Extracutaneous Angiosarcomas Metastatic to the Lungs: Clinical and Pathologic Features of Twenty-One Cases T

Extracutaneous Angiosarcomas Metastatic to the Lungs: Clinical and Pathologic Features of Twenty-One Cases T. Bocklage, M.D., K. Leslie, M.D., S. Yousem, M.D., T. Colby, M.D. Department of Pathology, University of New Mexico School of Medicine (TB), Albuquerque, New Mexico; Department of Pathology, University of Pittsburgh School of Medicine (SY), Pittsburgh, Pennsylvania; and Department of Pathology, Mayo Clinic Scottsdale (KL, TC), Scottsdale, Arizona

tic impression of non-neoplastic pericarditis. Thus, Angiosarcomas are rare malignant vascular tumors angiosarcoma in the lung may elude diagnosis until with a high rate of metastasis involving lungs (most histopathologic evaluation of the lung biopsy. commonly), liver, regional lymph nodes, bone, and other sites. In this study, we have reviewed the clin- KEY WORDS: Angiosarcoma, CD31, Lungs, Meta- ical presentation and histopathology of 21 cases of static, Pulmonary, Vascular tumors. extracutaneous angiosarcoma metastatic to the Mod Pathol 2001;14(12):1216–1225 lungs. Tumors with exclusively pleural involvement were excluded. Patients presented with dyspnea, This study of noncutaneous angiosarcomas meta- chest pain, and/or hemoptysis lasting a few weeks to static to the lungs was performed to determine the months. Radiologically, the most common finding most common site of origin (where this knowledge comprised multiple peripheral lung nodules (57%), was available), the range of clinical presentations, often accompanied by infiltrates. For 11 cases and the histologic differential diagnosis that would (52%), the primary tumor was not identified at the occur based on the appearance of the pulmonary time of presentation. Vasoformative areas were lesions. Primary angiosarcomas exhibit a variety of identified in 15 cases (71%). Nine cases comprised histologic appearances that may mimic carcinoma, spindle cells (43%), two contained epithelioid cells other sarcomas, melanoma, and even benign reac- (9.5%), and 10 consisted of both spindle and epithe- tive processes (1). Metastatic lesions in the lungs lioid cells (48%). Nuclear pleomorphism was at least may assume growth patterns that might provoke moderate in all cases. However, five tumors con- strong consideration of other diagnoses (2). Be- tained regions of minimal nuclear atypia. Hemor- cause the tumor is relatively rare, only a few series rhage, siderophages, and fibrosis were commonly of angiosarcomas metastatic to the lungs have been present. Immunohistochemical staining (IHS) was published, the largest comprising 15 patients performed on 14 cases. Thirteen tumors showed treated at the Mayo Clinic from 1950 to 1990 (3). For reactivity for vascular markers. Tumor cells reacted this study, cases were collected from consultation for Von Willebrand factor in 13 of 14 cases, and practice files. Noncutaneous angiosarcomas were CD31 and CD34 were each positive in 2/2 cases. Two specifically selected to further define patient demo- cases (of nine examined) also expressed cytokera- graphics and primary site of metastatic angiosar- tins. Because the tumor often first presented in the coma not derived from the skin. lungs before the primary sarcoma was identified, the clinical impression included both benign and malignant entities. For patients with primary car- MATERIALS AND METHODS diac tumors, symptoms referable to the primary tumor complicated the clinical presentation, and The consultative files of the authors were searched radiologic evaluation supported a clinical diagnos- for cases of angiosarcoma in the lungs seen between 1989 and 1997. Cases with a known primary tumor in the skin or that comprised entirely pleural-based, Copyright © 2001 by The United States and Canadian Academy of metastatic lesions were excluded. Twenty-one cases Pathology, Inc. VOL. 14, NO. 12, P. 1216, 2001 Printed in the U.S.A. had hematoxylin and eosin–stained tissue sections Date of acceptance: August 8, 2001. available for review. The specimens comprised 18 Address reprint requests to: T. Bocklage, M.D., UNM School of Medicine, Department of Pathology, BMSB 3rd Floor, 915 Camino de Salud NE, open lung biopsies, two lobectomies, and one com- Albuquerque, NM 87131. bination open lung biopsy and autopsy sampling of

1216 involved lung. Two to 55 slides were examined by the 16 patients: 15 patients succumbed to their disease authors (average of 3.6 slides per case). In 10 more with an average time of survival of 39 weeks after recent cases, representative sections of tumor were lung biopsy (range 2–206 weeks). The surviving pa- evaluated by means of immunohistochemical stain- tient had widespread metastases 38 months after ing (IHS). Formalin-fixed, paraffin-embedded tissue presentation. Survival for the 10 patients with a sections were deparaffinized in xylene, subjected to a known primary (three patients lost to follow-up) series of graded alcohols for rehydration, and then ranged from two weeks to 206 weeks, with an aver- placed on a DAKO Autostainer automated stainer age of 46 weeks. Survival for the 11 patients with no (DAKO, Carpenteria, CA) using the following antibod- known primary (three patients lost to follow-up) ies: von Willebrand factor (DAKO), CD31 (Qbend10, ranged from four weeks to 64 weeks, with an aver- DAKO), CD34 (DAKO), AE1/AE3 cytokeratins (DAKO), age of 19 weeks. Two-year crude survival percent- and S-100 protein (DAKO). Tissues were pretreated ages for those with known primary was 28% (seven with steam heating in citrate buffer for enhanced cases) and for those with no known primary, it was antigenicity. Four cases received in consultation were 0% (eight cases). accompanied by immunohistochemical stains per- Presenting symptoms were obtained for 13 pa- formed at the outside institution. These IHS slides tients. Of these, nine presented with hemoptysis were reviewed, and positive internal controls were with or without dyspnea, fever, and/or chest pain. present to assess for adequate reactivity of vascular After hemoptysis, dyspnea was the most common and epithelial antibodies. patient symptom, (7/9) followed by chest pain and fatigue (2/9 each). One 33-year-old man with dif- RESULTS fuse bilateral infiltrates also presented with fever. Radiologic findings most commonly consisted of The patient demographics, presenting signs and nodules or nodular infiltrates (12/18), which were symptoms, and treatment are summarized in Table usually bilateral. The second most common pulmo- 1. All patients were adults, comprising 17 men and nary pattern comprised bilateral infiltrates without three women (sex unknown in one case). Age nodularity (5/18 cases). All four patients with a ranged from 27 to 71 (n ϭ 20), with a median age of known pericardial angiosarcoma also exhibited a 47.8 years. Follow-up information was obtained for pericardial effusion radiologically (4/4). No pericar-

TABLE 1. Clinical Features of 21 Patients with Metastatic Angiosarcoma

Patient Case Presenting Symptoms Pulmonary Radiologic Findings Primary Tumor Outcome Age/Sex 1 33/M Dyspnea, hemoptysis, fever Infiltrates, diffuse bilateral Heart (right atrium) DOD at 2 weeks alveolar filling 2 45/M Hemoptysis Nodules, bilateral Heart DOD at 16 weeks 3 Unknown Unknown Heart (right atrium) DOD 4 28/M Hemoptysis Nodules, left lung Heart (right atrium) DOD at 24 weeks 5 35/M Dyspnea, chest pain Nodular infiltrates, bilateral, left Pericardium DOD at 4 weeks pleural effusion [also pericardial effusion] 6 35/F Dyspnea [Pericardial effusion]; 6 months Pericardium DOD at 206 weeks later, nodules, bilateral 7 45/M Unknown Nodules, bilateral, pleural Pericardium DOD at 24 weeks effusion [also pericardial effusion] 8 48/M Dyspnea, hemoptysis, [Pericardial effusion]; 2 months Pericardium LTFU chest pain later, nodules, bilateral and infiltrates, alveolar 9 68/M Unknown Infiltrates, bilateral Unknown DOD at 8 weeks 10 78/M Hemoptysis Unknown No known primary at Dx DOD at 4 weeks 11 38/M Dyspnea, fatigue, cough Infiltrates, bilateral No known primary at Dx DOD at 4 weeks 12 27/F Dyspnea, fatigue Infiltrates, bilateral No known primary at Dx DOD at 53 weeks 13 31/M Hemoptysis Nodular infiltrates, bilateral No known primary at Dx DOD at 64 weeks 14 43/M Unknown Nodular infiltrates, bilateral No known primary at Dx LTFU 15 71/M Unknown Nodules, bilateral No known primary at Dx DOD at 8 weeks 16 45/M Dyspnea, hemoptysis Infiltrates, diffuse interstitial, No known primary at Dx DOD at 7 weeks with a ground-glass pattern 17 65/F Unknown Nodules, bilateral No known primary at Dx DOD at 4 weeks 18 71/M Hemoptysis Nodules, bilateral, and right No known primary at Dx LTFU pneumothorax 19 56/M Hemoptysis Infiltrates, bilateral alveolar No known primary at Dx LTFU 20 52/M Unknown Unknown Retroperitoneum AWD at 152 weeks 21 43/M Unknown Nodules, unilateral Mediastinum LTFU

Notations in brackets are nonpulmonary radiologic findings. Dx, diagnosis; DOD, dead of disease; LTFU, lost to follow-up; AWD, alive with disease.

Angiosarcomas Metastatic to Lungs (T. Bocklage et al.) 1217 dial effusion was identified in the four patients with a known cardiac parenchymal angiosarcoma (0/4). The primary histologic features and immunohistochemical staining results of the cases are presented in Table 2. In all cases, tumor foci were peripheral, multiple, and generally formed nodules. Peripheral lung septae or the subpleural intersti- tium were involved in all cases (Fig. 1). Tumor extended into surrounding pulmonary alveoli to varying degrees. Lymphangitic spread, when present, usually, but not exclusively, involved septal lymphatics and vessels (Fig. 4A). Circumferential growth around small vessels and bronchioles was noted in seven cases (32%; Fig. 4B). This growth FIGURE 1. Tumor is peripheral, nodular, and contains fresh pattern often resulted in tumor thrombi or bron- hemorrhage (Case 14). chiole obstruction when tumor penetrated through the walls of the structure. Vasoformative regions were identified in 15 cases (71%). These regions consisted of anastomosing channels lined by mildly a collagen vascular disease, interstitial pneumonia, ϭ to markedly atypical tumor cells. These channels sarcoidosis, and metastatic adenocarcinoma (n often contained red blood cells (Figs. 3, A–B, and 13). The initial pathologic interpretation included 5A). Solid growth occurred in 17 cases (77%; Fig. 2). the following benign entities: bronchiectasis with Fresh hemorrhage, clusters of siderophages, and healed pneumonia (three cases), idiopathic pulmo- extracellular hemosiderin deposition occurred both nary hemosiderosis (two cases), and eosinophilic within tumor nodules and in immediately adjacent granuloma (one case). Thus, 6 of the 19 cases (32%) lung parenchyma (Fig. 5B). for which an initial pathologic interpretation was Ten of the patients had a known primary tumor obtained consisted of benign entities. Malignant at the time of lung presentation (10/21, 48%); of entities favored on the initial pathologic interpreta- these, eight of the primary angiosarcomas were car- tion included angiosarcoma (six cases), high-grade diac/pericardial, one was retroperitoneal, and one adenocarcinoma (three cases), Kaposi’s sarcoma was mediastinal in location. Eleven patients had no (two cases), malignant fibrous histiocytoma (one known primary angiosarcoma at the time of pre- case), and epithelioid hemangioendothelioma (one sentation (11/21, 52%). Initial clinical diagnostic case). Six of the 19 cases (32%) were initially inter- impressions included pericarditis, vasculitis due to preted on microscopic review as angiosarcoma.

TABLE 2. Histologic and Immunohistochemical Features of 22 Cases of Angiosarcoma Metastatic to the Lungs

Vasoformative Nuclear Case Cell Type Immunohistochemical Staining Areas Grade 1 No Spindle 1 and 2 VonWFϩ 2 Yes Spindle 1 and 2 VonWF, CD31, CD34ϩ; KerϪ 3 Yes Spindle and epithelioid 1 and 2 N/P 4 Yes Spindle 2 VonWFϩ; KerϪ 5 No Spindle and epithelioid 2 and 3 N/P 6 Yes Spindle and epithelioid 3 VonWFϩ; KerϪ 7 No Spindle and epithelioid 2 and 3 VonWFϩ 8 No Spindle 2 N/P 9 Yes Spindle 2 VonWFϩ; KerϪ 10 No Spindle 2 VonWFϩ and ulex lectinϩ 11 Yes Epithelioid 3 VonWF, Cam5.2, and AE1/AE3 Ker, ϩ 12 Yes Spindle 2 VonWFϩ; KerϪ 13 Yes Spindle 2 VonWFϩ, KerϪ 14 Yes Spindle 1 and 2 N/P 15 Yes Spindle and epithelioid 3 VonWF, ulex lectin, and AE1/AE3 Ker, ϩ 16 No Spindle and epithelioid 2 N/P 17 Yes Spindle and epithelioid 2 VonWF, CD31, and CD34, ϩ; KerϪ 18 Yes Spindle and epithelioid 3 VonWFϪ, KerϪ Only Vimϩ 19 Yes Epithelioid 3 VonWFϩ 20 Yes Spindle and epithelioid 1 and 2 N/P 21 Yes Spindle and epithelioid 2 and 3 N/P Nuclear grade 1 ϭ uniform nuclei with minimal nuclear shape variation, inconspicuous nucleoli; nuclear grade 2 ϭ moderate variation in nuclear shape and size; Nuclear Grade 3 ϭ marked pleomorphism and/or vesicular nuclei with macronucleoli and/or irregular chromatin clumping. VonWF, Von Willebrand Factor; Ker, Keratin; N/P, not performed; AE1/AE3, AE1/AE3 keratins; VIM, vimentin.

1218 Modern Pathology incipient vessel development was rare (Fig. 6A). Although five cases disclosed areas of minimal nuclear atypia consisting of small, oval nuclei with mild nuclear hyperchromaticity, all cases had at least one focus of higher grade tumor comprising cells with moderate to severe nuclear pleomorphism (including multilobulation, marked hyperchromaticity, coarse chromatin, and irregular nuclear borders with sharp-angled notching). High grade epithelioid cells commonly contained large, vesicular nuclei with macronucleoli (Fig. 6B). Multinucleated tumor giant cells were identified in several cases. Mitotic figures were typically easy to

FIGURE 2. At low magnification, this angiosarcoma mimics invasive, find, and high-grade foci contained cells with atyp- poorly differentiated carcinoma eliciting a desmoplastic stromal ical division figures. response (Case 21). Immunohistochemically, of 14 cases evaluated, 13 exhibited reactivity for at least one vascular marker. Von Willebrand factor (Factor VIII–related antigen) was positive in 13 of 14 cases where it was used (93%), as were CD31 and CD34 in two of two cases. These cases comprise archival specimens; therefore, CD31 and CD34, recently recognized as

FIGURE 3. A, At low power, this metastatic angiosarcoma mimics a hypocellular scar as may occur after an episode of pneumonia (Case 16). B, At higher magnification, there is only mild atypia of the spindle- shaped tumor cells, some of which line vascular spaces (Case 16).

Cytologically, the tumor cells were either spindle or round to polygonal (epithelioid) in shape (Fig. 6, A–B). Ten cases contained a mix of spindled and epithelioid cells. Nine cases were exclusively composed of spindle cells, and two cases were composed of epithelioid cells only. The nuclear to cytoplasmic ratio ranged from generally low in FIGURE 4. A, Metastatic tumor plugs small parenchymal vessels and spindle cells to progressively higher for high-grade is associated with intra-alveolar hemorrhage (Case 2). B, In this pattern of growth, instead of intraluminal deposits of tumor, the epithelioid cells. The cytoplasm was lightly eosino- angiosarcarcoma expands circumferentially around medium-sized philic, and intracytoplasmic lumina consistent with blood vessels (Case 9).

Angiosarcomas Metastatic to Lungs (T. Bocklage et al.) 1219 FIGURE 6. A, Mildly atypical epithelioid tumor cells focally contain FIGURE 5. A, Hyperchromatic spindle tumor cells form very thin- incipient vascular lunina reminiscent of epithelioid walled channels (Case 14). B, In this case, the histologic differential hemangioendothelioma (Case 2). B, Epithelioid tumor cells exhibit included idiopathic pulmonary hemorrhage. Only at high magnification vesicular nuclei, prominent nucleoli, and mimic adenocarcinoma, can markedly atypical tumor cells be appreciated (Case 1). melanoma, and other epithelioid sarcomas (Case 15).

useful identifiers of vascular differentiation, were nocarcinoma (n ϭ 13). Although it is a rare tumor, not employed in most of the specimens. Two epi- extracutaneous angiosarcoma most commonly me- thelioid tumors showed strong cytoplasmic staining tastasizes to the lungs, and the metastasis rate is at for AE1/AE3 cytokeratins. However, the same cells least 50% (number of primary tumors, 266; number also reacted with antibodies to von Willebrand of cases with metastases, 136 [51.1%]; 1, 4–6). In factor. this study, the cases in which a primary tumor site was discovered consisted of the pericardium (four DISCUSSION cases), heart (four cases, right atrium location), and one each in the retroperitoneum and mediastinum. Discovering metastatic angiosarcoma in a lung Although this study consists of cases culled from biopsy is often the initial manifestation of the dis- a consultation practice, thereby possibly increasing ease and an unexpected finding in an appreciable the number of lesions for which there was no percentage of patients with occult extracutaneous known primary at the time of presentation, other angiosarcomas. Metastatic angiosarcoma is usually series have found a similar high rate of initial diag- not a clinical consideration at the time of presen- nosis occurring with the lung biopsy (3, 7). tation of these patients. The clinical impression Presenting symptoms in this patient group are includes benign entities, especially thromboem- similar to those reported in other series: hemopty- bolic disease and alveolar hemorrhage syndromes, sis, dyspnea, chest pain, or cough, although in one or malignancies such as metastatic adenocarci- study, weight loss was noted in 40% (6/15 cases; 3, noma. In the present study, the initial clinical im- 7, 8). In some instances, tumor metastases have pression also included pericarditis, vasculitis as a caused hemopneumothorax or diffuse alveolar complication of a collagen vascular disease, inter- hemorrage (8). In the present study, the pulmonary stitial pneumonia, sarcoidosis, and metastatic ade- symptoms culminated in the patients undergoing

1220 Modern Pathology lung biopsy. In 12 cases, interpretation of the bi- 15). In this series, four patients with pericardial opsy findings was made more challenging because effusions were at first thought to have nonneoplas- of the lack of a known diagnosis of primary tic disease, the workups of whom included two angiosarcoma. negative bloody pericardial fluid cytology exams, Radiologically, pulmonary metastases of angio- and two patients were initially treated with pred- sarcoma most often comprise bilateral, peripheral nisone for presumed pericarditis. nodules, a typical distribution pattern for meta- By the time that open lung biopsy is performed static tumors to the lungs (2). However, other find- and reveals metastatic angiosarcoma, the patients ings may include a miliary pattern of spread, diffuse have high-stage disease, and the prognosis is grave. alveolar filling, diffuse interstitial infiltrates with a In their series of 15 patients treated at the Mayo ground glass distribution, pneumothorax, pleural Clinic from 1950–1990, Patel and Ryu (3) recorded effusions, and solitary endobronchial mass (2, 7, 9). an average survival time of nine months after diag- In many instances, there is a combination of bilat- nosis of metastatic angiosarcoma. Adverse prog- eral nodules and another finding such as infiltrates nostic factors portending a more aggressive course which was the finding in our series (3). The radio- in angiosarcomas from all sites include larger size logic differential diagnosis may consist of infection, (five cm in one study), older patient age (seventh vs. metastatic tumor of unknown primary site, multi- fourth decade or younger), mitotic rate greater than ple pulmonary emboli, Wegener’s granulomatosis, or equal to 10 division figures per 10 high-power Goodpasture’s syndrome, and idiopathic pulmo- microscopic fields, Ki-67 reactivity of at least 10% in nary hemorrhage. tumor cells, and high histologic grade (1, 6, 16, 17). In the current series, the most common known DNA diploidy does not predict a benign course (5). primary site was the heart (including the pericardi- There are no histologic features of pulmonary um). Other series of angiosarcomas metastatic to metastases of angiosarcoma that provide clues to the lungs concur that the heart and pericardium are the site of origin. The majority of the metastases in the most common sites of origin, once cutaneous this series of patients exhibited a mixed pattern of angiosarcoma is excluded (7, 9). Angiosarcoma is growth such as solid and vasoformative, a phenom- one of the more common primary malignant tu- enon also observed in primary angiosarcomas aris- mors of the heart comprising up to one third of the ing from diverse sites (1, 6–9, 18). The cytologic cases (10). Nearly all cardiac angiosarcomas arise in findings of pure or mixed spindle and epithelioid the right atrium or interatrial septum (10, 11). Pa- cells are no different from those of the cellular tients are generally younger compared with individ- populations that compose primary angiosarcomas uals with angiosarcomas originating elsewhere; a arising throughout the body. study of 12 cardiac angiosarcomas found a mean Immunohistochemical antibody markers of endo- age of 38 years contrasted to a mean age in the 60s thelial differentiation can elucidate the nature of a for soft tissue angiosarcomas and of 63 years for vasoformative tumor and distinguish it from its his- angiosarcomas arising in the head and neck (n ϭ tologic mimics. Antibodies used to detect endothelial 32; 1, 4, 6). differentiation are directed against von Willebrand Presenting symptoms of cardiac/pericardial an- factor (Factor VIII–related antigen), CD31 glycopro- giosarcomas without lung involvement can be vir- tein, (platelet endothelium cell adhesion molecule, tually identical to those of patients with angiosar- PECAM-1) and CD 34 protein (human hematopoietic coma metastatic to the lungs. These symptoms progenitor cell antigen; 19–20). Ulex europeaus lectin include dyspnea, hemoptysis, chest pain, and mal- stains endothelial cells but also a variety of carcino- aise (10, 13–14). However, more localizing symp- mas, thus hampering its usefulness in distinguishing toms may also occur such as a friction rub, dimin- between vascular and epithelial neoplasms (21). Al- ished heart sounds, tamponade (if a pericardial though CD31 antibody labels a variety of hematopoi- effusion is present) and angina, arrhythmias, and etic cells (platelets, megakaryocytes, plasma cells), it heart block (if the tumor infiltrates the myocar- rarely stains epithelial tumors and mesotheliomas dium; 15). Unfortunately, cardiac/pericardial an- and then only in a cytoplasmic rather than the more giosarcomas are often not diagnosed until late in specific membranous pattern (19). CD34 antibody the disease course (14). Reasons for delayed diag- also decorates a number of cell types ranging from nosis of primary cardiac angiosarcoma encompass fibroblasts to smooth muscle cells, meningothelium, the rarity of the tumor compared with benign and adipocytes (19). causes of pericarditis and pericardial effusions, the Comparisons of the sensitivity and specificity of relative young age of the patients and thus low these IHS markers in staining angiosarcomas reveal clinical suspicion of malignancy, the presence of a that, in general, anti–von Willebrand factor and pericardial effusion that is often bloody but may be anti-CD31 are the most specific antibodies in de- negative for malignant cells by cytology, and the tecting a vasoformative phenotype (19–22). In less sometimes lack of specificity of the symptoms (14, differentiated areas, antibody to CD31 is more sen-

Angiosarcomas Metastatic to Lungs (T. Bocklage et al.) 1221 sitive than anti–von Willebrand factor (20, 22). are associated with extensive fibrosis and inflam- CD34 antibody is less reliable in decorating cells mation in the surrounding lung parenchyma, a fea- that line lymphatic channels and therefore may not ture unusual in metastatic angiosarcoma. Numer- be reactive in malignant sarcomas with lymphatic ous siderophages may be seen with both benign lining cell differentiation (23). A recent review of hemorrhage and metastatic angiosarcoma (7, 9). these markers comparing them to thrombomodulin Rarely, diffuse alveolar hemorrhage (DAH) may oc- in 50 vascular and lymphatic tumors and malfor- cur secondary to the angiosarcoma metastases (8, mations (including eight angiosarcomas) found 18). It is therefore prudent to carefully search for that thrombomodulin antibody more consistently evidence of tumor in a case that otherwise, at low stained lymphatics and was more sensitive than power, exhibits characteristics of DAH. CD31 in staining angiosarcomas (24). Diffuse pulmonary lymphangitic spread of carci- Angiosarcomas presenting in the lungs may be nomas is a pattern of metastasis that most com- misinterpreted as a variety of other tumors or as monly occurs with stomach, breast, and prostate benign processes. In the latter circumstance, this carcinomas; melanoma; and angiosarcoma (2, 7). may be compounded by the fact that alveolar hem- The presence of vasoformative areas and reactivity orrhage or pulmonary emboli is the leading clinical for one and often multiple endothelial markers dis- diagnostic consideration. There are four groups of tinguishes angiosarcoma from the other tumors lesions to include in the differential diagnosis: 1) with lymphangitic spread. Rarely, a carcinoma may thromboembolic disease, 2) alveolar hemorrhage diffusely embolize to small pulmonary arteries and syndromes, 3) benign vasoformative lesions (pul- arterioles, a condition known as carcinomatous ar- monary capillary hemangiomatosis and diffuse pul- teriopathy or pulmonary tumor thrombotic mi- monary lymphangiomatosis), and 4) malignancies croangiopathy. Patients may present with dyspnea associated with intravascular or perivascular and other signs of chronic pulmonary hyperten- growth or that produce pseudovascular spaces (see sion. This pattern of metastasis is rare and is usually Table 3). diagnosed at autopsy. Carcinomas most commonly In this study, the initial pathologic interpreta- associated with this arteriopathy are those from the tions included infarct multiple theromboemboli, stomach, pancreas, breast, liver, and placenta. His- idiopathic pulmonary hemosiderosis, bronchiecta- tologically, there is widespread thrombus forma- sis with healed pneumonia, eosinophilic granu- tion comprising a fibrocellular intimal proliferation; loma, and malignancies including high-grade ade- multiple tissue sections may be required to find the nocarcinoma, malignant fibrous histiocytoma, malignant epithelial cells. Sarcomatoid carcinomas epithelioid hemangioendothelioma, Kaposi’s sar- of the lung may histologically contain areas that coma, sarcoma not otherwise specified, angiosar- appear to form vascular channels (26). In the sev- coma intravascular lymphoma, and melanoma. eral cases reported, however, each pseudovascular Benign entities were considered because the carcinoma also contained foci of identifiable squa- metastatic foci disclosed one or more of the follow- mous cell carcinoma (26). Immunohistochemical ing features at low to intermediate power: a wedge- staining in pseudovascular areas reveals epithelial shaped, subpleural mass that was fibrotic and/or marker reactivity but no staining for endothelial hemorrhagic, an intra-alveolar proliferation of antigens in the tumor cells. It is conceivable that a spindle cells with fibrosis and inflammation, intra- sarcomatoid carcinoma with nearly complete ma- alveolar acute hemorrhage with siderophages, and lignant mesenchymal metaplasia could arise in the intravascular deposits of spindle cells and fibrin. At lung and be difficult to distinguish from metastatic high power, however, neovascularization formed by angiosarcoma; such tumors with endothelial differ- cytologically atypical cells, solid growth, intravascu- entiation have been tentatively described in the lar deposits containing atypical cells, or invasive thyroid gland but not in the lungs (21, 26). Undif- growth by atypical cells could be appreciated. The ferentiated carcinoma is usually more architectur- degree of cytologic atypia and/or invasive growth ally monotonous than metastatic angiosarcoma thus precluded diagnosis of a benign entity. In par- and by IHS will show reactivity for epithelial mark- ticular, the presence of malignant vessel formation ers rather than endothelial antigens. and the marked degree of cytologic atypia excluded Melanoma may resemble epithelioid angiosar- Kaposi’s sarcoma and epithelioid hemangioendo- coma and often contains a mixture of spindle and thelioma, whereas immunohistochemical staining epithelioid cells of moderate to high nuclear grade; results confirming the endothelial nature of the small biopsies of metastatic melanomas may be malignant cells excluded the other malignancies in amelanotic (27). However, a vasoformative pattern the differential. of growth has not been described, and the reactivity Organizing hemorrhage and hemorrhagic inflam- of melanoma to antibodies to S-100 protein, matory conditions in the lungs show more air space HMB45, and MelanA 103 protein is dissimilar to the organization and less nuclear pleomorphism and IHS profile of angiosarcoma.

1222 Modern Pathology TABLE 3. Differential Diagnosis of Metastatic Angiosarcoma

Entity in Differential Clinical Findings Radiology Histology Immunohistochemistry Diffuse alveolar Hemoptysis, anemia; Alveolar-filling densities Necrotizing alveolitis; IPH has Not routinely performed hemorrhage may have known intraalveolar acute or old (Serology may be positive for collagen vascular hemorrhage ANCA, AGBM, RF, C4 disease, GPS depending on etiology.) Multiple thromboemboli Asymptomatic; dyspnea Infarcts are often Edema and hemorrhage, Not routinely performed wedge shaped, in followed by necrosis, then lower lobes, organization peripheral Diffuse pulmonary Dyspnea, hemoptysis; Interstitial lung disease Proliferation of lymphatic Not routinely performed lymphangiomatosis patients are often with prominent channels in septae, pleura children; rare disease septal and and around bronchovascular bronchovascular bundles; thickening on CT no atypia Pulmonary capillary Dyspnea, pulmonary Increased bilateral Proliferation of capillary-sized Not routinely performed hemangiomatosis hypertension; patients interstitial markings vessels in alveolar walls, are often young with prominent vessels, and airways; pulmonary arteries benign cytology Pseudovascular Asymptomatic, dyspnea, Central or peripheral Pseudovasoformative areas Epithelial markers, ϩ sarcomatoid weight loss nodule, usually with areas of conventional Vascular markers, Ϫ carcinoma solitary adeno- or squamous cell carcinoma Carcinomatous Progressive dyspnea, Increased bilateral Extensive distal arterial tumor Epithelial markers, ϩ arteriopathy pulmonary interstitial markings emboli; multiple sections Vascular markers, Ϫ (pulmonary tumor hypertension, right with prominent sometimes needed to find thrombotic heart failure; may have pulmonary arteries tumor cells microangiopathy) known carcinoma elsewhere Metastatic melanoma Asymptomatic, dyspnea; Peripheral nodules Solid areas, septal growth, S-100, HMB45, MelanA, ϩ may have obvious atypical spindle and Vascular markers, Ϫ primary disease and epithelioid cells; melanin metastases elsewhere often absent Pulmonary artery Dyspnea, systolic May include embolic Mesenchymal differentiation Mesenchymal markers, variety ϩ sarcoma murmur, chest pain, mets to peripheral of various types Epithelial markers, Ϫ cough, hemoptysis; lungs3peripheral rare disease nodules Kaposi’s sarcoma Cough, dyspnea, fever, Bilateral alveolar, Hemorrhagic nodules along CD31, CD34 and vWF ϩ; hemoptysis; usually interstitial, nodular lymphatic routes and keratins, Ϫ disseminated disease is infiltrates; ϩ/Ϫ bronchovascular bundles; present; often patient pleural effusion; otherwise histology same has AIDS bronchial lesions as KS elsewhere common Epithelioid Dyspnea, cough, Multiple, bilateral Nodules with central VWF, CD31, CD34, hemangioendothelioma asymptomatic; most nodules; may show hyalinization or necrosis; thrombomodulin, ϩ; patients are women; central calcification cells usually mildy atypical, cytokeratins, usually Ϫ 50% Ͻ40 years ϩ/Ϫ cytoplasmic lumens Intravascular Dyspnea, fever; often Diffuse infiltrates Alveolar capillaries, arerioles B-cell markers, ϩ (only rare T- lymphomatosis have disease elsewhere and venules filled with cell cases); vascular markers, large, atypical, noncohesive Ϫ cells Metastatic angiosarcoma Dyspnea, hemoptysis Multiple peripheral Vasoformative and solid VWF, CD31, CD34, nodules ϩ/Ϫ areas, septal and ringing thrombomodulin, ϩ; infiltrates perivascular and bronchial Cytokeratins, EMA ϩ/Ϫ Actin, growth, atypical spindle ϩ if pericytes present and/or epithelioid cells IPH, idiopathic pulmonary hemosiderosis; ANCA, anti-neutrophil cytoplasmic antibody; AGBM, anti-glomerular basement membrane antibody; RF, rheumatoid factor; C4, complement 4; CT, CAT scan; ϩ, positive; Ϫϭnegative; KS, Kaposi’s sarcoma; VWF, Von Willebrand factor; ϩ/Ϫ, sometimes positive; EMA, epithelial membrane antigen.

Kaposi’s sarcoma differs from metastatic angio- formation, for example, so corresponding immuno- sarcoma in that it usually is not as nodular, does not histochemical results may reveal positivity for a show intravascular growth (growth is primarily greater array of antigens than are seen in angiosar- perivascular), and is not as cytologically atypical (9, comas (25, 28). Most commonly, pulmonary artery 25). Pulmonary artery sarcoma, with an incidence sarcoma is composed of fibroblastic or myofibro- one-fifth that of primary cardiac sarcomas, is ex- blastic malignant spindle cells; angiosarcomatous tremely rare and usually lacks the hemorrhage and differentiation is rare (28). necrosis of metastatic angiosarcoma (9). The histo- Epithelioid hemangioendothelioma (EHE, previ- logic appearance of pulmonary artery sarcoma var- ously termed intravascular bronchoalveolar tumor) ies and encompasses malignant bone and cartilage is a low-grade sclerosing angiosarcoma. It most

Angiosarcomas Metastatic to Lungs (T. Bocklage et al.) 1223 commonly occurs in women under the age of 40 ential. Open-lung biopsy is often required to make (25). Like high-grade metastatic angiosarcoma, EHE what is commonly an unsuspected diagnosis. often forms multiple bilateral nodules in the lungs. However, grossly the nodules are much less hem- Acknowledgments: The authors thank Ms. Heather orrhagic with a typical translucent, gray appearance Pratt, M.S., University of New Mexico, Department resembling hyaline cartilage. Microscopically, the of Pathology, Albuquerque, New Mexico, and Dr. I. epithelioid hemangioendothelioma is composed of Bos, University of Lubeck, Institute for Pathology, balls of cells embedded in a myxohyaline or myxo- Lubeck, Germany, for assistance in obtaining patient chondroid matrix. Tumor cells are cytologically follow-up information. bland in contrast to high-grade angiosarcomas, and they contain well-defined cytoplasmic vacuoles, a REFERENCES feature seen less uniformly in higher grade angiosarcomas (25, 29). A few EHE may exhibit greater 1. Meis-Kindblom JM, Kindblom L-G. Angiosarcoma of soft nuclear atypia and an unusually high mitotic rate; tissue: a study of 80 cases. Am J Surg Pathol 1998;22:683–97. 2. Suster S, Moran CA. Unusual manifestations of metastatic such cases may be difficult to distinguish from tumors to the lungs. Semin Diagn Pathol 1995;12:193–206. high-grade metastatic angiosarcoma (25). 3. Patel AM, Ryu JH. Angiosarcoma in the lung. Chest 1993;103: Intravascular lymphomatosis, which comprises 1531–5. intravascular growth of a large-cell lymphoma, pre- 4. Naka N, Ohsawa M, Tomita Y, et al. Angiosarcoma in Japan. A review of 99 cases. Cancer 1995;75:989–96. dominantly of B-cell lineage, also enters into the 5. Fukunaga M, Shimoda T, Nikaido T, Ushigome S, Ishikawa E. differential of metastatic angiosarcoma (9). The Soft tissue vascular tumors: a flow cytometric analysis. Can- vessels involved are usually capillaries, whereas an- cer 1993;71:2233–41. giosarcomas may grow within a range of vessels, 6. Aust MR, Olsen KD, Meland NB, et al. Angiosarcomas of the usually larger in caliber (25). Lymphoma cells re- head and neck: clinical and pathologic characteristics. Annu Otol Rhinol Laryngol 1997;106:943–51. main confined within the vessels, whereas a heter- 7. Yousem SA. Angiosarcoma presenting in the lung. Arch ogeneous mixture of growth patterns is common in Pathol Lab Med 1986;110:112–5. angiosarcomas. Interestingly, there may exist a rare 8. Sheppard MN, Hansell DM, Du Bois RM, Nicholson AG. form of angiosarcoma that is entirely intravascular, Primary epithelioid angiosarcoma of the lung presenting as pulmonary hemorrhage. Hum Pathol 1997;27:383–5. a true neoplastic angioendotheliomatosis. Lin and 9. Colby TV. Malignancies in the lung and pleura mimicking coworkers (30) recently reported two cases in which benign processes. Semin Diagn Pathol 1995;12:30–44. the tumor was intravascular, in multiple organs 10. Raaf HN, Raff JH. Sarcomas related to the heart and vascu- including the lungs, and comprised tumor cells re- lature. Semin Surg Oncol 1994;10:374–82. active for at least two endothelial markers. There- 11. Basso C, Valente M, Poletti A, Casarotto D, Thiene G. Surgi- cal pathology of primary cardiac and pericardial tumors. Eur fore, even though the far likelier diagnosis for an J Cardiothorac Surg 1997;12:730–8. exclusive intravascular population of atypical cells 12. Donsbeck A-V, Ranchere D, Coindre J-M, Le Gall F, Cordier is lymphoma, carcinoma, or melanoma, immuno- J-F, Loire R. Primary cardiac sarcomas: an immunohisto- histochemical evaluation of such lesions should in- chemical and grading study with long-term follow-up of 24 cases. Histopathology 1999;34:295–304. clude endothelial markers if there is no IHS reac- 13. Rodriguez A. Angiosarcomas of the interatrial septum mim- tivity characteristic of the more likely causes. In icking atrial myxomas. J Am Soc Echocardiogr 1996;9:209– cases of intravascular lymphomatosis, IHS will re- 12. veal the hematopoietic nature of the malignant 14. Afzal MN. Primary cardiac angiosarcoma: clinical, patholog- cells, with staining for B-cell markers and panleu- ical, and diagnostic problems. Can J Cardiol 1997;13:293–6. 15. Mullick SS, Mody DR, Schwartz MR. Angiosarcoma at un- kocyte markers such as CD19, CD20 and leukocyte usual sites: a report of two cases with aspiration cytology and common antigen (LCA; 31). diagnostic pitfalls. Acta Cytol 1997;41:839–44. In summary, this study of 21 extracutaneous an- 16. Naka N, Ohsawa M, Tomita Y, et al. Prognostic factors in giosarcomas metastatic to the lungs indicates that angiosarcoma: a multivariate analysis of 55 cases. 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1224 Modern Pathology 21. Mills SE, Gaffey MJ, Watts JC, et al. Angiomatoid carci- 26. Ritter JH, Mills SE, Nappi O, Wick MR. Angiosarcoma-like noma and ‘angiosarcoma’ of the thyroid gland: a spec- neoplasms of epithelial origins: true endothelial tumors or trum of endothelial differentiation. Am J Clin Pathol 1994; variants of carcinoma? Semin Diagn Pathol 1995;12:270–82. 102:322–30. 27. Nakhleh RE, Wick MR, Rocamora A, Swanson PE, Dehner LP. 22. Poblet E, Gonzalez-Palacios F, Jimenez FJ. Different immu- Morphologic diversity in malignant melanomas. Am J Clin noreactivity of endothelial markers in well and poorly dif- Pathol 1990;93:731–40. ferentiated areas of angiosarcomas. Virchows Arch 1996;428: 28. Burke A, Virmani R. Tumors of the heart and great vessels. 217–21. In: Rosai J, editor. Atlas of tumor pathology. 3rd series, 23. Ramani P, Shah A. Lymphangiomatosis—histologic and im- Fascicle 16. Washington, DC: Armed Forces Institute of Pa- munohistochemical analysis of four cases. Am J Surg Pathol thology; 1996. p. 217–21. 1993;17:329–35. 29. Enzinger FM, Weiss SW. Soft tissue tumors. 3rd ed. St. Louis, 24. Appleton MAC, Attanoos RL, Jasani B. Thrombomodulin as a MO: Mosby Year-Book; 1995. p. 627–32. marker of vascular and lymphatic tumours. Histopathology 30. Lin BT-Y, Weiss LM, Battifora H. Intravascularly dissemi- 1996;29:153–7. nated angiosarcoma: true neoplastic angioendotheliomato- 25. Colby TV, Koss MN, Travis WD. Tumors of the lower respi- sis? Am J Surg Pathol 1997;21:1138–43. ratory tract. In: Rosai J, editor. Atlas of tumor pathology. 3rd 31. Mann RB. Are there site-specific differences among extran- series, Fascicle 13. Washington, DC: Armed Forces Institute odal aggressive B-cell neoplasms? Am J Clin Pathol 1999; of Pathology; 1995. p. 361–3. 111(1 Suppl):S144–50.

Book Review

Weiss SW, Goldblum JR: Enzinger and Weiss’s have lost a bit of their quality in this process and Soft Tissue Tumors, Fourth Edition, 1622 probably will need to be replaced in the next pp, St. Louis, Mosby ($295.00). edition; nevertheless, they convey the messages clearly and are important for the understanding Ever since it appeared for the first time in 1983, of the text. The color photographs, used exten- this textbook of soft tissue tumors has become sively in all the chapters, are a major new feature one of the “must-haves” for surgical patholo- and will be welcomed by most pathologists. The gists. Unquestionably on the list of the pathology layout of the text is still the same, but it is more equivalent of the books of “the great Western readable and the color added to the subheadings Canon,” it’s new editions have, up to now, been and tables makes it esthetically very pleasing. eagerly expected and usually welcomed by the pathology community. The new edition will not The text is very readable, authoritative, and most disappoint those aficionados. of us will find it very “user-friendly.” It is erudite The fourth edition has Dr. Enzinger’s name but not bookish, didactic but not dogmatic. In only in the title, but in spirit this is still the same addition to the new chapters reflecting the cur- book that was conceived in the 70s in the AFIP. rent trends in diagnostic pathology, all other In addition to the new co-author (Dr. Goldblum, chapters have been extensively revised and up- a former resident). Dr. Weiss has enlisted the dated. References are up-to date, including pa- help of eight contributors, who have written pers from the late 1990s and even the year 2000. parts of the text dealing with clinical aspects of The appearance of the fourth edition of En- soft tissue tumors, immunohistochemistry, mo- zinger and Weiss’s classic is the publishing event lecular genetics, and fine needle aspiration biop- of the year, and the book deserves to be greeted sies of these lesions. Dr. Irving Dardick is given in unison with kudos to the authors and the credit for the color renditions, which could al- publisher. As the leading textbook on soft part most all be judged as outstanding. tumors, it belongs in the core library of all pa- The readers who grew up using the previous thologists, and on the essential short list of books editions will recognize some of the old pictures in surgical pathology sign-out rooms. but also will find many more new ones. As before, illustrations are judiciously chosen and very helpful to neophytes and experienced patholo- Ivan Damjanov gists alike. Clinical photographs and electron mi- The University of Kansas School of Medicine crophotographs reprinted from previous editions Kansas City, Kansas

Angiosarcomas Metastatic to Lungs (T. Bocklage et al.) 1225