangman BC et at. Bronchioloalveolar carcinoma in a child with congenital cystic adenomatoid malformation. Chest 1997;112:548-51 MacSweeney F, Papagiannopoulos K, Goldstraw P, Sheppard MN, Corrin B, and Nisholson AG. An assessment of the expanded classification of congenital cystic adenomatoid malformations, and their relationship to malignant transformation. Am J Surg Pathol. In Press for 2003. Marotti RA, Cangiarella J, Gutierrez MC et at. Congenital cystic adenomatoid malformation of the lung (CCAM): -Evaluation of the cellular components. Hum Pathol 1999;30:618-25 Papagiaonopoulos K, Hughes S, Nicbolson AG et al. Cystic lung lesions in the pediatric and adult. population: surgical experience at the Brompton Hospital. Ann Tborac Surg 2002;73:1·594--8 P-richard MG, Brown PJ, Sterrett GF. Bronchioloalveolar carcinoma arising in longstanding lung cysts. Thorax 1984;39:5>15-9 Ribel ME, Copin MC, Soots JG et at. Bronchioloalveolar carcinoma and congenital cystic adenomatoid malformation. Ann Thorac Surg 1995;60: 112·6-8 Sheffield EA, Addis BJ, Corrin B et at. Epithelial hyperplasia and malignant change in congenital lung cysts. J Clin Patholl987;40:612-4. Stocker JT. Co!:F,enital and Developmental Diseases, Chapter 7. In: Dail DH, and Hammar SP. Pulmonary Pathology, 2 Edition, Springer, New York, 1994; pp. 155-190. Stocker )T. Congenital pulmonary airway malformation - a new name and an expanded classification of congenital cystic adenomatoid malformations ofthe lung. Histopathol 2002;41 (s'tlppl 2}:424-431.

Lung Cancer Precursors/Lesions While the cause--of many forms of lung cancer is well known (especially smoking) precursor lesions are less well characterized and identifiable in only a minority of cases. These include:

1. Squamous dysplasia and carcinoma in situ (CIS) in the large airways.

2. Atypical adenomatous hype1plasia (AAH) as a precursor to non-mucinous bronchioloalveolar carcinoma.

C'JTR I l71h Cancer Seminar Pulmonary Pathology 17 3. Diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) and carcinoid turnorlets as a precursor to peripheral carcinoid tumors.

4. Mucinous epithelium in lung cysts and congenital cystic adenomatoid malformations as a rare precursor to some· cases of adenocarcinoma, usually mucinous bronchioloalveolar type (and this association remains controversial).

AAH has received the most interest recently. AAH is generally encountered in lobectomy specimens for (adeno) carcinoma (up to 35% of resections) but is also recognized radiologically leading to biopsy or may be recognized at the time of surgery in lobes other than that in which a carcinoma has been found.

The WHO definition is as follows: "AOO>ical adenomatous hyperplasia (AAH) is a localized proliferation of mild to moderately atypical cells lining involved alveoli and, sometimes, Tespiratory bronchioles, resulting in focal lesions in peripheral alveolated lung, usually .less than 5 mm in diameter and generally in the absence of underlying interstitial inflammation and fibrosis."

Primary diagnostic consideration for AAH is non-mucinous BAC, which according to the WHO definition is an in situ proliferation (yet still classified among carcinomas). There have been a number of studies that have confirmed the close relationship between AAH and non-mucinous BAC (see Colby, Kerr, Kitamura references). Recognizing the close relationship between Ae.H ahd BAC, it is not surprising that there may be difficulty in distinguishing them . . Non-mucinous BAC is typically greater than 5 mm in diameter with marked cellular stratification, high cell density, marked overlapping of nuclei, coarse nuclear chromatin, the presence of nucleoli, columnar cell change with eel! crowding, and micropapillary tufting. AAH usually shows no more than one of these features.

Both BAC and AAH should be distinguished from peribronchiolar metaplasia, a common reparative phenomenon.

From a practical point of view the distinction betweenAAH and small BACs may be irrelevant if the lesion is entirely resected and the margins of resection are. negative (for example, in a wedge resection). Adenocarcinomas less than 2.0 em in diameter, even those with associated foci of invasive carcinoma (if less than 0.5 ·em) may be curable by wedge resection and thus at the time of frozen section for such a lesion one's main concern should be adequacy of excision. Some of the date for this includes:

Yokose' et a!. (2000) studied 200 adenocarcinomas 3.0 em or smaller. There was 100% seven-year survival in the 66 cases (33%) with greater than 75% BAC pattern, central fibrosis less than or equal to 0.5 em, and no elastic tissue destruction.

Suzuki et al. (2000; from the same institution as Y okose) studied 100 adenocarcinomas 3.0 em. or smaUer. There was 100% seven-year survival in the il patients (21 %) with central fibrosis less than or equal to 0.5 em.

18 Pulmonary Parhology CTTR 11711> Cancer Seminar Maeshima et al. (2002) studied 239 adenocarcinomas 3.0 em or smaller. There is 100% ten-year survival for the 29 cases ( 12%) with SAC pattern and /or no desmoplastic reaction.

Terasaki et al. (2003) studied 484 adenocarcinomas in 441 patients.

I. I 02 (21 %) were BAC (size 1.5 +!- 1.8 em). This group had no LN metastases, no lymphatic invasion, no vascular invasion, and no pleural invasion. 2. 54 (II%) were BAC plus invasive foci Jess than or equal to 0.5 em (size 2. 1 +1- 1.4 em). This group had no LN metastases and low rates of lymphatic (5.5%), vascular (14.8%), and pleural (1.9%) invasion.

Thus there is a 5-year survival of 100% for small resected BAC's and nearly 100% survival for small (2 em or less) mixed type adenocarcinomas with a predominant BAC pattern (or ground glass change on HRCT) and central scarring less than 0.5 em in diameter (even if focal invasion is present). Studies of regional lymph nodes in this setting (Ishiwa et al.) show an absence of metastatic disease (including and absence of micrometastases) in SACs Jess than 2.0 em in diameter.

References for AAH and Small BAC Aoki T, Tomoda Y, Watanabe H, Nakata H, K.asai T, Hashimoto H, Kodate M, Osaki T, Yasumoto K. Peripheral tung adenocarcinoma: correlation of thin-section cr findings with histologic prognostic factors and survival. Radiology 2001 ;220:803-809. Colby TV, Wistuba JJ, Gazdar A. Precursors to pulmonary neoplasia. Adv Anal Patbol 1998;5:205-215. Ginsberg RJ, Rubenstein LV, for the Lung Cancer Study Group. Randomized Trial of Lobectomy vs. Limited Resection for Tl NO Non Small Cell Lung Cancer. Ann Thorac Surg 1995;60:615-623. Goldstein NS, Ferkowicz M, Kestin L, Chmielewski OW. and Welsh RJ. Wedge nesection margin distances and residual adenocarcinoma in lobectomy specimens. Am J Clin Palhol 2003; 120:720-724. lshiwa N, Ogawa N, Shoji A, Maehara T, Yayashi Y, Takanashi Y, Y112awn T, Ito T. Correlation between lymph node micrometastasis and histologic classification of small lung adenocarcinomas, in considering the indication of limited surgery. Lung Cancer 2003;39: l 59-164. Kerr KM. Pulmonary preinvasive neoplasia. J Clin Pathol 200 I ;54:257-271. Kitagawa H, Goto A, Niki T, Hironaka M, Nakajima J, Fukayama M. Lung adenocarcinoma associated with atypical adenomatous hyperplasia. A clinicopalhological study with special reference to smoking and cancer multiplicity. Pathollnt 2003;53:823-827. Kishi K, Homma S, Kurosaki A, Motoi N, Kohno T, Nakata K. Yoshimllf8 K.. Small lung tumors with the size of I em or less in diameter: clinical, radiological, and histolopathologica1 characteristics. Lung Cancer 2004;44:43- 51. Kitamura H, Kameda Y, Ito T, ~l ayashi H. Atypical adenomatou.• hyperplasia of the lung: Implications for the putl1ogenesis of peripheral lung adenocarcinoma. Am J Clin Pathol 1999; Ill :610-622. Kodama K. Higashiyama M, Yokouchi H, Tllkami K, Kuriyama K. Mano M, Nakayama T. Prognostic value of ground-glass opacity found in small lung adenocarcinoma on high-resolution CT scanning. Lung Cancer 2001 ;33: 17-25. Kodama K. Higashiyama M, Yokouchi H, Takami K, Kuriyama K, Kusunoki Y, Nakaua, and Imamura F. Natural history of pure ground-glass opacity after long-term follow-up of more than 2 years. Ann Thorac Surg 2002;73:386-393. Koike T, Yamato Y, Yoshiya K, Shimoyama T, Suzuki R. Intentional limited pulmonary resection for peripheral Tl NO MO small-sized lung cancer. J Thorac Cardiovnsc Surg 2003; 125:924-928. Kondo 0, et al. Peripheral lung adenocarcinomas: I 0 mm or less in diameter. Ann Thorac Surg 2003;76:350-355.

CTTR 117'" Cancer Seminar Pulmonary Pathology 19 Maeshima AM, Niki T, Maeshima A, Yamada T, Kondo H, Matsuno Y. Modified scar grade. A Prognostic indicator in small periphenl lung adenocarcinoma. Cancer 2002;95:2546-2554. Miller RR. Bronehiolo-alveolar cell adeoomas. Am J Surg Palhol 1990; 14:904-912. Mori M, Rao SK, Popper HH, Cagle PT, Fraire AB. Atypical adenomalolls hyperplasia ofthe lung: A probable forerunner in the development ofaden ocarcinoma ofthe lung. Mod Pathol 2001;14:72-84. Nakahara R, Yokose T, Nagai K, Nishiwaki Y, Oehiai A. Atypical adenomatous hyperplasia ofthe lung: a clinicopathological study of I I 8 cases including cases with multiple atypical adenomatous hyperplasia. Thorax 2001 ;56:302-305. Nakamura H, Sl\i i H, Ogata A, Saijo T, Okada S, Kato H. Lung cancer patients showing pure ground-glass opacity on computed tomogrqaphy are good candidates for wedge resection. Lung Cancer 2004;44:61-68. Noguchi M, Morikawn A, Kawasaki M, Matsuno V, Yamada T, Hirohashi S, Kondo H, Shimosato Y (1 995). Small adenocarcinoma of the lung. Histologic characteristic.~ und prognosis. Cancer 75: 2844-2852. Okada M, Nishio W, Sakamoto T, Uchino K, Hanioka K, Ohbayashi C, Tsubota N. Correlation between computed tomographic findings, bronchioloalveolar carcinoma component, and biologic behavior ofsmall -sized lung adenocarcinoma. J. Thorac Cardiovasc Surg 2004; 127:857-861. Ruffini E. Bongiovanni M, Cavallo A, Filosso PL, Giobbc R, Mancuso M, Molinatti M, Oliaro A. The significance ofassocia ted pre-invasive lesions in patients resected for prirruuy lung neoplasms. Eur J. Cardiothorac Surg 2004;26: 165-172. Sakurai H, Maeshima A, Watanabe S, Suzuki K, Tsuchiya R, Maesbhlma AM, Matsuno Y, Asamura H. Grade of stromal invasion in small adenocarcinoma of the lung; histopathological minimal invasion and prognosis. Am J Surg Pathol 2004;28: 198-206. Staeher E. Ullmann R, Halbwedll, Gogg-Karnmere M, Bocoon-Gibod L, Nocho l.son AG, Sheppard MN, Carvalho L, Franca MT, Macsweeoey F, Morresi-Hauf A, Popper HH. Acypical goblet cell hyperplasia in congenital cystic adenomatoid malfonnation as a possible preneoplasia for pulmonary adenocarcinoma in childhood: a genetic analysis. Hum Patho12004;35:565-570. Suzuki K, Nogal K, Yoshida Jet al. The prognosis of resected lung carcinoma associated with atypical adenomatous hyperplasia. Cancer 1997;79:1521-1526 . Suzuki K, Asamurn H, Kusumoto M, Kondo H, Tsuchiya R. "Early" peripheral lung cancer: prognostic significance of ground glass opacity on thin-section computed tomographic scan. Ann Thorac Surg 2002;74: 1635-1639. Suzuki K, Yokose T, Yoshida J, Nishimura M, Takahashi K, Nagai K, Nishiwaki Y. Prognostic significance of the size of centrallibrosis in peripheral adenocarcinoma of the lung. Ann Thorac Surg 2000;69:893-897. Takashima S, Maruyama Y, Hasegawa M, Yamanda T, Honda T, Kadoya M, SoneS. Prognostic significance of high-resolution CT fmdings in small peripheral adenocarcinoma of the lung; a retrospective study on 64 patients. Lung Cancer 2002;36: 289-295. Terasaki H, Niki T, Matsuno Y, Yamada T, Maeshima A, Asamura H, Hayabuehi N,Hirohashi S. Lung adenocarcinoma with mixed bronchiolo-alveolar and invasive components: clinicopathological fearuresm subclassification by extent ofinvasive foci, and immunohislOChemical characterization. Am J Surg Pathol 2003;27: 937-95 I. Travis WD, Brambilla E, Harri.s CC, Muller-Hennelink HK Ed: World Health Organization Classification of Tumours, Pathology and Genetics: Tumours ofthe Lung, Pleum, Thymus and Heart. IARC, Lyon (in press). Watanabe S-1, Watanabe T, Arai K, Kasai T, Hamtake J, Urayama H. Results ofwedge resection for focal bronchioloalveolar carcinoma showing pure ground-glass altenuntion on computed tomography. Ann Tborac Surg 2002;73: I 071-I 075. Yamato Y, Tsuchida M, Watanabe T, Aoki T, Koizumi N, Umczu H, Hayashi J-L Early results ofa prospective study of limited resection for bronchioloalveolar adenocarcinom.a ofth e lung. Ann Thome Surg 200 I ;7 1:971- 974. Yokosc Y, Suzuki K, Nagai K, Nishiwaki Y, Sasaki S, Ochioi A. Favorable and unfavorable morphological prognostic factors in peripheral adenocarcinoma of the lung 3 em or less in diameier. Lung Cancer 2000;29: 179-188. Yokose T, Ooi M, Tanno K, Yamazaki K, Ochiai A. Atypical odenomarous hyperplasia of the lung in autopsy cases. Lung Cancer 2001 ;33:1 55-161.

20 Pulmonary Pathology CTTR 117'' Cancer Seminar figure I ~A~-~~- ~~~~~~~ of colloid adenocarcinoma with marked cellular adenocarcinoma carcinoma. The alveoli are stuffed by pale djscohcsion. There is complete·aJvcolar fiJii ng discohesion. rn this region there is cells somewhat rcsembJing hjstiocyres at d1is by cyiOiogically malignant epithelioid cells. recognizable adenocarcinomatous pov.-er. There is mild aJvcolar wall different1ation with malignant columnar cells inflammation. lining the wall ofan airspace with only modest sloughing into the ·rumen.

carcinoma Yo'ith Figur,e powet shows cytologically spiindled regions. There i:s an ObvjQus spindled regions. Other areas show obvious malignant nuclei in cells that have vacuolated malignant proceSs wilh epithelial carcinoma with features of large-ceU cytoplasm and some ·suggest a signet ring differentiation ceritrnlly and surrounding carcinoma~ pleomorphic malignant cells arc appearance (at 9 o'clock). malignant spindle cells. present (lower right center).

with Figure 3-1. Bronchioloalveolar carcinoma heterologous elements. There is malignant heterologous ele'mems. lm this fie ld there is complicating-cystic lung disease. A portion c.utiJage, undifferentilited mesenchyme "tumor" osteoid fonnation by atypical cells the lining of the cyst shows a unifonn (center), and keratinizing squamous and nests of squamous caiCinoma with population ofblnnd-appearing mucinous carcinoma. obvious Cy10iogic features of malignancy.

CTfR 1 I 7'b Cancer Seminar Pulmonary Pathology 21 complicating cystic lung disease. In the lung complicating cystic lung disease. The prior tissue surrounding the cyst then~ is a lepidic history ofsarcoidosis in this patient is attested proliferation ofbfllnd-appearin& mucinous to by the p!Cscnce ofscancted non­ cells lining alveolar m~lls typical of mucinous necrocizing pnuJomas "'hieh. oz SC4nning BAC. power microscopy. follow a lymphatic distribution.

C1TR 1 I 7,. Cancer Seminar P11lmonary Pathology 23 • ll. Acute Lung Injury and Granulomatous lnterstitial Pneumonias

CASE 4

Clinical History (CTTR Ace. #29896}: A 27-year-old woman was seen one week prior to death for cough. Her white count was elevated and she was started on antibiotics and her condition apparently improved. She was found dead at home after having told a friend that she was hot and had pain in both ears. The patient had a hot tub in the basement of her home: The lungs weighed 1550 grams combined.

Key histologic features: Identification of the basic pattern of acute and organizing diffuse alveolar damage with hyaline membranes; identification of centrilobular chronic inflammatory infiltrates associated with the granulomas.

Diagnosis: Diffuse alveolar damage superimposed on a granulomatous interstitial pneumonia with centrilobular accentuation (consistent with fatal bot tub lung).

Follow-Up: Rare acid fast organisms were identified in the lung tissue after multiple examinations. Cultures of the hot tub were positive for Mvcobacterium avium intrgcellulare. Smears of the hot tub were positive for acid fast bacilli.

Overview

This case illustrates two broad histologic patterns that may be encountered in diffuse lung disease and the first of these is acute lung injury with diffuse alveolar damage and hyaline membranes and the other is a granulomatous interstitial pneumonia. Both of these may be a cause of diffuse lung disease and the approach in this case is to trv to tie both together with one diagnosis.

Discussion: Acute Lung Injury

Acute lung jnjurv is a useful term introduced by Katzenstein. One can use this term to suggest recent or acute injury and recognize that the histologic features are nonspecific and there are a number of possible causes. Acute lung injury can be divided into two overlapping patterns: diffuse alveolar damage (DAD) and organizing pneumonia (OP; also called BOOP pattern). Both of these may show airspace organization. DAD tends to be more uniform and diffuse in its involvement of the lung parenchyma {and the patient is much sicker), whereas organizing pneumonia tends to be somewhat more patchy and lacks hyaline membranes.

CITR 117,. Cancer Seminar Pulmonary Pathology 25 n

Key histologic features of DAD.

Diffuse distribution. Uniform temporal appearance. Alveolar septal thickening due to organization, usually diffuse. Airspace organization (patchy or diffuse). Hyaline membranes (focal or diffuse)

Diffuse alveolar damage is extremely common and the usual histologic correlate Cif patients who have the adult respiratory distress syndrome. There are a number of cases (see below) but when none is identified the. possibility of the idiopathic interstitial pneumonia, acute interstitial pneumonia, should be considered. IfHarnman-Rich syndrome·as a present day counterpart (and that is debatable) then is comes closest to .acute interstitial pneumonia (i.e. idiopathic organizing diffuse alveolar damage). Diffuse alveolar damage goes through phases: acute with edema, fibrinous exudate, and hyaline membranes, organization with interstitial and airspace organization, and resolutio.n or fibrosjs. Most cases encountered histologically are in the acute or organizing phase. The causes of diffuse alveolar damage include:

Infections (any severe infection) Shock Toxic Inhalations Acute Allergic Reactions Drug Reactions Neurologic Disease Collagen Vascular Diseases Miscellaneous Radiation Idiopathic (=AIP) Alveolar Hemorrhage Syndromes

I would interpret this case as an example (albeit rare) of DAD as a manifestation of an acute allergic-reaction.

Key histologic features of OP.

• Organizing pneumonia: intraluminal organization in distal airspaces (bronchioles, alveolar ducts, alveoli). • Patchy distribution. • Preservation of background lung architecture. • Uniform temporal appearance. • Mild interstitial chronic inflammation.

Organizing pneum9nia is a very common pattern. A synonym is bronchiolitis obliterans organizing pneumonia/BOOP pattern, and when one encounters this pattern the possibility of the idiopathis interstitial pneumonia (idiopathic BOOP/cryptogenic organizing pneumonitis) is often what is considered but that is a lesion that should be considered only after the other numerous causes of this common pattern have been excluded. An organizing pneumonia pattern shows edematous tufts of granulation-type tissue predominantly within airspaces, usually alveolar ducts, but·eften bronchioles (hence, the "bronchiolitis obliterans" component of the diagnosis) as well as alveoli. There is a mild to moderate interstitial infiltrate in the regions of organization usually associated with a modest type II cell proliferation although markedly prominent type II

26 Pulmonary PaJhology CTTR 117" Cancer Seminar cells are unusual. Alveolar spaces may contain foamy macrophages. Eosinopb.ils and neutrophils are few in number. If the eosinophils are prominent, the possibility of chronic eosinophilic pneumonia or a COP/chronic eosinophilic pneumonia hybrid should be considered. There are a number of causes of a an organizing pneumonia pattern, and these include the following:

• Organizing Infections (viral, bacterial, fungal) • Organizing Diffuse Alveolar Damage • Drug and Toxic Reactions • Collagen Vascular Diseases • Extrinsic Allergic Alveolitis (hypersensitivity pneumonitis) • Chronic Eosinophilic Pneumonia • Organizing Infectious Pneumonias Cgmplicating Chronic Bronchitis and Emphysema, Bronchiectasis, Cystic Fibrosis, Aspiration • Inflammatory bowel disease • As a peripheral reaction around abscesses, infarcts, Wegener's granulomatosis, and others • Idiopathic (i.e., cryptogenic organizing pneumonitis/COP)

References for Acute Lung Injury Colby TV, Lombard CL, Yousem SA, Kitachi M. Atlas of Pulmonary Surgical Pathology. Philadelphia, Saunders, 1991. Colby TV. Bronchiolitis- pathologic considerations. Am J Clin Pathol 1998; I 09: I 01-109. Cordier J, Loire R, Brune J. Idiopathic bronchiolitis obliterans organizing pneumonia: definition of characteristic clinical profiles in a series of 16 patientS. Chest 1989;96:999·1004. Epler GR, Colby TV, McCloud TC, Carrington CB, Gaensler EA- Bronchiolitis obliterans organizing pneumonia. N Eng! J Med 1985;312-152-158. Kal%enstein ALA. Acute lung injury patterns: diffuse alveolar damage and bronchiolitis obliterans-organizing pneumonia. in Kattenstein and Askin's Surgical pathology of Non-Neoplastic Lung Disease (Ed 3). Philadelphia, Saunders, 1997 Katzenstein ALA, Bloor CM, Lie bow AA. Diffuse alveolar damage -the role ofoxyge n, shock and related factors. Am J Pathol 1976;85:209-228. Katzenstein A, Myers JL, Mazur M. Acute interstitial pneumonia: A clinicopathologic, ultrastructural, and cell kinetic study. AmJ Surg Patholl986;10:256-267. Katzenstein ALA and Myers JL. Idiopathic pulmonary fibrosis: State ofthe art. Am J Respir Crit Care Med 1998; 157:1301-1315. Lohr RH, Bowlan BJ, Douglas WW, eta!. Organizing pneumonia: Features and prognosis ofcryptogenic, secondary and focal varian!$. Arch lnt Med (in press). Ryu JH, Colby TV, Hartman TE. Idiopathic pulmonary fibrosis: current concepts. Mayo Clin Proc 1998;73: 1085- 1101. Travis WD, King TE (Co-Chairs) and ATSIERS Panel. ATSIERS International Multidisciplinary Consensus Classification ofIdiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002;165:277-304. Travis WD, Colby TV, Koss MN, Rosado-de Christenson M, Muller NL, King TE. Non-neoplastic disorders of the lower respiratory tract. Atlas of Non-Tumor Pathology, 1• Series, Fascicle 12, Anned Forces Institute of Pathology, 2002. Wright JL: Adult respiratory distress syndrome; in Thurlbeck WM, Churg AM (eds.): Pathology of the Lung (Ed 2). New York, Thieme, 1995.

CITR 117"' Cancer Seminar Pulmonary Pathology 27 Discussion: Granulomatous Interstitial Pneumonia.

The other histologic finding in this case is the presence of granulomas and one m'!Sl also approach this as an example of a diffuse granulomatous interstitial pneumonia. The possible causes of granulomatous inflammation and approach to differential diagnosis is shown below.

Given the follow-up in this case with positive smears and cultures for acid fast organisms fi'om the hot tub (usually MAC) and the histologic findings, the·scen.ario that seems most plausible and one which ties all the histologic findings together, is that this patient has a severe acute allergic reaction with diffuse alveolar damage that is superimposed on background more chronic changes manifested as bronchiolocentric granulomatous inflammation. I think this is an example of acute fatal hot tub lung.

Hot tub lung is a granulomatous interstitial pneumonia that is related to the inhalation of Mycobacterium avium complex that is growing in .hot tubs or is otherwise aerosolized. Hot tub lung appears to be a peculiar hybrid between a granulomatous infection (the cases are culture p\)sitive and rarely positive blood cultures have been documented) and a hypersensitivity pneumonitis to mycobacterial antigens. Management often includes both antimycobacterial therapy as well as steroid therapy.

There have been a number of reports of pulmonary disease in immunocompetent hosts related to inhalation of mycobacterial organisms growing in .hot tubs. The largest series in the pathology literature is that ofKhoor et a!.:

• I 0 immunocompetent patients with granulomatous interstitial pneumonia • Positive c.uJtures for nontuberculous mycobacteria (proven as MAC in 9 of 10) • Only one case positive with special stains • AlllO patients found (mostly inTetrospect) to have had hot tub exposure at the time of their disease; some with positive hot tub cultures o All improved on steroids, antimycobacterials, or both. Some went back to hot tub use, o Histology: Non-n·ecrotizing .granulomatous inflammation, frequently bronchiolocentric; necrosis in only one case.

The granulomatous interstitial pneumonias can be categorized into those that are commonly encountered and those that are only rarely encountered and interstitial pneumonias in which granulomas represent an inconstant finding.(as shown below).

28 Pulmonary Pathology CfTR 11 71h Cancer Seminar Commonly Encountered Infrequently Encountered (granulomas usually present) (presence ofgranul omas inconsistent)

Sarcoidosis Bronchiectasis/bronchiolitis with secondary granulomatous infection Infections Berylliosis and other pneumoconioses Mycobacteria, fungi (including Drug reactions pep), others Collagen vascular diseases (esp. Sjogren's syndrome) Hypersensitivity pneumonitis Intravenous talcosis Vasculitis (rarely) Wegner's granulomatosis, Churg-Strauss syndrome Eosinophilic pne11100nia Aspiration pneumonia Immunoglobulin deficiency Diffuse lymphoid hyperplasia (regardless ofcause) Giant celf interstitial pneumonia Diffuse neoplastic involvement of the lung (lymphoma, leukaemia, other) Inflammatory bowel disease Incidental granulomas• Unclassifiable • Granulomas are occasionaUy encountered as isolated inddeotal findings.

The histologic distribution of granulomas can give hint to a specific disease. Attempts should be made to determine if the granulomas show a predilection for specific structures (such as the lymphatics in sarcoidosis or airways in inhalational conditions). This is generally achieved at scanning power (unless the granulomas are too inconspicuous to see at this magnification).

Airway-centered granulomas

Granulomas are found predominantly along bronchi, bronchioles and alveolar ducts in several conditions; airway spread of infection is one of these. Mycobacterial and fungal infections may have bronchiolocentric granulomas following inhalation. Atypical mycobacterial infection, the majority being due to Mycobacterium avium intrace/lu/are complex (MAl) may complicate chronic airway disease, especially bronchiectasis. It has been commonly believed that MAI may complicate established chronic airway disease, particularly bronchiectasis however, that concept has recently been challenged by Fujita et al. Fujita et a! . studied, the resected lung specimen of MAI infection and found extensive peribronchial granuloma formation from large airways to the bronchioles and there was intraluminal protrusion of the granuloma resulting in narrowing of the bronchiole. These authors concluded MAI preceded the chronic airway disease. While the association of MAI infection in chronic airway disease is well established, the exact sequence of events remains to be established with further studies. Khoor et a!. described a different sort of diffuse lung disease with MAl infection. These patients had diffuse disease and thus from the clinical point of view represented a granulomatous interstitial pneumonia. Khoor et a!. showed that patients exposed to hot tubs contaminated by MAl could develop a diffuse lung disease with similarities to hypersensitivity pneumonitis, including bronchiolocentric granulomas, often within the bronchiolar lumens.

C'ITR I I 7'' Cancer Seminar Pulmonary Pathology 29 Granulomas along lvmphatic routes

The best example of lymphangitic granulomas is sarcoidosis. This pattern is one of the most helpful features in distinguishing it from other granulomatous lung diseases. In some cases, there may appear to be a preferential involvement" of airways or vessels producing dramatic involvement of these structures simulating a bronchocentric or angiocentric distribution. Chronic berylliosis is another disease which also shows well formed lymphangitic granuloma identical to the pattern of sarcoidosis.

Angiocentric granulomas

Intravenous talcosis results when talc of othc:r binders used in drugs intended for oral ingestion are. deposited in the lung as a result of intravenous injection of the pulverized drug. Characteristically, small granulomas and giant cells with associated birefringent gray-white talc particles are distributed along small blood vessels. Vascular involvement by granulomas is found in 40% to 70% of cases of sarcoidosis; granulomas involve the intima and media of pulmonary arteri.es and veins, but only rarely result in pulmonary hypertension.

In patients with chronic passive congestion (from either cardiac disease or pulmonary venous disease) and associated chronic hemorrhage the pulmonary veins not uncommonly show a giant cell reaction to iron that is encrusted on the elastica of the vessel. This has been (erroneously) termed endogenous pneumoconiosis.

Scattered randomly distributed granulomas

Miliary (mycobacterial and fungal) infection may produce diffuse interstitial lung disease having small granulomas without specific distribution histologically. Granulomas in hot tub lung can be seen randomly distributed in airspaces and the interstitium in addition to the bronchiolocentric pattern previously mentioned.

In addition to the distribution of granulomas, the qualitative features of the individual granulomas themselves are extremely important.

Are the granulomas well formed?

The •iwell formed" granuloma is best exemplified by sarcoidosis. The characteristic sarcoid granulomas are composed of tightly clustered epithelioid histiOcytes, occasional multinucleated giant cells and few lymphocytes. Chronic berylliosis also shows well formed confluent granulomas identical to those of sarcoid. Granulomas in many infections are also usually well formed; particularly in mycobacterial and fungal infections.

30 Pulmonary Pathology CTTR I 17>1> Cancer Seminar Are the granulomas "loose" accumulations ofepithelioid histiocytes?

The granulomas of hypersensitivity pneumonitis are characteristically smaller and less well formed than those of sarcoidosis, being composed of loose aggregates of epithelioid histiocytes. Numerous well-formed granulomas are unusual in hypersensitivity pneumonitis, and should lead to other considerations. Granulomas in hot tub lung (MAl infection) may closely resemble those in hypersensitivity pneumonitis except that larger and better-formed than those in hypersensitivity pneumonitis. Immunocompromised individuals with granulomatous (infectious) lung diseases may show less well-formed granulomas due to immunosuppression.

Granulomas may be seen in pulmonary manifestations of drug reactions. These granulomas are usually small, poorly cohesive, located in alve~lar septa and do not have necrosis.

Is the granulomatous character identifzable only as giant cells, single or in groups?

Isolated or clustered interstitial or intra-alveolar giant cells are typical of hypersensitivity pneumonitis; they frequently have cholesterol clefts. Intra-alveolar giant cells characterize hard metal (cobalt) pneumoconiosis (giant cell interstitial pneumonia); the giant cells often contain engulfed macrophages.

Are the granulomas necrotizing and what is the character ofnecrosis?

The presence of necrosis within granulomas should always alert one to the possibility of infection. Most necrotizing granulomas are caused by infection, and when the responsible organism is demonstrable it is usually the necrotic zones. However, the absence of necrosis and negative stains for organisms do not rule out infection. Necrosis associated with infection is often granular and eosinophilic character or microabscess-like with neutrophils in varying stages of degeneration. The best-known example is tuberculosis but similar necrotizing granulomas are also commonly seen in atypical myocbacterial infection. Necrotizing granulomas may also characterize pneumocystis. The necrosis in histoplasmosis and coccidioidomycosis is more like that seen in tuberculosis with caseation while granulomatous inflammation in blastomycosis and cryptococcosis more often features the presence of central microabscesses. Occasionally, bacterial (Norcardia and Actinomyces) and viral infections also have to be considered when necrotizing granulomatous inflammation is encountered. Miliary viral infections in immunosuppressed patients, notably herpes and cytomegalovirus, may show acute inflammation and necrosis associated with clusters of histiocytes resembling granulomas.

Up to 20% sarcoid granulomas in transbronchial biopsies show necrosis. This typically appears as a small amount of central fibrinoid necrosis. ln hypersensitivity pneumonitis, the granulomas are non-necrotizing, and the presence of necrosis virtually excludes the diagnosis.

ClTR 11 7,. Cancer Seminar Pulmonary Pathology 31 Are the granulomas scattered and single or do they coalesce?

Coalescence of granulomas along lymphatic routes is characteristic of sarcoidosis. Granulomas in infectious cases of granulomatous interstitial pneumonia and hypersensitivity pneumonitis as well as drug reaction tend to be scattered and single, and sometimes bronchiolocentric.

Are birefringent material and secondary structures associated with the granulomas?

The most common birefringent polarizable mate.rial in .granulomas in lung biopsy specimeo,s is calcium oxalate crystals in patients with sarcoidosis and hypersensitivity pneumonitis. Asteroid bodies, Schaumarui bodres and calcium oxalate crystals are all nonspecific and may be associated with a variety of grimulomatous processes. In the lung they are most frequently encountered in sarcoidosis, probably because of the frequency with which sarcoidosis itself is encountered. However, the presence of these inclusions is nonspecific and is usually not helpful in differential diagnosis. The importance of their recognition is in not over interpreting these endogenous products as foreign bodies and suggesting they are exogen~:ms (e.g. aspiration or pneumoconiosis).

Is there extensive fibrous tissue around the granulomas?

A rim of fibrous tissue around the granulomas is typical sarcoidosis. This perigranuloma fibrosis frequently manifests as lamellar hyalinized collagen. In healed sarcoidosis, the granulomas may disappear entirely leaving behind the concentric lamellar fibrous sear in a lymphatic distribution. Schaumann 's bodies embedded in fibrous tissue is also evidence of previous granulomatous inflammation, that may have been infectious or noninfectious. Some degree of fibrosis is also USl!ally associated with infectious granulomatous interstitial pneumonia. Perigranuloma fibrosis is rare in hypersensitivity pneumonitis and hot tub lung.

Lf there a mononuclear cell infiltrate associated with the granulomas?

Sarcoid granulomas tend to have little inflammation and hence the term "naked granulomas". They contain occasional giant cells with few intervening lymphocytes and are only surrounded by a thin rim of chronic inflammatory cells. The granulomas in hypersensitivity pneumonitis are commouly associated with rich infiltrates of lymphoid cells and plasma cells which frequently extend in alveolar walls. Infection-associated granulomas also have prominent mononuclear inflammatory infiltrates associated with them.

32 Pulmonary Pathology CrrR JJ7'b Cancer Seminar The table below summarizes the features of the most commonly encountered lesions.

Dlstrlbudon Salient Qualitative Features Necrosis Cellular Organizing of tbe Granulomas Interstitial Pneumonia lnfilrrates Sarcoidosis Lymphangitic; may show Coalescing, well formed, -/+ - . apparent preferential surrounding hyaline fibrosis, involvement of vessels, little inflammation airways or pleura lofeclions Randomly distributed Tend to besingle with little +/- -/+ .f+

(most common), some coal es~nce., peri,granuloma cases show bronchiolo· inflammation, +/· centricity pcrigrnnuloma fibrosis Hypersensitivity Airway centered Solitarr often "loose'' . + -1+ pneumonitis inllaromarion; including granulomas without associated alveolar duct rcgjons as fibrosis well as bronchioles

The presence of granulomas should lead one to do a routine battery of' special stains for organisms. However, absence of organisms on special stains does not rule out the possibility of infection. In the study by Khoor eta!., only 1 out of 10 cases ofMAI granulomatous interstitial pneumonia showed positive staining for acid-fast bacilli, while all cases showed positive cultures for atypical mycobacteria. The polymerase chain reaction (PCR), which is sensitive and specific, is a useful means to identifY MTb.

Lung culture data should be carefully monitored in cases of granulomatous interstitial pneumonia. ·Positive cultures or reports of positive cultures in the past -should not be dismissed and should be very carefully correlated with the oth.er clinical, radiologic, and histologic fmdings. hi some cases adequate clinicopathologic correlation and final diagnosis are not possible until culture results are available.

In. many transbronchial biopsies when one identifies only one or a few granulomas, the distribution and qualitative features may not be appreciable, In such cases, one may go little further than noting the presence of the granuloma. However, there are trans bronchial biopsies in which both distribution and some qualitative features of the granulomas may be appreciated and the above principles applied.

CTTR 117"' Cancer Seminar Pulmonary Pathology 33 an lung. A J?OO rly pr~css that a ttntrilobular fonned gmnuloma is present at 3 o ~clock. poorly formed granuloma shows epithelioid distribution with poorly ronned granulomas. and Hyaline· membmnes line an alveOhar duct on histiocytes with surrounding chronic inflammarion iochtding occasional plasma cells. The prcsc:ncc o hyaline membranes. The centriJobular distribution the left. is appa1~n since the Ge!Urilobular region is in 1he granulomas and the.c hronic inflammation attest th1 right side oflbe figure and Ibe interlobular septum part oftheprot.ess is histblogic<'llly older than the tQr this lobule is along the len border. acute diffuse alveolar damage with hyaline membrnnes.

Fig 4-4. Fatal hot t~b l~ng. Some foci showed only acute diffuse alveolar damage There is a portion Qf a with hyaline membrlllles. cyst. The cyst is lined by reactive cuboidaJ cyst, Thepowc lenr~ :~ de5~~~~~~~~~ sho~ cuboidal and lhc. right side shows bronc.hiolar type epithelium. epithelium. The stroma oflhe cyst shows a The! interstitial c.ells are hyperchromatic with only proliferation of primitive hyperchromatic They represent undlffcrcntinled cells with Cambium·layer formation. oells. No rhabdomyoblasti

some regions ~1e cysts were by olostorna. shows a high.gmde fields show prominent hypoccllulnr trabeculae: that were not overtly malignallcy with primitive polygonal cells differentiation wilh large polygonal with neoplastic. This appearance would be difficult with minima) spindling. Occasional abw1dant eosinophilic cytoplasm with suggestion c myofibril formation although ddinite cross stris.tio1 to separate from type 4 congenital pulmonary rhabdomyoblasts with abundant eosinophilic arc not soen. These cells were strongly desmin airw'dY malformation. cytoplasm are appll\'ent (at 9 o·clock). positive.

trrR 117"' CanccrBeminar Pulmonary Patltology 35 III. Blastomas of the Lung and Cystic Lung Lesions in Children

CASES

Clinical History (There are two cases on the slide.)

Case SA CCTIR Ace. # 29874): A I 0-month old boy presented with shortness of breath and was found to have two cystic masses involving the lingula and left upper lobe. These were resected; one measured 7.0 x 6.5 x 4.5 em and the other 9.0 x 6.0 x 3.5 em. The lesions were multiloculated without masses or nodules.

Key histologic features: Hypercellularity tielow the reactive type 2 cell proliferation that lines the cysts. Despite the absence of frank malignant features there is high cellularity and the cells are cytologically immature. Mesenchymal origin with focal skeletal muscle differentiation confumed immunohistochernically.

Case SB CCTIR Ace.# 14390): For several weeks prior to admission, a 4-year-old Caucasian male had been experiencing episodes of coughing which were occasionally productive of frothy white sputum in small amounts. Approximately one week before admission, there was an episode of possible dyspnea and difficulty in catching his breath. Admission x-ray revealed a tension pneumothorax in the right, with large blebs in the Tight lower lobe. Despite the insertion of chest tubes, the pneumothorax persisted, with alternating recurrence and resolution. During surgery, a large cystic lesion containing debris and blood clot was found to arise from the inferior aspect of the interfissural plane of the right middle lobe, which was on an approximately I x 2 em pedicle. Markedly thickened pleura was removed from the right lower lobe.

The specimen consisted of a pyramidal, 6.5 x 6.0 x 5.5 em multilobulated cystic fleshy mass. The walls of the cysts were smooth, although lobulated, and the cysts contained generally clear fluid which was focally inspissated. The fleshy portions were pink-tan, soft, focally honeycombed, and focally hemorrhagic. (Contributed by Seth Haber, M.D., Santa Clara, CA)

Diagnosis: .Pleuropulmonary blastoma illustrating cystic and solid patterns.

Follow-up (SB): The original CTIR diagnosis was rhabdomyosarcoma. This was changed to lJOssible mesothelioma at another institution. The patient was treated with radiotherapy but developed presacral, pelvic, and abdominal metastases and was lost to follow-up two months later.

C11'R I 17111 Cancer Seminar Pulmonary Pathology 37 Discussion

Pleuropulmonary blastoma is a tumor entirely unrelated to classic pulmonary blastoma, with the former being a form of sarcoma involving the lung and chest wall and the latter included among the sarcomatoid carcinoma category. Classic pulmonary blastoma is a biphasic neoplasm that includes an epithelial component resembling fetal adenocarcinoma (and some might call fetal adenocarcinoma a monophasic epithelial blastoma) and a mesenchymal component with a variety of forms of mesenchymal differentiation. The demographic features of classic pulmonary blastoma are as follows:

• Mean age - 40 years; rare in childhood • Males =females • Majority are smokers • Biphasic differentiation correlates with increasing size • Prognosis correlates with stage; overall 16% survive 5 years

Pleuropulmonary blastoma is defined by the WHO as "A malignant tumor of infancy and early childhood arising as a cystic and/or solid sarcomatous neoplasm, in the lung or less often from the parietal pleura. The cystic component is lined by benign metaplastic epithelium that may be ciliated." It is considered an embryonic or dysontogenetic neoplasm, analogous to Wilms' tumor, neuroblastoma, and others. The demographic features of pleuropulmonary blastoma are summarized as follows:

• Median age 2 years; range neonate to 12 years; most diagnosed on or before 4 years of age • Males = females • Up to one-fifth present with pneumothorax • Presenting complaints: respiratory distress, fever, chest pain, cough • Imaging: cystic, partially cystic, or solid mass that may involve an entire hemithorax

PleuropuJmonary blastomas have been shown to have some distinctive genetic abnormalities (trisomy 8, trisomy 2) and up to 25% of cases have familial association. In the study by Roque et al., pleuropulmonary blastoma was shown to have genetic similarities to rhabdomysarcoma, a not unexpected result given the histology.

Pleuropulmonary blastoma is not all that rare and cases reported prior to 1988 had been given a number of names, including embryonal rhabdomyosarcoma, malignant mesenchymoma, puJmonary blastoma, mesenchymal hamartoma, and others. In some instances the sarcoma was thought to arise in a congenital cystic adenomatoid malformation. The current interpretation is that the cystic change is part of the tumor and there is no pre-existing cystic adenornatoid malformation.

38 Pulmonary Pathology CTTR 117"' Cancer Seminar The tumors VIIIY in size; approximately two-thirds are 5.0 em or greater in diameter. The majority (over. 50%) involve the lung alone, whereas about one-quarter involve the lung and pleura and the remainder involve luni! and mediastinum(+/- pleura).

Histologically, there is a proliferation of mesenchymal cells which vary from paucicelhilar myxoid appearance to highly cellular primitive sarcoma. Neoplastic elements may include rhabdomyosarcoma, chondrosarcoma, fibrosarcoma, liposarcoma, myxosarcoma, and undifferentiated sarcoma. Some of the cases with a mesenchymal component of rhabdomyosarcoma show a typical cambium layer.

The immunohistologic findings depend on the histologic patterns present. Rhabdomyoblasts stain with muscle specific actin, sm.ooth qiuscle actin, desmin, myogenin, and myoglobin stains. The primitive appearing cells stain with vimentin. Some of the primitive spindled-appearing cells also stain with muscle specific actin. Immature cartilage/chondrosarcomatous component/lipoblasts/liposarcomatous components may show staining with S-100 protein.

Treatment is surgery combined with radiation and chemotherapy. Recurrent disease tends to develop in the ipsilateral thorax. Survival for patients with only the lung affected is better than that with patients who have involvement of the pleura or mediastinum. The most important aspect of treatment is complete surgical excision.

In the large series of 50 cases from Priest et a!. three groups were recognized: purely cystic, cystic and solid, purely solid. The median age at presentation of the purely cystic group was 10 months, the cystic and solid group 34 months, and the purely solid group at 44 months. The case under discussion fits into the last group. There was a statistically significant difference in survival between the three groups. Purely cystic groups had a local recurrence rate of 14%, wh,ereas the cystic and solid, and purely solid groups had a local recurrence rate of nearly 50%. Five-year survival for the purely cystic group was 83% and 42% for the other two groups combined.

The differential diagnosis depends on the histologic subtype of pleuropulmonary blastoma. The solid and cystic and solid tumors are readily recognized as primitive sarcomas based on the presence of primitive (heterologous) sarcomatous elements. The distinction of a soft tissue sarcoma in the chest wall and pleuropulmonary blastoma is somewhat arbitrl!ry, although the age of the patient, the presence of a cystic component, and involvement of the lung would all favor pleuropulmonary blastoma. The lesions that cause the most difficulty are .the purely cystic pleuropulmonary blastomas. These typically show septa lined by bland endothelial cells (type 2 cells) with a central stromal core showing a cambium layer that is characteristic of embryonal rhabdomyosarcoma in general, but when the cambium layer is focal or inconspicuous these lesions may be mistaken for congenital cystic adenomatous malformations, especially the subtype recently described by Stocker, type 4 (see Case 3).

C'ITR 117"' Cancer Seminar Pulmonary Pathology 39 Type 4 CCAMs are thought by Stocker to be malformations of the distal lung tissue and as such there are large cysts with thin septa lined by flattened epithelium resembling alveolar lining cells. These are difficult to distinguish from cystic pleuropulmonary blastomas which have only a focal interstitial malignant mesenchymal component. MacSweeney et al. concluded that in some cases there is sufficient overlap that the distinction between these two entities may not be possible on histology alone. They noted that the presence of stromal hypercellularity, even if focal, in a suspected type 4 CCAM should raise the possibility of a cystic pleuropulmonary blastoma. 0ne of their cases of type 4 CCAM proved at follow-up (at the time of a recurrence) to be a pleuropulmonary blastoma.

Practically speaking, any cystic lesion in a child should be thoroughly sampled to exclude the possibility of a pleuropulmonary blastoma. .

Cystic pleuropulmonary blastoma in a young child also brings into consideration cystic lesions· presenting in neonates and children. These include:

• Sequestrations (intralobar and extralobar), bronchopulmonary foregut malformations • Bronchogenic cysts • Congenital cystic adenomatoid malformation (synonym= congenital pulmonary airway malformation) • Interstitial emphysema • Cystic mesenchymal neoplasms (esp. pleuropulmonary blastoma) • Bronchial atresia • Cystic bronchiectasis • Post-traumatic/postinfarction cysts • Pneumatocele

References for Pleuropulmonary Blastoma Allan BT, Day DL,.Dehner LP. Primary pulmonary rhabdomyosarcoma ofthe lung.in children .. Cancer 1987; 59:1005-101 1. Baraniya J, Desai S, Kane S, Kurkure P, Nair C, Deshpande R, Borges A. Pleuropulmonary blastoma. Med Pediatr Oneal 1999;32:52-56. Dehner LP. Pleuropulmonary blastoma is THE pulmonary blastoma ofchildhood. Sem Diagn Pathol 1994; II: 144- 51. Dehner LP,Watterson J, Priest J. Pleuropulmonary blastoma: a unique .intrathoracic-pulmonary neoplasm of childhood. Perspect Pediatr Pathol 1995; 18:214-226. Domizio P, Liesner RJ, Dicks-Mireaux C et al. Malignant mesenchymoll)a associated with a congenita1lung cyst in a chlld: case report and review ofthe literature. Pediatr Pathol 1990;10:785-97. Gelven PL, Hopkins MA, Green CA, Harley RA, Wilson MMB. Fine-needle aspiration cytology of pleuropulmonary blastoma: case report and review of the literature. Diagn Cytopatholl997; 16:336-340. Hill DA, Sadeghi S, Schultz MZ, Burr JS, Dehner LP. Pleuropulmonary blastoma in·an adult: an initial case report. Cancer 1999;85:2368-2374. Hill DA, Dehner LP, Ackerman LV. A cautionary note about congenital cystic adenomatoid malformation (CCAM) type 4. Am J Surg Pathol2004;28:554-555. Hong B, Chen Z, CoffinCM, Lemons R, Issa B, Brothman A, Zhou H. Molecular cytogenetic analysis ofa pleuropulmonary blastoma. Cancer Genet Cytogenet 2003; 142:65-69. lndolfi P, Casale F, Carli M, Bisogno G, Ninfo Y, Cecchetto G, Bagnulo S, Santoro N, Giuliano M, De Tullio MT. Pleuropulmonary blastoma. Management and prognosis of I I cases. Cancer 2000;89: 1396-1401.

40 Pulmonary Pathology CTTR 117tll Cancer Seminar Lallier M, Bouchard S, Di Lorenzo M, YoussefS, Blanchard H, Lapierre JG, VischoffD,Tucci M, Brochu P. Pleuropulmonary blastoma: a rare pathology with an even rarer presentation. J Pediatr Surg 1999;34: 1057- 1059. Lopez-Andreu JA, Ferris J, Esquembre C, Verdeguer A, Gomez J, Castel V. Familial cystic nephroma and pleuropu.Jmonary blastoma. Cancer I 993;72:2792-2793. MacSweency F, l'apagiannopoulos K, Goldstraw P, Sheppard MN, Corrin 8, and Nisholson AG. An assessment of the expanded classification of congenital cystic adenomatoid malformations. and their relationship to malignant transformation. Am J Surg Pathol. In Press for 2003. MacSweeney F, Papagiannopoulos K, Goldstraw P, Sheppard MN, Corrin 8, Nicholson AG. An assessment ofthe expanded classificationof congenital cystic adenomatoid malformations and their relationship to malignant transformation. Am J Surg Pathol 2003;27: I 139-1I 46. Manivel JC, PriestJR, Watterson J, Steiner M, Woods WG, Wick MR, Dehner LP. Pleuropulmonary blastoma: the so-called pulmonary blastoma ofc hildhood. Cancer 1988;62: I 5 I 6- I 526. Novak R, Dasu S, Agamanolis S, Herold W, Malone J, Waterson J. Trisomy 8 is a characteristic finding in pleuropulmonary blastoma. Pediatr Pathol 1997; I 7:99-103. Papagiannopoulos K, Hughes S, Nicltolson AG, et al. Cystic lung lesions in the pediarric and adult population: surgical experience at the Brompton Hospital. Ann Thorac Surg 2002;73: 1594-8. Papagiannopoulos KA, Sheppard M, Bush AP, et al. Pleuropulmonary blastoma: is prophylactic resection of congenital lung cysts effective? Ann Thorac Surg 2001;72:604-5. Picaud J-C, Levrey Helene, Bouvier R, Chappuis J-P, Louis D, Frappaz D, Claris 0 , Bellon G. )3ilateral cystic pleuropulmonary blastoma in early infancy. J Pediatr 2000;136:834-836. Priest JR, Watterson J, Strong L. HuffY, Woods WG, Byrd RL, Friend SH, Newsham 1, Amylon MD, Pappo A, Mahoney DH, Langston C, Heyo R, Kohut G, Freyer DR, Bostrom B, RichJirdson MS, Barredo J, Dehner LP. Pleuropulmonary blastoma: 8 marker for familial disease. J Pediatr 1996; 128:220-224. Priest JR, McDermott MB, Bhatia S, et a!. Pleuropulmonary blastoma: 8 clinicopathologic study of 50 cases. Cancer 1997;80:147-61. Romeo C, lmpellizzeri P, Grosso M, Vitarelli E, Gentile C. Pleuropulmonary blastoma: long-term survival and literature review. Med Pcdiatr Oncol 1999;33:372-376. Roque L, Rodrigues R, Martins C, Ribeiro C, Ribeiro MJ, Martins AG, Oliveira P, Fonseca I. Comparative genomic hybri(lization analysis ofa pleuropulmonary blastoma. Cancer Genet Cytogenet 2004; 149:5862. Sciott R, Dal Cin P, Brock P, Moerman P, VanDamme B, De Wever I, Casteels-Van Daele M, Van Den Berghe H, Desmet V. Pleuropulmonary blastoma (pulmonary blastoma ofchildhood ): genetic link with other embryonal malignancies? Histopathology I 994;24:559-563. Stacher E, Ullmann R, Halbwedll, Gogg-Kammerer M, Boccon-Gibod L, Nicholson AG, Sheppard MN, Carvalbo L, Franca MT, Macsweeney F, Morresi-Hauf A, Popper HH. Atypical goblet cell hyperplasia in congenital cystic adenomatoid malformation as a possible prcneoplasia for pulmonary adenocarcinoma in childhood: a genetic analysis. Human Pathol 2004;35:565-570. Stephanopoulos C, Catsaras H. Myxosarcoma compliCating a cystic hamartoma. Thorax 1963; 18: 144-5. Tagge EP, Mulvihill D, Chandler JC, Richardson M, Ullacker R, Othersen Jr HB. Childhood pleuropulmonary blastoma: caution against nonoperative management ofcongenital lung cysts. J Pediatr Surg 1996;31 : 187-190. van Koningsbruggen S, Ahrens F, Brockmann M et al. Congenital cystic adenomatoid malformation type 4. Pediatr Pulmonol 2001;32:471 -5. Weinberg AG, Currarino G, Moore GC et a!. Mesenchymal neoplasia and congenital pulmonary cysts. Pediatr Radio! 1980;9: 179-82. \Veinblatt ME, Siegel SE, Isaacs H. Pulmonary blastoma associated with cystic lung disease. Cancer 1982;49:669- 71. Wright JR Jr. Pleuropulmonary blastoma. A case report documenting transition from type I (cystic) to type UJ (solid). Cancer 2000;88:2853-2858. Yang P, Hasegawa T, Hirose T, Fulrumoto R, Uyama T, Mooden Y, Sano T. Pleuropulmonary blastoma: fluorescence in situ hybridization analysis indicating rrisomy 2. Am J Surg Patbol 1997;16:336-340.

CITR I I 7,. Cancer Seminar Pulmonary Pathology 41 IV. Eosinophilic Lung Disease

Case6

Clinical History: fCTTR Ace. # 30081) A 63-year-old woman had a history asthma and chronic cough. She presented with an elevated white count (11,300) and eosinophilia (6.6%). She had a mass in the right lower lobe and eve}ltually underwent lobectomy. Grossly there was a consolidated region in the lobe measuring 9.0 x 8.0 x 7.0 em. This was yellowish gray in appearance and was not grossly suspicious for carcinoma. Mucus plugs were noted within the large airways. Areas of bronchiectasis were noted.

Key histologic features: Pathologic changes in both the airways and parenchyma; the large airways have inspissated mucus with the distinctive histologic features of "allergic mucin" being somewhat laminated and amphophilic in appearance. At higher power there is eosinophilic debris and numerous Charcot-Leyden crystals. The surrounding parenchyma shows airspace filling with histiocytes, eosinophils, organizing pneumonia and scattered granulomas. In some regions the eosinophilic infiltrate is interStitial and there is prominent airspace edema. Some of the airways show an acute and chronic cellular bronchiolitis. Finally, there are scattered necrotizing granulomatous nodules which, when carefully assessed, are seen to be bronchiolocentric. Fungi consistent with aspergillus were identified with special stains in the mucinous material.

Diagnosis: Mucoid impaction with bronchocentric granulomatosis and eosinophilic pneumonia consistent with allergic bronchopulmonary aspergillosis.

Follow-up: At the time of surgery the patient had a 6.6% eosinphilia. Hypersensitivity panel (for precipitating antibodies) to Asperftillus nifter. flavus ·and (umigatus was positive and her IgE twice normal. Two years later, after treatment her IgE was normal.

Approach to Case 6

This case shows a number of histologic findings and one's assessment revolves around determining how the various histologic patterns relate to one another. Could they all be due to proximal obstruction? Is the necrotizing. granulomatous inflammation the main lesion? Fortunately in this case all of the features can be nicely tied together under the umbrella of allergic bronchopulmonary fungal disease, in particular allergic bronchopulmonary aspergillosis.

Discussion: ABPA

Allergic bronchopulmonarv aspergillosis (ABPA) is the most common cause of allergic bronchopulmonary fungal disease. ABP A is a clinical syndrome that occurs in asthmatics who develop hypersensitivity to fungi, particularly Aspergillus fumigatus. The fungus grows in the proximal mucoid impaction and induces a distal allergic reaction in the lung with the variety of histologic appearances illustrated by this case.

42 Pulmonary Pathology CTTR 117"' Cancer Seminar Clinical features of ABP A can be summarized as follows:

• Asthma • Eosinophilia • Pulmonary opacities (may be transient of fixed) • Central bronchiectasis • Positive sputum cultures for Aspergillus fitmigatus • Immediate cutaneous reaction to aspergillus • Elevated serum 1gE • Elevated precipitating antibodies to aspergillus

The histologic patterns encountered in ABPA include (singly or in combination): !. Mucoid impaction 2. Bronchocentric granulomatosis 3. Eosinophilic pneumonia 4. Hypersensitivity pneumonitis

Note: 1, 2, 3 may occur together; #4 rare.

The radiologic findings in ABPA reflect the various pathologic changes encountered: combinations of central bronchiectasis with mucoid impaction apparent radiologically, mass lesions indicative of bronchocentric granulomatosis, and airspace consolidation characteristic of eosinophilic pneumonia. ·

The trearment for ABP A and the conditions described below is generally steroids. Some cases with focal lesions that are refractory or associated with extensive lung destruction may require resection (e.g. BCG).

1) Mucoid impaction of bronchi (M]B) is separated from other conditions with mucus plugging by the associated clinical findings (often ABPA), the distinctive radiologic findings and histologically on the basis of the "allergic mucin."

Most patients with MIB have evidence of ABP A. Some patients are asymptomatic and .first encountered as radiologic findings. Many (but not all) patients have concomitant clinical evidence of asthma.

The radiologic descriptions are quite colorful: "hand in glove", "gloved finger", "inverted Y or V", or "cluster of grapes" for the appearance of the central bronchiectasis. Rare cases present as a solitary nodule.

Allergic mucin is distinctive grossly being firm, rubbery, and greenish brown in appearance. These may be expectorated and identification of one of the distinctive features described below is the reason to histologically examine coughed up mucus _plugs.

CTTR 117"' Cancer Seminar Pulmonary Pathology 43 Histologically there is a distinctive laminated appearance with eosinophilic and amphophilic debris representing degenerated eosinophils, mucus, Charcot-Leyden crystals, neutrophils and necrotic debris. The surrounding lung tissue typically shows features of astluna in the airways and often eosinophilic pneumonia in the parenchyma.

Silver stains for fungi should always be performed in any case of suspected MIB and in any case in which there is a histologic suggestion of allergic mucin. The presence of fragments ofhyphae is usually indicative of allergic bronchopulmonary fungal disease.

The differential diagnosis of mucoid impaction includes the many conditions in which mucus accumulates in airways including: COPD, uncomplicate.d astluna, plastic bronchitis, proximal obstruction (and its many causes), and bronchiectasis, particularly cystic fibrosis. Large mucus plugs in bronchi should be distinguished from focal mucin plugging in small bronchioles which is a very common nonspecific finding.

2) Bronchocentric granulomatosis (BCG) was also present in the case presented. The necrotizing granulomatous inflammation should first lead to consideration of an infectious cause. In that regard, special stains for microorganisms were negative in this case and they are typically negative in bronchocentric granulomatosis in the setting of ABPA in which the BCG represents a downstream allergic necrotizing reaction to the more proximal fungal antigens found in the MIB.

BCG can be looked at as a histologic finding with a number of different causes which should be considered and excluded:

• Infections: mycobacterial, fungal, parasitic • Allergic: e.g. ABPA • Noninfectious: Wegener's granulomatosis, rheumatoid arthritis

The radiologic manifestations of cases of ABPA that show histologic BCG often include MlB and/or eosinophilic pneumonia in addition to mass lesion(s) that may cavitate.

Histologically BCG manifests as granulomatous destruction of the wall of an airway with central necrotic debris often rich in eosinophils when occurring in the setting of ABPA. The surrounding tissue may or may not show non-necrotizing granulomas. In the. case presented one can trace a cellular bronchiolitis to lesions with focal destruction of the bronchiolar wall to lesions that show the full histology of BCG. The surrounding lung frequently shows eosinophilic pneumonia.

3) Eosinophilic pneumonia is the most common pattern encountered in the distal lung parenchyma in ABPA. The key feature c:>f eosinophilic pneumonia is. obviously the presence of increased eosinophils, usually in clusters. Typically these are within airspaces associated with prominent increase in associated eosinophilic macrophages. Interstitially the eosinophils are also often present and the latter may occasionally predominate. The case presented is an example of ·a disease with numerous eosinophils and the differential diagnosis it engenders.

44 Pulmonary Pathology crrR I 171l> Cancer Seminat 4) HYPersensitivity oneumonitis is oile of the rare bistologic patterns encountered in allergic bronchopulmonary aspergillosis. The clinical findings and histology are similar to that of other cases of hypersensitivity pneumonitis such as farmer's lung and bird fancier's lung. Thus these cases show a bronchiolocentric inflarnmator.y process that is primarily a cellular infiltrate with. scattered non-necrotizing granulomas. Some organizing pneumonia may be present. Marked interstitial fibrosis is usually not a feature. Eosinophil& are generally not part of the inflammatory reaction in this condition.

Discussion: Eosinophilic Lung Disease

A generic designation of eosinophilic pneumonia or eosinophilic lung disease can be used when appreciable numbers of eosinophils infiltrate the lung parenchyma. The eosinophils may be interstitial or airspace, but typically they .are associated with a concomitant increase in alveolar macrophages. Eosinqphilia may or may not be present. Extrapulmonary disease may o~ may not be present. There are many syndromes associated with eosinophil infiltrates/eosinophilic pneumonia:

Asthma Idiopathic eosinophilic pneumonia o Chronic eosinophilic pneumonia o Acute eosinophilic pneumonia 0 eoffler's syndrome o Incidental eosinophilic pneumonia o Variants (such as eosinophilic pleuritis, eosinophilic bronchiolitis, et al.) Secondary eosinophilic pneumonia Infection associated: parasites, fungal (especially aspergillus, coccidioidomycosis)

Drug-induced (many are implicated) lmmunologic or systemic diseases [collagen vascular disease, hypereosinophilic syndrome, systemic vasculitis (PAN, WG, Churg-Strauss), HlV infection, malignancy-associated, inllarnmatory bowel disease-associated, eosinophilic gastroenteritis-associated]

Histologic features of eosinophilic pneumonia:

• Intra-alveolar eosinophils • Interstitial eosinophils • Airspace.macrophages • Organizing pneumonia • Prominent intra-alveolar fibrin (that is usually very red in color) • Necrotic eosinophils (within alveoli) • Granulomatous inflammation • Mild vascular infiltrate ("vasculitis")

CTTR 117"' Cancer Seminar Pulmonary Pathology 45 Histologic lesions of conditions associated with eosinophilic pneumonia:

• Vasculitis (Churg-Strauss, Wegener's, PAN) • Necrotizing granulomas (Churg-Strauss, Wegener's) • Asthmatic changes in the airways • Changes ofABPA (BCG, MJB) • Infections (fungi, parasites)

Acute eosinoohilic pneumonia has been recently recognized and defined (see Allen ref.):

• Acute febrile illness less than five days in duration • Hypoxemic respiratory failure • Diffuse alveolar or mixed alveolar interstitial radiographic infiltrates • BAL eosinophils greater than 25% • Absence of parasitic, fungal, or other infection • Prompt and complete response to corticosteroids • Failure to relapse after discontinuation of corticosteroids

This definition is very strict and can only be applied retrospectively, does not allow for cases that come to biopsy rather than bronchoalveolar lavage, and excludes cases greater than five days duration.

Tazelaar, et al. have adopted a definition that is more applicable to histolopathology: acute/organizing diffuse alveolar damage with large numbers of tissue eosinophils. Airspace fibrin may be prominent, and most cases also show increase in alveolar macrophages and more chronic inflammation in the interstitium than in otherwise uncomplicated acute/organizing diffuse alveolar damage.

There have been a number of reports of acute eosinophilic pneumonia developing in individuals who start smoking cigarettes. 1n some instances these are teenagers who are experimenting with cigarettes and ferreting out the exposure history may be difficult.

Chronic eosinophilic pneumonia is more common than acute eosinophilic pneumonia. Symptoms may be severe and prolonged; with cough, fever, dyspnea and pleuritic pain. Some patients are severely hypoxic. There may be a family history of allergy or asthma. If there is blood eosinophilia, it usually occurs at or around the onset of symptoms and radiographic changes.

In chronic eosinophilic pneumonia, the radiologic infiltrates are described as "ground glass" and are most often peripheral and apical. High resolution CT scan of the chronic disease may show a classic "photographic negative" of the perihilar infiltrates of acute pulmonary edema. Croften described such radiographic infiltrates of eosinophilic pneumonia as "clouds of smoke rising after an explosion in the region of the hilum and drifting up against the chest wall peripherally".

46 Pulmonary Pathology CTTR 117"' Cancer Semi!W The key histologic features are: increased parenchymal and airspace eosinophils, increased alveolar macrophages, and increased type n cells. There may be acute lung injury with markedly atypical reactive type n cells, macrophages in the airspaces, and eosinophils in variable numbers. The interstitium is edematous. There may be extensive BOOP pattern organization in the airspaces. There may be collections of plasma cells and lymphocytes in the interstitium. Desquamative interstitial pneumonia has less eosinophils, less prominent type ll cells, and less acute lung injury.

Churg-Strauss syndrome probably gets more press in the pathology literature than it deserves since it is actually very rare to see a full-blown case histologically. Churg-Strauss syndrome is defined as a systemic vasculitis occurring in a patient with asthma and eosinophilia. As a syndrome it has features to distinguish it from other forms of vasculitis, particularly Wegener's granulomatosis and microscopic polyangiitis'{based on frequency of organ system involvement, etc.).

The pathologist is often asked to "rule out Churg-Strauss disease" in a lung biopsy. This is not really possible since a patient must have evidence of a systemic vasculitis to confirm a diagnosis of Churg-Strauss syndrome and even the presence of all the classic histologic findings in the lung may not be indicative of a clinical diagnosis of Churg-Strauss disease. Lie bas suggested the concept of localized Churg-Strauss disease for cases that show the classic histologic findings (see below) but don't have systemic disease. The issue is somewhat of a tempest in a teapot since the frequency with which an individual pathologist has to deal with this issue is rare indeed.

The classic histologic findings of Churg-Strauss syndrome include vasculitis, necrotizing and non-necrotizing (often extravascular granulomas), and a marked eosinophil infiltrate. ln the lung of patients with proven Churg-Strauss disease the pathologist may encounter any or all of the following:

• The classic features described above (rarely) • Airway changes of asthma • Eosinophilic pneumonia • Granulomatous inflammation, giant cells • Eosinophilic capillaritis with hemorrhage • Hemosiderin deposition • Organizing pneumonia

References Abril A, Calamia KT, Cohen MD. The Churg Strauss syndrome (allergic granulomatous angiitis): review and update. Semin Arthritis Rheum 2003;33: 106-1 14. Allen JN, Davis WB. Eosinophilic lung diseases. Am J Respir Crit Care Med 1994;150:1423-1438. Angus RM, Davies ML, Cowman MD, McShany C, Thomson NC. Computed tomographic scanning of the lung in patients with allergic bronchopulmonary aspergillosis and in asthmatic patients with a positive skin test to Aspergillus fumigatus. Thorax 1994:49:586-589. Badesch, et al. Acute eosinophilic pneumonia: a hypersensitivity phenomenon? Am Rev Respir Dis 1989;239:249.

CTTR 117,. Cancer Seminar Pulmonary Pathology 47 Boccagni.C, Tesser F, Mittino D, Terazzi E, Naldi P, Columbi S, Zoppis E, Monaco F. Churg-Strauss syndrome associated with the Jctikotriene antagonist montelukast. Neurol Sci 2004;25:21-22. Bosken CH, Myers JL, Greenberger PA, Katzenstein AL. Pathoiogic features of allergic bronchopulmonary aspergillosis. Am J Surg Pathol1988; 12:216-222. Carrington, et al. Chronic eosinophilic pneumonia. NEJM 1969;280:787. Chitkara RK, Sarinas PSA. DirofJJaria, visceral larva migrans, and tropical pulmonary eosinophilia. Seminars in Respiratory Infections 1997; 12: I 38-148. Roberts T, Colby TV. Noninfectious necrotizing granulomatous disordj:rs. Chapter 27 ln. Haselton PS. Ed. Spencer's Pathology of the Lung, 51b Edition, McGraw Hill, New York, 1996, pp. 835-863. Chetty A. Pathology ofallergic bronchopulmonary aspergillosis. Front Biosci 2003; I :e I I 0- I I 4. Cockrill BA, Hales CA. Allergic bronchopulmonary aspergillosis. Ann Rev Mcd I 999;50:303-316. Cohen M, Sahn SA. Bronchiectasis in systemic diseases. Chest I 999; 116: I 063-1074. Duchheit, et al. Acute eosinophilic pneumonia with respiratory failure: a new syndrome? Am Rev Respir Dis 1992; 145:716. Folson B. Mucoid impaction (inspissated secretions) in segmental bronchial obstruction. Radiology I 979;1133:9- 16. Fink JN. Allergic bronchopulmonary aspergillosis. Chest I 985;87:81s'84s. Glazer CS, Cohen LB, Schwarz ML Acute eosinophilic pneumonia in AIDS. Chest 2001; 120: 1732-1735. Glimp RA, Bayer AS. Fungal pneumonias. Part 3. Allergic brochopulmonary aspergillosis. Chest 1981 ;80:85-94. Greenberger PA, Patterson R. Allergic bronchopulmonary aspergillosi·s. Model of bronchopulmonary disease with defined seorlogic, radiologic, pathologic and clinical findings from asthma to fatal destructive lung disease. Chest 1987;91:165s·l71s. Greenberger PA. Clinical aspects of allergic bronchopulmonary aspergillosis. Front Biosci 2003;8:sl 19-127. Hadase M, Iwasaki Y, Harada H, Kubota Y, Yokomura I, Ueda M, Hashimoto S,.Nakagawa M. Onset of acute eosinophilic pneumonia after resumption of smoking. Nihon Kokyuki Gakkai Zasshi I 999;37:560-564. Hellmich B, Ehlers S, Csemok E, Gross WL. Update on the pathogenesis ofChurg-Strauss syndrome. Clin Exp Rheumatol2003;21:s69-77. Hutcheson JB, Shaw RR, Paulson DL, Kee JL. Mucoid impaction ofthe bronchi. Am J Clin Pathol 1960;33:427- 432. Irwin RS, Thomas HM. Mucoid impaction ofthe bronchus. Diagnosis and treatment. Am Rev Respir Dis 1973; 108:955-959. Jederlinic PJ, Sicilian L, Gaensler EA. E:lironic eosinophilic pneumonia. A report of 19 cases and a review ofthe literature. Medicine t988, 67(3): 154. Jelihovsky T. The structure of bronchial plugs in mucoid impaction, bronchocentric granulomatosis and asthma. Histopathology 1983;7:153-167. Katzenstein AL. Angiitis and granulomatsis. In; Katzenstein and A.•kin's Surgical Pathology of Non-Neoplastic Lung Disease, 3"' ed. Philadelphia: WB Saunders; 1998; 193-222. Katzenstein AL. Immunologic lung disease. In: Katzenstein and A.•kin's Surgical Pathology of Non-Neoplastic Lung Disease, 3"' ed. Philadelphia: WB Saunders; 1998; 138-167. Katzenstein AL, Liebow AA, Friedman PJ. Bronchocentric granulomatosis, mucoid impaction, and hypersensitivity reactions to fungi. Am Rev Respir Dis 1975;111:497-537. Keogh KA, Specks U. Churg-Strauss syndrome: clinical presentation, antineutrophil cytoplasmic anboodies, and leukotriene receptor antagonists. Am J Med 2003; I I 5:284-290. Khan AN, Jones C, Macdonald S. Bronchopulmonary aspergillosis: a review. Curr Probl Diagn Radio12003; 32!156-I 68. Koss M, Robinson R, Hochholzer L. Bronchocentric granulomatosis. Hum Pathol1981;12:632-638. Kuhn FA, Swain R Jr. Allergic fungal sinusitis: diagnosis and treatment. Curr Opin Otolaryngol Head Neck Surg 2003; 11:1-5. Myers JL, Katzenstein AL. Granulomatous infection mimicking bronchocentric granulomatosis. Am J Surg Pathol 1986;10:3 17-322. l'anerson R. Allergic bronchopulmonary aspergillosis and hypersensitivity reactions to fungi. In: Fishman AP, eg. Pulmonary diseases and disorders. Philadelphia: McGraw-HiU; 1998; 777-782. Pope-Harman AL. Davis WB, Allen ED, Christoforidis AJ, and Allen JN. Acute eosinophilic pneumonia. A summary of 15 cases and review of the literature. Medicine 1996;75:334-343.

48 Pulmonary Pathology CTTR 117" Cancer Seminar Ricketti AJ, Greenberger PA. Mintter RA, Patterson R. Allergic brochopulmonary aspergillosis. Chest 1984; 86:773-718. Shah A, Panjabi C. Allergic bronchopulmonory aspergillosis: a review of a disease with a worldwide distribution. J Asthma 2002;39:273-289. Shiota Y, Kawai T, Matsumoto H, Hiyama J, Tolruda Y, Marukawa M, Ono T, Mashiba H. Acute eosinophilic pneumonia following cigarette smoking. Intern Med 2000;39:830-833. Tang MB, Yosipovitch G. Acute Churg-Strauss syndrome in an asthmatic patient receiving montelukast therapy. Arch Dcnnatol2003;139:715-718. Tazelaar HD, Linz U, Colby TV, Myers JL, Limper AH. Acute eosinophilic pneumonia: histopathologic findings in 9 patients. Am Rev Respir Crit Care Med 1997; 155:296. Travis WD, Colby TV, Koss MN, Rosad

CTTR I I 7"' Cancer Seminar Pulmonary Pathology 49 • •

Figure 6-2. Allergic brooehopulmonnry Figure a.

I I

Fig 6-5. Allergic bronchopulmonary aspergillosis. Some of !he pan:nchymul aspergillosis. Whole mount of one of ~1c regions show necrotizing granulomalou.' slides highlighiS the mucoid impaclion in th< inllammalion desaroying bronchioles. The dilated airways. the chronic inflamn\3tion pulmonary IU'Icry accompanying lhis around lhc smaller bronchioles, and lhe dill\. destroyed bronchiole is prescnl bclwccn 8 and consolidation. 9 o'clock.

CTTR 11 7'• Cancer Seminar P11lmonary Pathology 51 V. Fibrosiog Interstitial Pneumonias, Pseudotumors, and Histiocytic Proliferations

CASE7

Clinical History CCTTR Ace.# 29883): A 49-year-old man presented with progressive iri.terstitiallung disease and restriction on pulmonary function testing. He ultimately underwent orthotopic lung transplantation and the sections are from the explanted lung tissue. ·(Case courtesy of R. Sobonya, Tucson, AZ)

Key histologic features: The fibrotic process is exquisitely limited to the lymphatic regions in the pleura, septa, and lung bronchovascular bundles; intervening emphysema; features are not thatofUIP.

Diagnosis: Erdheim-Chester disease with pulmonary involvement.

Fotlow-up: Radiologic studies of lhe extremities confirmed the typical radiologic features of Erdheim-Chester disease. The patient developed recurrent Erdheim-Chester disease in the allograft one year after transplantation.

Approach to Case 7

Clinically and radiologically a progressive fibrosing interstitial pneumonia Histologically there is extensive fibrosis. UIP shoUld be the main condition to exclude.

Key feature is recognition that the fibrosis follows lymphatic routes and that this is not usual interstitial pneumonia. Erdheim-Chester disease is a rare cause of interstitial pneumonia with this distinctive pattern of fibrosis.

The most important aspect of this case is to recognize why it is not a fibrosing interstitial pneumonia. especially usual interstitial pneumonia CUJP) and fibrosis associated with emphysema. While_the emphysema is prominent the most obvious feature is fibrous thickening of the interstitium, however on careful examination the cellular infiltrate and fibrosis are limited to the lymphatic routes. In addition the character of the inflammatory reaction, rich in histiocytes, would be unusual for UIP. UIP tends to produc~ patchy fibrosis and honeycomb change involving subpleural and paraseptal lung tissue rather than the pleura and septa themselves. Once one appreciates the distribution of- the abnormality and its cytologic composition, Erdheim-Chester disease can be considered. Thi.s is quite rare in the lung but sufficiently distinctive that pathologists can suggest the diagnosis (as in this case) once one is familiar with the histology.

CTTR 117"' Cancer Seminar Pulmonary Pathology 53 Discussion: Fibrosing Interstitial Pneumonias

Usual interstitial pneumonia is the prototype fibrosing interstitial pneumonia and the pattern encountered in idiopathic pulmonary fibrosis (IPF), the classic cause of "pulmonary fibrosis." There are niany forms of interstitial pneumonia· that are associated with widespread fibrosjs and_ many of these are included below. In the older literature it was said that many of these conditions showed a "UIP pattern" yet with the recently more refined criteria for the pathologic diagnosis ofUIP, subtle differences are now apparent in many ofthese conditions.

Key Features of UIP:

• Dense fibrosis causing remodeling of lung architecture with frequent honeycomb fibrosis • Fibroblastic foci typically at the edge of the dense scars • Patchy lung involvement • Frequent subpleural, paraseptal, and/or peribronchovascular distribution (i.e. the alveoli around the larger bi'onchovascular bundles

The following list includes the more commonly encountered lung diseases that may be associated with widespread fibrosis. These include:

• Usual interstitial pneumonia: itself • Desquamative interstitial pneumonia • Lymphocytic interstitial pneumonia • Nonspecific interstitial pneumonia/fibrosis • Interstitial pneumonias associated with collagen vascular diseases • Drug reaction • Pneumoconioses • Sarcoidosis • Pulmonary Langerhans' cell histiocytosis • Chronic granulomatous infections • Chronic aspiration • Chronic hypersensitivity pneumonitis • Organized chronic eosinophilic pneumonia • Organized diffuse alveolar damage • Chronic interstitial edema • Radiation • Healed infectious pneumonias

54 Pulmonary Pathology CTTR 117"' Cancer Se)tlinar In typical cases these oonditions should be readily distinguishable from idiopathic U1P (IPF) based on the histologic findings themselves or ancillary finding$:

• Desquamative interstitial pneumonia - prominent airspaces macrophages, smoking changes, relative lack of honeycomb change; lack of fibroblastic foci • Lvmphocvtic interstitial pneumonia -lymphoid infiltrate is dense • Collagen vascular diseases - by history • Drug reactions- by history

• Pneumoconioses - identification of the foreign dust and the distinctive histopathologic patterns in the pneumoconioses • Sarcoidosis - presence of granulomas, hyaline eosinophilic fibrosis along lymphatic routes • Pulmonary Langerhans' cell histiocytosis - stellate centrilobular scarring; associated smoking-related changes • Chronic granulomatous infections- granulomas present • Chronic aspiration - bronchiolocentric distribution with foreign material and/or giant cell reaction • Chronic hvoersensitivitv pneumonitis - presence of small granulomas, presence of prominent centrilobular injury, appropriate history, distinctive HRCT • Organized chronic eosinophilic pneumonia - history, presence of eosinophils • Organized diffuse alveolar damage- history • Chr9nic interstitial edema history of cardiac disease, prominence of septal changes • Radiation - history • Healed infectious pneumonias - history

The distinction of nonspecific interstitial pneumonia with fibrosis from U1P is a difficult problem. In prototypical cases this is not difficult: . U1P shows the features described above, whereas NSIP is more uniform and diffuse with relatively little honeycomb and a relative lack of fi broblast foci. As NSIP get more and more fibrotic its distinction from U1P becomes more difficult, probably quite arbitrary, and may be of less clinical significance because both tend to fuir poorly when there is marked fibrosis.

Recently another fibrosing interstitial pneumonia has been described. Churg et al. called this small airway-centered fibrosis (SACF) and Y ousem et al. called it bronchiolocentric interstitial pneumonia (BriP). These authors describe a fibrosing interstitial pneumonia with centrilobular distribution and prominent peribronchiolar metaplasia without features of other forms of recognized interstitial pneumonias. The validity of this entity remains to be clarified.

References for Fibrosing Interstitial P neumonias Bjoraker JA, Ryu JH, Edwin MK. Myers JL, Tazelaar HD, Schroeder DR, Offord KP. Prognostic significance of histolopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998; I 57: 199·203. Churg A, et a!. Small airway centered interstitial fibrosis (SAC!F}: a new fonn of interstitial lung disease. Am J Respir Crit Care Med 2003; 167:a300. (Note: This was presented as SACF-small airway centered fibrosis at the meeting).

C1TR 117" Cancer Seminar Pulmonary Pathology ss Daniil ZD, Gilchrist f:C, Nicholson AG, Hansell DM, Harris J, Colby TV, duBois RM. A histologic pattern of nonspecific interstitial pneumonia is associated with a better prognosis than usual interstitial pneumonia in patients with cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 1999; 160:899-905. duBois RM, Wells AU. Cryptogenic fibrosing alveolitis/idiopathic pulmonary fibrosis. Eur Respir J 2001;18:Suppl. 32, 43S-55S. Hunning!lake GW, Gross TJ. Idiopathic pulmonary fibrosis. N Eng! J Med 200 1;345:517-525. Hunninghake G, Zimrnennao MB, Schwartz D, King TE Jr, et al. Utility oflung biopsy for the diagnosis of idiopathic pulmonary fibrosis. Am J Respir Grit Care Med 2001; 164:193-196. Katzenstein A, FioreUi RF. Nonspecific interstitial pneumonia/fibrosis: histologic features and clinical significance. Am J Surg Pathol 1994;18:136-147. Katzenstein ALA, Myers JL. Idiopathic pulmonary fibrosis: State ofthe art. Am J Respir Crit Care Med 1998;157: 1301 - 13 15. Katzenstein ALA, Zisman DA, Litzky LA, Nguyen BT, KotloffRM. Usual interstitial pneumonia. Histologic study of biopsy and explant specimens. Am J Surg Pathol 2002;26: 1567-1577. King TE, Costabel U, Cordier F, et at Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med'2000; I 61 :646-664. Leslie KO, Colby TV, Swensen SJ. Anatomic distribution and histopathologic patterns of interstitial lung disease. Chapter 2. In: Schwartz Ml and King TEeds. Interstitial Lung Disease, 4m Edition, BC Decker, Hamilton, Ontario, 2003; pp. 31-53. Nagai S, Kitaichi M, Itoh H, Nishimura K, lsumi T , Colby TV. Idiopathic nonspecific interstitial pneumonia! fibrosis: comparison with idiopathic plilinonary fibrosis and BOOP. Eur Respir J 1998; 12:10 I 0- 1019. Nicholson AG, Colby TV, duBois RM, Hansell DM, Wells AU. The prognostic significance ofhisto logical pattern of usual interstitial pneumonia in patients presenting with clinical entity ofcryptogenic fibrosing.alveolitis. Am J Respir Crit Care Med 2000;162:2213,2217. ltyu JH, Colby TV, Hartman TE. Idiopathic pulmonary fibrosis: current concepts. Mayo Clin Proc 1998;73: I 085- 1101. Travis WD, King TE (Co-Chairs) and ATSIERS Panel. ATSIERS International Multidisciplinary Consensus Classification of Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002; 165: 277-304. Travis WD, Colby TV, Koss MN, et al. Atlas ofTumor Pathology: Non-neoplastic disorders of the Lower Respiratory Tract. AFJP, Washington, 2002. Yousem SA, Dacic S. Idiopathic bronchiolocentric interstitial pneumonia. Mod Pathol 2002; 15: 1148-1153.

Discussion: Erdheim-Chester Disease

The disease now known as Erdheim-Chester disease was described by Erdheim 's pupil Chester in 1930 under the name "lipoid granulomatose." Less than 200 cases have been reported in the medical literature.

Erdheim-Chester disease is a rare, non-familial, sometimes multifocal, histiocytosis of unknown etiology. There are no serum lipid abnormalities. The characteristic and defining lesions are symmetrical, bilateral, mJ'ltaphyseal, and diaphyseal CQrtical sclerotic lesions of the long bones. Most patients are over 40 years of age. About half have extraskeletal manifestations.

Extraskeletal lesions may involve or present in the lung, central nervous system, orbit, kidney, retroperitoneum (where xanthogranulomatous inflammation may be misdiagnosed), breast, skin, skeletal muscle, heart, pericardium, aorta, and sinonasal region. Traditi·onal hematolymphoid sites such as lymph nodes, bone marrow, liver, and spleen are spared.

The histologic findings of Erdheim-Chester disease are nondescript. This has been described as a "lipid storing histiocytosis" when foam cell change is prominent. Toulon-type giant cells may

56 Pulmonary Pathology CTTR I 17'' Cancer Seminar be seen. There may be a sprinkling of lymphocytes, eosinophils, and plasma cells. The degree of fibrosis and cellularity vary from field to field as shown in lung case presented. The involvement of lymphatic routes in the lung for this hematolymphoid disorder of histiocytes. The histiocytes are typically positive for histiocyte markers and rarely positive for S-100. Electron microscopy shows an absence of Birbeck granules. Rare cases share features of both Erdheim-Chester disease and Langerhans' cell histiocytosis suggesting the possibility of a relationship between the two diseases.

The morbidity in the disease is generally not related to the bony involvement. The extraosseous involvement seems to determine mortality, and about 60% die of the disease, the majority due to respiratory failure or CNS involvement. Among those who die, one-third survive less than six months after initial diagnosis. There is no known effective treatment.

The differential diagnosis in this case includes' two groups of lesions: I) fibrosing interstitial pneumonias, and 2) histiocytic proliferative and infiltrative processes.

The fibrosing interstitial pneumonias that would enter into the differential diagnosis include usual interstitial pneumonia and nonspecific interstitial pneumonia. These entities are discussed elsewhere in the syllabus. Conceivably healed sarcoidosis could leave a residue of fibrosis along lymphatic routes but the histiocytes and other inflammatory cells would generally be lacking and healed sarcoid often has rounded hyalinized fibrotic nodules.

Among histiocvtic infiltrates that would enter into the differential are including Langerhans' cell histiocytosis and Rosai~Dorfrnan disease (also discussed elsewhere in the syllabus). Langerhans' cell histiocytosis is generally associated with smoking and produces stellate centrilobular fibrosis described elsewhere in this seminar. Even Langerhans' cell sarcoma and disseminated forms of Langerhans' cell histiocytosis in children should be readily differentiated on the basis of the the history, the larger number of histiocytes, their characteristic cytology, and their positivity for both S-100 and COla. Rosai-Dorfrnan disease has llistiocytes that tend to be larger with nuclei with more prominent nucleoli and lung involvement is even more rare than with Erdheim­ Chester disease. The few cases that I have seen have either presented as mass lesions in patients with typical lymph node findings and the characteristic emperipolesis is usually recognizable.

The recurrence of disease in the lung allograft following transplantation is an interesting phenomenon that has obvious clinical significance. 1 know of two cases of Erdheim-Chester disease with lung involvement that have undergone transplantation and in both cases there was recurrence in the allograft. Other conditions that have been documented to recur in the allograft include the following:

• Lymphangioleiomyomatosis • Pulmonary Langerhans' cell histiocytosis • Desquamative interstitial pneumonia • Bronchioloalveolar carcinoma • Cobalt pneumoconiosis (GIP) • Alveolar proteinosis

CITR I IT" Cancer Seminar Pulmonary Pallwlogy S7 • Diffuse panbronchiolitis • Sarcoidosis • Usual interstitial pneumonia • Idiopathic pulmonary hemosiderosis

References for Erdheim-Ches.ter Disease Bancroft LW, Berquist TH. Erdheim-Chester disease: radiographic findings in five patients. Skeletal Radio! 1998;27: 127-1 32. Bisceglia M, et a!. Erdheim-Chester Disease: Clinical and pathologic spectrum of four cases from the Arkadi M. Rywlin Surgical. Pathology Slide Seminars. Ann Diagnost Pathol (2003). In Press. Bourke SC, Nicholson AG, Gibson GJ. Erdheim..Chester disease: pulmonary infiltration r0$J>onding to cyclophosphamiae and prednisolone. Thorax 2003;58: I 004-1 005. Devouassoux G, Lantuejoul S, Chatelain P, Brambilla E, Brambilla C. Erdheim-Chester Disease. A primary macrophage cell disorder. Am J Respir Grit Car~ Med 1998;157:650-653. Egan AJM, Boardman LA, Tazelaar HD. Swensen SJ, lett JR, Yousem, SA, Myers JL. Erdheim-Chester Disease. Clinical, radiologic, and histopathologic findings in five patients with interstitial lung disease. Am J Surg. Pathol 1999;23: 17-26. Fink MG, Levinson PJ, Brown NL, Sreekanth S, Sobel GW. Erdheim-Chester disease. Case report with· autopsy findings. Arch Pathol Lab Med 1991; 115:619-623. Ivan D, Neto A, Lemos L, Gupta A. Erdheim-Chester disease: a unique presentation with liver involvement and vertebral osteolytic lesions. Arch Pathol Lab Med 2003;127:e337-339. Johnson MD, Aulino JP, Jagasia M, Mawn LA. Erdheim-chester disease mimicking multiple meningiomas syndrome. AJNR Am J Neuroradiol2004;25:1.34- 137. Kambouclmer M, Colby TV, Domenge C, Battesti JP, Soler P, Tazi A. Erdheim-Chester disease with prominent pulmonary involvement associated with.eosinophilic granuloma of mandibular bone. Histopathology 1997;30:353-358. Keno W, Stable A, Zachoval R, Ziet Ch, Raum W, Wittenberg G. Erdheim-Chester disease: a case report and literature overview. Eur Radio! 1999;9: 153-158. Lyders EM, Kaushik S, Perez-Berenguer J, Henry DA. Aggressive and atypical manifestations ofErdheim·Ches!er disease. Clin Rhaurnatol 2003;22:464-466. · · Miller RL, Sheeler LR,.BauerTW, Bukowski RM. Erdheim-Chester disease. Case report ·and review of the literature. American Journal of Medicine 1986';80:1230-1236. Ono K, Oshiro M, Uemura K-I, Ota H, Matsushita Y, ljima S, lwa~e T, Uchida M, Katsuyama T. Erdheim..Chester disease: a case. report with immunohistochemical and biochemical examination. Hum Pathol I 996;27:91-95. Rush WL, Andriko JA, Galateau-SaUeF, Brambilla E, Brambilla C, Zianybey I, Rosado-de-Christenson ML, Travis WD. Pulmonary pathology ofErdheim-Chester Disease. Mod Pathol 2000;7:747-54. · Valmaggia C, Neuweiler J, Fretz C, Gottlog I. A case ofErdheim..Chester disease with orbital involvement. Areh Ophthalmoll997;115:1467-1468. Veyssier-Belot C, Cacoub P, Caparros-Lefebvre D, Wechsler J, Brun B, Remy M, Wallaert B, Pettit H •. Grimaldi A, Wechsler B, Godeau P. Erdheim-Chester disease. Clinical and radiologic characteristics of59 eases. Medicine I 996;15: 157-169. Wittenberg KH, Swensen SJ, Myers JL. Pulmonary involvement with Erdheim-chestcr diseao;c: radiographic and CT findings. AmJ Roentgenol2000;5:1327-31. Wright RA, Hermann RC, ~Parisi IE. Neurological manifestations ofErdheim-Chester disease. J Neurol Neurosurg Psychiatry 1999;66:72-75.

58 Pulmonwy Pathology CTTR I 17"' Cancer Seminar CASES

Clinical History (CTTR Ace. #29884): A 40-year"old woman with cough was found to have a left lower lobe mass that involved the pleura and extended around the aorta. Pneumonectomy was performed because of the extent of lung involvement although some residual mass was left around the lower thoracic aorta. The patient had a prior history of"uterine sarcoma" three years earlier.

Key histologic features: Does not fit with any of the usual sarcomas; some foci definitely "inflammatory'' and fibrotic; infiltrative nature around large bronchova5cular structures; presence of large foamy histlocytes with associated acute and chronic inflammation admixed with zones of dense sclerosis; S-1 00 positivity confirmed in histiocytes.

Diagnosis: Rosai-Dorfman disease.

Follow-up: The patient was alive and well, with stable radiologic abnormalities three ¥ears after pneumonectomy. She had mild shortness of breath. Dr. Rosai concurred with the diagnosis.

Approach to Case 8

The patient has a mass lesion of concern for neoplasm. Exclude unusual sarcoma and sarcomatoid carcinoma. Recognition ofthe process as "basically inflammatory." Consider inflammatory masses in the lung: (see discussion below).

Discussion

It is unlikely that anyone would mistake this proliferation as some sort of neoplasm based on the histology. The surgeon thought that it was malignant and therefore performed the pneumonectomy. From the morphologist's point of view, a diagnosis of inflammatory pseudotumor. would not be unreasonable: an inflammatory mass that is not malignant. Making a diagnosis of inflammatory pseudo tumor would probably not hurt the patient but this case does have the distinctive features of Rosai-Dorfman disease as they are identified at a variety of extqmodal sites. The differential diagnosis is discussed below. While the term inflammatory pseudotumor may be reasonable at some sites (such as liver, spleen, lymph node), it is not particularly useful in the·lung and one should try to be more specific as outlined below.

Rosai-Dorfman disease was described in 1969 by Rosai and Dorfinan as sinus histiocytosis with massive lymphadenopathy. The acronym Rosai-Dorfman disease has proved more durable than the original name (l actually prefer the term "Juan Ron Fever"). Anyone who has heard Drs. Dorfman or Rosai speak on this entity will recall the pictures of a youngster with massive cervical lymphadenopathy despite being asymptomatic.

CTTR I 17"' Cancer Seminar Pulmonary Pathology 59 The lymph node histology of Rosai-Dorfinan disease is well known to all. There is dilatation of the sinuses,. which contain large ·pale histiocytes with vesicular nuclei. The cytoplasm of the histiocytes contains a variety of cells including lymphocytes, plasma cells, and neutrophils. Rosai points out that emperipolesis is often ~est appreciated with S-1 00 stains, in which the cytoplasm of the histiocytes stains positively and the cells withi.n the cytoplasm are easily picked out. The lymph nodes commonly show some associated fibrosis and plasma cell infiltrate in the capsule. Some cases show foci of acute inflammation and necrosis, but these are usually minor in degree.

Rosai-Dorfinan disease is now recognized to involve most organ systems, sometimes without associated lymph node involvement. The most common extranodal sites include slcin, soft tissues, bone, upper aerodigestive tract (in~luding nose and sinuses), eye, orbit, and central nervous system. Involvement of the gastrointestinal tract, breast, and male and female urogenital tracts have also been documented. The lung is one of the least commonly affected sites. A number of publications have documented the sites of involvement with Rosai-Dorfinan disease and an SHML registry bas been maintained (see Foucar reference).

One of the interesting aspects about Rosai-Dorfinan disease is that .a pattern similar to sinus histiocytosis may be recognized at extranodal sites, particularly beneath epithelia such as skin or mucosa of the upper respiratory tract. There is sinus-like change in the tissue, which ·shows an mfiltrate by the characteristic pale histiocytes and associated inflarmnatory change. This feature was identified in the bronchial mucosa in the case presented.

The pathogenesis of Rosai-Dorfinan disease is unknown. It represents a peculiar inflammatory process that may show spontaneous regression. Polyclonality has been confirmed. The condition is rarely familial; about 20 percent have some sort of identifiable illll11;une dysfunction.

The prognosis varies with the site(s) involved and the extent of disease. Patients with involvement restricted to lymph nodes typically show complete regression, although patients with multisystem extranodal disease may have a protracted course with relapses and rem.issions that extend over years or decades. Occasional cases are fatal when there is extensive involvement of vital organs.

The differential diagnosis of Rosai-Dorfman disease at any site is basically that of a chronic inflarnrnatory process and unless the distinctive fea~es of Rosai-Dorfinan disease are recognized, a descriptive (inflammatory) diagnosis is .usually rendered. Once one considers the possibility of Rosai-Dorfman disease, then the distinctive histologic features can be appreciated: irregular fibrosis, plasma cell infiltrate, and sheets of pale (S-100 positive) histiocytes with vesicular nuclei and emperipolesis.

60 Pulmonary Pathology CTTR I 17"' Cancer Seminar Depending on the site involved, the differential diagnosis ofRosai-Dorfman disease includes:

• A nonspecific inflammatory reaction with xanthogranulomatous features • Inflammatory pseudotumor • Inflammatory myofibroblastic tumor/plasma cell granuloma • Fibrous histiocytoma/fibroxanthoma • Pulmonary hyalinizing granuloma • Langerhans' cell histiocytosis • Erdheim-Chester Disease • Infections with histiocytic proliferation (Whipple's disease, malakoplakia, mycobacterial infection) • Storage diseases with histiocytic proliferation (including crystal storing conditions) • Neoplasms with pale cells (renal cell carcinoma and its mimics; Hodgkin's disease, non­ Hodgkin's lymphomas, melanoma, others)

The term "inflammatory pseudotumor" has been used in a generic sense for a variety of non­ neoplastic masses and in a more specific sense. In the lung the term has been used by the AFIP to include: plasma cell granuloma, fibroxanthoma/fibrous histiocytoma, and focal organizing pneumonia. It is a term that probably should be avoided unless there is some modifier or it is refe.rring to some specific usage as it has been in lymph nodes, liver and spleen.

Inflammatory myofibroblastic tumor is the current preferred term for the lesion originally described as plasma cell granuloma. These lesions occur at a variety of ages with one-third encountered before the age of 10. They may be-quite large and may invade adjacent structures but overall have a relatively benign follow-up. A small percent pursue a malignant course and the term inflammatory fibrosarcoma has been used. A significant proportion show ALK-1 positivity. It is difficult to tell up front which cases will pursue an aggressive course.

The case presented has distinctive fibrosis and pulmonary hyalinizing granuloma would certainly enter into the differential. This tends to be multifocal and to have denser and more hyaline sclerosis similar to that encountered in sclerosing mediastinitis (another lesion which would be in the differential considering that the mediastinum was involved in the case under discussion). Pulmonary hyalinizing granuloma and sclerosing mediastinitis are thought to be exaggerated fibrotic reactions to infection, particularly histoplasmosis. They are somewhat analogous to keloid scar.

Langerhans' cell histiocytosis differs by virtue of the presence of cytologically different histiocytes and CD I a positivity. The pattern of lung involvement with upper lobe micro-nodular and cystic disease is entirely different than this mass lesion in Rosai-Dorfman disease (although admittedly the latter is so rare in the lung that even considering differential diagnosis at this site is begging the issue).

Erdhejm-Chester disease is another peculiar histiocytic reaction in which there are histiocytes, fibrosis, and plasma cell infiltrates, and in which the histiocytes may (occasionally) be S-100 positive. The pattern of lung involvement (along the lymphatic routes) is distinctive but that

CITR 117

One final way that one could look at this case is as a mass lesion with large numbers of bistiocytes (albeit cytologically distinctive and S-100 positive). Other conditions that might be encountered whe.n sheets of histiocytes are found histologically include:

• Granulomatous infections with poorly formed granulomas • Other infections including actinomycosis, botryomycosis, chronic xanthogranulomatous reaction to other bacteria • Chronic aspiration • Proximal obstruction • Neoplasms with histiocytes or cells resembling histiocytes including fibrous histiocytoma, granular cell tumor, histiocytic malignancies • Malakoplakia, Whipple's disease • Crystal storage disease in lymphoma/plasma cell cyscrasia • Focal eosinophilic pneumonia without eosinophils • Macrophage accumulation in regions of scarring • Pneumoconioses, especially silicosis or silicatosis in the early cellular/histiocytic phase

References for Rosai-Dorfman Disease Cw:bone A, DeVaney KO, Passannante A, Rinaldo A, G1oghini A, Ferlito A. ReYiew of sinus histiocytosis with massive lymphadenopathy (Rosai·Dorfinan disease) of the head and neck. Ann Otol Rhino! Layngol 1999; I 08: I 095·1 04. Faulks, Stutte HJ, Frizzera G. Hodgkin's disease and sinus histiocytosis with massive lymphadenopathy-like changes. 1iistopatho1ogy I 991; 19:221-4. Foss HD, Herbst H, Araujo I, llummel M, BergE, Schmitt-Graff A, Stein H. Monokine expression in Langerhans' cell histiocytosis and sinus histiocytosis with massive lymphadenopathy (Rossi-Dorfman disease). J Pathol 1996;179:60-S. Foucar E, Rosai J, Dorfman RF. Sinus histiocytosis and massive lymphadenopathy: An analysis of 14 deaths occurring in a patient registry. Cancer 1984;54: 1834-40. Foucar E, Rosai J, Dorfinan RF. Sinus histiocytosis and massive lymphadenopathy: (Rosai-Dorfman disease) Review of the entity. Semin Diagn Pathol1990;7:19·73. Foucar E, Rosai J, Dor.fman RF, Eyman JM. Immunologic abn.ormalities and their significance in the pathogenesis of sinus histiocytosis with massive lymphadenopathy. Am J Clin Pathol 1984;82:5 15·25. Geara AR, Ayoubi MA, Achram MC, Chamseddine NM. Rosai·Dorfinan disease mimicking neurofibromatosis: case presentation and review of the literature. Clin Radiol2004;59:625-630. Green I, Dorfinan RF, Rosai J. Breast involvement by el(tr.jnodal Rosai-Dorfinan disease. Report of seven cases. Am J Surg Pathol 1997;21 :664-8. Huang HY, Huang CC, Liu CC, Chen HJ, Chen .WJ. Isolated intracranial Rosai-Dorfman disease: Case report and literature review. Pathollnternat 1998;48:396-402. Lauwers GY, Perez-Atayde A, Dorfman R, Rosai J. The digestive system manifestations ofRosai-Dorfinan disease (sinus histiocytosis with massive lymphadenopathy): Review of I I cases. Hum Patho12000;31:380-385. Levine PH, Jahan N, Murari P, Manak M, Jaffe ES. Detection of human herpes virus 6 in tissues involved by sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfinan disease). J Infect Dis 1992; 166:291·5. Montgomery EA, M.eis JM, Frizzera G. Rosai-Dorfinan disease of soft tissue. Am J Surg Pathol 1992; 16: 122·9. Ohori NP, Yu J, Landreneau RJ, Thaete FL, Kane K. Rosai-Dorfinan disease ofthe pleura: a rare extranodal presentation. Hum Pathol2003;34:1210-121 I.

62 Pulmonary Pathology CTTR 117"' Cancer Seminar Paulli M, Bergamaschi G, Tonon L, Viglio A, Rosso R, Facchctti F, Geerts ML, Magrini U, Cazzola M. Evidence for polyclonal nature of the cell infiltrate in sinus histiocytosis with massive lymphadenopathy (Rosai-Dortinan disease). BritJ Haematol 1995;91:415-18. Pulsoni A, Anghel 0, Falcucci P, Matera R, Pescannona E, Ribersani.M, Villiva N, Mandelli F. Treatment of sinus histiocytosis with massive lymphildenopathy (Rosai-Dortinan disease): report of a case and literature review. Am J. Heinatol 2002;69:67-71. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy. A newly recognized benign clinicopathologic entity. Arcb Pathol 196~;87:63.-70. Rosai J, Dorfman RF. Sinus histiocytosis with massive lymphadenopathy: A pseudolymphomatous benign disorder. Analysis of34 cases. Cancer 1972;30: 1174-88. Venoit JP, Eidus L, Jabi M. Soft tissue Rosai-Dortinan disease mimicking inflammatory pseudotumor: A diagnostic pitfall. Pathology 1998;30:14-16. Wright DH, Richards DB. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfuian disease): report ofa case with widespread nodal and extra nodal dissemination. Histopathology 1981;5:697-709.

CTTR 11711> Cancer Seminar Pulmonary Pathology 63 Figure 7-t. Pulmonary involvcmeni in Figure 7-2. Pulmonary involvement in Erdhcim·Chcstcr disease. Scanning power Erdhcim-Chestcr di.S<:asc. Detail of the diseai)C. The: mixed infiltmtc invades arounc microscopy shows marked septal and plcurnl infiltrate shows prominent fibrosis wlch an bronchus and widens the bronchial submucc ~t ickcning by a relatively acellular infiltnne infiltrate-of pale cells consistent with with apparently mottling due to the pale with associated fibrosis. Tho adjacent lung histiocytes (and which stained a.~ such). histiocytic cells. tissue shows emphysematous change. Occasional plasma cells and lymphocytes are

Fiau,.. 8-4. Pulmonary Rosai·Dorftuan disease. Whole mount scc1ion shows how li disease. Some regions show dense fibrosis disease. Detail of the shows large process surrounds a.nd nanows a large adjoccnt to pale regions composed of vesicular nuclei wi1h prominent nuc:lcoli and bronchus. histiocytic cells. abundant pale CytO)llo.

Fiauro 8-5. Pulmonary Rosai-Dorfinan disease. S-1 00 staining highlights the histiocytes ofRosai-Dorfinan disease. Some ""'seen to be stuffed with innummatory cells.

CTTR 117"' Cancer Seminar Pulmonary Pathology 65 VI. Pleural Tumors

WHO DEFINITIONS: MESOTHELIAL TUMORS Adenomatoid tumor: "A small, circumscribed, solitaty tumor composed of small cords, tubules or acini of mesothelial cells resembling adenomatoid tumors at other sites." Malignant mesothelioma is: "A malignant tumor of mesothelial cells showing a variety of histologic patterns." An epithelioid mesothelioma is: "A pattern consisting of tubules, acini, papillae or sheets of atypical, epithelioid mesothelial cells." A sarcomatoid mesothelioma is: "A pure spindled pattern resembling a fibrosarcoma or a malignant fibrous histiocytoma. (Synonym~: sarcomatous, spindled, or diffuse malignant fibrous mesothelioma)." A desmoplastic mesothelioma is: "A sarcomatoid mesothelioma with a predominant (>50%) dense collagenous stroma and haphazardly arranged slit-like spaces made up of cells with slightly atypical nuclei." A biphasic mesothelioma is: "A combined epithelioid and sarcomatoid pattern with each comprising at least 10 percent of the tumor."

CASE9

Clinical History CCTTR Ace.# 2988D: [There are two cases on the slide.]

Case9A. A 72-year-old asymptomatic man was found to have a nodule radiologically. This was eventually resected. Grossly the mass appeared to be centered on the pleura. Key histologic features: Monotonous cytology which, when the possibility is considered, is typical of mesothelial differentiation; histologically the mass .has a fibrous capsule and does not involve the lung parenchyma; mesothelial differentiation confirmed immunohistochemically.

Case9B. A 79-year-old man was initially thought to have a parapneumonic pleural effusion. When this did not resolve he underwent thoracotomy and decortication. Key histologic features: A fibrosing process that lacks the zonation typical of healing inflarnmatoty processes; foci of bland necrosis; invasion of underlying lung tissue by bland cells (imrnunohistochemically confirmed as being cytokeratin positive). ·

Diagnosis: 9A. Localized epithelioid mesotlielioma of the pleura. 9B. Sarcomatoid mesothelioma ofthe pleura.

Follow-up: Patient "9A" was alive and well five years after resection. Follow-up for "9B" is not available.

CITR 117"' cancer Seminar · Pulmonary Pathology 67 Discussion

Clinical Features of Mesothelioma

• Males>> females • Age: 7th and 8'h decades (with broad range) • Signs and symptoms - shortness of breath, chest pain, recurrent effusions • Sites: Pleura>> peritoneal>> other sites • Majority associated with asbestos exposure • Treatment: None proven; recent interest in extrapleural pneumonectomy and chemotherapy • Prognosis: Survival 6 to 18 months (epithelioid greater than sarcomatoid/desmoplastic) • Survival over five years is rare, but well documented.

Patterns of Presentation of Mesothelioma

• Diffuse process ofpleura, peritoneum, or pericardium-by far the most common • Localized pleural, mediastinal, or intraabdominal mass (allrare)-see below • Metastatic disease, usually as lymphadenopathy (also rare)

DIFFERENTIAL DIAGNOSIS

When confronted with a pleural process for histologic diagnosis, one needs to know as much clinical and radiologic information as is available. The gross findings at the time of surgery or autopsy are extremely useful and these can often. be inferred from radiologic studies. If these features do not· fit with the diagnosis that is being considered. then the pathologist should go back and re-assess ·the problem.

The differential diagnosis of malignant mesothelioma depends on whether one is dealing with:

1) An epitbellal/epltbellold proliferation 2) A spindle cell/fibroblastic proliferation and the approach to these two settings is entirely different.

The basic questions are whether the process is reactive or neoplastic, and if neoplastic is it mesothelioma or some other neoplasm mimicking a mesothelioma? The diagnostic approach, criteria of malignancy, and ancillary tests, particularly immunostains, for these two groups are entirely different:

68 Pulmonary Pathology CTTR 11 7"' Cancer Seminar Epithelioid proliferations: Reactive mesothelial hyperplasia vs. neoplasm If neoplastic, mesothelioma vs. carcinoma (or melanoma, etc.) For spindledlflbroblasticproliferations: Fibrous pleurisy vs. neoplasm If neoplastic, desmoplastic/sarcomatoid mesothelioma vs. other (sarcoma, melanoma, sarcomatoid carcinoma, etc.)

1. The distinction of benign mesothelial proliferations from mesothelioma is covered by Churg and recommendations summarized below:

Benign Mesothelial Reactions Malignant Mesothelial Neoplasms No true invasion ofstroma Invasion ofstroma (the deeper, the more definitive) (but superficial entrapment may be present in areas of organization) May be densely cellular in the pleural Dense cellularity (noninflammatoty) in stroma space, but not in the stroma favors malignancy Process becomes more fibrotic toward No "sidedness" (zonation) to process; often more chest wall ("sidedness" or "zonation") cellular away from effusion Cytologic atypia confined to area of Cytologic atypia present in any area, but many organizing effusion mesothelio11'13$ are deceptively gland and relatively monotonous Necrosis rare Necrosis usually a sign of malignancy Mitoses may be plentiful Many mesotheliomas show very few mitoses (but atypical mitoses favor malignancy) Storiform pattern absent or minimal Extensive storiform pattern favors malignancy (desmoplastic mesothelioma) but is not sufficient by itself Benign reactions may be keratin, p53, Mesotheliomas are almost always keratin and and EMA positive often EMA and p53 positive

2. The distinction between mesothelioma and metastatic carcinoma involving the pleura is the most common problem and the one that has engendered the largest number of papers in the literature and the situation in which immunohistochemical staining is most useful. The following are some of the features that l personally have found helpful over the years in distinguishing mesothelioma from carcinoma:

Is there fibrous stroma produced by the proliferation? This favors a neoplasm. Is there stromal invasion? This favors a neoplasm; beware of entrapment of mesothe.Jial cells particularly in the pericardium. Is there a histologically complex cellular proliferation or cohesive sheet-like proliferation? Favors neoplasm. Aie papillae present? Favors a neoplasm. Is necrosis present? Favors a neoplasm. Cytologic features? Cytologically bland, cells can be seen in reactive mesothelial proliferations~ mesothelioma; marked nuclear atypia usually favors carcinoma. Nuclear molding? Favors carcinoma. Columnar cell shape? Favors carcinoma.

CITR 111• Cancer Seminar Pulmonary Pathology 69 Mucous production? Faint mucicarmine positivity not uncommon in mesothelioma; intracellular droplet positivity with P ASd favors carcinoma (but rarely reported in mesothelioma). Iinmunohistochemical studies? These are ever changing (see also below). Cytokeratin: Good to confirm the cells actually stain; strong diffuse positivity characteristic of mesothelioma (as well as, obviously, some carcinomas); CK may highlight stromal invasion. Electron microscopy? Rarely helpful (to me!); cases that are diagnostic ultrastructurally tend to be easy light microscopy diagnoses (my bias).

The issue .of carcinoma versus mesothelioma remains the mcist common problem and the vast majority of these cases are recognized with clinical history, knowledge of gross/radiologic fmdings, knowledge of prior neoplasms, and car~ful attention to routine histology. Carcinomas look like carcinomas and mesotheliomas look like mesotheliomas! Immunohistochemistry is usually confirmatory.

Nevertheless, immunohistochemistry is considered by most to be the mainstay in this differential diagnostic problem and the horizon is ever changing as new antibodies are added and older ones are cast aside. The Cas yet unpublished) recommendation of an international mesothelioma working group is that one use at least two positive markers for mesothelioma and at least two positive markers for carcinoma in making this distinction. Some of these are listed below. I like a pancytokeratin, not for its discriminatory value, but to highlight the architecture of the proliferation, help highlight invasion, etc.

Markers favoring mesothelioma: • Cytokeratin 5/6* • Calretinin* • WT-1* • Tbrombomodulin • HBMEl • Membrane pattern with EMA

Markers favoring carcinoma: • CEA* • CDlS* • B72.3* • MOC 31* • TTF-1 (for lung ca)* • BerEp4 • EMA with cytoplastic pattern • Surfactant (for lung ca) • Others *The Abs I tend to use (but not all 8 aU the time)

70 Pulmonary Pathology CITR I 17th Cancer Seminar None of these antibodies is perfect and occasional mesotheliomas stain positively (usually only a few cells focally) with carcinoma markers and carcinomas may stain with mesothelioma markers. Squamous carcinoma, transitional carcinoma, and some oth.ers are frequently positive with cytokeratin 5/6 and adenocarcinomas of the lung not uncommonly stains with calretinin. It is said that cytoplasmic and nuclear staining with calretinin is a good marker for mesothelioma. The greater number of antibodies that one uses the greater the likelihood for discrepant staining and then one has to take a step back and try to prioritize the findings and keep a mental tally sheet of the positive and negative features that favor one diagnosis over the other. In a small minority a confident diagnosis is not possible.

3. Desmoplastic mesothelioma versus fibrous pleuritis. As defined above, a desmoplastic mesothelioma is a sarcomatoid meso!helioma that has greater than 50% dense collagenized stroma sometimes with a vague storiform appearance. These regions are not overtly sarcomatous. Since desmoplastic mesotheliomas may over grow hyaline pleural plaques it is sometimes difficult, if not impossible, to separate the pre-existing benign fibrotic reaction of the pleura from a desmoplastic mesothelioma since the latter may produce regions that are nearly indistinguishable from hyaline pleural plaque. Abrupt transitions in cellularity are one of the most useful clues that the process is neoplastic. The separation of desmoplastic mesothelioma from fibrous pleurisy is summarized as follows:

Fibrous Pleurisy Desmoplastic Mesothelioma

Cellularity greastest immediately No zonation; bulk of lesion is paucicellular; under effusion; becomes more fibrotic may have abrupt transitions to cellular, away from effusion (ie, shows frankly sarcomatous foci anywhere in the "sidedness'" or ·~nation") lesion Cells immediately under effusion may Cytologic atypia often hard to discern be very atypical Capillaries perpendicular to pleural surfuce Capillaries inconspicuous No stromal invasion Stromal invasion No necrosis Bland necrosis No sarcomatous foci Sarcomatous foci No nodular eXJ>ansion ofstroma Nodular expansions of stroma sometimes present

The series by Mangano et al. nicely showed that desmoplastic mesothelioma could be separated from fibrous pleurisy on the basis of the presence of a diffuse storiform proliferation of the pleura and one or more of the following features:

• Invasion of the chest wall or lung • Foci of bland necrosis • Frankly sarcomatoid foci • Distant metastases

Immunostaining in. the setting of desmoplastic mesothelioma vs. fibrous pleurisy is helpful in highlighting invasion of cytokeratin positive cells into structures adjacent to the pleura such as lung or chest wall. Doing carcinoma markers in this setting is inappropriate.

CITR I 11"' Cancer Seminar Pulmonary Patlwlogy 71 4. Sarcomatoid mesothelioma versus other sarcoma. Distinguishing sarcomatoid mesotheliomas from other sarcomas involving the pleura is such an uncommon scenario that it is rarely encountered by the surgical pathologist In such cases careful attention to any prior history of sarcoma, the pattern of growth in the pleural space (sarcomas tend to be multiple nodules rather than more diffuse growth) and selected immunostains based on the histology of the process should allow resolution of most cases. The only sarcomas seen in the pleura with any frequency, and ones which not uncommonly closely mimic a mesothelioma, are malignant vascular tumors and these are discussed with the next case (Case 10).

LOCALIZED MALIGNANT MESOTHELIOMAS

There have been isolated reports of localized mesotheliomas. Not surprisingly these have been somewhat difficult to get published because of the fact that mesotheliomas are generally considered (almost by definition) diffuse. Nevertheless, Crotty et al. reported six cases in 1994:

• 4 men, 2 women, age 42-76 years • 3 of 6 with history of asbestos exposure • Tumor size: 2.8 to 10.0 em 2 pedunculated, 4 sessile • All pleural in location

• Histology: pure epithelioid 3, biphasic 3 • Immunohistochemistry as for diffuse mesothelioma • Typical electron microscopy in 2 of 6 • 3 died at 4-18 months, 3 alive at 8-96 months

More recently, the US & Canadian Mesothelioma Panel has put together a series of22 cases that included both pleural and peritoneal locations (see Allen ref.).

• IS men, 7 women; age 37-83 years; mean 62.4 • 20 pleural, 2 peritoneal • Mean size: 6.1 em • IS epithelial, 6 biphasic, I sarcomatous • Immunohistochemistry and ultrastructural studies as for diffuse mesothelioma • Follow-up in 11 cases; 7 dead of disease at 7 months to 6 years, I dead of unrelated causes, 3 (27%) alive at 6-1 8 months. Those who died tended to die of metastatic disease as opposed to local spread.

Based on these srudies, localized malignant mesothelioma is now recognized as an unusual variant of malignant mesothelioma. These appear as localized masses that are usually pleural based. In !he peritoneum they may involve adjacent structures and simulate primary tumors of the colon, stomach, liver, etc.

72 Pulmonary Pathology CTTR 117., Cancer Seminar ASBESTOS AND MESOTHELIOMAS

While the vast majority of mesotheliomas are associated with asbestos exposure (the exact percent varies with the series) one essentially never encounters asbestos bodies in routine histologic sections of the pleura and the tumors that arise therein. The search for asbestos bodies should be in lung tissue if it is included with the pleural biopsy. The identification of asbestos bodies (even a single body) in routine histologic material of the lung suggests significant prior exposure and can be used to support an asbestos-associated mesothelioma. An attributio.n of cause or association between a mesothelioma and asbestos exposure can also be made if there is sufficient documentation of exposure in the clinical history.

References Allen TC, et al. Localized malignant mesothelioma (LMM): clinicopathologic review of22 cases. USCAP Abstrac~ 2004 (Mod Paiho12004). Argani P, Rosai J. Hyperplastic mesothelial cells in lymph nodes: Report ofsix cases of a benign pr<>cess that can simulatc.metastatic involvement by mesothelioma or carcinoma. Hum Pathol 1998;29:339-46. Attanoos RL, Biggs AR. Pathology ofmalignant mesothelioma. Histopathology 1997;30:403-418. Battifora H, McCaughey WTE. Tumors of the serosal membranes. Atlas ofTumor Pathology. Third Series, Fascicle 15. AFIP, Washington, DC, 1994. Brockstedt U, Gulyas M, Dobra K, Dejmek A, Hjerpe A. An optimized battery of eight antibodies that can distinguish most cases ofepithelial mesothelioma from adenocarcinoma .. Am J Clin Pathol 2000; 1)4:203-9. Churg A, Green FHY. Pathology of0ccupationa1 Lung Disease. 2"4 Ed. Williams and Wilkins, Baltimore, 1998. ChurgA, Roggli V, Colby TV, and the US Canadian Mesothelioma Panel. The separation of benign and malignant mesothelioma proliferations. Am J Surg Pathol 2000;24: 1183-1200. Crotty TB, et al. Localize_d malignant mesothelioma. Am J Surg Pathol 1994; 18:357-63. Cugell OW, Kamp OW. Asbestos and the pleura: ·a review: Chest 2004; 125:1103-1117. Cury PM, Butcher DN, Fisher C, Corrin B, Nicholson AG. Value of the mesothelium-associated antibodies thrombomodulin, cyto~eratin 5/6, calretinin, and CD44H in distingilisbing epithelioid pleural mesothelioma from adenocarcinoma metastatic to the ple\lra. Mod Pathol 2000;.13: I 07-112. Dogljoni C, Dei Tos AP, Laurino L, luzzolino P, Chiarelli C, Celio MR, Viale G. Calretinin: A novel immunocytochemical marker for mesothelioma. Am J Surg Pathol 1996;20:1 037-46. Hillerdal G. Malignant mesothelioma 1982: Review of 4710 published cases. Br J Dis Chest 1983;77:321-324 . .Khalidi HS, Medeiros J, Battifora H. Lymphohistiocytoid mesothelioma. Am J Clio Pathol2000;1 13:649-54. Koss M, Tr:avis W, Moran C, Hochholier L. Pseudomesotheliomatous adenocarcinoma: A reappraisal. Sem Diagn Pathol 1992;9:117-23. Livasy CA, Tisbko DJ, Maygarden SJ. Miliary pulmonary metastases from a clinically occult pleural mesothelioma. Ann Diagn Patho12003;7:249-253. Mangano WE, et al. The diagnosis ofdesmoplastic malignant mesotheliomas and its distinction from fibrous pleurisy. Am J Clin Pathol 1998; 110: 19.1-9. Mark EJ, Shin DH. Diffuse malignant mesothelioma of the pleura:· a clinicopathological study ofs ix patients with a prolonged symptom-free interval or extended survival after biopsy an~ a review of the ·literature of long-term survival. Virchows Archiv A Pathol Anal 1993;422:445-451. . .Ordonez NG. Epithelial mesothelioma with deciduoid features. Report of four cases. Am J Surg Pathol 2000;24: 816-23. Ordonez NG. Immunohistochemical diagnosis ofepithelioid mesotheliomas: a critical review ofold markers, new markers. Hum Pathol2002;33:953,967. Ordonez NG. The immunohistochemical diagnosis ofepithelial mes~thelioma. Hum Pathol 1999;30:313-23. Ordonez NG. Value ofcalretinin immunostaining in differentiating epithelial mesothelioma from lung adenocarcinoma. ModPathol 1998;11 :929-33. Ordonez NG. Value ofcytokeratin 5/6 immunostaining in distinguisbing epithelial mesothelioma of the pleura from lung adenocarcinoma. Am J Surg Pathol I 998;22: I 2 I5-21.

CITR I 17" Cancer Seminar Pulmonary Pathology 7.3 Aordonez NG. The immunohistochemical diagnosis ofmesothelioma. A comparative srudy of epithelioid mesothelioma and lung adenocarcinoma. Am J Surg Pathol 2003;27: I 031-1051. Parkash V, Vidwans M, Carter D. Benign mesothelial cells in mediastinal lymph nodes. Am J Surg Pathol 1999; 23:1264-9. Roggli VL, Greenberg SO, Pratt PC. Palhologyof Asbestos-Associated Diseases. Little Brown, Boston, 1992. Sosolik RC, McGaughy VR, DeYoung BR. Anti-MOC-31 : a potential addition to lhe pulmonary adenocarcinoma versus mesothelioma immunohistochemistry panel. Mod Pathol1997;10:716-19. Sussman J, Rosai J. Lymph node metastasis as the initial manifestation ofmalignant mesothelioma: Report ofsix cases. Am J Surg Pathol 1990;14;819-28. Wick MR, Mills SE. Mesothelial proliferations. Am J Clin Pathol 2000; 113:619-22. TTavis WD, Brambilla E, Harris CC, Muller-Hermelink HK, Ed: World Health Organization Classification of Tumours, Pathology and Genetics: Tumours ofthe Lung, Pleura, Thymus and Heart, !ARC, Lyon (in press).

CASE 10

CUnlcal History

Key histologic features: A spindle cell process that appears inflammatory but apparently "invades" the lung and is associated with small nodular areas of expansion not typical of an inflammatory process; cytologic identification of epithelioid vascular cells with intranuclear vacuoles, particularly in areas of invasion into alveolar spaces.

Diagnosis: Pleural epithelioid hemangioendothelioma.

Follow-up: Six months after surgery the patient had completed four cycles of adjuvant chemotherapy. She had no evidence of recurrence at that time. Additional follow-up not available.

Approach to Case 10

Key feature is to recognize that this is a neoplastic process as opposed to some peculiar reactive fibrosis. Clinical history and radiologic findings are helpful in this regard as is the appreciation that the proliferation has subtle differences from reactive fibrosis.

Epithelioid hemangioendothelioma represents one of a ·number of non-mesothelial tumors that may be encow1tered as primary processes of the pleura, sometimes exactly mimicking a mesothelioma from a gross and radiologic point of view. These include:

• Angiosarcomas: epithelioid hemangioendothelioma, high-grade (including epithelioid) angiosarcomas • Synovial sarcoma • Malignant localized fibrous tumor • Liposarcoma

74 Pulmonary Pathology CTTR 117'" Cancer Seminar • Extraskeletal myxoid chondrosarcoma • Mesenchymal chondrosarcoma • Smooth muscle tumors • Clear cell sarcoma • Desmoplastic small round cell tumor • Malignant fibrous histiocytoma • Rhabdomyosarcoma • Primitive neuroepithelial tumor (extraskeletal Ewing's) • Lymphomas

Some soft tissue sarcomas involving the pleura simply do so since they arise in structures adjacent to the pleural cavity and on clinical and radiologic grounds do not really simulate mesotheliomas. Thus, virtually any soft tissue· tumor could occasionally be encountered as an apparent pleural mass. Lymphomas may also mimic mesotheliomas; these include primary effusion lymphomas, pyothorax-associated lymphomas, and others. An angiosarcoma developing in the setting of chronic pyothorax has also been described.

Discussion: Pleural Epithelioid Hemangioendothelioma (EHE)

Epithelioid hemangioendothelioma is now recognized as a form of low-grade angiosarcoma that may present at a variety of site, both in organs (especially liver and lung) and in the soft tissue. In the lung these were originally designated as intravascular bronchioloalveolar tumors (IVBATs).

The WHO defines pleural epithelioid hemangioendothelioma as "A low to intermediate grade vascular tumor composed of short cords and nests of epithelioid endothelial cells embedded in a myxohyaline matrix. These tumors ar distinctive for their epithelioid character, sharply-defined cytoplasmic vacuoles, intra-alveolar and intravascular growth and central hyaline necrosis. High-grade epithelioid vascular tumors are called "epithelioid angiosarcomas."

It should be noted that the above definition does not emphasize the spindled areas which the case presented shows quite uicely and which would be the areas that would cause the most diagnostic difficulty in separating from reactive fibrosis.

The features of pleural EHE can be summarized as follows:

• Men>> women; mean age 52 years (range 34-85 years) • Symptoms include chest pain, dyspnea • .Imaging: diffuse pleural thickening, pleural effusion • Concomitant involvement of the lung, mediastinum (and other sites) may be evident

Note: Pleural EHE may mimic mesothelioma perfectly in its gross and radiologic features.

CITR I 17"' Cancer Seminar Pulmonary Pathology 75 The histology of EHE is well known and described in the definition above. The nests of epithelioid cells contain distinctive punched out vacuoles. The spindle cell stroma may be reactive or neoplastic and in some cases it is difficult to determine. High-grade EHEs merge with epithelioid angiosarcoma. The maintenance of a myxohyaline stroma suggests EHE over epithelioid angiosarcoma in cases with frankly malignant cytology.

Immunohistochemically the tumors stain for vascular markers (CD31 is generally better than CD34 and Factor VITI). Cytokeratin expressed in up to 50% of cases but it is usually weak to moderate.

The differential diaanosis of pleural EHE includes mesothelioma, particularly the ''adenomatoid variant" where nests of mesothelioma cells. have prominent vacuoles. This issue is usually readily sorted out immunohistochemically. Similarly, pseudomesotheliomatous carcinomas will show the morphology and immunophenotype typical of carcinoma.

What may be more difficult than separating pleural EHE from another neoplasm is recognizing the process as neoplastic at all. In this regard, attention to the low power growth patterns (at which power one can appreciate invasive and destructive growth) and cytologic recognition of the distinctive epithelioid cells is invaluable.

Pleural EHE is an aggressive neoplasm and there is no known therapy.

There is no association of pleural EHE and asbestos exposure.

Zhang el a\. have recently reviewed malignant epithelioid vascular tumors of the p!eura including epithelioid angiosarcoma. When high-grade epithelioid angiosarcoma is included the age range broadens to some extent. In this review, of 28 cases with follow-up only I was alive and that patient was alive with disease at 6 months. All the remaining were dead of disease. One of the 27 survived a year. The remaining 26 were dead in less than six months.

References Aozasa K, Naka N, Tomita Y, Obsawa M, Kanno H, Uchida A, Ono K. Angiosarcoma developing from chronic pyothorax. Mod Pathol 1994;7:906-909. Attanoos RL Suvama SK, Rhead E, Stephens M, Locke TJ, Sheppard MN, Pooley FD, Gibbs AR. Malignant vascular tumours of the pleura in "asbestos" workers and endothelial differentiation in malignant mesothelioma Thorax 2000;55.:860·863. Attanoos RL·, et al. Primary epithelioid hemangioendothelioma of. the peritoneum: an unusual mimic of diffuse malignant mesothelioma. Histopathology 1997;30:375-377 Aubry M-C, Bridge JA, Wickert T, Tazelaar HD. Primary monophasic synovial sarcoma ofthe pleura: five cases confirmed by the presence of SYT-SSX fusion transcript. Am J Surg Patbol 200 I ;25:776·781. Bury T. Hermans G, Alexis-Agnant R, Chevalier Ph, Limet R, Bartsch P. Clear cell sarcoma: an exttemely rare cause of pleural disease. Eur Respir J 1997;10:653-2656. Cagle PT, Hicks MJ, Haque A. Desmoplastic small round cell tumor ofthe pleura: report oftwo cases and review ofthe literature. Histopathology 2002 (Suppl 2) 41:164-170. Capepe1o F Barnes L. Synovial sarcoma and malignant mesothelioma ofthe pleura: review, differential diagnosis and possible role ofapoptosis. l'atbology 2001 ;33: 142-148. Colwell AS, D'Cunha JD, Vargas SO, Parker B, Oaf Cin P, Maddaus MA. Synovia] sarcoma of the pleura: A clinical and pathologic study ofthree cases. J Thorac Cardiovasc Surg 2002; 124:828-832.

76 Pulmonary Patlrology CTTR I l?lh Cancer Seminar Crotty BJ, McAdams HP, Erasmus JJ, Sporn TA, Roggli VL. Epithelioid hemangioendothelioma ofthe pleura: clinical and radiologic feanues. Am J Roentgenol 2000; 175: I 545-l 549. Essary LR Vargas SO, Fletcher CD. Primary pleuropulmonary synovial sarcoma: reappraisal ofa r«:ently described anatomic subset. Cancer 2002;94:459-469. Falconicri G, BussWJi R, Mirra M, Zanella M. Pseudomesotheliomatous angiosarcoma: a pleuropulmonary lesion simulating malignant pleural mesothelioma. Histopathology 1997:30:419-424. Gaertner B, Zeren EH, Fleming MB, Colby TV, Travis WD. Biphasic synovial sarcomas arising in the pleural cavity. A clinicopathologic study of 5 eases. Am J Surg Pathol 1996;20:36-45. Goetz SP, Robinson RA, Landas SK. Bxuaskeletal myxoid chondrosarcoma ofthe pleura. Report ofn case clinically simulating mesothelioma. Am J Clin Pathol 1992;97:498-502. Hattori H. Epithelioid angiosarcoma arising in the tuberculous pyothorax. Arch Patholl..ab Med 2001 ;125: 1477- 1479. Lin B T-Y, Colby T, Gown AM, Hammar SP, Mertens RB, Churg A, Battifora H. Malignant vascular rumors of the serous membranes mimiclcing mesothelioma. Am 1 Surg Pathol1006;20:1431 -1439. Luppi G, Cesinnro AM, Zoboli A, Morandi U, Piccinini L. Mesenchymal chondrosarcoma ofthe pleura. Eur Respir J 1996;9:840-843. McCaughey WTE, Dardick I, Barr R. Angiosarcoma ofserous membranes. Arch Pathol Lab Med 1983; 107:304- 307. Moran CA, Sustcr S, Koss MN . Smooth muscle tumours presenting ns pleural neoplasms. Histopathology 1995;27:227-234. Myoui A, Aozasa K, luchi K, Mori T, Yamamoto S, Kuratsu S, Obsawa M, Ono K, Matsumoto K. Soft tissue sarcoma ofthe pleural cavity. Cancer 1991 ;68:1550-1554. Ng SB, Ahmed Q, Tien SL, Sivaswaren C, Lau LC. Primary pleural synovial sarcoma. A case report and review of the literature. Arch Pathol Lab Med 2002; 127:85-90. Nicholson AG, Goldstraw P, Fisher C. Synovial sarcoma ofthe pleura and its differentiation from other primary pleural tumours: a clinicopathological and immunohistochemical review of three eases. Histopathology 1998;33:508-5 13. Nind NR, Attanoos RL, Gibbs AR. Unusual intraparencnymal growth patterns of malignant pleural mesothleioma. Histopathology 2003;42: 150-155. Okby NT, Travis WD. Liposarcoma of the pleural cavity. Clinical and pathologic features of4 cases with • review of the literature. Arch Pathol Lab Med 2000; 124:699·703. Proca DM, Ross P Jr, Pratt J, Frankel WL. Smooth muscle tumor ofthe pleura. A case report and review of the literature. Arch Pathol Lab Med 2000;124:1688·1692 Sporn T A, Butnor KJ, Roggli VL. Epithelioid hemangioendothelioma ofthe pleura: an aggressive vascular malignancy and clinical mimic of malignant mesothelioma. Histopathology 2002 (Suppl 2):41: 173-177. Travis WD, Brarnbilla E, Harris CC, Muller-Hermelink HK, Ed: World Health Organization Classification of Tumours, Pathology and Genetics: Tumours ofthe Lung, Pleura, Thymus and Heart, !ARC, Lyon (in press). Zhang PJ, Livolsi VA, .Brooks JJ. Malignant epithelioid vascular tumors of the pleura: report of a series and literature review. Hum Pathol 2000;3 1:29·34.

CITR 117"' Cancer Seminar Pulmonary Patltalagy 77 mesothelioma. CaJretinin shows diffuse $lror positiviry in the cytoplasm of the nuclei.

.. •• Fi1;:.'1.Jrc 9B .. J. Oesmoplasric mesothelioma. There is • densely sclerotic process which power of the collagcnir.ed tissue Dense hypocellular collagenized tissue invad merges with the visceral pleura (right) which showing storifom>patt ern. around individual skeletal muscle fibei'S. comains Mthraeotic pigment. A vague Some of the spindle cells in this region were SIOrifonn is J)I'CS<:nt in the den.

a;-\.....,.. - . Figure Fig\lrc 98-6. Desmoplastic mcsothellomll. There is invasion doMt an intro.lobular septum C)'1okemtin 11t11jning highlights infi l11l\1ion of the from the visceral pleura. process throuah the visceral pleura inlo Ihe lung. The visccnl plcunl is rq>laced by a spindle cdl prolifmtion of faintly ~tin pa

CTTR 117"' Cancer Seminar Pulmonary Patlwlogy 79 Figure I 0-1. Plcurul epithelioid hemang.iocndorhclioma. Scan.ning pOwer hL'Tllangioendnlhtlioma. Detnil of one ofthe heUU~ng:ioendorh e l io l'nB. Where the visccrnl microscopy of the thickened visceral pleura pr<>lifC'l'Utive nodules shows spindled and vaguely pleural process merge.~J wich the underlying shows expunsile nodular z.ones amidst a epithelioid cells (3 o'clock) which would be very lung tissue there is loss of uppnrent visceral difficulc 10 distinguish f'rom rct~ctivc fibrosis. There densely oollagcnizcd vi5Ccrul pleura. is some vacuolarion present but it appetN to be pleura architeCture end nests of cells can be related to mucopolysaccharide accumulation rather seen invading alveolar spaces. than the classic YOCUOies of I!HE.

Figure 10-4. Figure 10-5. Pleuml epithelioid hemangioendothelioma. Detail of the alveolar hemangiocndothcliomn. CD31 highlights tlle spaces in Figure 10-3 shows epithelioid cells positivity of the innu-alveolar cells. The type with abundant glwy eosinophilic cytoplasm 2 cells are ne!ll'tive. and occasional sharply demarcated Cytoplasmic vacuoles typical ofEHE.

CTTR 117'• Cflncer Seminar Pulmom•ry Pathology 81 YD. Vascular Tumors of the Lung

CASE 11

Clinical Historv (CTTR Ace.# 29885): A 53-year-old woman had a large lung mass resected by pneumonectomy. The mass was 14.0 x 8.5 x 5.0 em with satellite nodules in the surrounding lung tissue. She received chemotherapy.

Key histologic features: A frankly sarcomatous mass (although some foci resemble inflammatory myofibroblastic tumor) which in some sections is identifiable as being intravascular; some tumor emboli and organized thromboemboli can be identified in the surrounding lung tissue in some sections. -

Diagnosis: Pulmonary artery sarcoma.

Follow-up: Slightly less than two years after resection the patient had radiologic evidence of multiple intra-abdominal masses that were enlarging. These were clinically assumed to be metastatic disease and she was undergoing radiotherapy.

Approach to Case 11

This is clearly a spindle cell neoplasm that is at least low-grade sarcoma in its histology. Key feature is recognizing the prominent intravascular growth which may not always be apparent in the tissue sample. Surgical and radiologic findings are invaluable in recognizing these as primarily intravascular sarcomas.

Overview

Pulmonary artery sarcomas (and their rarer pulmonary venous counterparts) produce hilar masses radiologically that are the result of massive filling of the large pulmonary vessels by sarcoma. The process may invade through the vessel walls into the surrounding lung tissue and airways and even the mediastinum. The histologic findings depend on whether one receives the main mass or a portion thereof in which case the issue is simply of sarcoma classification, or whether one receives a peripheral biopsy which shows the distal thromboemboli related to the neoplasm. In the latter circumstance small pulmonary arteries ruay have a spindle cell prolife.ration that can be confused with an organizing thromboembolus (and many cases present clinically as thromboembolic disease). A key feature is the recognition of transmural invasion by the neoplastic spindle cells.

C1TR 117'• Cancer Seminar Pulmonary Pathology 83 Discussion: Pulmonary Artery Sarcomas

Given the gross and histologic findings in this case the diagnosis of a sarcoma involving the large branches of the pulmonary artery is clear. Where one· gets into difficulty in cases like this is in small biopsy samples which. may not show the obvious neoplastic foci and the small vessel lesions could be inteipreted as portions of an organizing thrombus. Peripheral wedge biopsies may show only organized thromboemboli in the small vessels. Nevertheless, with curreni imaging techniques neoplastic proliferations within the pulmonary artery are often distinguishable from large thromboemboli.

Pulmonary artery sarcomas are rare tumors of the lung, which until recently were rarely · diagnosed prior to death. Current radiologic imaging techniques are allowing premorbid diagnosis and attempts at curative resection in an appreciable percentage of patients.

Clinical findings in pulmonary artery sarcomas: • Sex incidence -Equal • Average Age - Approximately 50 years (range 13-81) • Symptoms (in decreasing order of frequency): Dyspnea, chest pain or back pain, cough, hemoptysis, weight loss, malaise, syncope, fever • Some patients experience sudden death

Physical fmdings frequently include systolic. ejection murmur and may show evidence of right ventricular failure. EKG frequently shows right ventricular hypertrophy.

Radiologic Findings: • Hilar/pulnionary enlargement- 53% • Pulmonary nodules - 40% • Enlargement of the cardiac/pericardia! contour - 3~% • Decreased pulmonary vascularity - 18% • CT - filling defect in central pulmonary circulation in over 80% of cases • Angiography - intraluminal masses in over 95% of cases

The pulmonary trunk is involved in 85% of cases, left pulmonary artery in 65%, the right pulmonary artery in 71%.

The only curative treatment is surgical resection if that can be accomplished. There are recent anecdotal reports of cure of pulmonary artery sarcomas by rese.ction in cases that are diagnosed premortem. Mattoo et al. reported a surgical cure with a five-year follow-up. In the surgical series by Mayer et al. of seven patients who underwent surgical treatment, four died of disease at 7-19 months post-surgery, two were alive witli metastatic disease and 21 and 35 months post­ surgery, and one was alive at five years without evidence of disease. The poor prognosis is related to the inherent aggressiveness of the tumor, the difficulties of complete resection, and the fact that these tumors may directly invade adjacent structures. In one review (Baker) of 45 cases, three extended directly into the heart, seven invades directly into the mediastinum, and twelve had metastases outside the lung.

84 Pulmonary Pathology CTIR 11 7"' Cancer Seminar The histologic findings in pulmonary sarcoma in some reports are designated as "undifferentiated sarcoma" but a variety of other differentiation(s) may be encountered including leiomyosarcoma, malignant fibrocystic sarcoma, fibrosarcoma, myxofibrosarcoma (pleomorphic), rhabdomyosarcoma, chondrosarcoma, osteosarcoma, myxosarcoma, hemangiopericytoma, angiosarcoma, hemangioendothelioma, and mixtures of these.

The immunohistochemistrv tends to parallel the differentiation. Although some of these have been described in the literature as "intimal sarcomas" most of these tumors stain as leiomyosarcomas with actin positivity. Desmin and endothelial markers such as Factor vm, CD34, and CD3 1 tend to be negative except in cases in which angiosarcomatous features are apparent. Vimentin is consistently positive. S-1 00 is negative except in areas of chondrosarcomatous differentiation.

Pulmonary artery sarcoma presents a differential diagnosis of a spindle-cell malignancy of the lung as well as a differential diagnosis of intravascular malignancies. In adequately sampled cases, the intravascular involvement becomes apparent and considerably helps narrow the differential diagnosis. Intravascular and perivascular growth by malignant tumors may be seen with the following:

• Pulmonary artery sarcoma • Metastatic angiosarcoma • Kaposi's sarcoma • Carcinomatous arteriopathy (due to intravascular metastatic carcinoma) • Sarcomatoid carcinomas primary in the tung • Intravascular lymphomatosis • Extension ofcardiac sarcoma and other tumors (e.g. renal cell carcinoma) in to pulmonary artery

When one knows the clinical and radiologic findings, the distinction among these is relatively easy. In a small peripheral biopsy in which malignant spindle cells are identified with intravascular growth, some clues may be useful. Metastatic angiosarcoma tends to be prim3rily intravascular, to show neoplastic vascular spaces, and to be quite hemorrhagic. Immunohistochemical staining for endothelial markers is positive. Kaposi's sarcoma tends to be a perivascular process with preservation of the vascular lumen. The perivascular infiltrate is identical to Kaposi's sarcoma at other sites. Pulmonary artery sarcomas tend to be both intravascular and perivascular and to lack the hemorrhagic character and immunohistochemistry of metastatic angiosarcoma and to lack the typical histology of Kaposi's sarcoma. Carcinomatous arteriopathy is usually cytologically distinct from the sarcomatous lesions and epithelial markers and/or mucin stains are positive. Sarcomatoid carcinomas of the lung show a propensity to invade vessels but this is in the context of a large mass clinically resembling a lung cancer. Immunohistochemistry is often helpful in confirming epithelial differentiation. Intravascular lvmphomatosis is exquisitely limited to the intravascular location and careful study of the cytology of the neoplastic cells with the aid of immunohistochemistry allows recognition of most of these cases as large B-cell lymphomas.

CTTR 117'" Cancer Seminar Pulmonary Pathology 85 Since the peripheral metastases from a pulmonary artery sarcoma are embolic, the differential diagnosis also includes organizing pulmonary emboli and in situ thrombi and frequently cases have been mistaken as pulmonary emboli clinically. While some peripheral foci in pulmonary artery sarcoma may be indistinguishable from organizing or organized embolus, with adequate sampling one invariably encounters more cellular lesions that are beyond the spectrum of organizing pulmonary emboli.

Sarcomas of the pulmonary vein and underlying sarcomas of the pulmonary vein are extremely rare but have been described. All have been designated as leiomyosarcomas.

References Akomea-Agyin C, Dussek JE, Anderson DR, Hartley RB. Pulmonary artery sarcoma mimicking pulmonary embolism: successful surgical intervention. Ann Tl\orac Surg 1996;61:1536-1538. Anderson MB, Kriett JM, Kapelanski DP, Tarazi R, Jamieson SW. Primary pulmonary artery sarcoma: report of six cases. Ann Thorac Surg 1995;59:1487-1490. Bleisch VR, Kraus FT. Polypoid sarcoma of!he pulmonary trunk: analysis of the literature and report of a case wiib leptomeric organelles and ultrastructural features of rhabdomyosarcoma. Cancer 1980;46:314-324. Burke AP, Virmani R. Sarcoma ofibe great vessels. A clinicopa!hologic study. Cancer 1993;71: 1161-1773. Ca~e Records ofthe Massachusetts General Hospital (Case 25-2000). NEJM 2000;343:4930500. Cox JE, Chiles C, Aquino SL, Savage P, Oaks T. Pulmonary artery sarcomas: a review of clinical and radiologic features. J Computer Assisted Tomography 1997;21:750·755. Ernmert-Buck MR, Stay EJ, Tsokos M, Travi's WD. Pleomorphic rhabdomyosarcoma arising in asSociation with the right pulmonary artery. Arch .Pathol Lab Med 1994; 118: 1220-1222. Goldblum JR, Rice TW. Epithelioid angiosarcoma of the pulmonary artery. Hum Patbol 1995;26: 1275-1277. Kaplinsky EJ, Favaloro RR, Pombo G, Perrone SV, Vigtiano CA, Schnidt JL, Boughen RP. Primllry pulmonary artery sarcoma resembling chronic thromboembolic pulmonary disease. Eur Respir J 2000; 16: 1202-1204. Kimura I, Kiucbi H, Sakamoto Y, Yamamoto K, Dohi Y, Takahama M. Primary osteogenic sarcoma of pulmonary artery. Jpn J Med 1990;29:32-36. Mattoo A, Fedullo PF, Kapelanski D, llowite JS. Pulmonary artery sarcoma. A case report of surgical cure and 5- year follow-up. Chest 2002; 122:745-747. Mayer E, Kriegsmann J, Gaumann A, Kauczor HU, Dahrn M, Hake U, Schmid FX, Oelert H. Surgical treatment of pulmonary artery sarcoma. J Thorac Cardiovasc Surg 200 I; 121 :77-82. McGiennen RC, Manivel JC, Stanley SJ, Slater DL, Wick MR, Dehner LP. Pulmonary artery trunk sarcoma: a clinicopathologic, ultrastructural, and immunohistochemical study of four cases. Mod Pathol 1989;2:486.-494. Okano Y, Satoh T, Tatewaki T, Kunieda T, Fukuyama S, Miyazaki N, Beppu Y. Pulmonary artery sarcoma diagnosed using intravascular ultrasound images. r'horax 1999;54:748-749. Parish 1M, Rosenow EC, Swensen SJ, Crotty TB. Pulmonary artery sarcoma: clinical features. Chest 1996;110:1480-1488. Redmond ML, Shepard JW, Gaffey T A, Payne WS. Pulmqnary artery sarcoma: a method of resection. Chest 1990;98:752-753. Shmool

Discussion: Other Pulmonary Vascular Tumors

There are a number of pulmonary vascular lesions in the lung and some bridge the gap between malformation and neoplasia, These include:

86 Pulmonary Pathology CTTR 117'" Cancer Seminar • Arterio-venous malformation - congenital or acquired; many patients have hereditary hemorrhage telangectasia (Rendu-Osler-Weber disease) • Pulmonary telangectasias - dilatations ofprecapillary vessels encountered in hemorrhagic telangectasia and cirrhosis of the liver • Pulmonary peliosis - extremely rare • Hemangiomatous proliferations - hemangioma, hemangiomatosis • Lymphangiomatous proliferations- cystic hygroma, lymphangioma, lympbangiomatosis • Glomus/glomangioma • Hemangiopericytoma • Kaposi's sarcoma (KS) • Epithelioid hemangioendothelioma (EHE) • Angiosarcoma • Sarcomas of the pulmonary arteries and veins

Hemangiomas Very rare; affect children and adults; endobronchial or parenchymal in location; cavernous and capillary type.

Hemangiomatosis Pulmonary hemangiomatosis includes two groups of lesions. The better recognized is called pulmonary capillary hemangiomatosis (PCH). This is associated with pulmonary hypertension and discussed elsewhere.

Pulmonary hemangiomatosis is also applied to a very rare condition, primarily in children, in which there is a hemangiomatous proliferation that is more diffuse than in hemangiomas and that may involve the lungs, pleura, mediastinum, and a number of other organs.

Lymphangioma Solitary lymphangiomas of the lung are rare. Children and adults are affected.

Diffuse Pulmonarv Lvmphangiomatosis

A diffuse proliferation of abnormal anastomosing lymphatic channels along the normal lymphatic routes of the lung (bronchovascular bundles, septa, pleura). Patients present with interstitial lung disease, often with hemoptysis (probably related to mucosa ulceration) and chylous pleural effusions·. Concomitant mediastinal involvement common. Most patients are children and young adults. cr scans confmn prominent septal .lines and bronchovascular thickening.

The disease should be distinguished from pulmonary hemangiomatosis, diffuse pulmonary lymphangiectasis (which simply shows lymphatic dilatation), lymphangioleiomyomatosis (which is distinguished by the parenchymal location of the cysts, the radiologic findings, and the character and immunostaining of the smooth muscle proliferation being HMB-45 positive in LAM), interstitial emphysema, Kaposi's sarcoma, and angiosarcoma.

CTTR 117"' Cancer Semi nil{ Pulmonary Pathology 87 Glomus Tum.or/Glomangiosarcoma Very rare with approximately a dozen cases reported in the literature; may be parenchymal or endobronchial in location. Primarily a disease of adults (M > F). Most reported cases appear to be benign. Rare reports of lymph node metastases and malignant behavior.

Hemangiopericytoma This has been a controversial tumor in soft tissue pathology and it is debatable whether this should be considered a vascular tumor of the lung. From a practical point of view, when a diagnosis of hemangiopericytoma is being considered in the lung the following possibilities should first be excluded: primary monophasic synovial sarcoma of the lung, primary and metastatic localized fibrous tumors of the lung; a spindling carcinoid tumor with prominent vascularity, primary and metastatic melanoma, primary and metastatic thymoma, lymphangiomyoma (and PEComa), primary and metastatic carcinomas with spindling (especially renal cell carcinoma, and others).

Kaposi's Sarcoma

Radiologically pulmonary KS is encountered as single or multiple masses, multiple nodules, bronchovascular thickening, pleural effusions, and mixtures of these patterns. KS may be an incidental finding at autopsy, an asymptomatic but radiologic apparent condition in living patients, and a clinically significant pulmonary disease often indistinguishable from pneumonia.

In HIV infection, pulmonary involvement usually follows mucocutaneous lesions, is more frequently documented at autopsy than clinically, and among patients with known KS who develop new pulmonary findings a treatable co-existing infection is more likely than KS involvement of the lung.

Gross finding$ are those of single or multiple hemorrhagic masses or nodules often showing a distribution along broncho:vascular bundles, septa, or pleura. Histologic findings are typical of KS at other sites: typical spindle cells with slit-like spaces containing red blood cells, hemosiderin, and variable amounts of plasma cells are identifiable. Lymphatic distribution is helpful in diagnosis and separating KS from reactive fibrosis.

hnmunohistochemistf¥: vascular markers Factor VIII, CD31, and CD34 positive in 50-90% of cases.

88 Pulmonary Pathology CTTR I 17th Cancer Seminar The differential diagnosis includes reactive fibroblastic proliferations as seen around infarcts, in organizing pneumonia, in organizing diffuse alveolar damage, metastatic angiosarcoma, pulmonary artery sarcoma, spindling carcinomas, DLP, hemangiomatosis, and bacillary angiomatosis. The key features ofiCS are its distinctive (classic) histology and cytology and its propensity in the lung to follow lymphatic routes and to be ~ascular rather than intravascular.

Epithelioid Hemangioendothelioma (EBE) EHE is a distinctive low-grade angiosarcoma with a colorful history in the lung, having originally been called intravascular bronchioloalveolar tumor - lVBAT. This distinctive tumor involves a variety of sites including lung, liver, soft tissue, bone, and others, either alone or in combination in multifocal disease. In the setting of multifocal disease the differentiation from metastatic disease is often difficult.

The majority of patients(- 70%) are women with broad age range (7-76 yrs; mean 39 yrs); most present between 20 and 60 years of age (mean 39). Many are asymptomatic at presentation (SO- 75%). Symptoms are nonspecific (chest pain, cough, sputum). Typical radiologic findings: multiple bilateral nodules (often I em or less); occasionally solitary nodules (10-20%). Distinctive gross features: firm nodules with a cartilaginous character; occasional central necrosis.

Histologic patterns: nodules with central degenerative change with viable cells at the periphery showing invasion of alveolar spaces. Intrabronchiolar and intravascular spread may also be demonstrated; preservation of elastic framework on elastic tissue staining. Myxohyaline or chondroid matrix containing eosinophilic epithelioid cells in chains or clusters with punched out vacuoles (intraplasmic lumens). Some cases show increased cytologic atypia with necrosis.

Immunohistochemistry: uniform vimentin positivity; positivity for endothelial markers including CD31, CD34, Factor VIII; some cytokeratin positivity noted (AE1/AE3 positive in - 60% of cases). Weibel-Palade bodies on EM but EM rarely necessary.

The prognosis is variable. Most patients have a chronic course although some patients experience rapidly progressive disease. Multifocal disease may be a factor in the prognosis in individual cases. Some patients have a clinical course spanning decades.

Differential diagnosis: tumors. with sclerotic or myxohyaline connective tissue including chondromas, hamartomas, or sclerosing hemangioma; carcinomas with signet ring cells (readily separated with mucin stains and immunohistochemistry); reactive fibrosis (for the cases with prominent spindle cells).

Metastatic Angiosarcoma These are cases of angiosarcoma that involve the lung that do not fulfill the criteria of EHE. These include tumors that form neoplastic blood vessels as well as high-grade epithelioid angiosarcomas. These tumors are typically multifocal and bilateral, thus suggesting metastatic disease. In a significant proportion (up to ball) no primary is identified and some of these cases may arbitrarily be considered primary multi focal angiosarcomas of the lung. When identified,

CTTR 117" Cancer Seminar Pulmo11ary Pathology 89 the primary sites from metastatic angiosarcoma include heart, pericardium, skin, breast, and other sites.

Most affected patients are adults, M > F. Typical presentation is dyspnea and hemoptysis; some cases masquerade as an alveolar hemorrhage syndrome. The prognosis is dismal with virtually all patients dying of disease usually within a couple of months.

Radiologic findings include nodules (typically bilateral) as well as infiltrates sometimes with accompanying pleural and pericardia) effusions.

Pathologic findings: hemorrhagic nodules or infiltrates grossly and histologically apparent. Vasoformative differentiation is usually (-75%) apparent and lesions are typically in and around pulmonary arteries, thus suggesting metastali\) spread. Lymphangitic spread may also be identified. Histologic patterns include spindled and/or epithelioid cells. Cytologic variation from relatively low-grade angioformative histology to high-grade epithelioid angiosarcomas that are identifiable only immunohistochemically. lmmunohistochemistry: positivity for endothelial markers including Factor vm and CD31. CD34 positive in some cases.

The differential diagnosis includes diffuse alveolar hemorrhage and its various causes, thromboembolic disease, pulmonary capillary hemangiomatosis, diffuse pulmonary lymphangiomatosis, pseudoangiosarcomatous sarcomatoid carcinoma, carcinomatous arteriopathy, pulmonary artery sarcoma, Kaposrs sarcoma, epithelioid hemangioendothelioma, intravascular lymphomatosis.

Sarcomas of the Pulmonary Veins Less than a dozen cases reported; women more frequently affected than men; disease of adults (range 27-67 years). ·

Presenting symptoms - dyspnea, chest pain, hemoptysis, cough; two cases identified as incidental radiologic findings.

Treatment is surgical resection; most reported cases were dead of disease or alive with disease; a few apparent long term surgical cures.

Histology: all reported cases have been interpreted lis leiomyosarcomas with appearances similar to leiomyosarcomas at other sites and with conftrmatory immunohistochemistry (positive vimentin, desmin, actin). Aberrant keratin reactivity observed in 2 of5 cases in one study. One case with epithelioid features reported.

Different.ial diagnosis: metastatic sarcoma from some other sites; extension from primary sarcoma or sarcomatoid carcinoma in the lung.

90 Pulmonary Pathology ClTR 117'" Cancer Seminar Mimics of Pulmonary Vascular Neoplasms

• Chronic passive congestion with prominent capillaries. • Pulmonary capillary hemangiomatosis-like changes identified as an incidental finding. • Prominent vascularity associated with inflammation, infarction, particularly venous infarction. • Pseudoangiosarcomatous sarcomatoid carcinoma. • Intravascular lymphomatosis. • Thromboembolic disease. • Metastatic (highly vascular) carcinoma, especially renal cell carcinoma.

References

General References Colby Tv, eta!. Tumors ofthe Lower Respiratory Tract. AF!P Atlas ofTumor Pathology, 3roJ Series, Washington, DC, 1995. Corrin B. Pathology ofthe Lungs. Churchill Livingston, London, 2000.

HemangiomaJHemangiomatosis Abrahams NA, Colby TV, Pearl RH, ChippsBE, Luris AL, Leslie KO. Pulmonaty hemangiomas of infancy and childhood: report oftwo cases and review of the literature. Pediatric and Developmental Pathology 2002;5:283- 202. Vevoina JR, Mark EJ. Thoracic hemangioamtosis masquerading as i.nterstitiallung disease. Chest 1988;93:657- 659.

Lymphangioma/Lymphangiomatosjs Faul JL, Berry GJ, Colby TV, Ruoss SJ, Walter MB, Rosen GD, Raffin TA. Thoracic lymphangiomas, lymphangiectasis, lympbangiomatosis, and lymphatic dysplasia syndrome. Am R Respir Crit Care Med 2000;161 :1037- 1046. Hamada K, Ishii Y, Nakaya M, Sawabata N, Kukuda K, Suzuld H. Solitary lymphangioma of!he lung. Histopalhology 1995;27:482-488. Takahashi K, Takahashi H, Maeda K, Homma S, Uekusa T, Dambara T, Kira S. An adult case of lymphangiomatosis of the mediastinum, pulmonaty interstitium and retroperitoneum complicated by chronic disseminated intravascular coagulation. Eur Respir J !995;8: 1799-1802. Tazelaar HD, Kerr D, Yousem SA, Saldana MJ, Langston C, Colby TV. Diffuse pulmonary lymphangiomatosis. Hum Palhol1993;24:1313-1322.

Gtomu., Tumors Gaenner EM, Steinberg OM, Huber M, Hayashi T, Tsuda N, Askin FB, BcU SW, Nguyen B, Colby TV, Nishimura SL, Miettineo M, Travis WD. Pulmonaty and mediastinal glomus tumors. Report of five cases including a pulmonary glomangiosarcoma: A clinicopathologic study with literature review. Am J Surg Pathol 2000;24:1105-1114. Hishida T, Hasegawa T, Asamura H, Kusumoto M, Maeshima A, Matsuno Y, Suzuld K, Kondo H, Tsuchiya R. Malignant glomus rumor oflhe lung. Pathollnt 2003;53:632-636. Koss MN, Hochhol.zer L, Moran CA. Pri!ll8l')' pulmonary glomus tumor: a clinicopathologic and immunohistochemical study of two cases. Mod Patbol 1998; II :253-258. Zhang Y, England OM. Pri!ll8l')' pulmonary glomus tumor with contiguous spread to a peribronchial lymph node. Ann Diagn Patbol 2003;7:245-248.

C1TR I I 7'" Cancer Seminar Pulmonary Pathology 91 Hernangjopericytoma Meade JB, Whitwell 1', Bickford BJ, Waddington JK. Primary haemangiopericytoma oflung. Thorax 1974;20:1-15. Shin MS, Ho KJ. Primary hemangiopericytoma of lung: radiography and pathology. A1R Am J. Roentgenol 1979;133: 1077-1 083. Yousem SA, Hochholzer L. Primary pulmonary hemangiopericytoma. Cancer 1987;59:549-555.

Kaoosj's Sarcoma Aboulafia OM. The epidemiologic, pathologic, and clinical fcatun:s ofAIDS -associated pulmonary Kaposi's sarcoma. . Chest 2000; 117: I L28-1145. Hengge UR, RllZicka T, Tyring SK, Stuschke M, Roggendorf M, Schwartz RA, Seeber S. Update on Kaposi's sarcoma and other HHV8 associated diseases. Part 2: pathogenesis, Castleman's disease, and pleural effusion lymphoma. Lancet Infect Dis 2003; 2:344-352. Antman K, Chng Y. Kaposi's sarcoma. New Eng J Mcd 2000;342:1027-1033. Khalil AM, Carette MF, Cadranel JL. Mayaud CM, Bigot JM. Intrathoracic Kaposi's sarcoma. CT findings. Chest 1995; I 08: 1622-1626. Purdy U, Colby TV, Yousem SA,Battifora H. Pulmonary Kaposi's sarcoma. Premomrtcm histologic diagnosis. AmJ SurgPatholl986;l0:30l-311. Tamm M, Reichenberger F, McGandy CE, Stalder A, Tietz A, Oalquen P, Penuchoud AP, Cathomas G. Diagnosis of pulmonary Kaposi's sarcoma by detection of human herpes virus 8 in broocboalveolar lavage. Am J Respir Crit Care Med 1998; I 57:458-463.

Epithelioid Hemangioendothelioma Oail DH, Liebow AA, Gmelick JT, Friedman PJ, Miyai K, Myer W, Patterson SD, Hammar SP. Intravascular, bronchiolar, and alveolar tumor ofthe lung (I VBA T). An analysis of twenty cases of a peduliar sclerosing endothelial tumor. Cancer 1983;51:452-464. Hristoga EN, Krishnamurthy S, Ro JY, Ayala AG. Pulmonary epithelioid hemangioendothelioma with prominent signet ring cell features mimicking metastatic adenocarcinoma. Ann Diagn Pathol 2003;7: 160-164. Kitaichi M, Nagai S, Nichimura K, ltoh H, Asamoto H, lsumi T, Dail DH. Pulmonary epithelioid haemangioendotholiojma in 21 patiems, including three with partial spontaneous regression. Bur Respir J. 1998; 12:89-96. Weiss SW, Ishak KG, Dail DH, Sweet DE, Bnzinger FM. Epithelioid hemangioendothelioma and related lesions. Seminars in Diaf,'llOStic Pathology 1986;3:259-287.

Angiosarcoma Adem C. Aubry M-C, Tazelaar HT, Myers JL. Metastatic angiosarcoma masquerading as diffuse pulmonary hemorrhage. Clinicopathologic analysis of7 new patients. Arch Patbol Lab Med 2001; 125: 1562-1565. Bocklage T, Leslie K, Yousem S, Colby T. Extracutaneous angiosarcomas metastatic to the lungs: clinical and pathologic features of twenty-one cases. Mod Pathol 2001 ;14:1216-1225. Patel AM, Ryu JH. Angiosarcoma in the lung. Chest 1993;103: 1531-1535. Sheppard MN, Hansell DM, Du Bois RM, Nicholson AG. Primary epithelioid angiosarcoma ofthe lung presenting as pulmonary hemorrhage. Hum Pathol 1997;27:383-385. Y ou.~e m SA. Angiosarcoma presenting in the lung. Arch Pathol Lab Med 1986;112-115.

Sarcomas of the Pulmonary Vejn Kaiser LR and Um1acher C. Primary sarcoma of the superior pulmonary vein. Cancer 1990;66:7898-795. Okuno T, Matsuda K, Ueyama K, Oota N, Tcreda Y, Hohjoh Y, Sakurai T, Nakayama T, Kitaichi M, Yamnbe H. Leiomyosarcoma of the pulmonary vein. Pathology Intematiooal 2000;50:839-846. Oliai BR, Tazelaar HD, Lloyd RV, Doria Ml, Trastek VF. Leiomyosarcoma oftbe.pulmonary veiltS. Am J Surg Pathol 1999;23: 1082-1088. Tsutsumi Y, Oeng Y. Alveolar soft pan sarcoma ofthe pulmonary vein. Acla Patho1 Jpn 1991;41 :771 -777.

92 Pulmonary Pathology CTTR 117" Cancer Seminar ~~~:r.~~~~a~nery sarcoma. ~~i1':'f some fields the intravascular are reminiscem of inflam~1tory myofibroblastjc process is apparent. A rim of pre-existing tumor. As such there is an apparent prolifcnuion o pulmonary arterial muscle can be seen around myofibroblastic cello; with prominent lntcr... .:n ing the neoplastic spindle cell nodule. inflammatory cells including numerous pl~ma .cetJ

~~artc~ry Figure ll·S. Pulmonary artery sarcoma. Some of the small vessels are filled by Some pulmonary arteries show an appearance There is a cdlular thrombi composed entirely of neoplastic cells. histologically indistinguishable from old luminal mucus and acute. cells, mural thickening-and chronic thrombosis. tnnamm.atory infilt:rote, and surrounding lung injur with fibrin in alveoli. The degree of chronic inOamo,adon :~.nd th.ickcr~in_g oithc bronchiole a chronic process typical of that Sc:en dist<

Figure 12-2. Bronchiectasis with distal Figure 12-3. Bronchiectasis with distal Figure 12-4. BronchiectaSis with distal bronchiolitis and organizing pneumonia. The bronchiolitis and organizing pneumonia. bronchi"olitis and organizing pneumonia. lung parenchyma shows patchy foci of Highe.r power shows cypicaJ intraluminal Higher power of one of the bronchioles.shQw: organizing pneumonia. organization offibroblastic tissue in tbe acute inflammatory exudate in the lumen nnd setting of organizing pneumonia. chronic inflammatory infiltt:atc in the wall.

C'ITR 117" Cancer Seminar Pulmonary Pathology 93 VITI. Airway Disease

CASE12

Clinical History (CJTR Ace. # 29895): A 72-year-old man presented with three months of fever, cough, and bilateral lower lobe infiltrates. He had extensive travel history and mycobacterial and fungal infections were considered. Cultures grew Haemophilus injluenzae. Key histologic features: Patchy organizing pneumonia manifesting as airspace fibrin undergoing organization; acute and chronic bronchiolitis with some bronchioloectasis and pooling of neutrophils within the lumens of the bronchioles; the bronchiolar changes appear to be older and thus probably predated the org~zing pneumonia. Diagnosis: Bronchiectasis with acute and chronic cellular bronchiolitis with secondary patchy organizing pneumonia consistent with Haemophilus injluenzae pneumonia. Follow-up: At follow-up, bilateral lower lobe bronchiectasis was confirmed radiologically. This is bronchiolitis associated with bronchiectasis and we are seeing the distal manifestations of the airway disease. A history of chronic sinusitis was also elicited and ultimately required surgery. For the lung disease, the patient responded to antibiotic therapy and his symptoms and radiologic findings cleared with a small residue of "scarring" of the lungs. Approach to Case 12 The main changes in this case are acute and chronic bronchiolitis and patches of organization and one's approach is to detennine whether these two basic pathologic changes are all part of the same process or whether one is secondary to the other, or whether they are unrelated. Common sense would suggest that they are likely related.

Discussion

The case presented represents a good example of bronchiolitis with patchy orgaruzmg pneumonia that does not represent idiopathic bronchiolitis obliterans organizing pneumonia (BOOP) which is currently tenned cryptogenic organizing pneumonia (COP). In BOOP, the bronchiolar component (BO) is part of the same organizing process (OP) in the more distal parenchyma. Thus they both appear to be part of the same process temporally that is undergoing organization.

In the case presented, there are chronic changes in the small airways with scarring and architectural distortion and the OP component appears recent with nbrin. Thus the airway disease appears also and most likely preceded the organizing pneumonia component. Chronic airway disease and this was confirmed radiologically with bronchiectasis. This patient has developed an infection (H flu) that is a complication of the airway disease and at the time of biopsy the organizing residue of this infection was present (as BOOP) along with the underlying airway disease.

CTTR I 17"' Cancer Seminar Pulmonary Pathology 95 Surgical lung biopsies tend to come from the periphery of the lung and one can be fooled by the apparent prominence of the organizing pneumonia or interstitial-type changes due to (sometimes inconspicuous) proximal airway disease. Bronchiectasis tends to involve larger airways, many of which are not included in surgical lung biopsies.

In this case one can construct a differential by looking at the possibilities for the two .main patterns present. On the one hand there is a prominent inflammatory process involving the airways. There is acute inflammation in the lumen and chronic inflammation in the wall with some architectural distortion, all suggesting a chronic process. As described below, cellular bronchiolitis is one of the broad patterns of airway disease that the surgical pathologist can recognize.

Conditions featuring a cellular bronchiolitis (acute and/or chronic) are many and varied and include diseases generally considered airway diseases as well as some that are generally considered interstitial diseases:

• Bacterial bronchopneumonia • Viral infections • Mycoplasma pneumoniae pneumonia • Fungal, mycobacterial, and other infections • Fume or toxic exposures • Transplant-associated airway injury (lymphocytic bronchiolitis, GVH) • Bronchiectasis (regardless of cause) • Connective tissue diseases (especially Sjogren's and rheumatoid arthritis), inflammatory bowel disease • Extrinsic allergic alveolitis • Respiratory bronchiolitis (see below) • Aspiration • Diffuse panbronchiolitis • Distal to an obstructing lesion • Asthma • COPD • Wegener's granulomatosis (rare) • Bronchiolocentric granulomatosis • Distal to an obstructing lesion

Even without knowing the history and the radiologic findings (which are extremely important in this case) one can look down the above list and exclude many lesions quite readily based solely on the histology. Bronchiectasis is highlighted as the cause in this case. The other major histologic pattern present in this case is a patchy organizing pneumonia. As noted in Case 3 of this seminar, this represents one of the acute lung injury patterns. There are a number of causes of an organizing pneumonia (OP) pattern and these include the following:

96 Pulmonary Pathology CTTR l 17lh Cancer Seminar • Organizing Infections (viral, bacterial, fungal) • Organizing Diffuse Alveolar Damage • Drug and Toxic Reactions • Collagen Vascular Diseases • Extrinsic Allergic Alveolitis (hypersensitivity pneumonitis) • Chronic Eosinophilic Pneumonia • Organizing Infectious Pneumonias Complicating Chronic Bronchitis and Emphysema, Bronchiectasis, Cystic Fibrosis, Aspiration • Inflammatory bowel disease • As a peripheral reaction around abscesses, infarcts, Wegener's granulomatosis, and others • Idiopathic (i.e., cryptogenic organizing pneumonitis/COP)

Approach to Ainvay Disease for the Surgical Pathologist

BRONCIDOLITIS = INFLAMMATION OF BRONCIDOLES This definition is simplistic, but it reminds us that bronchiolitis is an inflammatory process. An inflammatory reaction is a response to injury and reflects an interplay of inflammatory cells and vascularized mesenchymal tissue (including fibrosis). The distribution and amounts of the cellular and mesenchymal components vary from case to case. Inflammation and fibrosis may distributed in a nodular or a diffuse fashion along airways, may or may not involve the peribronchiolar alveoli, and may or may not be associated with luminal narrowing.

The interplay seen between inflammatory cells and mesenchymal tissue seen histologically in bronchiolitis explains the various radiographic findings or bronchiolitis: nodules, branching lines, air trapping, mosaic perfusion, ground glass change, and mixtures of these.

The bronchiole cannot be separated from the bronchus at ope end and the alveoli at the other and in terms of its pathologic reactions, and it is not possible to define only one or two clinicopathologic patterns of bronchiolar disease. Cases of bronchiolitis may be associated with obstructive or restrictive pulmonary function, wheezing or crackles, radiographic nodules, infiltrates, or hyperinflation, and nodular and diffuse inflammation and scarring pathologically.

Bronchiectasis, chronic bronchitis, cystic fibrosis, and similar conditions of the bronchi typically include pathologic changes in the small air\vays that reflect the full spectrum of bronchiolar pathology described below.

Conversely (but less well recognized) primary pathology in the small airways (for example, diffuse panbronchiolitis and transplant-associated constrictive bronchiolitis) frequently result in proximal bronchiectasis. Similarly, inflammatory lesions of the distal bronchioles (especially respiratory bronchioles) usually include involvement of the adjacent alveoli and in such cases the separation of "parenchvmal disease" from "airwav disease" clinically or histologically becomes impossible.

CTIR 117'" Cancer Seminar Pulmonary Pathology 97 There are direct communications between bronchioles and surrounding alveoli (Lambert's canals), and it is through these canals that bronchiolar epithelium may grow in the healing of bronchiolitis. This has been called Lambertosis, bronchiolarization of alveoli, and peribronchiolar metaplasia.

Pathologic changes in the bronchioles, including bronchiolitis and related lesions, are tied to the clinical circumstances with which they are associated, and any discussion of these conditions requires clinicopathologic correlation. In most cases, however, pathologic changes in the bronchioles are associated with many conditions, and ascribing etiology and pathogenesis cannot be based solely on the histologic features. As mentioned above, pathologic changes in the small airways are frequent in cases with primary pathology in the bronchi such as cystic fibrosis, chronic bronchitis, and bronchiectasis; these conditions are conventionally classified by their bronchial changes and not included as part of primary bronchiolar pathology. The spectrum of bronchiolar pathology usually encountered by the surgical patholgist is shown below.

Spectrum o]Bronchiolar Pathology Asthmatic-type changes Chronic bronchitis/emphySema-associated bronchiolar changes Cellular bronchiolitis (acute, chronic, with or without fibrosis) Subtypes: follicular bronchiolitis, diffuse panbronchiolitis Respiratory bronchiolitis . Bronchiolitis obliterans with intraluminal polyps (syn. bronchiolitis obliterans) Constrictive bronchiolitis (syn. bronchiolitis obliterans) Mineral dust-associated airway disease Peribronchiolar fibrosis and bronchiolar metaplasia Bronchiolocentric nodules

Each of the groups above includes a spectrum of changes, and at the ends of the spectrum there is overlap among the groups; for example, cellular infiltrates involving bronchioles (cellular bronchiolitis) are seen in asthma and chronic bronchitis/emphysema, and mucostasis is found in asthma, chronic bronchitis/emphysema, and in the airways in cases of constrictive bronchiolitis. There may also be evolution from one group to another: cellular bronchiolitis may be associated with, or show progression to, bronchiolitis obliterans with intraluminal polyps or constrictive bronchiolitis.

CELLULAR BRONCHIOLITIS

Cellular bronchiolitis (see list above) is used as a morohologic descriptor: inflammatory infiltrates of bronchioles: luminal, mural or both. This term is useful in settings in which an etiologic diagnosis cannot be ascribed. Other modifiers are often helpful: acute or chronic depending on the cell type present, necrotizing, and follicular if there is germinal center hyperplasia. Mural or peribronchiolar fibrosis are common in cellular bronchiolitis, particularly

98 Pulmonary Pathology CTTR 1!7'" Cancer Seminar in chronic cases such as bronchiolitis associated with bronchiectasis and m cases with constrictive bronchiolitis.

Bronchiolar necrosis may be seen in suppurative bacterial infections as well as in viral bronchiolitis, particularly those due to Herpes simplex and adenovirus. Bronchiolar mucosal necrosis may also be seen in acute fume or toxic exposures. In broochocentric granulomatosis, the bronchiole is destroyed and the wall replaced by a palisaded histiocytic reaction; most patients have allergic bronchopulmonary aspergillosis. In Wegener's granulomatosis, bronchiolar necrosis may be seen to arise as collections of giant cells and neutrophil microabscesses in the bronchiolar submucosa. Diffuse panbronchiolitis is a cellular bronchiolitis with a predilection for the respiratory bronchioles; interstitial accumulations of foamy macrophages are tlie most distinctive feature of diffuse panbronchiolitis.

RESPIRATORY BRONCHIOLITIS (RB)

RB was described by Niewoehner and colleagues as an incidental autopsy finding primarily in young male smokers. RB is now recognized as extremely conimon in cigarette smokers, and the term "smokers' bronchiolitis" is descriptively appropriate.

RB primarily affects respiratory bronchioles, bt~t inflammatory changes may also be seeil in terminal bronchioles. Mild chronic inflammation is found in the wall of the respiratory bronchioles associated with slight fibrosis, smooth muscle hypertrophy, and thickening of the adjacent alveolar walls, which also may show mild chronic inflammation. The most characteristic feature of RB is the accumulation of tan pigmented macrophages in the lumens of respiratory bronchioles and the adjacent alveoli. The alveolar macrophages stain positivity with digested PAS and iron stains. They typically contain dark flecks of dark particulate material.

RB is most commonly seen as an incidental finding in lobectomy specimens for carcinoma and as an incidental fmding in lung tissue· from smokers. RB may rarely be sufficiently extensive in its involvement of lung tissue to cause mild interstitial hirig disease: respiratory bronchiolitis associated interstitial lung disease

BRONCHIOLITIS OBLITERANS

"Bronchiolitis obliterans" has been the one term describing bronchiolar pathology that has been associated with the most confusion. This is because the term has been used to describe a clinical syndrome as well as two subsets of histologic findings herein described as I) bronchiolitis obliteraiJ.s with intraluminal polyps and 2) constrictive bronchiolitis.

Clinically speaking, bronchiolitis obliterans refers to a syndrome of chronic airflow obstruction with radiographic hyperinflation due to pathologic changes in the small airways. Pathologically, bronchiolitis obliterans has referred to two groups of lesions, and it was thought that the two might be temporally related; i.e., one lead to the other. However, these two groups show little

ClTR 11 7'' Cancer Seminar Pulmonary Pathology 99 clinical overlap and are only rarely temporally-related histologically; they represent two · clinicopathologic groups:

I) .Bronchiolitis Obliterans with Intraluminal Polvos (the BO ofBOOP) Bronchiolitis obliterans with intraluminal polyps is a common reparative reaction occurring in a number of settings, it is usually associated with patchy organizing pneumonia in the more distal lung tissue; the two terms are combined in the name "bronchiolitis obliterans with patchy organizing pneumonia" (BOOP pattern, a.k.a. organizing pneumonia). A BOOP pattern may be a component of other pathologic changes and as such may be seen in many conditions, such as with Wegener's granulomatosis, around neoplasms, or in the wall of abs eesse~. A BOOP pattern may also be the only histologic change present. In either setting, there are many conditions in the differential diagnosis, and only a minority of cases showing a BOOP pattern represent the idiopathic syndrome crvotogenjc organizing pneumonitis (COP).

2) Constrictive Bronchiolitis Constrictive bronchiolitis is a much less common pattern than organizing pneumonia. Complete luminal obliteration in constrictive bronchiolitis is relatively uncommon when compared with the wide spectnun of less than obliterative changes which may be very subtle. Constrictive bronchiolitis is usually a pure lesion of the bronchioles, with few changes in the distal parenchyma (i.e., organizing pneumonia is usually lacking). Constrictive bronchiolitis refers to luminal narrowing by scarring rather than smooth muscle contraction. The histologic features of constrictive bronchiolitis include a broad spectnun from very subtle abnormalities to complete luminal obliteration. There is mural thickening of the bronchioles due to submucosal collagenization. Progressive concentric narrowing is then associated with distortion of the lumen, mucostasis, and chronic inflammation (cellular bronchiolitis). Bronchioliectasis with mucus stasis may also be seen, as may bronchiolar smooth muscle hypertrophy. Subtle changes can be best appreciated with an elastic tissue stain, which highlights the submucosa scarring. Adventitial scarring may be a finding in some cases of constrictive bronchiolitis. Constrictive bronchiolitis is the usual histologic finding in patients with the clinical svndrome of bronchiolitis obliterans wjth airflow obstruction from lesions in the small airways. Conditions in which constrictive bronchiolitis may be seen include: • Healed infections (especially viral and mycoplasma) • Healed toxin or fume exposure • As a component of chronic bronchitis/emphysema, cystic fibrosis, bronchiectasis • Connective tissue disease • Bone marrow or heart-lung transplantation • Inflammatory bowel disease • Drug reactions (e.g., penicillamine, Sauropu.s androgynus)

100 Pulmonary Pathology CTTR 117m Cancer Seminar • Neuroendocrine cell hyperplasia • Healed bronchopulmonary dysplasia (BPD) • Aspiration • Idiopathic Although many of the causes of an organizing pneumonia pattern are similar to those of constrictive bronchiolitis, one rarely can document the former evolving into the latter, re-emphasizing that they represent separate and distinct clinicopathologic groups.

PERIBRONCHIOLAR FIBROSIS AND BRONCHIOLAR METAPLASIA

There is a group of poorly understood cases that are associated with bronchiolar and peribronchiolar scarring and metaphistic changes: distorted bronchioles with thickened walls, smooth muscle hypertrophy, mild chronic inflammation, and metaplastic bronchiolar epithelium extending onto adjacent fibrotic alveolar walls (bronchiolarization). There may be a history of a prior inflammatory event (for example, viral bronchiolitis or extrinsic allergic alveolitis); some cases are associated with bronchiectasis and reflect distal chronic inflammatory changes. Clinically and radiographically. the cases often maiufest as interstitial lung disease, which may be misinterpreted histologically as idiopathic pulmonary fibrosis.

The fact that fibrotic changes primarily involving the small airways produces evidence of restrictive/infiltrative lung disease is not surprising (see Case 7 discussion). Sufficient scarring and inflammation along the bronchovascular bundles can result in. decreased compliance ("stiff lung") as well as radiographic evidence of infiltrates.

References Aguayo SM, Miller YE, Waldron JA,.et al. Idiopathic diffuse hyperplasia of pulmonary n ~uroendocrine cells and airway disease. . N£ng1 J Med 1992; 327:1285-1 288. Colby TV. Bronchiolitis- pathologic considerations. Am J Clin Pathol1998; I 09: 101-109. Epler GR (ed). Diseases of the Bronchioles. Raven Press, NY, 1994. . Epler GR, Colby TV, McCloud TC, Carrington CB, Gaensler EA. Bronchiolitis obliterans organizing pneumonia. N Eng! J Med 1985; 312-152-158. K.itaichi M, Nishimura K, Izumi T. Diffuse panbronchiolitis. In: Sharma OP, ed. Lung Disease in the Tropics. NY:Marcel Dekker; 1991, 479-509. Lai RS, Chiang AA, Wu MT. et ai. Outbreak of bronchiolitis obliterans associated with consumption ofSauropus androgynus in Taiwan. Lancet 1996; 348:83-85. Lohr RH, Bowlan BJ,-Douglas WW, et al. Organizing pneumonia: Features and pr

CTTR 117m Cancer Seminar Pulmonary Pathology 101 IX. Lymphoreticular Lesions of the Lung

CASE 13

Clinical History CC I I RAce.# 29889): An 80-year-old man was having preoperative evaluation for a large squamous carcinoma of the head and neck. He was found to have multiple pulmonary nodules and following a nondiagnostic needle biopsy one of the pulmonary nodules was resected. Key histologic features: The findings do not suggest metastatic carcinoma; mixed lymphoid infiltrate including granulomas and occasional foci with eosinopbils; lymphangitic distribution away from the larger nodules; pleomorphic cellular background includes occasional cells. with features of Reed-Sternberg cells (immunophenotype of Hodgkin lymphoma confirmed immunohistochemically). · Diagnosis: Primary pulmonary Hodgkin lymphoma (HD). Follow-up: lmmunohistochemically the atypical large cells showed focal CD15 positivity, were CD30 positive, and were negative for CD3, CD20, CD45. Cytokeratin stain was negative in the atypical cells. EBV in situ hybridization was negative. The patient had definitive resection of the head and neck lesion but had postop problems with wound healing and osteomyelitis. He was treated with two cycles of combination chemotherapy and his lung nodules significantly decreased in size and then subsequently increased in size. He had an acute myocardial infarction. Four months after lung biopsy the patient was referred for hospice care.

Approach to Case 13

The presence of mass lesions radiologically suggests neoplasm (initially metastatic disease was considered}. Biopsy showed a lymphoid infiltrate with granulomas. Lymphoreticular lesion vs. granulomatous process?

Reed-Sternberg cells and the appropriate cellular milieu are identified leading to the diagnosis of HD. A granulomatous reaction is a common finding in HD at a variety of sites.

Discussion: Overview

The most interesting aspects of this case are the history which suggested metastatic carcinoma from the head and neck and the relatively advanced age of the patient. Otherwise the histologic features of the infiltrate are quite characteristic of HD, albeit at a relatively uncommon site for HD to present primarily.

Virtually all forms oflympboma identified in lymph nodes and other sites may be encountered in the lung although some are extremely rare. The lung is a relatively common site for extranodal lymphoma.

102 Pulmonary Pathology CTTR 117"' Cancer Seminar • Extranodallow-grade marginal zone B-celllymphoma (MALTOMA)- the most frequently encountered type (60-80% ofcases) • Lymphomatoid granulomatosis (the next most frequently encountered subtype) • HD, other non-Hodgkin lymphomas- all relatively rare

The lvmphatic routes of the lung are located in the pleura, septa, and along bronchovascular bundles and larger pulmonary veins. When a process affects the lymphatic routes it is usually recognizable at scanning power microscopy. This is often the first clue to the pathologist that the process may be a hematolymphoid infiltrate. With mass lesions such a distribution may not be apparent except at the edge or away from the large nodule(s).

Discussion: Hodgkin lymphoma (HDl in the Lung

Lung involvement in disseminated HD is not uncommon, however presentation at this site is unusual.

Among patients who present with HD in the lung, women are more frequently effected by a ratio of2: I and there is an average in the 30s for men and 50s for women although there is a wide age range. Most of the cases that I have seen recently have been in individuals over 60 years of age.

Svmptoms include cough, fever, weight loss, dyspnea, fatigue, anorexia, chest pain, and sometimes pleuritis.

Radiologically most patients show multiple nodules, as in the case presented, but single nodules, localized zones of consolidation or infiltrate, and bilateral reticulo nodular disease are also recognized. Cavitation may be present and that is not surprising given that nodules of HD at any site not uncommonly undergo central necrosis.

The histologic features and immunophenotype of HD in the lung is similar to that in lymph nodes. In most cases, particularly those with mass lesions, classification into nodular sclerosis or mixed cellularity subtypes is readily accomplished. Lymphocyte predominant HD presenting in the lung is distinctly unusual.

The differential diagnosis of HD involving the lung depends on the histologic features in the individual case. Broadly speaking the differential can be grouped as follows: 1) Inflammatory lesions 2) Other lymphomas 3) Vasculitis/angiitis and granulomatosis 4) Pleomorphic/sarcomatoid carcinomas and pleomorphic sarcomas rich in inflammatory cells

Because of the mixed inflammatory infiltrate that characterizes HD, inflammatory conditions, particularly abscesses, organizing pneumonia, so-called inflammatory pseudotumor, and other inflammatory conditions enter into the differential diagnosis. HD may have extensive necrosis associated with neutrophils and be mistaken as an abscess. Careful attention to the presence of

CTTR 117"' Cancer Seminar Pulmonary Pathology 103 (and immunophenotype of) atypical large cells (Reed-Sternberg and Reed-Sternberg variants) and to lymphatic distribution (if discernible) are key features in separating HD from inflammatory processes.

MALT lymphomas are usually easily distinguished from HD by the predominance of small lymphocytes, plasma cells, germinal centers, lymphoepitheliallesions, and lack of necrosis. The patients are typically asymptomatic and present with a solitary mass.

Large B-cell lymphomas of the lung, most of which fall into the category formerly known as lymphomatoid granulomatosis, may show necrosis but cells showing typical features of Reed­ Sternberg cells are generally inconspicuous (although a few may be present) and the heterogeneity so characteristic of HD, including eosinophils and s.ometimes granulomas, are usually lacking in this form of lymphoma. This form of lymphoma also typically shows vascular invasion but that is a feature that may also be encountered in HD.

Other large cell lymphomas, including anaplastic large-cell lymphoma, occasionally present in the lung and for the most part tend to be monomorphous and to lack the heterogeneity ofHD.

Since HD may infiltrate vessels, vasculitides and the angiitis and granulomatosis group enter into the differential diagnosis. One member of this group, lymphotnatoid granulomatosis (see above), is now considered (for the most part) a form of large 8-celllymphoma. Bronchocentric granulomatosis tends to center on airways rather than lymphatic routes. Necrotizing sarcoid granulomatosis is considered a form of sarcoidosis and is dominated by granulomas along lymphatic routes lacking the other lymphoid elements and cellular heterogeneity characteristic of HD. Wegener's granulomatosis is a necrotizing process with geographic necrosis and scattered giant cells lacking the atypical large cells of HD. The clinical fimtings in cases of Wegener's granulomatosis as well as serologic findings (ANCA studies) are of value.

Finally, pleomorphic/sarcomatoid carcinomas and pleomorphic sarcomas with intense inflammatory infiltrates may mimic HD. In general, the atypical cells in these conditions don't show the cytologic features of classic Reed-Sternberg cells and the immunophenotype is different.

References: Hodgkin's Disease Cartier Y, Johkoh T, Honda 0, Muller NL. Primary pulmonary Hodgkin's Disease: CT finding.• in three patients. Clin Radio! 1999;54: 182-184. Cherty R, Slavin JL, O'Leary JJ, Ansari NA, Ganer KC. Primary Hodgkin's Disease of the lung. Pathology 1995;27: 111 -114. Colby TV, Koss MN , Travis WD. Tumors of the lower rcspin11ory tract. In: Atlas ofTumor Pathology. Tbird Series, Fascicle 13, AFIP, Washington, DC 1995. Colby TV, HoppeRT, Warnke RA Hodgkin's Disea.•e at autopsy: 1972-1977. Cancer 1981;47:1852-1862. Pinson P, Joos G, Pratt M, Pauwels R. Primary pulmonary Hodgkin's Disease. Respiration 1993;59:314-3 16. Radin AJ. Primary pulmonary Hodgkin's Disease. Cancer 1990;65:550-563. Richardson GE. Long OL. Multiple cavitating pulmonary nodules in Hodgkin's Disease. Cancer 1991 ;68:930-933. Yousem SA, Weiss LM, Colby TV. Primary pulmonary Hodgkin's Disease. A clinicopathologic study of 15 cases. Cancer 1986;57:1217-1224.

104 Pulmonary Pathology CTTR 111<> Cancer Seminar Discussion: Pulmonary Lymphomas in General

Background

Benign lymphoreticular disorders of the lung are uncommon; some are associated with collagen vascular disease (esp. Sjogren's syndrome). Pulmonary lymphomas - 0.3% of primary pulmonary neoplasms. Low-grade lymphomas (esp. MALT type) more common than high-grade lymphomas.

Lymphatics and Lymphoid Tissue In the Lung

Most pulmonary lymphoreticular disorders follow lymphatic routes. Lymphatic routes - pleura, septa, and along bronchovascular bundles.

There is an inducible mucosa-associated lymphoid tissue (MALT) in the lung called bronchus­ associated lymphoid tissue (BALT). BALT is not found in normal (adult) lungs but is common in chronic inflammatory conditions. . BALT includes B-cell follicles along bronchovascular bundles; lymphocytes frequently infiltrate the overlying bronchiolar epithelium; cuff around the follicle of B lymphocytes, T lymphocytes and plasma cells.

Pseudolymphoma/Nodular Lymphoid Hyperplasia

Many question the very existence of pseudolymphomas. If they occur they are verv rare and a diagnosis of exclusion (of a MALT lymphoma). Localized mass or infiltrate that is histologically polymorphous and immunologically polyclonal; germinal centers and fibrosis may be prominent

Lymphoid/Lymphocytic Interstitial Pneumonia (LIP) and Diffuse Lymphoid Hyperplasia (DLH)

Most of the cases in Liebow's original defining paper of LIP were low-grade lymphomas! Nevertheless, we still use the term LIP for cases described below. Histologic spectrum of LIP: from a dense diffuse polyclonaVpolymorphous lymphoid infiltrate to diffuse lymphoid hyperplasia with germinal centers distributed along lymphatic routes {DLH); overlap cases between these two ends of the spectrum. Granulomas, giant cells, histiocyte clusters, interstitial fibrosis, honeycombing, type IT cell metaplasia, and foci of organization all may also be encountered. Typical immunohistochemical profile - scattered B cell follicles. along lymphatic routes with more diffuse infiltrate ofT cells and polyclonal plasma cells. LIP is an interstitial lung disease clinically; diffuse and bilateral. Associated collagen vascular disease (e.g. Sjogren's syndrome) in many cases. Acquired immunodeficiencies (including HIV) may be the underlying disease. L[p should be considered a reaction pattern with a differential diagnosis to include: low-grade lymphomas, extrinsic allergic alveolitis, and infections (especially Pneumocystis).

CITR 11710 Cancer Seminar Pulmonary Pathology 105 Low-grade Lymphomas of BALT and other Small Ly,mphocytic Lymphomas

(Included are: small lymphocytic lymphoma, lymphoplasmacytoid lymphoma and, most commonly, extranodal marginal zone B-celllymphoma.)

Most common type of lymphoma encountered in the lung: Most cases called pseudolymphoma are now in this category. Most present .as localized masses or infiltrates; 5-l 0% as diffuse interstitial lung disease (with corresponding symptomatology); localized lesions can be treated with resection. A minority (< 20%) have a monoclonal serum spike and/or bone marrow involvement; Waldenstrom's macroglobulinemia may be present. Histologic findings: dense, diffuse, homogeneous/monomorphous lymphoid infiltrates; scattered germinal centers and"granulomas may be. present. Mono- or polyclonal plasma cells may be present; appreCiable numbers ofT cells may be present; the neoplastic B cells may have plasmacytoid or even plasmacytic features. Ig crystals occasionally present in histiocytes. The histologic heterogeneity of low-grade BALT lymphomas recapitulates that of MALT itself. Flow cytometry, immunohistochemical and molecular studies to confirm clonality not necessary in all cases; histologic heterogeneity (and appreciable numbers of polyclonal plasma cells and T cells) may confound these studies (particularly flow cytometiy). Differential diagnosis: LIP, pseudolymphoma, leukemic infiltrates (especially CLL), MALT lymphomas .in transformation, other lymphomas.

Lymphomatoid Granulomatosis (LYG)

These cases are recognized as diffuse large B-celllymphomas. Currently accepted as an EBV-driven diffuse large B-celllymphoma in which the large cells can be shown to be clonal B cells, infected by EBV. The existence ofT-cell lymphomas showing features oOymphomatoid granulomatosis is controversial. Typically multiple bilateral nodules that cavitate; solitary nodules and infiltrates are also recognized. Multi-system disease common, particularly with skin and nervous system involvement. Pathology: nodular infiltrates of lymphoid cells with central necrosis and prominent vascular infiltration; heterogeneous cell population with scattered large B cells, sheets of small T cells, and scattered histiocytes; well-formed sarcoid-like granulomas are unusual. Immunohistochemical findings: T-cell rich lesion with scattered large B cells which can be shown to be clonal and infected with EBV. The bl!ckground T cells are heterogeneous; a variable proportion express markers of cytolytic T cells and NK cells (by CD8, TIA-1, and granzyme B staining).

Other Lymphomas Presenting in the Lung

Similar spectrum to that seen in lymph nodes, although all are relatively unusual. Anaplastic large-cell lymphomas are occasionally encountered.

106 Pulmonary Pathology CTTR 117'' Cancer Seminar Intravascular Lymphomatosis/Angiotroplc Lymphoma

Rare; B-cell phenotype>> T-cell phenotype. Concomitant involvement of other organ systems, particularly CNS. Neoplastic cells found within vessels, especially capillaries; may be a subtle finding.

Post-Transplant Lympboproliferative Disorders and Lymphomas Occurring in the Setting oflmmunodeficiency (esp. HIV infection)

Bear a resemblance to lymphomatoid granulomatosis. Majority are EBV -related. Clinical and radiologic findings: single or multiple nodules, single or multiple infiltrates. Histologic spectrum - as for post-tran.splant lymphoproliferations in lymph nodes; plasma cell proliferations, polymorphous plasmacytoid proliferations, monomorphous (+/- plasmacytoid) proliferations identical to large-cell lymphoma; vascular infiltration and necrosis may be prominent in these lesions. Immunology - most are B cell; rarely T cell or ALCL

Discussion: Recognition ofLvmphomas in the Lung

In addressing difficult pulmonary lymphoreticular infiltrates, one may encounter the following scenario:

Pulmonary pathologists' point of view - The infiltrate has prominent lymphoid tissue and does not show the pattern of an inflammatory process and a lymphoreticular process is favored.

The hematopathologist cannot prove with immunohistochemistry or other techniques that the process is abnormal (or clonal or ''neoplastic") and therefore think it is probably inflammatory.

Each specialty has its own point of view. It is probably best to take some information from both rather than one to the exclusion of the other.

The following represents comments regarding some of the features that may be encountered in low grade (primary MALT type) lymphomas and high grade (primarily LYG and diffuse large­ cell) lymphomas and lesions in their differential diagnosis.

A. Dense sclerosis (to be distinguished from amyloid) - common in low-grade lymphomas; uncommon in high-grade lymphomas. B. Type 2 cell hyperplasia and interstitial inflammation - common at the edge of all lymphoreticular infiltrates. C. Organizing pneumonia, fibrinous exudate - rare in low-grade lymphomas; relatively common in high-grade lymphomas and HD.

CTTR I 17"' Cancer Seminar Pulmonary Pathology 107 D. Vascular infiltration- uncommon in low-grade lymphoma; common in high­ grade lymphomas (to be distinguished from vasculitis - vasculitis usually includes necrosis of the vessel wall and mixed infiltrate including granulocytes; lymphomas with vascular infiltration usually show primarily lymphoid cells within the vessel). E. Granulomas - common in low-grade lymphomas; unusual in high-grade lymphomas. F. Necrosis - rare in low-grade lymphomas; common in high-grade lymphomas; necrosis may be extensive and sampling error is an issue. G Lymphomatoid granulomatosis without B cells - in patients with LYG who have multiple nodules biopsied occasional nodules (in the given sample) may lack B cells even though other nodules sampled show all the classic features. Thus, sampling error may be an issue.in LYG. H. Bronchioloceniric presentation - occasionally encountered in low-grade lymphomas (and CLL); may correlate with clinical evidence ofwheezing. I. Most important clue to a low-grade lymphoma - sheer densitv of the infiltrate; inflammatory processes tend to have inflammatory ·changes (organizing pneumonia, fibrin, etc.) that are relatively prominent compared to the lymphoid infiltrate whereas the opposite is true with lymphoreticular infiltrates.

References Abbondazzo SL, Rush W, Bijwaard KE, Koss ME. Nodular lymphoid hypefPiasia of the lung. A clinicopathologic study of 14 cases. Am J Surg Patbol2000;24:587-597. Addis BJ, Hyjek E, Isaacson PG. Primary pulmonary lymphoma: a re-appraisal of its histogenesis and its relationship to pseudolymphoma and lymphoid interstitial pneumonia. Histopathology 1988;13:1-17. Begueret H, Vergier B, Parrens M, Lehours P, La.urent F, Vemejoux JM, Dubu.• P, Velly JF, Megraud F, Taytard A, Merlio JP, de Mascarel A. Primary lung small B-celllymphoma versus lympohid hyperplasia: evaluation of diagnostic criteria in 26 cases. Am J Surg Pathol 2002;26:76-81. · Bienenstock J, DefusD. Gtll· and bronchus-associated lymphoid tissue. Am J Anat 1984; 170:43 7-445. Colby TV. Lymphoproliferative diseases. Chapter 31, In: Dail DH and Hammar SP eds. Pulmonary Pathology, 2"" Edition, Springer, New York, 1994. Colby TV, Koss MN, Travis WD. Tumors Qfthe lower respiratory tract. In: Atlas ofTumor Pathology. Third Series, Fascicle 13, AFIP, Washington, DC t995. Cordier J-.F, Chailleux E, Lauque D, Reynaud-Gaubert M, Dietemann-Molard A, Dalphin JC, Blanc-Jouvan F, Loire R. Primary pulmonary lymphoma.•. A clinical study of 70 cases in nonimmunocompromixed patients. Chest 1993; 103:201·208. Ferry JA, Harris NL, Picker U , Weinberg DS, Rosales RK, Tapia J, Richardson EP. Intravascular lymphomatosis (malignant angioendotheliomatosis): a B cell neoplasm expressing surface hpming receptors. Mod Pathol 1988; I :444-452. . Gould SJ, Isaacson PG. Bronchu.<-associated lymphQid tissue (BALT) in human fetal and infant lung. J Pathol, 1993; 169:229-234. Guinee DG Jr, Perkins SL, Travis WD, Holden JA, Tripp SR, Koss MN. Proliferation and cellular phenotype in lymphomatoid granulomatosis. Am J Surg Pathol 1998;22:1093-IIOO. Guinee DG, JaffeE, Kingma D, Fishback N, Wallber_g K, Krishnan J, Frizzera G, Travis W, Koss M. Pulmonary lymphomatoid gnanulomatosis: evidence for a proiiferation ofEpstein-Barr virus infected B lymphocytes with .a prominent T cell component and vasculitis. Am J Surg Pathol. In press (1994). Hansmann ML, Zwingers T, Lennert K. Primary lymphomas ofthe lung: mofl)bQlogical, immunohistochemical, and clinical features. Histopathology 1990;16:519-531.

108 Pulmonary Pathology CTTR 1 17"' Cancer Seminar Harris NL, Isaacson PG. What are the criteria for distinguishing MALT from non-MALT lymphoma at extranodal sites? Am J Clin Pathoi1999;1 11:SI26-SI32. Harris NL Extranodallymphoid infiltrates and mucosa-associated lymphoid tissue (MALT). A unifying coneepL Am J Surg Pathol1991;15:879-884. Jaffe BS, Lipford EH Jr, Margo lick JB, et al. Lymphomatoid granulomatosis and angioccntric lymphoma: a speclrum of post-thymic T -cell proliferations. Semin Respir Med 1989; I 0:167. Jaffe ES, Harris NL, Stein H, Vardaman JW. Tumors ofthe Hematopoietic and Lymphoid Tissues. WHO Classification ofTumors,IARC Press, Lyon, 2001. Katzenstein ALA, Carrington CB, Liebow AA. Lymphomatoid granulomatosis. A clinicopathologic study of 152 cases. Cancer 1979;43:360-373. Koss MN, Hochhotzer L, Moran CA, Fri2:zera G. Pulmonary plasmacytomas: a clinioopathologic and immunohiS1ochemical study of five eases. Annals ofDiagnostic Palhology 1998;2:1-1 t. Koss MN, Hochbolzer L, Nichols PW, Wehunt \VO,Lazarus AA. Primary non-Hodgltin's lymphoma and pseudotympbomaoflung: Astudyoft61 patients. Hum Pathot 1983;14: 1024-1038. Kurtin PJ , Myers JL, Adlakha H, Strickler JG, Lohse C. Pankratz VS, Inwards DJ. Pathologic and clinical features of primary pulmonary extranodal marginal zone B-celllymphoma of MALT type. Am J Surg Pathol 2001;25:997-1008. Li G, Hansmann M-L, Zwingers T, Lennon K. Primary lymphomas of the lung: morphological, immunohistochemical, and clinical t\:atures. Histopathology 1990; 16:5 19-531. Liebow AA, Carrington CB. Diffuse pulmonary lymphoreticular infiltrations associated with dysproteinemia. Med Clin Nonh Am 1973;57:809-843 . Lipford EH, Margo lick JB, Long DL, Fauci AS, Jaffe ES. Angiocentric immunoproliferative lesions: a clinicopalhologic spectrum of po51-tbymic T -cell proliferations. Blood 1988;72: 1674-1681. Miyahara N, Eda R, Umemori Y, Murakami T, Kunich.ika N, Makihata K, Aoe K. Murakami K, Takeyama H. Harada M. Pulmonary lymphoma of large B-cell type mimicking Wegener's granulomatosis. Intern Med 2001 ;40:786-790. Morice WG, Kunin PJ, Myers JL. Expression of cytolytic lymphocyte-associated antigens in pulmonary lymphomatoid granulomatosis. Am J Clin Pathol 2002; 118:391-398. Myers JL, Kurlin PJ, Katzenstein ALA, Tazelaar HD, Colby TV, Strickler JG, Lloyd TV, Isaacson PG. Lymphomatoid granulomatosis. Evidence of immunophenotypic diversity and relationship to Epstein-Barr virus infection. AmJ Surg Patholl995;19:1300-1312. Nakamura N, Yamada G, ltoh T, Suzuki A, Morita-lchimura S, Teramoto S, Shijubo N, Koba H, Satoh M, Abe S. Pulmonary MALT lymphoma with amyloid production in apatient with primary Sj ogren's syndrome. Intern ' Med 2002;41 :309-31 I. Nicholson AG, Wotherspoon AC, Jones AL, Sheppard MN, Isaacson PG, Corrin B. Pulmonary B-ccll non­ Hodgkin's lymphoma associated wilh autoimmune disorders: a clinicopalhological review ofsix ca~es. Eur Respir J 1996;9:2022-2025. Philippe B, Delfau-Laure M-H. Epardeau B, Autran B, Clauvel J-P, Farcct J-P, Couderc L-J. B-cell pulmonary lymphoma. Gene rearrangement analysis ofbronchoalveolar lymphocytes by polymerase chain reaction. Chest 1999; 11 5:1242-1247. Prasad ML, Charney DA, Sari in J, Kelley SM. Pulmonary immunocytoma wilh massive crystal storing histiocytosis. A case report with review of !he literature. Am J Surg Palhol 1998;22: 1148-ll 53. Randhawa PS, Yousem SA. Epstein-Barr virus associated lympboprolife rative disease in a heart-lung allograft: demonstration ofhost origin by restriction fragment length polymorphism analysis. Transplantation 1990;49:126-130. Ray P, Antoine M, Mary-Krause M, Lebreue M-g, Wislez M, Duvivier C, Meyohas M-C, Girard P-m, Mayaud C, Cadranel J. AIDS-related primary pulmonary lymphoma. Am J Respir Crit Care Med 1998; I 588:1221-1229. Saxena A, et at. Post-transplant diffuse large B-celllymphoma of lymphomatoid granulomatosis type. Virchows Arch 2002;441 :622-628. Snyder LS, Harmon KR, Estenson RD. Intravascular lymphomatosis (malignant angioendotholiomatosis) presenting as pulmonary hypertension. Chest 1989;96:1 i99-l200. Tao J, Valderrama E. Epstein-Barr virus-associated polymorphic B-cclllymphoproliferative disorders in the lungs ofchildren with AIDS. Am J Surg Pathol 1999;23:560-566. Turner RR, Colby TV, Doggett RS. Well-differentiated lymphocytic lymphoma. A srudy of4 7 patients wilh primary manifestation in the lung. Cancer 1984;54:2088-2096.

CTTR 11 7,. Cancer Seminar Pulmonary Pathology 109 Vaiman E, Odeb M, Attias D, Ben-Arie Y, Oliven A T-cell chronic lymphocytic leukaemia with pulmonary involvement and relapsing BOOP. Bur Respir J 1999; 14:471-474. Weiss LM, Yousem SA, Warnke RA Non-Hodg!

CASE 14

Clinical History fCTTR Ace.# 29890): Due to paucity of material for two of the cases, the distributed slides each include three cases. The larger fragment on each slide represents autopsy tissue from Case 14A. The smaller fragments represent either Case 14B or 14C.

Case 14A. A 60-year-old woman was severely anemic due to a myelodysplastic syndrome which had been characterized as refractory anemia with excess blasts. She required transfusion of two units of blood every two weeks. She bad a history of COPD and smoking. She was admitted to her final hospitalization with fever, increasing -shortness of breath and pleural effusions. She developed increasing leukocytosis (without frank leukemia), respiratory failure and died ten days after admission. Autopsy confirmed infiltrates of immature cells in the lung, pleura, liver, spleen, peritoneum, lymph nodes, soft tissues, and multiple other·sites.

Key histologic features: An immature cellular infiltrate with features of a lymphoreticular malignancy following l}mphatic routes, particularly in the pleura and septa; immunohistochemical confirmation of myeloid nature of these cells.

Case 14B. An adult woman presented with shortness of breath and pulmonary infiltrates. A clinicaJ diagnosis could not be made and a surgical lung biopsy was performed.

Key histologic features: Background pattern is that of ac.ute lung injury with airspace fibrin and mild interstitial widening with type 2 cell metaplasia; perivascular infiltrates of atypical cells; atypical cells confirmed as myeloid.

Case 14C. A 40-year-old roan presented with symptoms of anemia and ultimately was found to have a "packed" marrow with 3-5% blasts. The main considerations were acute and chronic royeloroonocytic leukemia. Adequate aspirates could not be obtained to evaluate. He also had a history of incre3$ing shortness of breath for four months and this resulled in surgical lung biopsy.

110 Pulmonary Pathology CfTR I 17"' Cancer Seminar Key histologic features: Obvious infiltrates of immature cells which can be confirmed to have myelomonocytic differentiation with specials studies; associated acute lung injury for which infection must be excluded.

Diagnosis:

14A. Acute myelogenous leukemia. 14B. Acute myelogenous leukemia with associated alveolar injury. 14C. Myelomonocytic leukemia with extensive pulmonary infiltration.

Follow-up: Not available.

Approach to Case 14

Key feature is identification of a process with abnormal cells infiltrating along lymphatic routes. Address the alveolar injury ifpresent and exclude possible causes, particularly infection.

Discussion

From a practical point of view one's primary problem is distinguishing clinically significant pulmonary infiltrates from leukemic infiltrates that represent an incidental (and clinically insignificant) finding. Each case must be individualized but one's first consideration is to exclude the possibility of infection, particularly if there is associated alveolar injury or other histologic features (necrosis, neutrophils, etc.) to suggest infection. This is done with a routine battery of cultures and special stains with additional studies (i=unohistochemistry, in situ hybridization, etc.) as necessary.

The cases presented represent examples of primary presentation in the lung as well as relapse in the lung with blastic transformation apparent histologically (in the autopsy case).

Leukemic Infiltrates and Related Conditions

Any leukemia may have pulmonary involvement. Leukemia pulmonary infiltrates represent a rare primary manifestation at the time of presentation and patients may or may not be documented (at that time) to have concomitant bone marrow disease. A small percent have clinically significant pulmonary involvement during life (but leukemic infiltrates are a co=on histologic finding at autopsy}, Pulmonary disease may (rarely) be the initial manifestation of the leukemia. Leukemia-related pulmonary conditions: Pulmonary leukostasis - leukemic blasts occlude pulmonary vasculature (usually in patients with> 200,000 cells/ Leukemic cell lysis pneumopathy - seen within days of onset of chemotherapy in patients with high blast counts; congested capillaries have blast cell aggregates; the lung shows small infarcts and hemorrhage.

CTTR 117"' Cancer Seminar Pulmonary Pathology Ill Hyperleukocytic syndrome- acute respiratory distress in patients with rapidly increasing peripheral blast cell counts (usually > 245,000 cells/); blasts are found in small vessels associated with microhemorrhages and alveolar edema. Myelofibrosis (agnogenic myeloid metaplasia) may have pulmonary involvement with variable degrees of fibrosis and extramedullary hematopoiesis, usually following lymphatic routes. The fibrosis may be nodular or more widespread and associated with signs and symptoms of a fibrosing interstitial pneumonia.

References Asakura S, Colby TV. Two cases of agnogenic myeloid metaplasia with extramedullary hematopoiesis and fibrosis in the lung, Chest 1994;105:1866-1868. Azoulay E, Fieux F, Moreau D, Thiery G, Rousselot P, Parrot A, Le Gall JR, Dombret H, Schlemmer B. Acute monocytic leukemia presenting as acute respiratory failure. Am J Respir Crit Ca:re Med 2003; 167: 1329-1333. Berkman N, Polliack A, Breuer R, Okon E, Kramer M. PuJR\Qnary involvement as the major manifestation of chronic lymphocytic leukemia. Leuk Lymphoma 1992;8:495-499. Colby TV, Koss MN, Travis WD. Tumors of the lower respiratory tracL In: Atlas of Tumor Pathology. Third Series, Fascicle 13, AFIP, Washington, DC 1995. Glew RH, Haese WH, Mcintyre PA. Myeloid metaplasia wilh myelofibrosis. Clinical spectrum ofextramedullary hematopoiesis and twnOr formation. Hopkins Med J 1973;132:253-270. Heyneman Ll!, Johkoh T, WardS, Honda 0, Yoshida S, Muller NL. Pulmonary leukemic infiltrates: high- resolution CT fi ndings in 10 patients. AJR Am J Roentgenol2000;174:.511-.521. Palosaari Dl!, Colby TV. Bronchiolocentric chronic lymphocytic leukemia. Cancer 1986;.58:1695-1698. Rollins SD, Colby TV. Lung biopsy in chronic lymphocytic leukemia. Arch Pathollab Mcd 1988; 112:607-611. Sueyoshi E, Uetani M, Hayashi K, Tawara M. Adult T -cell leukemia with multiple pulmonary nodules due to leukemic cell infiltration. AJR Am J Roentgenol 1996; 167:540-541. Snyder LS, Cherwitz DL, Dykoski RK, Rice KL. Endobronchial Richter's syndrome. A rare manifestation of chronic lymphocytic leukemia. Am Rev Respir Dis 1988;138:980-983. Tanaka Nn, Matsumoto T, Miura G, Emoto T, Matsunaga N, Satoh Y, OkaY. CT fi:ndings of leukemic pulmonary infiltration with pathologic correlation. Eur Radio! 1002; 12: 166-174. Trisolini R, Lazzari Agli L, Poletti V. Bronchiolocentric pulmonary involvement due to chronic lymphocytic leukemia. Haematoloigca 2000;85: 1097. Vaiman E, Odeh M, Attias D, Ben-Arie Y, Oliven A. T -cell chronic lymphocytic leukaemia with pulmonary involvement and relapsing BOOP. EurRespir J 1999;14:471-474. Yoshioka R. Yamaguchi K, Yoshinaga T, Takatsuki K. Pulmonary complications in patients with adult T -cell leukemia. Cancer 1985;55:2491-2492.

11 2 Pulmonary Patltology CTTR 117"' Cancer Seminar pulmonary HD. Away pulmonary HD. pulmonary H.D. from the large masses, lhcrc urc nodular foci show recogni ...blc wanulomatous Cytologic study allows.ldcntlficolion of infiltrates along vessels renecting a lymphatic features with mixed innam.matory al)picallargecclls, some or which show distribution. bac-kgroond. features of Reed-Sternberg cells (at9 o'clock).

Figure 14A-1. AML the lung at Figure 146-J. AMI.. ucute autopsy. There Is a cellular Infiltrate in the injury. The alveoli Bhow oirspuce 1ibrin and visceral pleura and ex lending down an hemorrhage. The intervening olvcolar walls interlobular septum. show edema and o mixed cellular infiltrate without obvious malignancy in lhis field.

11eute lung injury. In some fields there were pullmo•nary involvement. The shows p~~:;~~~ involvement interstitial infiltrates or immature cell& which alveolar, alveolar septal, and pleural cellular ir shows immature cells with obvious were proven histochemically and infiltrates with associated airspace and myeloid differentiation including eosinophilic immunohistochemically to be myeloid cells. interstitial edema. myclocylcs and cells reeogni:t.able as myelocytcs (a1 12 o'clock).

CITR 117., Cancer Seminar Pulmonary Parlrology 113 X. Pulmonary Metastases

CASE 15

Clinical History: [There are two cases on the slide.]

Case lSA (CTTR Ace. # 29873) A 53-year-old woman underwent resection of what were described as "multiple pulmonary blebs." Tissue containing blebs and bullae up to 15.0 em in diameter were resected. The patient had had a prior hysterectomy for a "large leiomyoma."

Key histologic features: An interstitial proliferation of spindle cells typical of benign-appearing smooth muscle; cystic change with cysts lined by cells with typical histologic (and immunohistologic) features of reactive pneumocytes; immunohistochemical confirmation consistent with genital tract origin (PR positive) and features of lymphangioleiomyomatosis and related proliferations (HMB-45 negative).

Case JSB (CITR Ace. # 21388) For four to six months prior to admission, this 62-year-old Caucasian female experienced episodes of shortness of breath, which was brought on by mild activity while walking in her kitchen. She also noted a weight gain of 25-30 pounds. Routine chest x-ray revealed two suspicious areas in the left lung field, in addition to pleural effusion. The patient had undergone a hysterectomy fourteen years previously for uterine fibroids. Physical examination revealed decreased breath sounds in the lower half of the right chest, and rhonchi in the left lung, along with rates.

The specimen consisted of a pinkish-red piece of focally anthracotic lung tissue weighing 19 grams and measuring 6.0 x 3.5 x 3.0 em. Half of the specimen consisted of a hard mass which, ' when sectioned, measured 3.0 em in maximum dimension. The cut surface of the mass was pinkish-white and had a fibrous consistency. The cut surface protruded above the rest of the specimen, and had an interlacing ropy appearance. (Contributed by Theodore Tsuyuki, M.D.; La Habra, CA)

Diagnosis: Benign metastasizing leiomyoma (BML).

Follow-up:

lSA. The patient has had persistent somewhat indolent disease for several years with mild shortness of breath. lSB. The patient was confirmed as having hysterectomy for "fibroids" fourteen years earlier. No additional follow-up available.

CITR 111"' Cancer Seminar Pulmonary Palhology 115 Approach to Case 15

These represent women with multiple nodules. The nodules have spindle cells resembling smooth muscle cells. Awareness of the entity of benign metastasizing_ leiomyoma. And don' t forget metastatic endometrial stromal sarcoma!

Discussion: Overview

Pulmonary metastases from high-grade sarcomas and carcinomas at a variety of sites are not unexpected but there are a number of low-grade or "benign" tumors that occasionally are associated with pulmonary metastases. These include:

• Uterine leiomyoma (BML) • Thymoma • Mixed tumor ofs alivary gland • Chrondroblastoma of bone • Giant cell tumor ofbone • Meningioma • Dermatofibroma/cellular fibrous histiocytoma • Dermatofibrosarcoma protuberans • Others

References Adlakha A Rao K, Adlakha H, Perry A, Crotty TB, Scheithauer BW, Ryu JH. Meningioma metastatic to the lung. Mayo Clin Proc 1999;74:1129-1133 . Aumann JL, van den Bosch JM, Elbers JR, Wagenaar SJ. Metastatic meningioma of tbe lung. Thorax 1986;41 :487- 488. Cerda-Nichola M, Lopez-Gines C, Perez-Bacete M, Roldan P, Talamantes·F, Barbera J. Histologically benign metastatic meningioma: morphological and cytogenetic study. Ca~c report. J Neurosu.rg 2003;98: I 94- I 98. Colby TV. Metastasizing dermatofibroma. Letter to the Editor. Am J Surg Patbol 1997;21 :976. Colome-Grimmer MI, Evans HL. Metastasizing cellular dermatofibroma. A report oftwo cases. Am J Surg Patbol 1996;20: 1361 -1367. . Fadare 0. Benign metastasizing giant cell tumor. Arch Pathol Lab Med 2002;126:1133-1134. Inwards C. Benign gianH:ell tumor of bone with pulmonary metastases: a report on 16 cases with an emphasis on long term follow-up. Mod Patholi995;8:7A. Jambhekar NA, Desai PB, Chitale DA, Patil l', Arya S. Benign metastasizing chondroblastoma. A case repprt. Cancer 1998;82:675-678. Joseph M, Colby TV, Swensen SJ, et al. Multiple cystic fibrohistiocytic tumors of !he lung; a report of two cases. Mayo Clin Proc 1990;65:192-19'7. Kaminski JM, Movsas B, King .E;, Yang C, Kronz JD, Alii PM, Williams J, Brem H. Metastatic meningioma to the lung with multiple pleural metastases. Am J Clin Oncol 200 I ;24:579-582. Ng TH, Wong MP, Chan KW. Benign meta.~tasizing meningioma. Clin Neurol Neurosurg 1990;92: I 52-154. Osborn M, Mandys V, Beddow E, Ladas G, Florio R, Sheppard MN, Fisher C, Bell SW, Travis WD, Nicholson AG. Cystic fibrohistiocytic tumours presenting in the lung: primary or metastatic disease? Histopathology 2003;43:556-562. Patil PK, Krishnamurthy PS, Mistry RC, Deshpande RK, Desai PB. Dermatofibrosarcoma protuberans metastatic to the lung. A case report. Tumori I 992;78:49-51. Rotter G, Schneider U, Tunn PU. Thymoma with primary osseous and pulmonary metastases. Ca.•e report and review of the literature. Orthopade 200 I ;30:559-564. I 16 Pulmonary Pathology CTTR 117'b Cancer Seminar Sanjay BKS, Kadhi SM. Giant cell tumour of bone with pulmonary mctastases. A report ofthree cases. International Orthopaedics (SICOT) 1998;22:200-204. Siebeorock KA, Unni KK, Rock MG. Giant-cell tumour of bone metastasizing to the lungs. A long-term follow-up. J Bone Joint Surg Br 1998;80:43-47. Som PM, Sacher M, Strenger SW, Bfller HF, Malis Ll. "Benign" metastasizing meningiomas. Am J Neuroradiol 1!187;8: 127-130. Suzuki R, Oondo K, Hongo H, Mori T, Kitamura N. Metastatic lung tumor developing 15 years after resection of invasive thymoma. Jpn J Thorac Cardiovasc Surg 1998;46: 1358-1362. Tognetti F, Donati R, Bollinl C. Metastatic spread of benign intracranial meningioma. J Neurosurg Sci 1987;31 :23- 27.

Discussion: Benign Metastasizing Leiomyoma/BML

The two cases presented illustrate some' of the differences in cellularity that may be enco\Ultered in so-called benign metastasizing leiomyoma. In one case the process is so paucicellular and the smooth muscle so well differentiated that one would probably not consider a neoplastic process without knowing the clinical and radiologic findings. The second case (158 ) is somewhat more cellular and while some might consider this a very low-grade leiomyosarcoma I still think that it is within the spectrum of (cellular) leiomyoma of the uterus. The discussion of whether benign metastasizing leiomyoma represents a low-grade sarcoma or a form of metastasis of a benign lesion is somewhat irrelevant since this is a fairly well defined clinico-pathologic entity.

Benign metastasizing leiomyoma (BML) is a confusing and controversial entity. This condition is virtually restricted to women, most of whom have had prior hysterectomy that showed leiomyoma(s). Several years after hysterectomy, the patients present (usually in the fourth to fifth decade) with multiple (rarely single) pulmonary nodules, which show histologic features of benign appearing smooth muscle. In some cases, the nodules undergo cystic degeneration analogous to metastatic low grade sarcomas mimicking lymphangioleiomyomatosis. The lesions slowly enlarge over many years and a small portion of patients die of respiratory failure. One would assume that the tumors are hormonally responsive, but the condition is sufficiently rare enough that it is not known whether hormonal manipulation will consistently alter the course of the disease. Most if not all cases of BML are positive for estrogen and progesterone receptors by immWlohistochemical techniques.

There are several hypotheses for the occurrence of BML:

• Metastasis of a truly benign tumor analogous to other tumors (see above) • Metastasis of a very low grade sarcoma • In situ formation and proliferation of smooth muscle in the lung

One recent case report supports the theory that BML is a clonal disease, and as such, BML represent metastases rather than multi focal de novo proliferations within the lung. Tietze, et al, showed that with comparative genomic hybridization and X-chromosome inactivation analysis, the uterine tumor and the nodules in the lung had an identical X-chromosome inactivation pattern consistent with a monoclonal origin of the lesions.

CTTR 11 7"' Cancer Seminar Pulmonary Pathology 117 The question of whether benign tumors can metastasize to the lung is an interesting one and the philosophical problem is probably more complicated than the practical one. Be that as it may, many "benign" tumors may occas~onally develop pulmonary nodules as· note~ above.

The differential diagnosis of benign metastasizing leiomyoma includes metastatic low-grade leiomyosarcoma (with which lesions of BML probably merge), metastatic high-grade spindle cell sarcomas and carcinomas, mesenchymal cystic hamartoma, metastatic non-leiomyomatous spindle cell neoplasms (dermatofibroma, dermatofibrosarcoma protuberans), EBV-associa ted smooth muscle tumors in immunosuppressed individuals, pulmonary hamartomas with smooth muscle component, and LAM. The spindle cells ofBML are negative for HMB-45, whereas this stain is positive in LAM.

The lung is one of the sites that EBV-associated smooth muscle proliferations may be encountered in the setting of immunosuppression. Both lung parenchymal and endobronchial EBV -associated smooth muscle proliferations have been described.

Many tumors in the lung may show dramatic interstitial growth. This may or may not be associated with cystic change that can be microscopic or macroscopic. In this setting the presence of reactive alveolar lining cells may suggest a biphasic process. TTF-1 staining may be useful in confirming the pulmonary origin ofthe epithelial cells present.

Smooth muscle proliferations in the lung may also be encountered in: • Honeycomb change and other forms of lung scarring • Scarring along alveolar ducts and bronchioles

In LAM there is usually associated cystic change and the smooth muscle proliferation is phenotypically different from normal smooth muscle. It tends to be more cellUlar and "immature" in appearance and, most importantly, shows distinctive HMB-45 positivity. lleferences:lJ~ Colby TV, Koss M, Travis WD. Tumors of the lower respiratory test (AFIP fascicle, series #3). . American Registry of Pathology, Washington, DC, 1995. Esteban JM, Allen WM, Scliaert RH. Benign metastasizing leiomyoma ofthe uterus. Histologic and immun.ohistochernical characterization of primary and metastatic lesions. Arch Pathol Lab Med 1999; I 23;960- 962. JauiZke G, Muller-Ruchholtz E, Thalmann .U. Immunohistological detection ofestrogen and progesterone receptors in multiple and well differentiated leioroyomatous lung tumors in women with uterine leiomyomas (so-called benign metastasizing leiomyomas). A report on 5 cases. Path Res Pract 1996;192:215-223: Lipton JH, et al. Miliary pattern as presentation ofleiomyomatosis of the lung. Chest 1987;91 :781-782. Takemura 0 , Takatsu Y, Kaitani K, Ono M, Ando F, Tanada S, Niwa H, Tankawa H, Fujiwara T, Yamabe H. Metastasizing uterine leiomyoma. A case with cardiac and pulmonary metastasis. Path Res Pract 1996; 192:622-629. Tietze L, Funther K, Horbe A, Pawlik C, Klosterhalfen B, Handt S, MerkelbachBruse S. Benign metastasizing leiomyoma: a cytogenetically balanced but clonal disease. Hum Pathol 2000;31: I 26. Winkler TR, et al. Benign metastasizing leiomyoma. Ann Thorac Surg 1987;43: I 0()-1 0 I. WolffM, et al. Pulmonary metastases (with admixed epithelial elements) from smooth muscle neoplasms. Report ofnine cases, including three males. Am J Surg Pathol 1979;3:325-342.

118 Pulmonary Pathology CTTR I 17"' Cancer Seminar Discussion: Lung Metastases in General Despite the frequency of primary lung carcinoma, metastases represent the most common neoplasm encountered in the lung. Metastases to the lung are encountered in up to 54% of solid malignancies and in up to 25% of the cases the lung is the sole site of metastasis. The most common extrapulmonary tumorS metastatic to the lung are (in order of frequency): breast, colon, stomach, pancreas, kidney, melanoma, prostate, liver; thyroid, adrenal, male genital, female genital.

The symptomatology of metastases to the lung is varied and depends on the structure(s) involved and the pattern of spread (see below). Ali appreciable percentage of patients are asymptomatic and discovered to have lesions radiologically.

Radiologic findings include single or multiple well-defined nodules (with or without cavitation), interstitial infiltrates (in lymphangitic carcinoma), atelectasis (with endobronchial lesions) and mixtures of these. The lower lobes are more frequently affected than the upper lung zones. PET scanning is usually positive but some inflammatory conditions may give false positive PET scans.

Grossly metastases tend to be peripheral and to be sharply defined. In general they have the sarne·macroscopic appearances that the tumors have in their primary site. ·

The gross and histologic patterns of metastases are quite varied and include: • Multiple nodules - most typical • Single nodules- 1-5% ofextrapulmonary malignancies have solitary metastases; 3-9% of solitary pulmonary nodules are metastases • Regarding nodule(s): • Distribution ofnodule(s): parenchymal, endobronchial, pleural, mixtures • Cavitation ofnodules may be present (approximately 4% ofmetastatic carcinomas; seen with tumors from head and neck, bladder, colon, breast) • Endobronchial metastases uncommon as a sole lesion (less than 5% of lung metastases; breast, colon, lcidney most often implicated) • Pleural metastases: esp. with carcinomas of the lung, stomach, breast, ovary • Lymphangitic spread within pulmonary lymphatics - seen in 6·-8% ofmetastatic carcinomas, particularly lung, breast, GI tract, pancreas; well visualized with HRCT • Interstitial growth- true interstitial growth (as opposed to 1ymphangitic spread) is rare but recognized; especially associated with metastatic sarcomas (which may produce a pseudobiphasic appearance) • Intravascular/embolic metastases- seen in l 0-26% of autopsies in patients with extrapulmonary malignancies: Usually an incidental fmding at autopsy May involve small or larger arteries; may have thrombotic microangiopathy and/or acute or chronic pulmonary hypertension

CTIR I 17'" Cancer Seminar Pulmonary Pathology 119 • Intra-alveolar spread ("tumoral pneumonia") - unusual pattern.; may show simply airspace filling or true lepidic growth ( 15% of colon metastases said to show the latter pattern) • Mixtures/combinations of these patterns • Cystic change (secondary to interstitial growth) mimicking cystic lung disease; seen with metastatic low grade sarcomas (including BML)

The differential diagnosis of primary lung carcinoma vs. metastasis is usually solved by knowledge of the clinical setting and radiologic findings (input from the radiologist is very helpful here), assessment of the routine histology (most lung carcinomas look like lung carcinoma!), and comparison of the tumors at the two sites (if possible/available). Histochemistry and imrnunohistochemistristry may be helpful but they should not replace comparison of tumors if slides of the original cancer can be obtained.

The most common scenarios are: 1. Metastasis vs. new lung primary in a patient with a history of breast carcinoma. (Note: Patients who have received radiotherapy for breast cancer and who are smokers may have an increased risk to develop lung cancer). • Most breast carciuomas are histologically different from lung carcinoma. • Breast carcinomas may be positive for Brst-2 antigen, ER, iPR, and S-100; often CEA negative. • Lung carcinoma is often positive for TTF-1, may be CEA positive, and usually negative for Brst-2 antigen, ERIPR, and S-1 00. (Note: Some recent studies (see Dabbs et al.) have suggested ER may be positive in some lung adenocarcinomas.) 2. Now lung carcinoma vs. metastasis in a patient with a history of colon carcinoma. • Routine histology very helpful - colon carcinoma is distinctive and usually recognizably different than carcinoma of the lung - tends to have "dirty necrosis" and to lack lepidic growth; frequently CDX2 p·ositive and tend to be cytokeratin 20 positive and cytokeratin 7 negative. • Lung carcinoma is often positive for TTF-1 and frequently positive for cytokeratin 7; variable cytokeratin 20 immunoreactivity. 3. Other metastases a. Renal cell carcinoma-distinctive histology and tends to stain weakly for AEI/AE3 and cytokeratin 7 and to show strong vimentin immunoreactivity. b. Ovarian carcinomas usually express CA-125, N-Cadherin, vimentin, estrogen receptor, and/or inhibin and are usually CEA negative. c. Thyroid carcinoma may be TTF-1 positive but also frequently shows thyroglobulin reactivity.

While immupohistochemistry is considered invaluable, the. findings in routine histology are very helpful. Lung carcinomas, particularly adenocarcinomas, tend to show considerable heterogeneity with variable differentiation from field to field. The presence of foci of atypical

120 Pulmonary. Pathology CTTR 117" Cancer Seminar adenomatous.hyperplasia and non-mucinous bronchioloalveolar carcinoma adjacent to invasive foci are also very helpful clues to primary carcinoma of the lung.

References Aubry MC. Myers JL, Colby TV, Leslie KO, Tazelaar HD. Endometrial stromal sarcoma metastatic to the lung. Am J Surg Pathol2002;26:440-449. Barbareschi M, Murer B, Colby TV, Chilosi M, Macri E, Loda M, Doglioni C. CDX-2 homeobox gene expression is a reliable marker of colorectal adenocarcinoma metastases to the lungs. Am J Surg Pathol 2003;27: 141-149. Colby TV, Koss MN, Travis WD. Tumors ofthe lower respiratory tract. AFIP Atlas ofTumor Pathology, 3"' series, Washington, DC 1995. . Corrin B. Pathology of the Lungs. Churchill Livingston, New York, 2000, pp. 574-584. Bejarano PA, Baughman RP, Biddinger PW, Miller MA, Fenoglio-Preiser C, AI-Kafaji B, Di Lauro R, Whitsett JA. Surfactant proteins and thyroid tr.mscription factor-! in pulmonary and breast carcinomas. Mod Pathol 1995;9:445-452. . Bocklage T, Leslie K, Yousem S, Colby T. Extracutaneous angiosarcomas metastatic to the lungs: clinical and pathologic features of twenty-one cases. Mod Pathol 2001; 14:1216-1225. Dabbs DJ, Landreneau RJ, Liu Y, Raab SS, Maley RH, Tung MY, Silverman JF. Detection ofestrogen receptor by immunohistocbemistry in pulmonary adenocarcinoma. Ann Thorac Surg 2002;73:405-405. Deutsch M, Land SR, Begovic M, Wieand HS, Wolmark "N, Fisher B. The incidence oflung carcinoma after surgery for breast carcinoma with and without postoperative radiotherapy. Results of National Surgical Adjuvant Breast Cancer 2003;98: 1362-1368. Flint A, Lloyd RV. Pulmonary metastases of colonic carcinoma. Distinction from pulmonary adenocarcinoma. Arch Pathol Lab Med 1992; 116:39-42. Ford MB, Sigurdson AJ, Petrulis BS, Ng CS, Kemp B, Cooksley C, McNeese M, Selwyn BJ, Spitz MR, Bondy ML. Effects ofsmoking and radiotherapy on lung carcinoma in.breasrcarcinoma survivors. Cancer 2003;98:1457- 1464. Ghoneim AHA, Brisson ML, Fuks A, Mobasher AAMT, Kreisman H. Monoclonal anti·CEA antibodies in the discrimination between primary pulmonary adenocarcinoma and colon carcine>ma metastatic to the lung. Mod Pathol1990;3:613·620. Hasegawa S, lnui K, Karnakari K, Kotoura Y, Suzuki K, an dFukumoto M. Pulmonary cysts as the sole metastatic manifestation ofsoft tissue sarcoma. Chest 1999; 116:263-265. Heitmiller.RF; Marasco WJ, Hruban RH, Marsb BR. Endobronchial metastasis. J Thorac Cardiovasc Surg 1993;106:537-542. Pfannschrnidt J, Muley T, Hoffinann H, Dienernann H. Prognostic factors and survival after complete resection of pulmonary metastases fi-om coloreetal carcinoma: experiences in 167 patients. J Thorac Cardiovasc Surg 2003;126:732-739. Raab SS, Berg LC, Swanson PE, Wick MR. Adenocarcinoma in the lung in patients with breast cancer. A prospective analysis ofthe discriminatory value ofimmunohistology. Am J Clio Pathol 19.93; 100:27-35. Roberts KE, Harnele-Bena D, Saqi A, Stein CA, Cole RP. Pulmonary tumor embolism: a review ofthe literature. Am J Med 2003; 11 5:228-232. Saynajakangas 0, Maiche AG, Liakka KA- Multiple progressive pulmonary leiomyomatous metastases treated with tarnoxifen - a case report with a review of the literature. Acta Oncoi2004;43(J): 113-4. Savera AT, Torres FX, Linde!! MD, Bacchi'CE, Gown AM, Zarbo RJ. Primary versus metastatic pulmonary adenocarcinoma. An immunohistochemical study using Villin and cytokeratins 7 and 20. Appl lmmunobistochem 1996;4:86-94. Suster S, Moran CA. Unusual manifestations ofmetastatic .tumors to the lungs. Seminars in Diagnostic Pathology 1995; 12:193-206. Travis WD,'Brarnbilla E, Harris CC, Muller-Hermelink HK. WH9 chissification of tumors, pathology and genetics. Tumor ofthe lung, pleura, thymus, and heart, !ARC, Lyon (In press for 2004). Traweek ST, Rotter AJ, Swartz W, Azurni N. Cystic pulmonary metastatic sarcoma. Cancer 1990;65: 1805-1811. Werling RW, Yaziji H, Bacchi CE, Gown AM. CDX2, a highly sensitive and specific marker ofadenocarcinoma of intestinal origin: an immunohistochemical survey of 476 primary and metastatic carcinomas. Am J Surg·Pathol 2003;27:303-31 0.

CITR 117'" Cancer Seminar Pulmonary Pathology 121 ... . Figure 15A-2. Beoigo IIJOI3SiaSizing leiomyoma. Detuil of the spindle cells typical lci<>myorna. 11tis case is considernbly mon: ofs mooth muscle cells. Smooth muscle ccllultt.r lhun 15A an

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Figure I SB-2. 13enign mctastasirjng Figure ISB-3. llcnign mctaslasizing figure 1511-4. Benign mcUIStaSiJj ng leiomyoma. Detail ol'the proliferation shows leiomyoma. The neoplastic cells show .).1rong leiomyoma. The neoplastic cells show only incn:ased celluJwi1y and an occasional mitotic positivity for proacsterooereceplor. weol: scaucrcd positivity for estrogen n:ccptc figun:. On cytologic grounds one could not exclude the possibility or metastatic low· grudc leiomyosarcoma.

Aonio,dar,onc pulmonary toxicity. figure pulmonary Figure 16-3. 1\miodarunc pulmonary toxicit) Scanning power shows nodulc!

CITR 11 7'" Cancer Seminar Pulmonary Pathology 123 XI. Drug Reactions

CASE 16

Clinical History (CTTR Ace.# 29888): • A 72-year-old woman presented with shortness of breath and was found to have multiple nodular infiltrates radiologically. She had a history of arniodarone therapy for atrial arrhythmias. Several of the nodular lesions were removed for histologic diagnosis.

Key histologic features: Despite the lower power suggestion of a necrotizing granulomatous process, higher power confirms the absence of true granulomas and an absence of giant cells. The necrosis appears to be the result of degeneration of histiocytes and ·accumulations of neutrophils. Surrounding lung tissue sliows changes typical of arniodarone toxiCity.

Diagnosis: Nodular necrotizing histiocytic .infiltrates with associated alveolar injury consistent with amiodarone toxicity.

Follow-up: All special stains were negative. All cultures Iemaitied negative. The arniodarone was stopped. Her pulmonary infiltrates were gradually clearing ten weeks following biopsy while she was in a pulmonary rehabilitatiQn hospital.

Discussion: Overview

From a practical point of view, the histologic diagnosis in this case should include: I) infection, 2) a noninfectious necrotizing process, and 3) unusual necrotizing process. The infection differential· would include the usual causes of necrotizing (granulomatous) infection, including mycobacteria, fungi, and (in this case) unusual organisms such as actinomycosis, Burkholderia ' cepacia, tularemia, etc. Noninfectious granulomatoses (especially Wegener's granulomatosis), and unusual necrotizing processes such as Sweet's syndrome and inflammatory bowel-related pulmonary disease would then be considered. While clinically and radiologically a neoplasm was considered, this was readily excluded histologically. Pulmonary nodules associated with drug reactions are unusual but well described, especially with Bleomycin, but also with amiodarone.

Discussion: Drug Reactions

Drugs may have a variety of effects on the lung that may be direct or indirect.

Direct effects of drug in the lung may be separated into toxic and idiosyncratic reactions.

Indirect effects include complications such as thromboembolic disease, CNS depression and aspiration, drug-induced immunosuppression and secondary infection. At high levels, some drugs become direct toxins.

CTTR 117m Cancer Seminar Pulmonary Pathology 125 Regarding pulmonary drug reactions: One drug may be associated with multiple clinical or pathologic patterns of disease. A given clinical or pathologic pattern of disease may be caused by multiple drugs (i.e. the lung has a limited number of response patterns to injury). Most (but not all!) pulmonary drug reactions stop when the drug i:S stopped. A drug reaction may manifest years after a drug has been stopped (e.g. BCNU­ associated pulmonary fibrosis). Cofactors may enhance drug effects such as chemotherapeutic agents, increased age, prior radiotherapy, elevated oxygen tension. Drug reactions may present acutely in patient who have been on a. drug chronically. Some peculiarities are noted with drug reactions such as presentation as localized infiltrates or nodular disease. Relatively few drug reactions come to biopsy and the pathologist's perspective is biased. The clinical frequency of drug reactions is increasing.

The clinical svndromes associated with pulmonary drug reactions run almost the entire gamut of lung disease. Pathologic patterns of drug reactions include:

• Chronic interstitial pneumonias • Diffuse alveolar damage • Bronchiolitis obliterans organizing p~eumonia (BOOP pattern) • Bronchiolitis obliterans (constrictive bronchiolitis with airflow obstruction) • Eosinophilic infiltrations • Pulmonary edema • Pulmonary hemorrhage • Pulmonary hypertension • Pulmonary veno-occlusive disease • Granulomatous inflammation • Histiocytic nodules(+/- necrosis) as in the case presented

The pathologist's approach to a drug reaction (for those that come to biopsy) is to define the pattern present and then try to determine if that pattern (or. patterns) has been associated with the drug(s) implicated in a given cas.e. In clinical practice, a putative diagnosis of a drug reaction is often made on the basis of BAL findings: increased lymphocytes with suppressor phenotype in the absence of infection or other cause of pulmonary.

Most importantly, a drug reaction is a diagnosis of exclusion, primarily· of infection.

References Camus PH. Foucher P; Bonniaud PH, Ask K. Drug-induced infiltrative lung disea.,e. Eur Respir J Suppl. 200 I Sep; 32:93s-1 00s. Churg A, Green FH. Miscellaneous conditions: pulmonary lesions associated with intravenous dru~ abuse and iatrogenic conditions. In: Churg A, Green FJ, eds. Pathology of occupational lung disease, 2" ed. Baltimore: William & Wilkens; 1998;451-460.

126 Pu/mon01y Patliology CTTR lt?'b Cancer Seminar Colby TV, Carrington CB. Interstitial lung disease. In: ThurlbeckWM, Churg AC, eds. Pathology ofthe lung, .z•• ed. New York: Thieme;l995:589-737. Cooper JA Jr, White DA, Matthay RA. Drug-induced pulmonary disease. Part 1: Cytologic drugs. Am Rev Respir Dis 1'986;133:321-340. trey NS. Tissue reactions·to drugs. Am J Patholl976;82:614-647. Kreisman H, Wolkove N. Pulmonary toxicity of antineoplastic therapy. Semin Oncoll992; 19:508-520. Martin WJ U. Drug-induced lung disease. In: Baughman RP, ed. Bronchoa:tveolar lavage. St. Louis:Mosby Year Book; 1992;193-211. Myers JL. Pathology ofdrug-induced lung disease.. In: Katzenstein AL, ed. Katzenstein and Askin's surgical pathology of non-neoplastic disease, 3"' ed. Philadelphia: WB Sanders; 1997;81-111. O'Driscoll BR, Hasleton PS, Taylro PM, Poulter LW, Gattameneni RR, Woodcock AA. Active lung fibrosis up to 17 years after chemotherapy with carmustine (BCNU) in childhood. N Eng! J Med 1990;323:378-382. Rosenow EC, Myers JL, Swensen SJ, Pisani RJ. Drug-induced pulmonary disease: an update. Chest 1992; 102:239· 250. Travis WD, Colby TV, Koss MN, Rosado-de-Christiansen M, Muller N, King TE. Noninfectious disorders of the lower respiratory·tract. AFIP Atlas of Tumor Pathology, Volume 2. Waihington, DC, 2002. Zitnik RJ, Matthay RA. Drug-induced lung disease. In: Schwan Ml, King TE Jr, ·eds. Interstitial lung disease, 3"' ed. Hamilton: BC Decker; 1998:423-450.

Discussion: Amiodarone Pulmonary Toxicitv

Amiodarone toxicity has become well known in the last two decades. Amiodarone is a relatively common drug used in the treatment of arrhythmias, and in some patients it is the only effective drug. Amiodarone toxicity affects 2% or less of patients receiving the drug, although the incidence varies from 0-6)% depending on the study. Mortality has been estimated at 1-33% in various studies. Currently it is estimated that 5-l 0% of patients who develop amiodarone pulmonary toxicity will die of the disease. The onset of the disease is rarely before two months of therapy and can occur in patients receiving 200 mg per day. As a rule of thumb, amiodarone toxicity is unusual in patients on 400 mg per day who have had it for less than four months and unusual in patients on 200 mg p.er day unless they have had it for two years or more. Exceptions occur. The drug bas a long half life and it may take weeks for the drug to be completely cleared from the system. Advanced age and pre-existing pulmonary dysfunction may be cofactors in the development of amiodarone toxicity.

Amiodarone-associated liver disease, thyroid dysfunction, and toxicity to a number of other organ systems are described.

Clinically patients with amiodarone toxicity present with pulmonary disease that may be acute, subacute, or chronic in onset. Acute fulminant respiratory failure has been noted in patients on amiodarone who have undergone surgery. The patients develop cough, dyspnea, weight loss, and occasionally fever. Localized infiltrates may be present, as initially present in the case presented. Radiologic abnormalities may even be apparent in patients on amiodarone who are asymptomati~. There are some cases with an acute fulminant. presentation mimicking an infectious pneumonitis. The clinical differential obviously includes congestive heart failure and pulmonary embolism, given the history of cardiac diseas.e in most of these·patients.

CTTR ll7oh Cancer Seminar Pulmonary Pathology 127 Radiologically there may be localized or diffuse bilateral inftltrates. Nodular lesions have been described in many reports but necrotizing lesions are unusual. On CT scan the infiltrates may have higher attenuation due to the presence of the iodinated compound that is part of amiodarone.

The histologic oattems vary from acute diffuse alveolar damage to organizing diffuse alveolar damage, to a pattern resembling BOOP, to a pattern resembling a more chronic interstitial pneumonia with interstitial fibrosis. Some cases have foci resembling eosinophilic pneumonia. Extensive honeycomb change and features similar to usual interstitial pneumonia are generally not encountered. Necrosis, as in the case presented, is Wlusual. The most distinctive feature histologically is the presence of foam cell change in alveolar macrophages and type n cells. There may be some associated pigment due either to hemosiderin (from the cardiac disease). or the tan-brown flecks of material common in cigarette smokers. The foam cell change may be relatively subtle unless it is looked for. In some cases it is dramatic and resembles a phospholipidosis (which it in fact is).

Bronchoalveolar lavage shows similar accumulations of foamy macrophages and a presumptive diagnosis of amiodarone effect can be made on the basis of lavage alone (in the appropriate clinical setting). Bronchoalveolar lavage studies also may show increase in lymphocytes showing suppressor phenotype which is similar to hypersensitivity pneumonitis due to other drugs or following inhalation of organic dust. In one BAL study (Akoun), two patterns were identified: in one there was no abnormal lymphocytosis and only an increase in foamy macrophages. In the other, the features were those of a lymphocytic alveolitis with suppressor- type lymphocytes. ·

The ultrastmctural frndings in amiodarone toxicity include the presence of membrane boWld lamellar inclusions that represent the accumulated phospholipids from the long term amiodarone therapy. The ultrastmctural findings of lameltated lysosomal bodies is consistent with the appearance noted in other phospholipidoses. In contrast to lamellar bodies of normal type n cells, the inclusions in patients receiving amiodarone are larger and less Wliform in size and have layers of lipid material more closely stacked together.

The initiation of amiodarone pulmonary toxicitv is thought to include the direct effects of the drug-induced phospholipidosis, altered calcium ion regulation, generation of reactive oxygen species, formation of an amiodarone aryl radical, and pertubation of cellular energy production (Massey, et at.). Thus, the pathophysiology of arniodarone toxicity is complex and no one factor can always be implicated. In fact, there may be different factors in different cases. In summary, there appear to be both direct toxic effect of the drugs (or its metabolites) as well as indirect effects of inflammatory or immunologic origin.

The diagnosis of amiodarone pulmonarv toxicjtv is one of exclusion, primarily of infection and congestive heart failure due to concurrent cardiac disease. The diagnosis of amiodarone effect can be made on the basis of finding increased numbers of foamy macrophages in bronchoalveolar lavage and biopsy material. A diagnosis of arniodarone toxicity is ultimately made by the clinician based on exclusion ofother possible causes.

128 Pulmonary Pathology CTTR 117"' Cancer Seminar References Akoun OM, Cadranel JL, Blanchette 0 , Milleron BJ, Mayuaud CM. Broncboalveolar lavage cell daUI in amiodarooe-associated pneumonitis. Evaluation in 22 patients. Chest 1991;99:1 177-1182. Amon R, Raz I, Chajek-shaul T, Berkman N, Fields S, Bar-On H. Amiodarone pulmonary toxicity presenting as a solitary lung mass. Chest 1988;93:425-427. Bedrossian CWM, Warren CJ, Ohar J, Bhan R. Ami.odarone pulmonary toxicity: cytopathology, ultrastructure, and immunocytochemistry. Ann Diagn Pathol 1997; I :47·56. Coudcrt B, Bailly F, Lombard JN, Andre F, Camus P. Amiodarone pneumonitis. Bronchoalveolar lavage findings in 15 patients and review ofthe literature. Chest 1992;102:1005-1012. Dean PJ, Oroshart KD, Porterfield JO, lansmith DH, Golden EB. Amiodarone-associatcd pulmonary toxicity. A clinical and pathologic study of eleven cases. Am J Clin Pathol 1987;87:7-13. Drug and Therapeutics Bulletin. Using oral amiodarone safely. 2003;4 I :9-14. Jessurun GAJ, Boersma WG, Crigns HJO. Amiodarone-induced pulmonary toxicity. Drug Safety 1998; 18:339· 344. Kennedy Jl, Myers JL, Plumb VJ, Fulmer JD. Amiodarone pulmonary toxicity. Clinical, radiologic, and pathologic correlations. Arch Intern Mcd 1987;147:50-55. Kennedy JJ. Clinical aspects of amiodarone pulmonary toxicity. Clinics in Chest Medicine 1990; II: 119· I 29. Malhotra A, Muse VV, Mark EJ. Cn.~e 12-2003: An 82-year-old man with dyspnea andpulrnonnry abnormalities. N Engl J Med 2003;348: 1574-1585. Martin \VJ, Osborn MJ, Douglas WW. Amiodarone pulmonary toxicity. Assessment by bronchoolveolar lavage. Chest 1988;88:630-631. Martin \VJ, Rosenow EC. Amiodarone pulmonary toxicity. Recognition and Pathologeoesis (POrt I). Chest 1988;93: I 067-I 079. Martin \Vj, Rosenow EC. Amiodarone pulmonary toxicity. Recognition and Pathologenesis (POrt 2). Chest 1988;93: 1242· I 248. Mossey TE, Leeder RG, Rafciro E, Brien JF. Mechanisms in the pathogenesis of amiodarone-induced pulmonary toxicity. Canandion Journal ofPhysiology & Pharmacology 1995;73:1675-1685. Myers JL, Kennedy Jl, Plwnb VJ. Amiodarone lung: pathologic findings in clinically toxic patients. Hum Pathol 1987; 18:349-354. Ott MC, Khoor AN, Leventhal JP, Patorick TE, Burger CD. Pulmonary toxicity in patients receiving low-dose amiodarooe. Chest 2003; 123:646-651. Pollak PT, Sami M. Acute necrotizing pneumonitis and hyperglycemia after arniodarone therapy. Am J Med 1984;76:935-939. Standertskjold-Nordenswn CO, Wandtke JC, Hood WB, Zugibe FT, Butler L. Arniodarone pulmonary toxicity. Chest radiography and CT in asymptomatic patients. Chest 1985;88:143-145. Sunderji R, Kanji Z, Gin K. Pulmonary effects of low dose amiodarone: a review of the risks and recommendations for surveillance. Can J Cardiol 2000;16:1435-1440. Van Mieghem W, Coolen L, Malysse I, Lacquet LM, Deneffe GJD, Demedts MOP. Amiodarone and the development ofARDS after lung surgery. Chest 1994; 105:1642-1645. Wood DL, Osborn MJ, Rooke J, Holmes DR. Amiodarone pulmonary toxicity: report of two cases associated with rapidly progressive fatal adult respiratory distress syndrome aller pulmonary angiography. Mayo Clio Proc 1985;60:60 1-603.

CTTR I 17" Cancer Seminar Pulmonary Pathology 129 California Tumor Tissue Registry

Departm.ent Qf Pathology U021 Campus Avenue , AH 33S Lwna Lind~ California 92350

Vuic.~ (969) 553-4788 Fb (969) 558-0188

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CTTR 117"' Cancer Seminar Pulmonary Pathology 131