CTfR STI Seminar June 2, 1996 Brooks Page I q? I

California Tumor Tissue Registry t OOth Semi-Annual Cancer Seminar Sunday, June 2, 1996

Soft Tissue Tumors

John S. J , Brooks, M .D., M RCPath Roswell Park Cancer Institute, Buffalo, NY 716-845-7700 Order of Case Presentation 8:30-10:15 Cases 1-7 10:30-12:00 Cases 8-12 1:30-2:30 Cases 13-16 2:45-.430 Cases 17-21

CASE 1. 26757 HISTORY: The patient was a 14-year-old male with a mass in the left upper forearm. It enlarged in size over a three to four month period, bul was non-tender and not painfuL An excision of the mass was performed. The specimen consisted of a partly sliced, irregularly shaped, fleshly mass of light pinkish tissue which measured about 3.5 em in diameter. In some areas there was a suggestion of a ·capsule. The cut surface of the mass had a sem.itranslucent appearance in some areas.

CASE 2. 27742 H ISTO RY: A 20-year-old Hispanic female discovered a mass in her left buttock located close to the m.idline approximately 3 months ago. She stated the mass had grown in size and caused her discomfort with sitting. MRI revealed a 4 x 5 em mass associated with irregular spiculated margins involving the gluteus maximus muscle. Past medical history was non­ contributory. Physical examination was significant for tenderness in the suprapubic region, fhot1gh there were no palpable masses; and the buttock mass. An excision of left buttock mass was performed on March 23, l995. The specimen consisted of multiple irregular fragments of dense tan-white fibrous tissue. The largest piece was parti~lly covered by skeletal muscle tissue and measured 3. 7 x 3.0 x 2.0 em.; this had on sectioning a dense white fibrous appearance.

CASE 3. 27740 HISTORY: This 26-year-oldfemalehad progressive left n.asa.l stuffiness over several weeks, which had not responded tO multiple medications, including steroid nasal spray, antibiotics, antihistamines, and decongestants. CT scan revealed a large intranasal mass with extension into the anterior ethmoid air cells. Excision of the nasal tumor was performed on Febmary 8, 1995. On gross exam, the specimen was a slightly firm, red-pink, irregularly-shaped tissue mass which measured 5.0 x 3.5 x 2..0 em in greatest djmension. Accompanying it was a tlat, irregularly-shaped portion of bone with pink-tan, soft tissue plating the bone, 4.0 x 2.0 x 0.7 em in greatest dimension. Also received were a portion of pink-tan soft tissue 3.5 x l.O x 1.0 em in greatest dimension, two dark red to pink irregularly-shaped soft. tissues with the same appearance of the tumor, 1.5 and 1.0 em in greatest dimension. Multiple fragmeots of thin and irregularly-sh_aped bone were also submitted, l.O x 1.0 x 0.5 em in loose aggregate dimension. Serial sections of the tumor mqss revealed w.hi're-tan, hqmogenous em surfaces with red-pink, hemorrhagic borders.

CASE 4. 22060 HISTORY: A 33-year-old male presented with a skin and subcutaneous mass of the scalp and head. The specimen consisted of 3 fragments of previously dissected gray· tan, rubbery tissue. some of which was covered by brown hairy skin. The tumor appeared to involve the epidermis in some areas. fn addition, 7 irregular fragments of tissue were received, which were grayish · tan, smooth, rubbery and uniform throughout. The largest fragment measured 4.3 x 4.0 x 3.2 em, und wa~ partially covered by thin translucent capsule. Tn some areas, the skin was separated from the nodules by adipose tissue, while in Others, it appeared to be in filtrated by the p.roccss , although no u lcerations were seen. . ; CITR SIT Seminnr June 2, 1996 Brooks Page 2

CASE 5. 26964 HISTORY: A 64-year old male presented with a tumor on the back. Grossly, the tumor was located just below the skin surface and the specimen consisted of a tannish, hair-bearing elliptical portion of skin that measured 6.5 x 2.8 x 0.3 em, with an underlying nodular, firm, tannish-white, solid area measuring 5.9 x 5.3 x 5.3 em.

CASE 6. 27871 HISTORY: This 51-year-old female bad a small bowel carcinoid resected in July of this year. There had been a cul-de-sac metastasis, and she is thought to have metastatic carcinoid in cervical lymph nodes. A thigh mass had been present for years, not changing, not tender. It was removed incidentally at the time of cervical node biopsy. This specimen consisted or a 6.3 gram, 3.5 em greatest dimension piece of mucousy white rubbery soft tissue anached to strands of skeletal muscle.

CASE 7. 27666 HISTORY: This 36 year-old otherwise healthy female was several years status-post removal of a mass from the left lati~simus dorsi. She had noticed a recurrent lump in this area, approximately 3 inches superior to the pre-existing incision, and elected for surgical removal. Excision of the soft tissue mass of the left chest wall was performed on August II, 1994. The lesion was gray-tan and brown, gritty, with muscular tissue, and measured 5.0 x 4.0 x 2.2 em.

CASE 8. 24412 HISTORY: This 54-year-old female presented with a lesion in the left upper back and left axilla. The specimen consisted of a skin ellipse which measured 7.0 x 3.5 x up to 1.5 em. There was a rough gray-pink, slightly raised circumscribed lesion protruding from the epidermal surface, which measured 4.0 x 2.0 x up to 0.2 em. Sectioning revealed a reddish­ gray lesion, measuring up to 0.8 em in thickness. It was surrounded by normal-appearing skin and subcutaneous fat. In addition, a second specimen, labeled "left axilla" was received. It consisted of a roughly ell iptical segment of skin which measured l.3 x 0.6 x up to 0.5 em. There was an ill-defined, slightly raised gray-pink nodule protruding from the center of the superior surface, which measured up to 0.7 em in dimension.

CASE 9. 27593 HISTORY: This 77-year-old female presented with a mass on the left foot. Radiologically, the tumor did not involve the bone and was surgically "scraped off' the underlying bone.

CASE 10. 26907 HISTORY: This 26-year-old male presented with a lump over his left shoulder joint at the site where a sebaceous cyst was removed four years prior. The mass was painless, without discharge or associated underlying bone pain. He underwent excision, but returned six months .later with a recurrent mass, approximately 5 em in diameter, under the surgical scar. It was slightly raised and fl uctuante. This was re-excised. The specimen was a discoid 70 x 55 x 25 mm portion

CASE I 1. 24834 HISTORY: This 29-year-old female presented with a 3.0 em mass arising from the tendon sheath of the left great toe. CITR STI Seminar June 2, 1996 Brooks Page 3

CASE 12. 27730 HISTORY: This 20-year-old male presented with a mass in his right thigh area. He was otherwise asymptomatic, and denied weight loss, night sweats or chills. MRl demonstrated a soft tissue mass. An incisional biopsy was done, and found to be consistent with a sarcoma. Physical exam done at the time of admission demonstrates a mid-lateral right thigh mass, 4 x. 5 em. with increased warmth and a healed biopsy site. The mass appeared adherent to underlying tissue, and was non-tender. Awide local excision of right thigh sarcoma with margins was performed. The specimen was a 9.5 x 6.5 x 4.5 em portion of red-tan muscle surmounted by an 8.0 x 2.0 em ellipse of white-tan skin. There was a 4.5 x 3.0 x 3.3 em yellow-tan, well-circumscribed mass located centrally, 1.0 em below the skin surface, without areas of hemorrhage or necrosis. The tumor did nor involve the subcutaneous tissue. The mass was located 1.5 em from the proximal margin, 1.5 em from the distal margin, 2.0 em from the deep margin, 2.0 em from the medial margin, and 1.0 em from the lateral margin; all margins were free of tumor.

CASE 13. 25209 InSTORY: A 37-year-old Black female presented with a raised, 2.0 x 2.0 em lesion on the left labium. An excisional biopsy was performed. Gross exam showed a tan piece of skin and fibroadipose tissue measuring 2.5 em in greatest dimension. There was a hard, white, homogeneous. nodular area occupying 80% of the cut surface.

CASE 14. 25806 HISTORY: A 53-year-old female presented with pain in her right leg, down the posterior aspect, and then onto the anterior aspect Physical exam disclosed r, mass in the right pelvic area, slightly tender to palpation. Pelvic ultrasound revealed the mass to be 7 em in the right pelvis; a barium enema showed no involvement of colon; and an NP revealed no compression of the ureters or kidney involvement. Exploratory laparotomy and excision of the abdominal mass were performed. The specimen consisted of a lobulated firm mass which measured 11 x 10 x 5 em and weighted approximately 280 grams. The outer surface of the mass was partially bossilated and nodular, partially irregular and disrupted. Cut sectioning revealed firm, fleshy, glistening tan tissue. Approximately one-third of the tumor was hemorrhagic. necrotic and friable. An additional specimen consisted of an II x 8 x 3.3 em ovoid, flattened fragment of rubbery tissue which weighted I 00 grams. The external surface of the tissue was partially invested by a thin, semi­ translucent membrane, and there was attached lobulated fat The surface showed a 5.5 x I .5 em area of disruption leading into a flattened cyst which measured 8.0 x 7.0 em. The internal surface of the cyst was irregular, wrinkled and varied from gray-tan to hemorrrhagic and red-purple. Protruding from one end of the specimen was a 2.5 em long x 1.5 em wide rubbery, gray-tan, cord-like structure , possibly representing a nerve. Further sectioning of the wall of the tumor revealed rubbery, gray-tan to slightly softer, yellow-tan tissue throughout the areas of yellow softening and necrosis. The wall of the tumor ranged from .2 to 1.8 em thick.

CASE 15. 26060 HISTORY: A 67-year-old white female noted gradual "swelling" of the left hip for a 5 month duration. A cr revealed a mass involving the left anterior thigh. A needle biopsy was performed, followed by definitive resection. · On gross exam, the specimen consisted of a 600 gram, 17 x 17 x 6.5 em mass composed over 90% of adherent tumor nodules, and rare identifiable structures, including fascia and skeletal muscle. Tumor nodu les varied from myxoid to firm, white-tan and were separated by thin fibrous septae. Fascia bounded the tumor inferiorly. Skeletal muscle was presem in a thin rim along one edge. A separate mass of tumor weighing 30 grams and measuring 4.5 x 4.0 x 2.0 em was also submitted. The tumor grossly involved the deep and lateral margins of resection. with only a thin band of fibrous tissue surrounding it. Post-operatively, the patient received irradiation for 5 weeks. Because of a past history of congestive heart failure. chemotherapy with adriamycin was not used. CTIR STI Seminar June 2, 1996 Brooks Page 4

CASE 16. 27941 IDSTORY: A 75-year-old female presented with acute abdominal catastrophe, bleeding intraperitoneally with increasing abdominal size. Her hemoglobin was 6.8 on admission, with a low blood pressure. CT scan revealed a 20 em mass in her left lower quadrant. An exploratory laparotomy, sigmoid colectomy with primary anastomosis, and gastrostomy tube placement were performed. The specimen of sigmoid colon and mesentery contained a large hemorrhagic soft tan and mostly necrotic tumor located in the mesenteric fat, in aggregate measuring 15 x 15 x I 0 em. The tumor extended through the mesenteric fat to the serosal surface. The colonic mucosa had a normal mucosal pattern. Further sections showed a predominantly gelatinous mass of tissue. No discrete lymph nodes were identified in the pericolonic fatty tissue.

CASE 17. 26417 HISTORY: A 27-year-old Hispanic male initially presented with a large deformity of the mandible, especially on the Jigbt side. He bad previously undergone antibiotic treatment of what was thought to be an abscess while living in Mexico. He was reevaluated in this country and told that this might be a tumor. An oral surgeon did a biopsy, which confirmed malignancy. Physical examination of the oral cavity revealed a large mass which was arising from the floor of the mouth and pushing the tongue up and backwards. The mass was involving the entire mandible and floor of the mouth, more on the left side than on th.e right. On gross exam, the specimen weighed 316 grams, and showed an overall dimension of 12 x 9 x 7 em. The specimen included mandible with molar teeth, and showed a large fungating tumor mass which occupied !he mid-ponion of the specimen, including the entire area between the symphysis oflhe mandible. The tumor mass measured a maximum of7 x 7.5 em and was roughly spherical in configuration. Molar teeth were present on the right and left sides. The submaxillary salivary glands were also included, as well as some hyoid membranous tissue and lymph node tissue. The platisma muscle was included at tbe base. In the mid-portion, ar the superior surface, the specimen was ulcerated and showed a 2.0 x l.5 em grayish-red protruding area. Sectioning through the tumor itself showed a lobulated grayish-white appearance. The tumor mass was quite extensive, and in the midline, near the fungating nodule, there were zones of mahogany red blood clot and reddish-tan hemorrhage. A yellow soft grumous area of necrosis was also noted grossly.

CASE 18. 27639 HISTORY: This 42-year-old male presented with an occipital mass. The specimen consisted of a soft tan mass which measured 2.5 em in diameter.

CASE 19. 26175 HISTORY: A 41-year-old white male presented with a chief complaint of a painless rapidly enlarging left thigh mass which had been present for 8 months. There was no history of trauma. Physical exam revealed a firm subcutaneous mass measuring 16 em in greatest dimension. There was no palpable lymphadenopathy. CT scan showed a solid soft tissue mass with a central area of necrosis. An open biopsy was performed on 12/30/87. Wide local excision was performed on l/14/88. Received fresh was an encapsulated firm mass with an overlying ellipse of tan-white skin, and a ponion of attached red-brown muscle. The specimen weighed 835 grams and the mass measured 16 x I 0.5 x 7 em. The capsule is composed of thick fibrous ~bite tissue. The cut surface bulged above the capsule and showed numerous nodules of tan-while to pink-tan mucoid soft tissue with a central area of green yellow cystic degeneration.

CASE 20. 27720 HISTORY: A 62 year old man had a 5 year history of increasing right scrotal swelling. There was no prior history of cancer. The right paratesticular mass was resected. The en block resection weighted I070 grams and included spermatic cord, testicle and soft tissue overlying a large bosselated mass. The distal spermatic cord was wilhout gross abnormalities. More proximally, the spermatic cord was enveloped by the mass and difficult to identify. The CTrR STI Seminar June 2, )996 Brooks PageS bosselated mass measured 18 x 7 x 17 em and did not grossly perforate the surrounding soft tissue nor did it involve the testicle or head of the epididymis. On sectioning, the mass consisted of multiple nodules of a variegated appearance, ranging from translucent and myxoid (10%) to firm, medium pink-tan with areas of white fibrosis (60%) and a gritty texture on cut section. These nodules ranged up to 7 em in diameter and in many areas were confluent. The surrounding tissue was pale yellow lobulated adipose tissue of variable thickness. The inked soft tissue margin juxtaposed adipose tissue, in no areas directly overlying the finn tumor nodules. The gross estimate of necrosis volume was less than 5%.

CASE 21. 27705 HISTORY: This 67-year-old male who had no previous history of seeking medical care due to religious beliefs first presented with a lump in the right breast near the axillary area, noticed 14 months earlier. He stated that it began as a small nodule near the tail of the breast, but had noted a rather rapid enlargement of the mass beginning in March 1994. About 1 month prior to biopsy, the mass began draining and bad become painful about I month prior to that. The patiem stated that the mass had enlarged to the point where he could no longer lower his right arm. Past medical history was significant for an empyema secondary to pneumonia which was drained, at age 8. A partial right chest wall resection and axillary dissection, with reconstruction with a right latissimus myocutaneous flap and multiple split-thickness skin graftS [rom both thighs were performed on February 3, 1995. This 3,838 gram specimen included a portion of chest wall that, from inferolateral to superomedial, measured 38 em and 90 degrees to that measured 26 em. The specimen measured from the skin surface 13 em in depth, but total depth from the top was roughly 19 em. Occupying most of the specimen was a pink-white, fleshly mass which protruded from the surface of the skin. The fungating mass consisted of multiple lobules which were necrotic and gray-red. These protruded up to 6.0 em above the skin surface. On the deep margin, there was a portion of axillary contents. Also OQ ti:!e deep mnrgin medially, almost directly underneath the nipple, there was a _ small white nodule not covered by fascia or muscle. There was a separate large lobule of tumor in the axillary fat that measured 8 x 7 x 3.5 em, which may have been a lymph node. '

California Tumor Tissue Registry lOOth Semi-Annual Cancer Seminar Sunday, June 2, 1996

Soft Tissue Tumors John S. J. Brooks, M.D., MRCPath Roswell Park Cancer Institute, Buffalo, NY 716-845-7700 Order of Case Presentation 8:30-10:15 Cases 1-7 10:30-12:00 Cases 8-12 1:30-2:30 Cases 13-16 2:45-4:30 Cases 17-21

CASE 1. 26757 Nodular Fasciitis, cellular HISTORY: The patient was a 14-year-old male with a mass in the left upper forearm. It enlarged in size over a three to four month period, but was non-tender and not painful. An excision of the mass was performed. The specimen consisted of a partly sliced, irregularly shaped, fleshly mass of light pinkish tissue which measured about 3.5 em in diameter. In some areas there was a suggestion of a capsule. The cut surface of the mass had a semi translucent appearance in some areas. ADDITIONAL HX: Blunt injury : according to the patient, he was hit during an altercation with some of his colleagues. He stated that a few days after being hit he noted a small lump. Differential Diagnosis Fibrous histiocytoma Leiomyosarcoma Fibromatosis Nodular fasciitis Neurofibroma Fibrosarcoma Immunohistochemical Results Desmin SIOO CD34 - HHF35 + HMB45 CD31 SMActin ++ F13a FVIII Myoglob. CD68 EMA It is imponant to note that these results, while suggestive of a smooth muscle lesion, are also completely consistent with nodular fasciitis- the lesion of myofibroblasts. NF is consistently positive w.itb alpha smooth muscle actin (SMA>as well as HHF35, although less frequently. While this is known to occur in myofibroblastic lesions like this wound-like reaction, such results have caused mjsdjagnosis as leiomyosarcoma. Nodular Fasciitis (NF): NF is the classic example of an important dictum: non-malignant reactive lesions may be quite mitotically active and thus mitoses are to be ignored and malignancy not pronounced until the nature of the lesion is decided. Characterized by its extremely rapid growth (more so than the usual sarcoma), NF achieves its small size of 2-3 em in a matter of weeks; only rarely are lesions larger or of longer duration (3 mo. - I yr.). This is a very important aspect of the gross appearance - the small size -over 70 % are less than 2 em and only 8 % greater than 5 em. Usually well circumscribed, NF is often tan to greyish-white with a slimy or myxoid appearance; it is not distinctive from other tumors grossly. In the usual or typical type ofNF, there are 6 key histologic findings: I) Low power view­ most, but not all, cases display a zonation effect or maturation from the center (hypocellolar or hyalinized) to the periphery (hypeccellular with inflammatory cells, vessels); in between, a loose myxoid area is populated by spindly cells. Significantly, the lesion is deep and just above the muscle layer with the lateral thick bands of collagen representing the fascial layer; 2) Predominate cell - variably sized spindle-shaped cells with large oval nuclei, small nucleoli, and long cytoplasmic processes; the cells are loosely arranged in a "tissue culture" like manner and true pleomorphism is lacking; 3) Cell panem - while most cases have a random panem, some will contain storioform areas, interconnecting bundles, myxoid areas, hyalinized areas, or cystic areas focally, even in the same lesion; 4) Inflammatory component -lymphocytes and monocytes are practically always present to some degree; scattered mast cells and histiocytic giant cells can be seen; plasma cells and neutrophils are rare and large numbers of these should cause alarm as they are a common component of other lesions such as Inflammatory Fibrous Histiocytoma.; 5) Red cells - scattered RBC's are often seen and may superficially remind one of Kaposi's sarcoma; however, the pattern is different and hemosiderin is hardly ever found; 6) Mitoses- mitotic activity is variable but most cases contain 1-2 per 5 hpf; lesions with over the upper limit of 1/hpf should be viewed with caution and may represent a malignant process. Variants or Subtypes: Although mlll,ly authors group NF into a variety of subtypes (for example, Allen discussed 12 different variant types), perhaps the simplest and most useful such subclassification has been that of Bernstein and Lanes. They divide NF into 5 subtypes: 1) the J.!lil!.lll ~described above; 2) the reactive~ - with its radially oriented vessels around a central loose area (corresponding to the "repair" variant of Allen); 3) the cellular tvne -(seen here) with no zonation effect resembling fibrous histiocytoma; 4) a metaplastic Mle - these show focal osteoid or chondroid metaplasia; and 5) the proliferative O£pe- which is the same as "proliferative fasciitis" described by others, and which they and others believe is part of the spectrum of NF. Nevertheless, this type, unlike NF, occurs in patients over the age of 50. More recently, Shimizu eta!. (1984) analyzed 250 cases and noted that the three subtypes they described were definitely temporally related to lesion duration: the myxoid type was associated with a short history, the cellular type intermediate, and the fibrous type with the longest duration. The cellular type is recognized by the presence of focal myxoid and loose areas forming "microcysts", its circumscription, and its deep subcutaneous location. Natural History: NF is clearly a reactive and non-recurrent lesion as demonstrated by Bernstein and Lattes. Of their 134 cases, all of the recurrent cases (18) were re-diagnosed as something else upon review. Even partially excised NF did not recur in that study. Shimizu reported only one well documented recurrence (within one month) in 250 cases. This author has seen at least 2 recurrent cases, one on the vulva which bad been only partially excised.

Allen P. Nodular f=iitis. Palhology 4:9-26, 1972. Azua J, Arraiza A, Delgado B, Romeo C. Nodular fasciitis intially diagnosed by aspiration cytology. Acta Cytol 29:562-565, 1985. Bernstein K. Lattes R. Nodular (pseudosarcomatous) fasciitis, a nonrecurrent lesion: Clinicopathologic study of 134 cases. Cancer 49: 1668-1678, 1982. Chung E. Enzinger F. Proliferative fasciitis. Cancer 36:1450-1458, 1975. Culberson 1, Enterline H. Pseudosarcomatous fasciitis: A distinctive clinicopalhologic entity: report of five cases. Ann Surg 151:235-240, 1960. Hutter R, Stewart F, Foote F. Fasciitis. A report of 70 cases with follow.up proving the benignity of the lesion. Cancer I 5:992- 1003. t 962. Konwa1er B. Keas)ley L, Kaplan L..Subcutancous pscudosarcomatous fib romatosis (fasciitis). Am J Clin Pathol 25:241- 252, 1955. Meister P, Buckmann F, Konrad E. Extent and level of fascial involvement in 100 cases with nodular fllSCiitis. Virch Arch Path Anat380:117-185. 1978. Patchefsky A. Enzinger F. Intravascular f35Ciitis (IVF): A report of 15 cases. Lab Invest42:46, 1980. Price E. Silllphant W. Shuman R_ Nodular fasciitis. A clinicopathologic analysis of 65 cases. Am J Clin Pathol 35:122- 136. 1961. Sbimizu S, Hashimoto H, Enjoji M. Nodular fasciitis: An analysis of250 patients. Pathology 16: 161-166, 1984. Thompson J, Van dcr Walt J. Nodular fibrous proliferation (nodular pseudorumor) of the tunica vaginalis testis. HistopalhollO: 741-748, 1986. Ushigone Setal. Proliferative Myositis and fasciitis: report of 5 cases with an ultrastructura.l and immunohistochemical study. Acta Pnthol Jpn 36; 963-97 1, 1986. Wirmon J. Nodular fasciitis. A lesion of myolibroblasts. Cancer 38:2378-2389. 1976. Montgomery EA. Meis JM: Nodular faseiitis: lis morphologic speCtrUm and immunohistochemical profile. Am J Surg !'athol 15:942-948, 1991.

Perosio PM, Weiss SW: Ischemic fasciitis: a juxta-skeletal fibroblastic proliferation with a predilection for elderly patients. Modem Pathology 6:69-72, 1993. Proliferative peribursitis: another reactive lesion This is the name given to an angiomyxoid tumor-like mass occurring near joints and ligaments. While this lesion does not have a classic zonation panem, it does exhibit organization into vascular and non-vascular regions. Clusters of vessels sometimes in a nodular configuration occupy the myxoid substance along with actin-positive spindle cells with bipolar and stellate shapes. Similar to other reactive lesions, small numbers of lymphocytes and histiocytes are found and Uie spindled cells are evenly dispersed throughout. Sometimes small rounded histiocytes contain vacuoles and can mimick lipoblasts. Many lesions contain cysts some of which resemble ganglion cysts while others have a definite synovial lining. Dense scarring may also be present. This highly vascular lesion is different from the hypovascular juxta-articular myxoma and is mistaken for myxoid liposarcoma; it is distinguished from liposarcoma by its variability from area to area, the lack of lipoblasts, and by the stellate nature of the putative myofibroblasts causing it. While it can be seen in any age group, proliferative peri bursitis typically presents as a complication of previous joint disease (degenerative joint disease, ruptured ganglion cyst) and multiple dislocations or external trauma have been nored in these patients.

Brooks JJ. Proliferative peribursitis: a pseudosarcoma with angiomyxoid features occurring near joints and ligaments. Diag Surg Pathol Chapter on Soft Tissue Tumors, 1993. CASE 2. 27742 Fibromatosis, Desmoid

HISTORY: A 20-year-old Hispanic female discovered a mass in her left buttock located close to the midline approximately 3 months ago. She stated the mass had grown in size and caused her discomfort with sitting. MRI revealed a 4 x 5 cm.mass associated with irregular spiculated margins involving the gluteus maximus muscle. Past medical history was non-contributory. Physical examination was significant for tenderness in the suprapuoic region, though there were no palpable masses; and the buttock mass. An excision of left buttock mass was performed on March 23, 1995. The specimen consisted ofmultiple irregular fragments of dense tan-white fibrous tissue. The largest piece was partially covered by skeletal muscle tissue and measured 3.7 x 3.0 x 2.0 em.; this had on sectioning a dense white fibrous appearance. Differential Diagnosis Neurofibroma Healing scar Fibromatosis Fibrosarcoma, well diff. Fibromyxoid sarcoma (Evans) I mmunohistochemical Results Desmi.n SIOO CD34 - HHF35 +f HMB45 CD31 SMActin + F13a FVTII Myoglob. CD68 EMA

Note the presence of actin, particularly SMA, which is very common in fibromatosis. An important negative is CD34, excluding solitary fibrous tumor. The negative SlOO excludes neurofibroma. Fibromatosis A variety of fibromatoses occur in the adult and the lesions are sometimes misdiagnosed; occasional problems arise with very cellular forms, when mitoses appear increased, or the .lesion takes on a neural-like appearance with wavy nuclei. Those occurring on the hands and feet appear as cellular fibrotic lesions with variable amounts of collagen. Although they are frequently multi-nodular, a single dominant nodule may be presem. As opposed to scars, the proliferation is uniform, relatively hypovascular, and lacks hemosiderin. In the desmoid fibromatosis, the cellular appearance is typical: in most areas, the cells have a bipolar nature with extremely scanty cytopl!ISm and a· thin but oval pointed nucleus. In certain regions where the cells are cut in a parallel plane, the cells are polygonal and the periphery of the cytoplasm appears to merge imperceptively with the surrounding collagen, indicating an intimate relationship with it and identifying the cells as fibroblastic in nature. Infiltration of surrounding tissues is typical. The fibromatoses as a rule have cells quite evenly scattered and the overall cellulariry is low to intermediate in narute. In other words, cellularity is never marked and the cells rarely touch one another; this in itself is a rule about (myo)fibroblasts - they occur singly. Mitoses are usually not identified. The abdominal and pelvic fibromatoses occur almost exclusively in females .and some of these are hormonally responsive as mentioned above; these may be quite myxoid in appearance. In Gardner's syndrome, it is common for the fibromatosis to be mesenteric and post-operative. Fibromatosis: Locally Agressive Lesion Characte.ristic Histology Cells: Distributed as Single cells Uniform, No oundles or pleomorphism Myofibroblasts = Stellate or multipolar Cytoplasm merges with collagen Occasionally wavy nuclei (neurofibroma) Background: Continuous sheet of collagen No thin bands of collagen (SFr) Occasional Keloid like collagen Mitoses: rare, usually < 1/10 hpf (>5/lO consider WD fibrosarcoma) Local recurrence: high Therapy: different from DDx tumors like neurofibroma, SFT Fibromatosis often recurs, but if left alone, it may solidify and stop growing. There is disagreement about the ultimate treatment: some recommend only an initial excision followed by observation in the hope that growth cessation may occur; others recommend radiotherapy which in the past had long term untoward consequences - probably because bulk disease was being irradiated. Prediction of recurrence in fibromatosis is difficult but is more common in Gardner's syndrome cases and more common if the lesion Js myxoid and has increased vessels. Low Grade or Well Differentiated Fibrosarcoma In the adult, the distinction between an aggressive fibromatosis and low grade fibrosarcoma is based upon mitotic rate; any significant and consistent mitotic rate above 5/10 hpf in a fibroblastic tumor warrants its designation as a low grade fibrosarcoma. Congenital and infantile forms of fibromatosis are highly cellular, mitotically active, and mimick fibrosarcoma. Desmoid/Fibromatosis -Cytogenetics Telomeric associations common (seen in MFH) Loss of Y (seen in Dupytren's, Peyronies [trisomy 8]) Abnormalities of 5q with and without FAP/Gardner's interstitial deletions of 5ql3-q31 APC gene ofFAP = 5q2 1-22 suggests APC plays role in genesis of desmoids Low Grade Fibromyxoid Sarcoma of Evans Similar in appearance to both fibromatosis and a nerve sheath rumor, this deceptively bland sclerosing lesion metastasizes. Of the two or three cases originally reponed all have been females and the metastatic lesions appear years after the removal of a primary rumor. A slight whirling and partially storiform appearance is noted and areas may be extremely hypocellular. The cells are small and spindly and occasionally the nuclei are bent and wavy. However, the lesion is SlOO negative and mitotic activity in the primary lesion can be extremely low. This entity should be thought of whenever an unusual appearing fibromatosis or neurofibroma is suspected. Evans latest report has an equal male to female ratio, multiple different sites, and 7 cases with distant metastases. Fibromyxoid Sarcoma Pattern: hypocellular, slight swirling Histology: elongated nuclei, occasionally wavy Mitoses: extremely low Irrununohistochemistry: S 100 negative Differential Diagnosis: fibromatosis, nerve sheath tumor Biology: metastases after long intervals Desmoplastic fibroblastoma This is a new entity described by Evans which may mimic fibromatosis, although the significance of the distinction awaits further study. Evans Ht: Desmoplastic fibroblastoma- A report of seven cases. Am I Surg Pathol 19:1077· !081, 1995.

Fibromatosis Allen, P. The fibromatoses: A clinicopathologic classification based on 140 cases. Am J Surg Pathol 1977; I :255-269 and 305-321. Bridge JA. Sreekantaiah C. Mouron B, Neff JR. Sandberg AA, Wolman SR. Clonal chromosomal abnormalities in desmoid tumors: implications for histopathogenesis ..Cancer 1992; 69:430-436. Briselli, M, Soule, E, Gilchrist, G. Congenital fibromatosis: Report of 18 cases of solitary and 4 cases of multiple tumors. Mayo Clin Proc 1980; 55:554-562. Burke AP, Sobin LH, Shekitka KM, Federspiel BH. Helwig EB. Intra-abdominal fibromatosis: A pathologic analysis of 13(\ tumors with comparison of clinical subgroups. Am J Surg Patl!ol 1990; 14:335-341. Burke AP, Sobin LH, Shekitka KM. Mesenteric fibromatosis: A follow-up study. Arch Parhol Lab Med 1990; 114:832- 835. Erdmann lvlWH, Quaba li.A, Sommerlad BC: Epithelioid sarcoma masquerading as Dupuytren's disease. Br J Plast Surg 48:39-42, 1995. Fletcher JA, Naeem R, Xiao S, Corson JM: Chromosome aberrations in desmoid tumors> Trisomy 8 may be a predictor of recurrence. cancer Genet Cytogenet 79; 139·143, 1995. Guerneri S, Stioui S, Manwvani F. Austoni E, Simoni G. Multiple clonal chromosome abnormalities in Peyronie'.s disease. Cancer Genet Cytogenet 1991; 52:181-185. Hayry, P, Raitamo. J, Totterman, S, Hopfner-Hallikainen, D, Sivula, A . The desmoid tumor. IT. Analysis of fac tors possibly contributing to the etiology and growth behavior. Am J Clin. Pathol 1982; 77:674-680. Keil, K, Suit, H. Radiation therapy and the treatment o.f aggressive fibromatosis (desmoid tumors). Cancer 1984; 54:2051-2055. McCollough WM, Parsons JT, Vander Griend R, Enneking WF, Heare T. Radiation therapy for aggressive fibromatosis. The experience at the University of Florida. J Bone Joint Surg [Am I 199 J; 73A:717-725. Miralbell R. Suit HD, Mankin HJ, Zuckerberg LR, Stracher MA Rosenberg AE . .Fibromatoses: From postsurgical surveillance to combined surgery and radiation therapy ./nr J Radiat"011co/ Bioi Phys 1990; 18:535-540. Mukherjee A, Malcolm A, De Ia Hunt M, Neal DE: Pelvic fibromatosis (desmoid)--Trcatment with steroids and tamoxifen. Br J Urol 75:559-560,1995. Raitamo. J, Hayry, P, Nyl,:yri, E, Saxen, E. The aesmoid tumor. !. Incidence, sex, age, and anatontic distribution in the Finish population. Am J Clin Pathol 1982; 77:665-673. Raitamo. J. The desmoid tumor: Choice of treatment, results and complications. Arch Surg 1983; 118:1318-1322. Richards. . R, Rogers. S. Gardner, B. Spontaneous mesenteric fibromatosis in Gardner's syndrome. Cancer I 981; 47:597- 601. Suarez, V, Hall, C. Mesenteric fibromatosis. Br J Surg 1985; 72:976-978. Weiss SW. Proliferative fibroblastic lesions: from hyperplasia to neoplasia. Amer J Surg Patliol1986; 10: 14-25. Weiss, S, Enzinger, F. Soft tissue tumors. C.V. Mosby Co,, 1983 (Chapter 4). Yokoyama et al. Extra-abdominal desmoid tumors: correlation between histologic features and biologic behavior. Surg Pathol 2: 29-42, 1992. Low Grade Fibromyxoid sarcoma Evans HL. Low-grade 6bromyxoid sarcoma: A report oftwo rnetasUJSizing neopfasms having a deceptively benign appearance. Am J Clin Pathol 88:615-619, 1987. Devaney OM, Dervan P, O'NeiUS, Carney D, LeaderM. Low-grade fibromyxoid sarcoma. Hisroparhology 1990;17:463- 465. Evans HL. Low grade fibromyxoid sarcoma: a report of 12·cases. Am J Surg Pathol17: 595-600, 1993. Good lad JR, Mcn12el T, Fletcher COM: Low grade fibromyxoid sarcoma: Clinicopathological analysis of eleven new cases in support of a distinct entity. Histopathology 26:229-237. 1995. CASE 3. 27740 Solitary Fibrous Tumor, nasal cavity HISTORY: This 26-year-old female had progressive left nasal stuffiness over several weeks, which had not responded to multiple medications, including steroid nasal spray, antibiotics, antihistamines, and decongestants. CT scan revealed a large Intranasal mass with extension into the anterior ethmoid air cells. Excision of the nasal tumor was performed on February 8, 1995. On gross exam, the specimen was a slightly flrm, red-pink, irregularly-shaped tissue mass which measured 5.0 x 3.5 x 2.0 em in greatest dimension. Accompanying it was a flat, irregularly-shaped portion of bone with pink-tan, soft tissue plating the bone, 4.0 x 2.0 x 0.7 em in greatest dimension. Also received were a portion of pink-laO soft tissue 3.5 x 1.0 x 1.0 em in greatest dimension, two dark red to pink irregularly-shaped soft tissues with the same appearance of the tumor, 1.5 and 1.0 em in greatest dimension. Multiple fragments of thin and irregularly-shaped bone were also submitted, 1.0 x 1.0 x 0.5 em in loose aggregate dimension. Serial sections ofthe tumor mass revealed white-tan, homogenous cut surfaces with red-pink, hemorrhagic borders. Differential Diagnosis Fibromatosis Neurofibroma Solitary fibrous tumor (SFT) Hemangiopericytoma (HPC) Fibrosarcoma, well diff. This case raises several differential diagnostic possibilities: low grade fibrosarcoma (but no mitoses or herringbone pattern), fibromatosis (but the collagen pattern in fibromatosis is that of a smooth bed in most areas, and the ceUs are larger), a nerve sheath tumor, and bemangiopericytoma (which must have the HPC pattern throughout; interestingly, HPC is CD34 positive as is SFT). Immunoh.istochemical Results - this case Desmin S lOO CD34 ++ HHF35 HMB45 CD31 SMActin Fl3a FVm - Myoglob. CD68 EMA Viment. + MIC2 CK-AE - These results fail to support a diagnosis of fibromatosis (SMA-) or nerve sheath tumor (S 100-). With CD34 being the only positive reaction, a solitary fibrous tumor is confirmed. Solitary Fibrous Tumor (SFT) Tumors described originally as localized fibrous mesothelioma have come to be known as "solitary fibrous tumors" (SFT), since it seems clear they are not of mesothelial origin. SFT develop not only from the pleura, but also near other serosal surfaces such as pericardium, peritoneum, and liver. They may appear to arise from the retroperitoneum as well. lmportantly, they can occur without an association to a serosal surface as in the mediastinum, nasal cavity, orbit, and thyroid. They seem to belong to the category of myofibroblastic tumors since some authors describe histologic identity to previously describe.d breast tumors ("myofibroblastomas"), because they rarely express actin (and desrnin), and because they have (myo-)fibroblastic ultraStructural 'features. Regardless of location, they are identical histologically to those in the pleura: they are composed of non-descript spindle-cells dispersed among elongated thin collagen fibers in a "patternless" pattern. Actually, the parallel arrangement of the thin collagen bundles js a verv characteristic design. The nuclei are bland and mitoses are difficult to flnd in the average case. Foci of storiform or hemangiopericytomatous growth are typical. In a DNA flow cytometry study on 14 cases of pleural SFT, all tumors were diploid had a low proliferative index. Sarcoma is in the differential diagnosis and needle biopsies may be misinterpreted as fibrosarcoma for example, as was tnJe here. Inununohistochernically, the tumors are typically vimentin-positive and cytokeratin-negative. While rare cases in the pleura have stained with muscle markers such as muscle-specific actin and des min. !his was not noted in the nasal cases. The tumors were also typically S 100 -negative. Of very practical value is the consistent presence of CD34 immunoreactivity, described recently by multiple authors including Dorfman and Van de Rijn. Such a result would help exclude fibromatosis (CD34 negative) in odd soft tissue sites; also fibrosarcoma is said to be CD34 negative as well. Malignant SFT, which may mimic a variety of sarcomas including MFH and fibrosarcomatous mesothelioma, have been described and criteria defined by several groups including Carter and Otis, England et al., Okike et al., and Hanau & Miettinen. Briefly, rumors with pleomorphism, increased cellularity, mitotic activity >4/10 hpf, with hemorrhage and necrosis are considered malignant, possibly signify ing a more aggressive course. However, these criteria do not always predict the patient's course; in particular, those pleural lesions which are pedunculated do well regardless of such findings. This likely accounts for the 45% cure rate of all malignant pleural SFT. As these factors were also applicable to rumors in the mediastinum, Witkin and Rosai recommend that the same criteria be provisionally applied to SFT in other locations in order to predict biologic behavior.

SFT of pleural & peritoneal sites Briselli M, Mark E.J, Dickersin GR. Solitary fibrous tumor of the pleura: Eight new cases and review of 360 cases in the literature. Cancer 1981; 47:2678·89. Carter D, Otis CN. Three types of spindle cell tumors of the pleura: fibroma, sarcoma, and sarcomatoid mesothelioma. Am J Surg Pathol 1988; 12:747-53. Dervan PA, Tobin B, O'Connor M. Solitary (localized) fibrous mesothelioma: evidence against mesothelial cell origin. Histopathology 1986; 10:867-75. ' ei-Nnggor AK, Ro JY, Ayala AG. Ward R. Ordonez NG. l ocalized fibrous rumor of the serosal cavities: immunohistochenaical, electron-microscopic, and flow-<:ytomelric DNA study. Am J Clin Pnthol 1989; 92:561-5. Englund OM. Hochholzer L, McCanhy MJ. Localized benign and malignant fibrous tumors of the pleura; a clinicopathologic review of223 cases. Am 1 Surg Pathol 1989; 13:640-58. Flint A, Weiss SW. CD34 and keratin expression distinguishes solitary fibrous tumor (fibrous mesothelioma) of pleura from desmoplastic mcso~>elioma. Hum Pathol 26: 428-43 1, 1995. Hanau CA. Miettincn. Solitary fibrous tumor: histological and immunohistochemical spectrum ofbenign and malignant variants presenting at different sites. Hum Palhol 26: 440-449. 1995. O'Connell JX, Logan PM, Beauchamp CP. Solitary fibrous tumor of the periosteum. Hum Pnthol 26: 460-462, 1995. Okike N, Bematz PE, Woolner LB. localized mesothelioma ot' the pleura: benign and malignant variants. J Thorac Cardiovasc Surg 1978; 75:363-72. Renshaw AA. Pinkus GS, Corson JM. CD34 and AEUAE3: diagnostic discrinainants in the distinction of solitary fibrous tumor of the pleura from sareomatoid mesothelioma. Applied Immunohistochem 2: 94-102. 1994. Said JW. Nash G. Sanks-Schlegel S. Sassoon AF, Shintaku IP. Localized fibrous mesothelioma: an immunohistochenaical and electron microscopic study. Hum Pathol 1984; 15:440-3. Saifuddin A, On Costa P, Chalmers AG, Carey BM, Robenson RJH. Primary malignant localized fibrous tumours of !he pleura: Clinical, radiological and pathological features. Cli11 Radial 1992; 45:13-1 7. Steinet~ C, Clarke R, Jacobs GH, Abdul-Karim FW, Petrelli M, Tomashefski JF. Localized fibro us tumors of !he pleura: correlation of histopathological, immunohistochemical, and ultrastructural features. Pathol Res Pract 1990; 186:344-57. Stout AP. Solitary fibrous mesothelioma of the peritoneum. Cancer 1950; 3:820-5. Van de Rijn M. lombard CM, Rouse RV: Expression of CD34 by solitary fibrous tumors of the pleura, mediastinum. and lung. Am J Surg Pathol 18:814-820, 1994. Young RH, Clement PB, McCaughey WTE. Solitary fibrous tumors ("fibrous mesotheliomas") of the peritoneum. Arch Patbol Lab Med 1990: 114:493-5. Youscm SA, Aynn SO. Intrapulmonary localized fibrous tumor: introparenchymal so-called localized fibrous mesothelioma. Am J Clio Pathol 1988: 89:365-9. SFT of non-pleural, non-peritoneal sites Balassiano M, Reichert N, Rosenman Y, Hercheg E. Liberman Y, Yellin A. l ocalized fibrous mesothelioma of the mediastinum devoid of pleural connections. Postgrad Med J 1989; 65:788-90. Begin LR: Myogenic strOmal tumor of the male breast (so-called myofibroblastoma). Ultrastruct Pnthol 15:613-622. 1991. Compngno J, Hyams VJ. Hemangiopericytoma-like intranasal tumors: a clinicopathologic srudy of23 cases. Am J Clin Pathol 1976: 66:672-83. Damiani S. Mieuinen M, Peterse JL. Euse'Oi V: Solitary fibrous tumour (myofibroblastoma) of the breast. Virchows Arcbi.v 425:89-92, 1994. Dol'ftnan OM. To.K. Djckersin GR. Rosenberg AE, Pilch BZ: Solitary fibrous tumor of the orbit. Am J Surg Patnol 18:281-287, 1994. Fisher C, Bisceglia M: Solitary fibrous tumour of the spermatic cord. Br J Urol 74:798-799, 1994. Goodlad JR, Fletcher CDM. Solitary fibrous tumour arising at unusual sites: Analysis of a series. Histopathology 1991; 19:515-522. . Hanau GA, Miettioen. Solitary fibrous tumor: histological and immunohistochemical spectrum of benign and malignant variants presenting at different sites. Hum Pathol 26: 440-449, 1995. Ibrahim NBN, Briggs JC, Corrin B: Double primary localized fibrous tumours of the pleura and retroperitoneum. Histopathology .22:282-284, 1993. Konkc-Marchant K, Han WR, Broughan T. Localized fibrous tumor (localized fibrous mesothelioma) of the liver. Cancer 1.9.89; 64:1096-102. · Taccagni G. Sam bade C, Nesland J, Terreni MR, Sobrinho-Simoes M: Solitary fib,rous tumour of the thyroid: Clinicopathological, immunohistochemical and ultrastructural study of three cases. Vinchows Arch A Pathol Anat Histopatltol 422:491-497, 1993. Van de Rijn M. Lombard CM, Rouse RV: Expression of·CD34 by solitary fibrous rumors of the pleura, mediastinum, and lung. Am J Surg Pathol18:814-820, 1994. Wargon·ES. Weiss SW, Norris HJ. Myofibroblastoma of the breast: sixteen cases of a.distinctive berugn mesenchymal tumor. Am J Surg i'athol 1987; 11:493-502. Wei~ner N. Soliiary fibrous tumor of the mediastinum. Ulrrasrruct Pathol 1991 ;15:489-492. Witkin OB, Rosai J. Solitary fibrous tumor of the mediastinum: a report of 14 cases. Am J Surg Patl\ol 1989; 13:547-57. Witkin GB, Rosai J. Solitary fibrous tumor of the upper respiratory tract: A report of six cases. Am J Surg Pathol 1991; 15:842-848. :Z..ker~rg LR, Rosenberg AE. Randolph G, Pilch BZ. and Goodman ML: Solitary fibrous tumor of the nasal cavity and paranasal sinuses. Am J Surg Pathol 15(2): 126-130, 1991. CASE 4. 22060 Dermatofibrosarcoma protuberans (DFSP) HISTORY: A 33-year-old male presented with a skin and subcutaneous mass of the scalp and head. The specimen consisted of 3 fragments of previously dissected gray-tan, rubbery tissue, some of which was covered by brown hairy skin. The tumor appeared to involve the epidermis in some areas. In addition, 7 irregular fragments of tissue were received, which were grayish -tan, smooth, rubbery and uniform throughout. The largest fragment measured 4.3 x 4.0 x 3.2 em, and was partially · covered·by thin translucent capsule. In some areas, the skin was separated from the nodules by adipose tissue, while in others, it appeared to be infiltrated by the process, although no ulcerations were seen. Differential Diagnosis Neurofibroma Fibrous histiocytoma Atypical fibroxanthorna (AFX) Dermatofibrosarcoma (DFSP), with or ~¥ithout giant cell fibroblastoma Melanoma, spindle cell

AFX must be pleomorphic and is excluded on that basis here. Neurofibroma, while simulating the wavy cells in this case, tends to be looser and without the storiforrn pattern present throughout this lesion. Spindle cell melanoma has a plumper cytoplasm and larger nuclei; also it displays a separated bundle pattern not seen here. The main differential diagnosis is between DFSP and BFH (benign fibrous histiocytOma) - see below. Immunohistochemical Results - this case Desmin SlOO CD34 ++ HHF35 HMB45 CD3l SMActin F 13a FVIII Myoglob. CD68 Bv1A The irnmunoprofile of CD34+/Fl3a- is most consistent with DFSP; melanoma excluded by S 100-. Dermatofibrosarcoma protuberans (DFSP) This tumor is quite similar in appearance to ordinary Fibrous Histiocytoma. Indeed it is the storiforrn tumor par excellence. This pattern is basically present throughout the lesion, which is ordinarily fairly cellular. The lesion is characteristically large and produces bulges in the overlying skin and a thick plaque-like lesion. In general, only lesions which have recurred multiple times ultimately metastasize, often after a histologic change to a fibrosarcoma or an MFH-like lesion. Recently, a myxoid variant bas been described; although this raises the differential diagnosis of other myxoid lesions, the myxoid DFSP is quite superficial, again infiltrating just below the epidermis. This position alone should lead one to question the diagnosis of liposarcoma, which it mimicks. It may contain characteristic storiform areas which are not myxoid, aiding in the diagnosis. DFSP is a locally recurrent lesion with metastases appearing only after multiple uncontrolled recurrences; if completely resected the first time, the prognosis is good. Differential diagnosis: D:fSP vs BFH: As these are both locally recurring skin lesions of similar histogenesis, this difference is not critical for the biology of the lesion. Nonetheless, it is important not to give someone a sarcoma diagnosis if unnecessary. Both entities have the storiforrn pattern, an infiltrating lateral border, and similar cellular features. However, DFSP ordinarily must be large (>3cm), nearly touch the overlying epidermis, often a spreading plaque, and without epithelial hyperplasia. The term "fibrous histiocytoma" should be used for lesions which are small ( l-2cm), superficial, with a rounded overall contour, and epithelial hyperplasia is common; there is no boscillated bulging cutaneous surface nor flat plaque-like·appearance. The inftltrating border, even to the point of subcutaneous fatty infiltration, is a feature shared in common with DFSP, but unlike OFSP where the fatty inflltration is usually extensive, that in BFH is incipient- surrounding the first few fat cells.

Fletcher C. Evans B. Macartney J, Smith N. Jones E, McKee P. Dermatofibrosarcoma protuberans: a clinicopathological and immunohistochemical study with a review of the literature. Histopathology 1984; 9:921-938. Brenner W, Schaener K. Chhabra H. Postea A. Dermatofibrosarcoma protuberans rneUtstatic to a regional lymph node. Cancer 1975; 36: 1897-1902. Frierson H. Cooper P. Myxoid variant of dermatofibrosarcoma protuberans. Am J Surg Patholl983; 7: 445-450. Fisher ER, Hellstrom HR. Dermatofibrosarcoma with metaStases simulating Hodgkin's disease and reticulum cell sarcoma. Cancer 1966; 19;1165·1171. Rockley PF, Robinson JK, Magid M. Goldblan D. Dermatofibrosarcoma protuberans of the scalp; A series of cases. J Am Acad Demtato/ 1989; 2 1:278-283. Mnrlcs LB, Suit HD, Rosenberg AE. Wood WC. Dermatofibrosarcoma protuberans treated with radiation therapy. /111 J Radiat Oncol Bioi Phys 1989; 17:379-384. Dupree WB,langloss JM. Weiss SW. Pigmented dermatofibrosarcoma protuberans (Bednar tumor). A pathologic. ultrastructural, and immunohistochemical study. Am J Surg Pathol 1985; 9:630.639. Zeiger BW, Ofncr D, Zeiger BG: Atrophic variants of dermatofibroma and dermatofibrosazcoma protuberans. Histopathology 26:519-527, 1995.

Giant Cell Fibroblastoma & Relation to DFSP These superficial tumors occur mainly in very young male patients (less than 10 years of age) and may be found in a variety of locations. Frequently misiJlken for a sarcoma, this rare fibroblastic tumor is highly sclerotic and hypocellular with highly atypical cells scattered about. In some cases, regions may be quite cellular with prominent thick walled vessels. Adipose tissue is often present scattered throughout. One tell-tale characteristic is the formation of very wide vascular-like spaces which are incompletely lined by the fi broblastic cells (Factor VIII negative and non-endol.helial). The lesion may resemble a neurofibroma with ancient change, a liposarcoma (lacking capillary vascularity) or a peculiar angiosarcoma (but the huge spaces are unusual and only incompletely lined). About half the patients experience local recurrence but no metaStases have occurred. Recently, Smookler et al. have proposed this to be a variant of DFSP found in childhood; it has recently acquired the designation of "childhood dermatofibrosarcoma proruberans (DFSP)" because occasional cases show zones consistent with that storiforming adult tumor and adult DFSP may contain GCF-like areas.

Abdul-Karim. F, Evans. H, Silva, E. Giant cell fibroblastoma: A repon oi three cases. Am J Clin Patbol 1985; 83:165-170. Alguacii-Garcia A. Giant cell fibroblastoma recurring as dermatofibrosarcoma protuberans. Am J Surg ?athol 1991; 15:798-801. Allen PW, Zwi J: Giant cell fibroblastoma cransfonning into dermatofibrosarcoma protuberans. Am J Surg Pathol 16; 1127- 1128. 1992. Be ham A. Fletcher CD. Dermatofibrosarcoma protuberans with areas resembling giant cell fibroblastoma: repon of two cases. Histopathology 1990;17:165-167. Chou P, Gonzalez-Crussi F. Mangkomkanok M. Giant cell fibroblastoma. Cancer 1989; 63:756-762. CraverRD, Correa H. Kao YS, Van Brunt T, Golladay ES: Aggressive giant cell fibroblastoma with a balanced 17;22 translocation. Cancer Genet Cytogenet 80:2().22, 1995. De Chadarevian J-P, Coppola D, Billmi.rc DF: Bednar tumor pattern in recurring giant cell fibroblastoma. Am J Cli n Pathol 100:164- 166, 1993. • Dymock, R. Allen, P. Stirling, J, Gilben. E. Thombery, J. Giant cell 6broblastoma: A distinctive recurrent tumor of childhood. Am J Surg Patbol 1987; II :263·271. Fletcher CD. Giant cell fibroblastoma of $Oft tissue; a clinicopathological and immunohistochemical study. Histopathology 1988; 13:499-508. Michal M. Zamecnik M: Giant cell fibro blastoma with a dermatofibrosarcoma protuberans component. American Journul of Dermatopathology 14:549-552, 1992. Shmookler BM. Enzinger FM, Weiss SW. Giant cell fibroblastoma: A juvenile form ofd ermatofibrosarcoma protuberans. Cancer 1989; 64:2154-2161. . Shmoolder BM: Giant cell fibroblastoma transforming into dennarofibrosan:oma protuberans. Reply. Am J Surg Pathol 16:1128-1129, 1992. Smookler, B. Enzinger, F. Giant cell fibroblastoma: A peculiar childhood tumor. Lab Invest 1982; 46:76A. CASE 5. 26964 DFPS with fibrosarcomatous transformation

HISTORY: A 64-year old male presented with a tumor on the back. Grossly, the tumor was located just below the skin surface and the specimen consisted of a tannish, hair-bearing elliptical portion ofskin that measured 6.5 x 2.8 x 0.3 em, with an underlying nodular, fmn, tannish-white, solid area measuring 5.9 x 5.3 x 5.3 em.

Differential Diagnosis Fibrous histiocytoma Atypical fibroxanthoma (AFX) Dermatofibrosarcoma (DFSP) DFSP with fibrosarcoma Malignant fibrous histiocytoma (MFH) Melanoma, spindle cell

Immunohistochemical Results Des min SlOO CD34 ++ HHF35 HMB45 CD31 SMActin Fl3a FVm Myoglob. CD68 ENIA Viment. MIC2 CK-AE

Note the CD34 reactivity of this type of fibrosarcomatous tJransformation, similar to DFSP itself (Goldblum).

Progression of DFSP DFSP may progress or transform to either fibrosarcoma or MFH, either in a primary tumor or as a recurrence. Such high grade pathology may lead to clinical aggression or metastases, but that is .not always the case.

Connelly JH, Evans HL: Dermatofibrosarcoma procuberans: A clinicopathologic review with emphasis on fibrosarcomato\IS areas. Am J Surg Palhol16:921-925, 1992:. Pitt MA, Coyne JD, Harris M, McWilliam U: Dermatofibrosarcoma protuberans recurring as a giant cell fibroblastoma with subsequent fibrosarcomatous change. Histopathology 24:197-198, 1994. O'Dowd J, Laidler P. Progression of dermatofibrosarcoma protuberans to malignant fibrous histiocytoma: report of a case wilh implications for tumor histogenesis. Hum Parhol 19: 368-370. 1988. Ding J. Hashimoto H. Enjoji M. Dermatofibrosarcoma protuberans with fibrosarcomatous areas: A clinicopathologic study of nine cases and a comparison with allied tumors. Cancer 19&9; 64:721-729. Goldblum JR: CD34 positivity in fibrosarcomas which arise in.dermatotibrosarcoma protuberans. Arch Pathol Lab Med 119:238-241, !995. CASE 6. 27871 Intramuscular Myxoma

HISTORY: This 51-year-old female had a small bowel carcinoid resected in July of this year. There had been a cul-de-sac metastasis, and she is thought to have metastatic carcinoid in cervical lymph nodes. A thigh mass had been present for years, not changing, not tender. It was removed incidentally at the time of cervical node biopsy. This specimen consisted or a 6.3 gram, 3.5 em greatest dimension piece of mucousy white rubbery soft tissue attached to strands of skeletal muscle. Differential Diagn os is Myxoma,IM Myxoma, juxtaarticular Neurofibroma Angiomyxoma Angiomyxoid reaction (peribursitis) Fibromyxoid sarcoma (Evans) Myxofibrosarcoma (Gr 0.5 MFH) Immunohistochemical Results Des min SI OO CD34 + HHF35 IDvffi45 CD31 SMActin Fl3a FVlli Myoglob. CD68 EMA ANGIOMYXOID LESIONS These lesions present as a distinct category morphologically, having an overall myxoid background, variable and some times characteristic vascularity ("angiomyxoid"), and variable cellularity. It is helpful to note comparative histologic features. The entities found here include:

I umor Nodules Y~SS!l iS Cellul!l[ eJsoQilll!l!llb .Mitose§ !HC Myxoma Single=S +1- +1- - (+I-) Myoid+/- . Angiomyxoma, sup. Multiple=M + + +1- Angiomyxoma, agg . Single + + +1- Myoid+/- Angiomyofibroblastoma Single + + +1- Des+,MSA- Myxofibrosarcoma Sor M + + + + MyxoidMFH S orM ++ +++ ++ ++ Myoid+/- Myxoid Liposarc S orM ++"' ++ + S!OO [The vessels of myxoid liposarcoma are very thin capillaries & grow in small arcs, angles; the vessels of all the others are similar= thicker due to prominent pericytic layer, grow in larger arcs, are more dispersed. Key point regarding vessels for this group is that "thick" does not have the same connotation as in nerve sheath tumors where it means "invested by sclerosis".] Myxoma, intramuscular The IM myxoma is avascular to bypovascular. extremely hypocellular, and is usually uninodular. Typical locations for the myxoma include several sites: the heart (cardiac myxoma), the jaw (myxoma of bone), and the soft tissue intramuscular location (commonly found in the extremities with the thigh the most common site. The 1M myxoma presents clinically as a mass, and is occasionally described as "rapidly growing". Perhaps this is due to the sudden accumulation of the myxoid ground substance, probably a mixture of various proteoglycans. The differential diagnosis includes nerve sheath myxoma (which shows aggregates of cells in small groups with epithelioid appelll'llnce and scattered giant cells), myxoid liposarcoma (which is a vascularized tumor). myxoid nerve sheath tumor (which contains a peripheral rim of intact spindly tumor}, and myxoid chondrosarcoma (which contains strings of eosinophilic cells with granular cytoplasm in a multi­ nodular configuration). Myxoma, Juxta-articular In this lesion, vessels are also not prominent although the cellularity may be increased. These.are found mainly around the knee arid other large joims.

Me is JM, Enzinger FM: Juxta-articular myxoma: A clinical and pathologic study of 65 cases. Hum Pathol 23:639-646 .. 1992. Angiomyofibr.oblastoma Fletcher CDM, Tsang WYW, Fisher C. Lee KC, Chan JKC: Angiomyofibroblastoma of the.v ulva: A benign neoplasm dis tinct from aggressive angiomyxoma. Am J Surg Pathol 16:373-382, !992. Superficial Angiomyxoma This unusual group of tumors was described recently by Allen and co­ workers. They are superficially located in the skin and subcutaneous regions of the body and many lesions contain epithelial elements. The relationship to Carney's syndrome of myxomatous lesion is unclear. Micrpscopically, the lesions contained.a multinodular growth with a prominent myxoid ground substance within which there are scattered vessels with perithelial cells, scattered histiocytes, and spindled shaped cells. The nodules are ill-defined and invade the surrounding dermal tissues and structures.

Allen PW, Dymock RB, MacCormac LB: Superficial angiomyxomas with and without epithelial components. Report of 30 tumors in 28 patients. Am J Surg Pathol 12:519-530, 1988. Yavner D.L. Red line RW: Angiomyxoma of the umbilical cord with massive cystic degeneration of Wbarton's jelly. Arch Pathol Lab Med 113:935-937, 1989. Wilson RD. MageeJF, Sorensen PHB, Johnson A: fa utero decompression of umbilical cord angiomyxoma followed by vaginal delivery. Am J Obstet Gynecol 171: 1383-1385, 1994. Aggressive Angiomyxoma These lesions are typically large tumors found in the female pelvis. In fact, practically all cases have occurred in females, in the pelvis or vaginal areas. Microscopically, they consist of a myxoid lesion with scattered vessels, a number of which are open with a gaping dilated appearance. Some of these have an unusual fibrinous appearance around them. Spindled cells are scattered throughout the myxoid substance and appear to mark with muscle actin consistent with a myofibroblastic origin. The lesions are locally aggressive, but distant metastases have not been reported. The differential diagnosis centers mostly around my:xoid liposarcoma and neurofibroma. Both lesions are .vascular and both may have small spindle shaped cells. However, the capillary network of liposarcoma is absent in the angiomyxoma; on the other han.d, liposarcomas Jack the open gaping vessels of the angiomyxoma. Thus, while occasional cases may be difficult to distinguish, most are separable. AGGRESSIVE ANGIOMYXOMA • GYN location: vulva, vagina, pelvis • Young females, 20-40 years • Size: large (2-20 em, up to 60 c~) • Pathology: spindle & stellate cells (myofibroblasts • thick and thin vessels; trapped fat - infiltrative borders - mitotic rate low to nil (0110 .hpf) • Course: high local recurrence (4/5, ·6/6)

Steeper TA, Rosai J: Aggrcssiveangiomyxoma of the female pelvis and perineum. Report of nine cases of a distinctive type of gynecologic soft-tissue neoplasm. Am J SurgPathol 7:463-475, 1983. Begin LR, Clement PB, Kirk ME, Jothy S, McCaughey WTE, Ferenczy A: Aggressive angiomyxoma of pelvic soft parrs. A clinicopathologic study of nine cases. Hum Pathol 1;():621-628, 1985. Clement PB, Prat J, Young RH: Diagnostic problems in gynecological tumor pathology. Mod.Pathol3:234-255, 1990. Tsang WYW. Chan JKC. Lee KC, Fisher C. Fletcher CDM: Aggressive angiomyxoma: A report of four cases occurring in men. Am I Surg Pathol 16:1059-1065, 1992. Sim6 M. Zapatn C. Esquius J, Domingo 1: Aggressive angiomyxoma of the female pelvis and perineum. Report of two cases and review of the literature. Br J Obsret Gynaecol99:925-927. 1992. Stephenson BM. Williams EV, Sturdy DE. Vellacott KD: Aggressive angiomyxoma of the perineum and pelvis. Br I Surg 79:1 181, 1992. Clatch RJ, Omke WK. Gonzalez JO: Aggressive angiomyxoma in men: A report of two cases associated with inguinal hernias. Arch Palhol Lab Med 117:911-913. 1993. Oondo T. Takahashi M, Hoshli Y, Iwata T, Kashiwagi T, Ishihara T: Angiomyxoid tumour in the renal peripelvic tissues with features of aggressive nngiomyxoma. I Clin Pathol 48:82-83, 1995. Sknlova A, Michal M, Husek K. Zamecnik M, Lcivo 1: Aggressive angiomyxoma of the pelvioperincal region. Immunohisrological and ultrastructural study of seven cases. American Journal of Dermatopathology 15:446- 45 1, 1993. ArM SS, EI-Mnllah KO: Aggressive angiomyxoma of the vagina. lnt J Gynecol Obsret 43:207-210, 1995. Myxold OFSP Frierson HF. Cooper PH: Myxoid variant of dermatofibrosarcoma protuberans. Am J Surg Pathol 7:445-450, 1983. Myxofibrosarcoma . Mentu:l T, Calonge E, Wadden C. Camplejohn RS, Beham A, Smith MA. Aetcher COM: Myxofibrosnrcoma ­ Clinicopathologic analysis or 75 cases with emphasis on rhe low-grade variant. Am J Surg Pnthol 20:391 -405, 1996. Myxoid MFH Weiss S. Enzinger F. Myxoid variant of malignant fibrous histiocytoma. Cancer 1977; 39:1672-1685. CASE 7. 27666 Intramuscular Hemangioma

HISTORY: This 36 year-old otherwise healthy female. was several years status-post removal of a mass from the left latissimus dorsi. She had noticed a recurrent lump in this area, approximately 3 inches superior to the pre~existing incision, and elected for surgical removal. Excision of the soft tissue mass of the left chest wall was performed on August 11, 1994. The lesion was gray-tan and brown, gritty, with muscular tissue, and measured 5.0 x 4.0 x 2.2 em. Differential Diagnosis Angiolipoma Angiomyolipoma liemangioma,I11 Lipoma, infiltrating Immunohistochemical Results Des.rnin SlOO CD34 liliF35 liMB45 CD31 + SMActin Fl3a FVITI Myoglob. CD68 EMA Viment. MIC2 CK-AE CollN + Chromog CK-CAM Intramuscular Hemangioma Occasional hemangiomas occur within muscle (intramuscular type), where it may also be called intramuscular an~omatosis if extensive. These are noncircurnscribed tumors occurring particularly in the muscles of the thigh in young adults with pain as a frequent symptom. The intramuscular type is often accompanied by adipose tissue and may recur yet is clearly benign. It can be distinguished from angiosarcoma by the presence of a two-cell layer (en do- and perithelial) and by the formation of round to elongated vascular spaces without anastomoses. These may actually be congenital and gradually grow over time to the point where pain calls attention to them. Arterio-venous malformations are more localiZed and consist solely of the malformed large vessels; the smaller venules of 1M Hemangioma are absent.

Allenby PA, Boesel CP. Marsh WL,Jr.. Diffuse angiomatosis of the e.xtremities presenting a$ a sarcoma. Arch Parlwl Lab Med 1990; 114:987-990. · Silverman RA. Hemangiomas and vascular malformations. Pediatr CJin North Am 1991;38:81 1-834. Angiolipoma, including cellular type Most angiolipomas are easily recognized as the mainly fatty subcutaneous tumors they are: circumscribed with venule-like proliferation and microthrombi. Unusual cases manifest such an overgrowth of the vascular component as to mimick Kaposi's sarcoma or even other solid lesions like smooth muscle tumors . .Because the vessels are probably small venules, spindle-cells representing pericytes dominate the appearance and are intermingled with endothelial.cells. The cellular angiolipoma is set apart from -Kaposi's sarcoma by the following features: it is too deep being a subcutaneous tumor, it is circurnscqbed, it nearly always contains small vessel thrombi, and it will incorporate mature fat (however little) within it,s confines. Some of the atypical vascular lesions of the breast bear a resemblance. to these.

Hunt SJ, Santa Cru:~; Df, Barr RJ. Cellular angioli(Xlma. Am J Surg POlhol1990;14:75-81. Yu G, Fishman SJ, Brooks JJ. Cellular angiolipoma of the breast. Mod Pathol 6: 497-499, 1993. Proliferative Cutaneous Angiomatois: a cellular tumor mimicking Kaposi's sarcoma and angiosarcoma Angiomatosis is an unencapsulated vessel-forming condition affecting the extremities of young adults; the vessels are large and dilated and involve the aeep soft tissues and the skin is affected only in rare cases. In contrast, we have encountered a localized but highly cellular form of angiomatosis which presented as cutaneous disease in 4 patients on the shoulder and foot A diffuse proliferation was seen throughout the dermis, causing a plaque-like lesion clinically. Irregular interconnecting cords and sheets of cells infiltrated the dermis, dissecting the dermal collagen. Small cells with scanty cytoplasm were present with spindled cells which dominated many fields. The main findings included: vacuolated cells, microlurninal spaces with RBC's, anastomosing spaces, nuclear atypia, scattered mitoses, and infiltrative borders. Proliferative Capillary Angiomatosis of Skin - Histology Irregular interconnecting cords and sheets in dermis Small spindled cells with dissection of dermal collagen Main findings: vacuolated cells. micro! uminal spaces with RBC's, anastomosing spaces, nuclear atypia, scattered mitoses, and infiltrative borders Skin ulceration. rutery and bone involved in I case Areas like Kaposi form hemangioendothelioma & angiosarcoma Stasis phenomena in all: extravasated RBC's, hemosiderin, chronic inflammation; these and rare hyaline globules mimicked Kaposi's sarcoma Subcutaneous invasion: more vascular differentiation with lobular pattern small capillary and venule-like channels Iwo cell types were d,etectable immunohistochemjcally. Vascular spaces were lined by Factor VITI positive endothelial cells; these were outlined by muscle actin positive perithelial cells. The presence of 2 ceU types in proper architectural arrangement separates this unusual proliferation from angiosarcoma and KS. Follow-up: 1 death of pulmonary embolism after excision, I persistent but now stable tumor at 2 years; I alive and free of rumor at 3 years after local recurrence and radiation at I yr.; and l recent amputation due to extensive pain and tumor. We call attention to this unusual and uncharacterized entity to alert pathologists and avoid confusion with angiosarcoma and KS on both biopsy and resection specimens.

Brooks JJ, Elenicsas R. Hicks D, Elder DE. Proliferative cutaneous angiomatosis: a cellular tumor mimicking angiosarcoma and IU!posi's sarcoma. Mod Pathol 1993 (abstract section). CASE 8. 24412 Angiosarcoma, epithelioid

HISTORY: This 54-year-old female ~;>resented with a lesion in the left upper back and left axilla. The specimen consisted of a skin ellipse which measured 7.0 x 3.5 x up to 1.5 ern. There was a rough gray-pink, slightly raised circumscribed lesion protruding from the epidennal surface, which measured 4.0 x 2.0 x up to 0.2 em. Sectioning revealed a reddish-gray lesion, measuring up to 0.8 ern in thickness. It was surrounded by nonnal-appearing skin and subcutaneous fat. In addition, a second specimen, labeled "left axilla" was received. It consisted of a roughly elliptical segment of skin which measured l.3 x 0.6 x up to 0.5 em. There was an iln-defined, slightly raised gray-pink nodule protruding from the center of the superior surface, which measured up to 0.7 em in dimension.

Differential Diagnosis Carcinoma, pd squamous Adenocarcinoma, metastatic Lymphoma, Ki-1 Melanoma Angiosarcoma, epithelioid

Imm unohistochemical R esults Des min SJOO CD34 - HHF35 HMB45 CD31 ++ SMActin Fl3a FVIli + Myoglob. CD68 EMA Viment. MIC2 CK-AE CEA Chrornog CK-CAM

Angiosarcoma (AS) Angiosarcomas (AS) account for less than 1% of all sarcomas. This tumor may occur in any location such as the skin and superficial soft tissues (33% AS), deep soft tissues (25% AS), breast (25% AS), bone, and visceral organs such as the liver and the spleen. In some cases there are predisposing factors such as chronic lymphedema (found in 10% of skin lesions, including post-mastectomy cases), radiation (again found with skin cases), and thorium and vinyl chloride (in liver cases). Skin & Subcutaneous AS Somewhere between one-third to one-half of all angiosarcomas occur in the skin, particularly on the head and neck of elderly patients. Males are affected more commonly than females, and the tumor appears as either re:ddlsh-blue nodules or, more commonly, as flat spreading bruises. While this might be evident clinically, ihe spreading bruises, if under the scalp as is often the case, are discovered late after they have reacbed a large size. The full extent is frequently underestimated by the clinician. Due to this "iceberg" effect, local excision is often inadequate, and recurrence is incredibly common. In this fonn, a high percentage of patients frequently develop early metastatic disease, and the overall prognosis is quite poor. This group is the largest and most common presentation. Deep S oft Tissue AS. Like skin AS, primary deep soft tissue angiosarcomas occur predominately in males. However, these tumors may occur at any age and are located predominately on the extremities, in the abdominal cavity, and in association with major. vessels. Occasional cases are associated with vascular stasis as noted by Maddox and Evans. Since there are so few cases, not much is known about the natural history; it is unlikely to vary considerably from other AS. Regardless of site, angioslj!'conia is a highly aggressive lesion and in most instances the degree of differentiation or grade does nor affect the overall survival (exception: the breast). Only· size is important prognostically, with tumors <.5 ern being more favorable in terms of survival (Maddox & Evans). Other P·resenting Forms of AS There are two other common presenting forms of AS. Patients with long-standing lymphedema have an increased chance of developing AS in the affected extremity. In the days of radical breast surgery for cancer, ·post-masiectomy angiosarcoma developed after a latent period of about 10 years in a number of cases. These patients were frequently in the seventh decade of life and had a mean survival of 19 months. Since these tumors express Factor Vill- related antigen, they have a derivation from blood vessel rather !han lymphatic endothelium. The other common site is within the ~ affecting patients in the third and fourth decade of life. While rumors may be small, they frequently produce diffuse enlargement of the breast with overlying skin discoloration. The histology can be deceptively bland, and it is important to realize !hat there is also a full spectrum of benign vascular lesions of the breast which must be considered. The location within the breast may provide some key because many superficial cutaneous or subcutaneous vascular lesions are commonly benign; in contrast the mammary AS involves the actual breast parenchyma. Morphology The majority of AS disclose !heir nature by the formation of easily recognizable and frequently open vascular channels. Unlike benign tumors, these channels freely anastomose and branch. They are lined by "too many cells" to cover the space, and the cells are plump with prominent hyperchromatic nuclei. In addition, tufts of endothelial cells protrude into the vascular channels. In the skin, the proliferation frequently utilizes existing collagen bundles as a "scaffold" aod these small circular and separated pillars are a clue to the diagnosis. Also, AS has only one cell layer • endothelial • aod thus staining with SMA [smooth muscle actin] will be negative, unlike angiomatoses which have the second layer of pericytes. Angiosarcoma: SubtypesfYariations Hemangioma-like PapiUary/vascular Kaposi's-Jike Sclerosing (fibromatosis-like) Choriocarcinoma-like Epithelioid Fibrosarcoma-like Epithelioid AS Some cutaneous & deep forms are quite epithelioid in appearance, with round to polygonal cells growing in diffuse sheets. This cutaneous and highly aggressive epithelioid variant should be distinguished from melanoma & carcinoma, particularly adenocarcinoma, because the vacuoles in epithelioid AS resemble signet ring cells. Also, one needs to exclude epithelioid hemangioendothelioma, a tumor of much lower malignant potential. In this more poorly differentiated form, the cells commonly have enlarged nuclei with nucleoli, a.nd the only hint at vascular structure is found either at the edge with vessel formation or centrally with the septated vacuole. There are deep variants of epithelioid angiosarcoma as well where they may arise from arterial endothelium. Recently, a granular variant has also been described. Still other forms may resemble Kaposi's sarcoma, or they may be extremely bloody and similar to choriocarcinoma (particularly in the lung). Highly cellular cases may spindle. resembling fibrosarcoma, but open vascular channels are usually visible in foci. Last, there is a peculiar sclerosing form resembling fibromatosis. However, at high power, one realizes that the cells are growing in thin strands which frequently branch and which often have a double row of celts. Occasionally the cells split apart, forming vascular channels, or have septated vacuoles with red cells. It is common for epithelioid angiosarcoma to express cv10keratin. leadjn<> to a mjs-djasnosjs of carcinoma or even mesothelioma at times, _ Mimics of Angiosarcoma include cutaneous spindle cell carcinomas which can be angiomatoid when acantholytic. Other carcinomas such as Merkel cell carcinoma aod thyroid carcinoma may occasionally take on a similar appearance and contain bloody areas simulating vascular channels. Aggressive Nature of AS Regardless of site, angiosarcoma·is a highly aggressive lesion, and in most instances the degree of differentiation or grade does not affect the overall survival (exception: the breast where there is ao apparent relationship between histologic grade and survival) . . Abrau R. Williams M. Dodd N, Uys, C. Angiosareoma of the superior vena cava. Cancer 52:740-743, 1983. Alles. J. U., and Bosslet. K.: Immunocytochemistry of angiosarcomas. A study of t9 cases with special emphasis on the applicability of endothelial cell specific markers to routinely prepared tissues. Am J Clin Pathol, 89:463· 471, 1988. Cooper P.H.. Angiosarcomas of the Skin. Sem. Diag. Pathol. 4: 2-17, 19 87. Donnell RM, Rosen PP, Lieberman PH, Kaufman RJ, Kay S, Braun OW Jr, Kinne OW. Angios3J'coma and other vascular tumors of the breasL Am J Surg Parilol 1981;5:629-642. Fineberg S, Rosen PP: Cutaneous angiosarcoma and atypical vuscular lesions of !he skin and breast after radiat.ion therapy fa breast carcinoma. Am J Clin Palhol 102:757-763. 1994. Heyman J, Huygens H. Angiosarcoma developing around a foreign body. J Clio Pathol 36:515-518, 1983. Hodgkinson OJ. Soule EH, Woods JE. Cutaneous angiosarcoma of the head and neck. Cancer 1979;44:1106-1113. Holden C, Spittle M, Jones E. Angiosarcoma of the face aod scalp: prognosis and treatmenL Concu 1987;59:104~1057. Hunter TB. Martin PC, Dietzen CD. Tyler LT. Angiosarcoma of the breast. Two ease repons and a review of the literature. Cancer 1985;56:2099-2106. Maddox JC. Evans HL. Angiosarcoma ofskin and soft tissue: a study of forty-four cases. Cancer 1981:48:1907-1921. McWilliams U. Harris M. Granular cell angiosarcoma of the skin: histology, electron microscopy and immunohistochemistry of a newly recognized tumor. Histopathology 1985;9:1205-1216. McWiiHarns U , Harris M. Histogenesis of post-mastectomy angiosarcoma· an ulcrastructural study. Hisroparlrology 1985;9:331-343. Merino M. Bertnan M, Carter D. Angiosarcoma of the breast. Am J Surg Pathol 1983;7:53-60. Morales P, Lindberg R, Barkley H. Soft tissue angiosarcomas. 1m J Radiar Oncol Bioi Phys 1981;7: 1655-1659. Rosai J, Sumner H, Kostianovsky M, Perez-Mesa C. Angiosarcoma of tfle skin: a clinico-palhologic and line structural study. Hum Par!Jo/ 1976;7:83-109. Mimics of Angiosarcoma Calonje E. Fletcher COM, Wilson-Jones E, Rosai J: Retiform hemangioendothelioma: A distinctive form of low-grade angiosarcoma delineated in a series of 15 cases. Am J Surg Pathol 18: 115-l25, 1994. ( 10400} Mills S.E., SL:lllinss R.G., Austin M.B., Angiomatoid Carcinoma of the Thyroid Gland: Anapluslic Carcinoma Wilh Follicular and Medullary Fearures Mimicking Angiosarcoma. Am. J. Clin. Pathol. 86:674-678, 1986. Tyring S.K.. Lee P.C., Omura E.F., Green L.K.. Merot Y., Recurrent and Mewuuic Cutaneous Neuroendocrine (Merkel cell) Carcinoma Mimicking Angiosarcoma. Arch. Dermatol. 123:1368-1370. 1987. Angiosarcoma 1990-1996 Fletcher COM, Beharn A, Bekir S, Clarke AMT, Marley NJE. Epithelioid angiosarcoma of deep soft tissue: A distinctive tumor readily mistaken for an epilhelial neoplasm. A m J Surg Parhal 1991 ; 15:915-924. Fukunasa M, Shimoda T, Nikaido T, Ushigome S, Ishikawa E: Soft tissue vascular tumors: A flow cytometric DNA analyt Cancer 71:2233 -2241, 1993. {9322} Goldblum JR, Rice TW: Epithelioid angiosarcoma of the pulmonary artery. Hum Pathol 26: 1275-1277, 1995. Mark RJ, Tran LM. Sercarz J, Fu YS, Calcaterra TC, Juillard GF: Angiosarcoma of !he head and neck: The UCLA experien 1955 through 1990. Arch Otolaryngol Head Neck Surg 11 9:973-978, 1993. Miettinen M, Lindenmayer AE, Chaubal A: Endothelial cell markers CD31, CD34, and BNH9 antibody to H· and Y-antige evaluation of their specificity and sensitivity in the diagnosis of vascular tumors and comparison with von Willeb factor. Modern Pathology 7:82-90, 1994. McCiuggage WG, Clarke R, Toner PG: Cutaneous epithelioid anlliosarcoma exhibiting cytokeratin positivity. Histopalhology 27:29 1-294, 1995. Morrison WH, Bye!'$ RM, Garden AS, Evans HL, Ang KK. Peters U: Cutaneous angiosarcoma of the bend and neck: A lherapeutic dilemma. Cancer 76:319-327, 1995. Orchard GE, Zeiger B, Jones EW, Jones RR: An immunocytochemical assessment of 19 cases of cutaneous angiosarcoma. Histopalhology 28:235-240, 1996. Prescott RJ, Banerjee SS. Eyden BP, Haboubi NY: Cutaneous epithelioid angiosarcoma: A clinicopalhological study of four cases. Histopathology 25:421-429, 1994. Tomita Y. Naka N, Aozusa K, Cesarman E. Knowles OM: Absence of Kaposi's-sarcoma-associated herpesvirus-like DNA sequences (KSHV) in angiosarcomas developing in body-cavity and other sites. Int J Cancer 66:141-142, 1996. Wenig BM, Abbondanzo SL, Heffess CS: Epithelioid angiosarcoma of the adrenal glands: A clinicopalhologlc study of nine with a discussion of the implications of finding "epithelial-spec itlc" markers. Am J Surg Palhol 18:62-73, 1994. CASE 9. 27593 Mesenchymal Chondrosarcoma HISTORY: This77-year-old female presented with amass on the left foot. Radiologically,the rumor did not involve the bone and was surgically "scraped off" the underlying bone. Differential Diagnosis Hemangiopericytoma (HPC) Langerhans Cell Histiocytosis Malignant nerve sheath (MPNST) Chondrosarcoma, mesenchymal Synovial sarcoma Leiomyosarcoma This ltighly cellular tumor had nuclei which were uniform and slightly grooved. Thus, Langerhans cell histiocytosis may be considered but the mitotic rate was high and there were no other elements like eosinophils. Foci of pale cells were seen which are suggestive of chondroid differentiation. Immunohistochemical Results Desmin + SlOO ++ CD34 - HHF35 HMB45 CD31 - SMActin F l3a FVlll Myoglob. CD68 EMA Viment. .tvnC2 + CK-AE These results confirm a chondroid nature to the pale areas. Oddly, there was focal desmin and MIC2 in a cytoplasmic staining pattern -both aberrant. The lack of cytokeratin excludes monophasic synovial sarcoma as long as no other suggestive findings are present. Mesenchymal Chondrosarcoma This tumor is much Jess common in soft tissue than the myxoid type (about 1/4) as common; and less common in soft tissue than in bone (1/3, Nakashima 1986). In one fonn, it is easy to recognize since large areas of well differenti.ated cartilaginous or chondrosarcomatous regions are present accompanied by a population of highly cellular small rounded printitive appearing cells. It is more difficult to recognize when the cartilaginous foci are extremely small and very widely scattered. Here, the small primitive cell component frequently grows in a hemangiopericytomatous pattern; the diagnosis is clinched by the recognition of the sometimes minute areas of cartilaginous differentiation. Indeed, finding this bimowhie-pattem, even when nearly concealed, is pathognomonic. It might be thought of as a hemangiopericytorna with cartilaginous differentiation. Because it often has HPC areas, an S l 00 stain is an important marker to order for nay HPC-like tumor. Prognosis The survival of soft tissue tumors is the same as primary bone tumors [Nakashima 1986] with the 5 year survival = 54% and the 10 year= 27%. Lesions with mainly small cell lesions can respond to chemotherapy [Huvos 1983]; otherwise, there are no reported prognostic factors.

Bertoni F, Picci P. Bacchini P, Capanna R, lnnao v. Bacci G. Campanacci M. Mesenchymal chondrosarcoma of bone and soft tissues. Cancer 1983; 53:533-541. • Guccion JG. Font RL, Enzinger FM. Zimmerman LE. Extraskeletal mesenchymal chondrosaiWma. Arch Pazho/1913; 95:336- 340. Huvos AG, Rosen G. Dabska M. Marcove RC. Mesenchymal chondrosl1l'COma. A clinicopathologic analysis of 35 patients w emphasis on treaunent. Cancer 1983: 51:1230-1237. Manlnez-Tello F, Navas-Palacios J. UltrasU'Uctural study of conventional chondrosarcomas and myxoid and mesenchymal chondrosarcomas. Virchows Arch [Pathol Anat] 396: 197-21 1, 1982. Nakashima Y, Unni KK, Shives TC. Swce RO, Dahlin DC. Mese11chymal chondrosarcoma of bone and soft tissue. A review Il l cases. Cancer 1986: 57:2444-2453 . Swanson P, Mnnivel J, Lillemoe T, Wick M. Mesenchymal chondrosarcoma: nn immunohistochemical study. Lab Invest 58: 90A, 1988. Uno K, Kataoka H. Kadota K. Extr.lskeletal mesenchymal chondrosarcoma in • cow. J Comp Patho/1989: 101:31-38. CASE 10. 26907 Malignant Hemangiopericytoma

H ISTORY: This 26-year-old male presented with a lump over his left shoulder joint at the site where a sebaceous cyst was removed four years prior. The mass was painless, without discharge or associated underlying bone pain. He underwent excision, but returned six months later with a recurrent mass, approximately 5 em in diameter, under the surgical scar. It was slightly raised and fluctuante. This was re·excised. The specimen was a discoid 70 x 55 x 25 mm ponion of skin and subcutaneous tissue. On sectioning, the subcutaneous fat contained two adjacent well-demarcated dark red to tan-red, soft circumscribed masses, one measuring 12 mm in diameter, and the other measuring 50 x 25 x 20 mm. Each mass extended to but did not penetrate the deep fascial membrane.

Differential Diagnosis (see also below) Hemangiopericytoma (HPC) MFH, angiomatoid Malignant nerve sheath (MPNST) Rhabdomyosarcoma (RMS) Synovial sarcoma Leiomyosarcoma Ewing's sarcoma. ST

Tllis concerns cases which, at least initially, appear to have a hemangiopericytoma (HPC) appearance. A diagnosis ofHPC js one of exclusion, and should only be made after an exhaustive attempt at identifying other specific fearures of rumors which can contain this panem. The diagnosis of fibrosarcoma is best reserved for cases with large. areas of so-called "herringbone" pattern, a fearure which if found in SS is very focal. In monophasic synovial sarcomas, spindle cells with slightly more eosinophilic cytoplasm can be seen and resemble the earliest suggestion of epithelial differentiation. These may be brought out by a reticulin stain which outlines such "nests". MPNST often have alternating hyper- and hypo- cellular regions and in the latter the cells take on the wavy appearance. Only 70% of MPNST are S 100 positive, and only in scattered fashion at best. Leiomyosarcoma is usually well recognised despite foci of HPC.

Immunohistochemical Results - this case Desnlin SlOO CD34 HHF35 HMB4S CD31 SMActin Fl3a FVm Myoglob. CD68 EMA - Viment. MIC2 + CK-AE Chromog CK-CAl'VI These results exclude synovial sarcoma, most MPNST, and muscle tumors. Note the aberrant expression of MlC2, although the staining was largely cytoplasmic - a known non-specific pattern. Here, with the pattern of HPC throughout and these results, a default diagnosis of HPC was made (and confirmed by Enzinger at the AFIP).

Hemangiopericyt oma (the tumor that usually isn't) What is an hemangiopericytoma? Most of the time one thinks a rumor may be an HPC, it is probably not. A wide variety of lesions may show the non-specific branching and staghom open vascular pattern. Although HPC was originally described by Stout, he himself rejected most cases diagnosed as such. A modem day defmition might be: a tumor which shows a consistent HPC pattern throughout the entire tumor, with reticulin surrounding individual cells (everywhere!; no epithelial-like islands), and which is immunohistochemically negative (muscle, nerve sheath, and epithelial markers). As such, HPC usually occur in the soft tissue, but cases are reported in the breast, nasal cavity, and CNS as well. Hemangiopericytoma Pattern: Differential Diagnosis Cellular hemangioma Nerve sheath tumors (inf. hemangioendothelioma) Thymoma Glomus rumor Mesenchymal chondrosareoma CASE 11. 24834 Clear Cell sarcoma HISTORY: This 29-year-old female presented with a 3.0 em mass arising from the tendon sheath of the left great toe. Differential Diagnosis Leiomyosarcoma Clear cell sarcoma (CCS) Rhabdomyosarcoma MPNST Synovial sarcoma

The nesting pattern of CCS may mimic the alternating bundle/fascicular pattern of a smooth muscle tumor, but in the latter, the bundles are not usually separated by collagen, the reticulin stain is decidedly different surrounding cells rather than nests, and the cells are not as uniform with the same nucleus/nucleolus throughout. Interestingly, melanoma of skin origin does come into the differential, due to the closeness of the skin 10 lesions of the foot and anke. Here, cutaneous melanomas or metastases thereof show more nuclear pleomorphism, larger cell size variation, discohesion within nests, and frequently more in the way of a lymphocytic host response. The key to this case is the nesting pattern which is present throughout, unlike rare epithelioid MPNST or leiomyosarcoma. Immunohistochemical Results - this case Desmin S lOO + CD34 - HHF35 HMB45 + CD31 SMActin F13a FVIll Myoglob. CD68 EMA - Viment. MIC2 CK-AE Clear Cell Sarcoma (CCS, melanoma of soft parts) The most immediately recognizable feature of this tumor is its growth pattern- nests of tumor cells are seen divided by fine fibrous tissue septa at low power. Occasionally, it can appear to be growing in sheets. The presence of this nesting pattern can be best illustrated on a reticulin stain (with cell groups rather than cells outlined, one of the few sarcomas with this reticulin pattern). The cells themselves are also highly characteristic having a nucleus which is round to oval with a central prominent nucleolus. There is marked uniformity of the nuclei and essentially no pleomorphism is present. While the name implies a clear cell cytoplasm, occasional cases have more eosinophilic cytoplasm resembling melanomas. Glycogen is identifiable in 2/3rds of cases. The vast majority of cases look remarkably alike. Mitoses usually scarce at about l-3/10 hpf, although some do divide at a much higher rate. Like melanoma, a significant number of cases will display actual melanin which can be identified on Fontana or argyrophilic stains. Chung & Enzinger (1983) could demonstrate such positive staining for melanin in 70%, but actual pigmem could be visualized on the H&E section in only 10/141. Microscopic Summary (after Chung & Enzinger I 983): 1) solid nests with fascicles - absence of reticulin in groups 2) clear to eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli 3) scattel'ed giant cells 4) rare mitoses Like melanoma, this lesion is commonly S 100 positive, approaching 100% of cases. The marker more specific for melanoma - HMB45 - is also nearly always positive as reported by Swanson et a! and Hasegawa eta!. Synaptopbysin & Leu 7 may be positive rarely, but CK, EMA, CEA, MSA, DES, and LCA are all negative. Clear Cell Sarcoma -Molecular Biology t(l2;22) (q12;ql2-13) -not seen in malignant melanoma! EWS, RNA binding protein on 22 ATF-1, transcription factor on 12q 13 Leiomyosarcoma (focal) Synovial Sar coma Liposarcoma (focal) Endometrial stroma sarcoma Malignant fibrous histiocytoma (focal) Hemangiopericytoma

It is therefore a diagnosis of exclusion, being most frequently mimicked by 1) synovial sarcoma, which may occasionally present as a pure HPC lesion requiring many blocks or additional tissue to demonstrate the epithelial differentiation. Thus, cytokeratin immunoreactivity is quite important and excludes HPC as a diagnosis. Probably next in frequency of HPC like tumors is a 2) malignant peripheral nerve sheath tumor (MPNST); therefore, any SlOO reactivity would also exclude HPC from the diagnosis. If focal cartilage is present in the form of small islands, the diagnosis becomes 3) mesenchymal chondrosarcoma. Even today some cases still remain which in the.end must be diagnosed as HPC after an extensive work-up. The natural histor y of HPC cannot always be predicted from the histology. A benign HPC is one which lacks necrosis, cellular pleomorphism, and has a low mitotic rate (either less than 4/l0 hpf in the Enzinger and Smith series or less than 1/20 hpf in that by McMaster et al). Malignant HPC is diagnosed whenever the above findings are present. With this definition somewhere between 20.-60% of HPC behave in a benign fashion. However, some histologically benign cases have metastasized. Clear-cut malignant cases, with necrosis and mitotic rates higher than above, have five and ten year survival rates of 40 and 29% respectively. Lessons: First, this case call attention to the fact that some sarcomas are originally mistaken for epithelial tumors, even of the skin. I have seen this in ·a recent case of a mesenchymal chondrosarcoma, ·also thought to b.e a skin adnexal tumor. Second, never diagnose HPC unless you can't use another label. So many are other tumors in disguise. Third, although it didn't work here, make use of CD34 when faced with this differential diagnosis.

Angervall L, Kindblom LG, Nielsen JM, Stener B, Svendsen P. Hemangiopericytoma: a clinicopathologic, angiographic and microangiographic study. Cancer 1978; 42:2412-2427. Battifora H: Hemangiopericytoma: ultrastructural study of five cases. Cancer 31: 1418·1432, 1973. Enzinger FM, Smith BH: Hemangiopericytoma. An analysis of I 06 cases. Hum Pathol7:61-82, 1976. Han L. Weinberg J. MetaStatic hemangiopericycoma with prolonged survival. Cancer 1987; 60: 916-920. Lnrigan JG, David CL. Evans HL, Wallace S. The clinical and radiologic manifestations ofhemangiopericytoma. Am J Roentgenol Radium 11Jer Nuc Med 1989.; 153:345- 349. McMaster MJ, Soule EH. Ivins JC: Hemangiopericytoma. A clinicopathologic study and loog·tenn followup of 60 patients. Cancer 36:2232-2244. 1975. Ramsey HJ. Fine structure of hemangiopericytoma and hemangio-endothelioma. Cancer 1966; 19:2005-2018. Tavassoli FA, Weiss S. Hemangiopericytoma of tbe breast. Am J Surg Parhol1981; 5:745-752. HPC 1990-1996 Eichhorn JH, Dickersin GR. Bhan AK. Goodman ML: Sinonasal hemangiopericytoma: A reassessment with electron microscopy, immunohistochemistry, and long-term follow-up. Am J Surg Pathol14:856-866, 1990. Finn WG. Goolsby CL, Sambasiva Rao M: DNA flow cytometric analysis of hemangiopericytoma. Am J Clin Pathol 101:181-185, 1994. Herath SE, Stalboerger PG, Dahl RJ, Parisi JE, Jenkins RB : Cytogenetic studies of four hemangiopericytomas. Cancer Genet Cytogenet 72:137-140, 1994. Middleton LP. Duray PH, Merino MJ: The histologic spectrum of hcmangiopericytoma: correlation with immunohistochemistry and proliferative matke•s. Mod Pathol 8:9A, 1995. Nemes Z: Differentiation markers in hemangioperieytoma. Cancer 69: 133-140, 1992. Nielsen GP, Diclcersin GR, Provenza! JM. Rosenberg AE: Lipomatous hemangiopericytoma: A rustologic, ultrastructural and immunohistochemical study of :a unique variant of hemangiopericytoma Am J Surg Pachol 19:748-756, 1995. . Poner PL, Bigler SA, McNutt M, Gown.AM: The immunophenotype of hemangiopericytomas and glomus tumors, with special reference to muscle protein expression: an immunohistochemical study and review of the literature. Mod Pathol4:46-52, 1991. . . . Yu CC-W, Hall PA. Fletcher COM, Camp1ejohn RS, Waseem NH, Lane DP, Levison DA: Haemangiopericytomas: The prognostic value of immunohistochemical staining with a monoclonal antibody to proliferating cell nuclear antigen (PCNA). Histopathology 19:'29-33, 1991. Fusion= EWS/ATF-1, most of ATF-1 with DNA binding Chimeric protein no longer regulated by cAMP as ATF-1 was Common oncogenic mechanism mediated by N-tenninal EWS like EWSIFLI-1 Prognostic Factors & Natural History: This tumor is aggressive with a high frequency of local recurrence (LR, in series of older cases this was as high as 80-100% ); LR is also found after some delay (i.e., beyond 4-5 years). Metastases are also very common, being primarily to lungs and lymph nodes. This is one of the sarcoma types (along with rhabdomyosarcoma, synovial sarcoma and MFH) which commonly metastasizes to regional lymph nodes, which should therefore be critically examined by clinicians. The metastatic rate is about 60-70% and in a number of cases the interval after diagnosis may be as long as 5-6 yrs (Chung & Enzinger). The prognosis is better if the lesion is small and superficial. Survival data for 2, 5, and I 0 year survival rates are not known or can't be calculated from published reports. Just recently, an MD Anderson study by Sara, Evans & Benjamin (Cancer 65: 367-374, 1990) analyzed 17 cases and correlated survival & metastases with tumQI' size > Scm; after size was corrected for, there were no other prognostic factors (including age/sex./site/mitoses & necrosis). Other authors have shown that a size >2.5 em portends a poorer prognosis.

Angervnll L, Sieoer B. Clenr-<:ell sarcoma of tendons. A study of 4 cases. Acta Patlwl Microbiol Sccuu/ 1969; 77:589- 597. Bearman R, Noe J, Kempson R. Clear cell sarcoma with melanin pigment. Cancer 1975; 36: 977-984. Bridge JA, Borek DA, Neff JR, Huntrakoon M. Chromosomal abnormalities in clear cell sarcoma: Implications for histogenesis. Am J Clin Pathol 1990; 93:26-3 1. Chung E, Enzinger F. Malignant melanoma of soft partS. A reassessment of clear cell sarcoma. Am J Surg Palhol 1983; 7:405-413. Enzinger F. Clear-cell sarcom• of tendons and aponeuroses: An analysis o£21 cases. Cancer 18: 1163-ll74, 1965. Hasegawa T. Hirose T, Kudo E, Hizawa K. Clear cell sarcoma; an immunohistochemical and ultrastructural study. Acta Palhol Jpn 39: 321-327, 1989. . Kindblom L, Lodding P, Angervall L. Clear-cell sarcoma of tendons and aponeuroses: an immunohistochemical and electron microscopic analysis indicating neural crest origin. Virchows Arch (Pathol A nat) 1983; 40 I: I 09- 128. Lucas DR, Nascimento AO. Sim FH. Clear cell sarcoma of soft tissues: Mayo Clinic experience with 35 cases. Am J Surg Pathol !992: 16:1197-1204. Mii Y. Miyaucbi Y, Hohnoki K, et al. Neural crest origin of clear cell sarcoma of tendons and aponeuroses: ultraSttUctural and enzyme histochemical study of human and nude mouse-uansplanted tumours. Virchows Arch Polhol Anat 415: 51-60, 1989. Mukai M, Torikata C, lri H, Mikata A, Kawai T. Hanaoka H, Yakumaru K. Kageyama K. Histogenesis of clear cell sarcoma of tendons and aponeuroses. Am J Pathol l984; ll4:264-272. Povlidis N, Fisher C, Willshaw E. Clear-cell sarcoma of tendons .and aponeuroses: a clinicopathologic study. Cancer 1984; 54: 1412-1417. Sara AS, Evans HL, Benjamin RS. Malignant melanoma of soft partS (clear cell sarcoma): A study of 17 cases. with emphasis on prognostic factors. Cancer 1990; 65:367-374. Swanson PE. Wick MR. Clear cell sarcoma: an immunohistochemical analysis of six cases and comparison with other epithelioid neoplasms of soft tissue. Arch Palhol Lab Med 113: 55-60, 1989. Tsuneyoshi M, Enjoji M. Kubo T. Clear cell sarcoma of tendons and aponeuroses: a comparative study of I 3 cases with a provisional subgrouping into the melanotic and synovial types. Cunc.er 1978; 42: 243-252. 1993· 1995 Sonobe H, Furihata M.lwnta J, Ohtsuki Y, Mizobuchi H, Yamamoto H, Kumano 0. Establishment and characterization of a new human clear-cell sarcoma cell-line. HS-.MM. J Pat hoi 1993; 169:317-322. Ekfors TO, Kujari H. Isomllki M: Clear cell sarcoma of tendons and aponeuroses (malignant melanoma of soft partS) in the duodenum: The first visceral case. Histopathology22:255-259. 1993. Fujimura Y. Ohno T, Siddique H, Lee L, Rao VN, Reddy ESP: The EWS-ATF-1 gene involved in malignant melanoma of soft partS with t(J2;22) chromosome translocation, encodes a constitutive 1ranscriptional activatOr. Oncogene 12:159-167. 1996. • Yates AJ, Banerjee SS. Bishop PW, Graham KE: HMB-45 in non-melanocytic tumours. Histopathology 23:477-478. 1993. CASE 12. 27730 Alveolar Soft Part Sarcoma (ASPS)

IDS TORY: This 20-year-old male presented with a mass in his right thigh area. He was otherwise asymptomatic, and denied weight loss, night sweats or chills. MRI demonstrated a soft tissue mass. An incisional biopsy was done, and found to be consistent with a sarcoma. Physical exam done at the time of admission demonstrates a mid-lateral right thigh mass. 4 x 5 em, with increased warmth and a healed biopsy site. The mass appeared adherent to underlying tissue, and was non-tender. A wide local excision of right thigh sarcoma with margins was performed. There was a 4.5 x 3.0 x 3.3 em yellow-tan, well-circumscribed mass located centrally, 1.0 em below the skin surface, without areas of hemorrhage or necrosis. The rumor did not involve the subcutaneous tissue. All margins were free of rumor grossly.

Differ ential Diagnosis Granular cell tumor Paraganglioma Renal cell carcinoma Granular leiomyosarcoma Adrenal cortical carcimoma Rhabdomyosarcoma Alveolar soft part sarcoma

True pleomorphism virtually excludes ASPS; it is common in adrenal tumors and random pleomorphic cells are seen in paraganglioma. While ASPS has a granular cytoplasm, the other granular rumors above lack the characteristic alveolar morphology.

Immunohistochemical R esults - this case Des min + SlOO CD34 - HHF35 HMB45 CD31 SMActin Fl3a FVIII Myoglob. CD68 EMA - Viment. MIC2 CK-AE Chromog + CK-CAM These results help exclude other muscle tumors, granular cell tumor etc.; they are consisten with ASPS, with the odd result of some chromogranin (which I have never seen in this tumor, which is not a paraganglioma).

Alveolar soft part sarcoma (ASPS) The histologic features of a ASPS are extremely consistent from case to case, and no other sarcoma has quite the same appearance as this one. On lower power, one finds thick fibrous trabeculae dividing the tumor into large compartments. Immediately apparent is the classic alveolar structure of the rumor. These alveolar structures are surrounded by small capillary vessels and contain within them groups of tumor cells; the alveolar pattern is well illustrated by a reticulin stain (surrounding nests rather than individual cells). Central degeneration and loss of cohesion is a common feature within these alveolar structures. The cells themselves are large, round to polygonal, and contain granular eosinophilic cytoplasm; occasional cells are clear or vacuolated. The nuclei are also classic and very uniform in appearance, being round with a single prominent nucleolus. Occasional tumor cells are either binucleated or multinucleated. Rarer still are true pleomorphic appearing tumor giant cells with irregular nuclei. There is generally no pleomorphism; if tbis is present think of another tumor. Mitoses as a rule are scarce and difficult to ftnd. A common feature js vascular jnva!ljon PAS positive diastase resistant crystalline material, apparently actin, can be found in most cases but it is quite variable in quantity.

Alveola r soft part sarcoma (ASPS) remains a tumor of undetermined origin. While a number of studies have shown scattered muscle marker reactivity (particularly desmin and MSA), there has been no reactivity for myoglobin or titin. Ukewise, tbe recent finding of MyoD I irnmuno reactivity has been doubted to define ASPS as a myogenic tumor. However several groups have now failed to identify MyoDl in ASPS, calling such fmdings into question. Likewise miogenin is not found in ASPS. Therefore, while ASPS may be of a miogenic origin, it certainly is an e)(tremely unusual miogenic tumor. It is also possible that muscle marker reactivity in such tumors is a result of uptake as the tumor overgrows skeletal muscle in the region. Clearly further work needs to be done to elucidate a true origin of ASPS. Literature - Immunohistochemistry 1982 DeScluyver Renin+ 1983 Mukai Renin- 1983 Denk Desmin+ 1985 Mukai Desmin+ (& 1989) 1987 Auerbach Desmin- 1988 Foschini Myosin+ 1990 Miettinen Desm.in+, MSA+ 1991 Hirose Desm.in+, MSA+, SMA+ 1991 Rosai MyoD 1+ protein 1992 Cullinane MyoD l- mRNA 1993 Sciot Desm.in+, l7q25 abn. 1995 Wang Myogenin-, MyoDl- in nuclei Prognostic Factors & Natural History: The course in the usual patient may be quite prolonged due to the slow growth rate of these tumors. However, the ultimate prognosis is poor as there have been no known cures. The patients need to be followed for an extremely long period of time, since delayed metastases and death may occur in the 10 to 20 to 30 year range. The largest series, by Leibennan eta!., gives the following survival figures: 83% 2 year; 59% 5 year; and 47% 10 year rates. Only 13 of their 53 original patients were alive and well without local recurrence and metastases. Local recurrence occurs in approximately V3 of the cases and metastases .in nearly 213. Most common sites of metastases are the lung (42% ), bones (19% ), brain (15%, more common than any other soft tissue tumor), and lymph node (7% ). It is important to remember that patients may survive for long periods following resection of pulmonary metastases. In the recent update of the Memorial experience, the newest survival figures are 60% 5 year, 38% 10 year, and 15%20 year survival. Prognostic Factors: There is only a suggestion that young .females and patients with the non-alveolar pattern fare better than average. Tumor size >Scm has been reponed to be prognostically important (Evans ) but th.is was based on a small series; it may be that size is related to d.isease free interval, but, as all patients have eventually succumbed to th.is tumor if followed long enough [Leiberman 1966, 1989], a small size does not at all imply curability. Nonetheless, size does have a statistically significant negative impact on survival as does age at diagnosis (due to increased mets in older patients [Leiberman 1989).

ASPS 1990-1995 Carstens PHB : RelrOperitoncal sarcoma wilb fearures suggestive of alveolar soft part sarcoma. Ultrasttuct Patbol 15:509- 513. 1991. . Cbeuy R: Alveolar sofl pan sarcoma with -psammoma bodies. Histopalhology 17:188, 1990. Coira BM, Sachdev R, Moscovic E: Skeletal mu_~cle markers in alveolar soft pan sarcoma. Am J Clin Pathol 94:799- 800, 1990. Cullinan~ C, Thorner PS, Greenberg ML. Ng YK, Kumar M, Squire J: Molecular genetic-. cytogenetic. and Immunohistochemical characterization of alveolar soft-part sarcoma: Implications for cell of origin. Cancer 70:2444-2450, 1992. Guillou L. Lamoureux E. MasseS, Costa J: Alveoll!f soft-pan sarcoma of the uterine corpus: Histological, immunocytochemical and uHrasttuctural study of a case. Virchows Arch [AI 418:467-471, 1991. Heller OS, Frydman CP, Gordon RE, Jagirdl!f J, Schwanz IS: An unusual organoid tumor: Alveolar soft pan snrcoma or pat:lgangliomn? Cancer 67:1894-1899, 1991. Hirose T, Kudo E. Hasegawa T. Abe J-1. Hizawa K: Cytoskeletal propenies of alveolar soft pan sarcoma. Hum Palhol 21:204-211. 1990. Ullehei KO, Kleinschmidt-DeMasters B, Mitchell DH. Spector E. Kruse CA: Alveolar soft part sarcoma: An unusually long interval between presen~ation and brain metastasis. Hum Palhol24:103().1034. 1993. Menesce LP, Eydcn BP, Edmondson D. Barris M: Immunophenotype and ultrastructure of alveolar son part sarcoma. J Submicrosc Cytol Pathol 25:377-3871 1993. Mieuincn M, Elders T: Alveolar soft pan sarcoma: Immunohistochemical evidence for muscle cell differentiation. Am J Clin Patbol 93:32-38, 1990. Mukai M, Torikata C. Iri H: Alveolar soft pan sarcoma: An electron microscopic study especially of uncrystallized granules using a tannic acid-containing fixative. Ultrnstruct Pathol 14:41-50, 1990. Nakashima Y, Kotoura Y, Kasakura K, Yama,muro T. Amitani R. Ohdera K: Alveolar soft-pan sarcoma: A report of ten cases. Clin Onhop 294:259-266, J 993. Perry JR, Bilbao JM: Metastatic alveolar soft part sarcoma presenting as a dural-based cerebral mass. Neurosurgery 34:168-170, 1994. Rosai J, Dias P, Parham DM, Shapiro ON, Houghton l': MyoD I protein expression in alveolar soft part sarcoma as conftrmatory evidence of its skeletal muscle nature. Am J Surg Pathol 15:974-98\, 199 I. Sciot R. Dal Cin P. de Vas R, Van Damme .B, De Wever!, Van Den Berghe H. Desmet VJ: Alveolar soft-part sarcoma: Evidence for its myogenic origin and for the involvement of 17q25. Histopathology 23:439-444, 1993. Sreekantaiah C, Li FP. Weidner N, Sandberg AA: Multiple a11d complex abnormalities in .a case of alveolar soft-part sarcoma. Cancer Genet Cytogenet 55:167-171, 1991. Tallini G, Parham DM, Dias P, Cordon-Cardo C, Houghton PJ, Rosai J: Myogenic regulatory protein expression in adult soft tissue sarcomas: A sensitive and specific marker of skeletal muscle differentiation. Am 1 Pathol 144:693-701, 1994. Temple HT, Scully SP, O'Keefe RJ. Rosenthal Dl, Mankin HJ: Clinical presentation of alveolar soft-part sarcoma. Clin Orthop 300:213-218, 1994. Tucker JA: Crystal-deftcient alveolar soft part sarcoma. Ultri>struct Pathol 17:279-286. 1993. Wang NP, Marx J, McNutt MA, Rutledge JC, Gown AM: Expression of myogenic regulatory proteins (myogenin and MyoDI) in small blue round cell tumors of childhood. Am J Pathol 147:1799-1810; 1995. Yagibasb.i S, Yagihasbi N, Hase Y, Nagai K, Alguacii-Garcia A: Primary alveolar soft-pan sarcoma of stomach. Am 1 Surg Pathol 15:399-406, 1991. Selected older references Auerbach, H.. Brooks. J. Alveolar soft pan sarcoma: A clinicopathologic and immunohistochemical study. Cancer QQ.: 66-73, 1987. Evans H. Alveolar soft pan sarcoma: a study of 13 typical e:xamples and one with a histologically atypical component. Cancer 55 : 912-917, 1985. Foschini MP, Ceccarelli C, Eusebi V, Skalli 0, Gabbiani G. Alveolar soft pan sarcoma: immunological evidence of rhabdomyoblastic differentiation. Hislopathology 1988; 13:101-108. Lieberman PH, Brennan MF, Kimmel M, Erlandson RA, Garin-Chesa P, Flebin.ger BY. Alveolar soft-pan sarcoma: A clinico-pathologiC study of half a century. Cancer 1989; 63: 1- L3. CASE 13. 25209 Granular Cell Tumor

IDSTORY: A 37-year-old Black female presented with a raised, 2.0 x 2.0 em lesion on the left labium. An excisional biopsy was performed. Gross exam showed a tan piece of skin and fibroadipose tissue measuring 2.5 em in greatest dimension. There was a hard, white, homogeneous, nodular area occupying 80% of the cut surface. Differential Diagnosis Granular cell tumor Malignant granular cell tumor (MGCT) Granular leiomyosarcoma Rhabdomyosarcoma Granular angiosarcoma Melanoma Immunohistochemical Results ~min SlOO ++ CD34 - HHF35 HMB45 CD31 SMActin Fl3a FVlll Myoglob. CD68 ++ EMA Viment. MIC2 CK-AE Benign Granular Cell Tumor (BGCT) This is a tumor which is fairly common and is usually diagnosed after biopsy. It is most common in patients in the fourth, fifth and sixth decades of life and twice as common in women as in men. lt presents as a solitary painless lump usually within the dermis. Tl\e tumor may also be found in the viscera. Patients may present with multiple BGCT's; this is not a rare findii!g and may occur in anywhere from 7-16% of all patients, according to Moscovic and Azar. Although it's nature is now known to be Schwannian (see below), multiple BGCT's are almost never found in neurofibromatosis. The histology is quite straightforward. The vast majority of lesions are small, usually less than 3 em. The characteristic feature histologically is the presence of abundant eosinophillc and granular cyteplasm coupled with a small often pyknotic nucleus. The tumor cells tend to grow in clusters, sheets or trabeculae and for the most part have indistinct cell borders. The presence of nucleoli is quite unusual and mjtotjc figures and necrosjs are essentially never fougd. The tumor characteristically invades surrounding structures and may often show neurotropism (involvement of local small nerves). The granules, ultr1J,structurally shown to be autophagosomes, are PAS positive and diastase resistant and may vary quite a lot in size. Variable. granules are actually diagnostic. The(apy for the BGCr includes total surgical excision. Local recurrences will in about 6% of cases, Essentially all BGCT display immunoreactive S 100 protein. The immunohistochemical profile is that of a altered Schwannian cell, a fact in keeping with the occasional observance of granular morphology focally within Schwanommas and neurofibromas. Differential Diagnosis: Tumors with Granular Cytoplasm* Polypoid melanoma • Schwannoma Ameloblastoma • Leiomyoma *Only OCT's have Other odontogenic tumors • DFSP variably-sized granules. Certain reactive lesions • Leiomyosarcoma • Juxtaglomerular tumor • Alveolar soft part sarc Glioblastoma • Angiosarcoma Primitive polypoid GC tumor •MFH

Malignant Granular CeU Tumor (MGCT) may occur in a very wide age range (23-82 years). Like its benign counterpart, the majority of cases occur within the fourth to sixth decades of life. The average age of all 23 patients was 45.7 years. Information concerning the patient's sex also parallels ihat seen in the benign granular cell tumor: the female/male ratio i.s 2.3, approximating the 2:1 ratio seen in the benign counterpart. Most patients present with an asymptomatic solitary nodule on the external body. While most lesions were located on the external surfaces, either in the superficial skin or deep soft tissues, four cases were located in the viscera (including the case by Powell et al). Once again, a parallel is noted here regarding location in comparison to the benign variant. Most cases have been recognised after metastases develop. Are there criteria for diagnosing MGCT prospectively? Yes. MGCT: Comparison with Be1.1ign Tumor BGCT MGCT Size 1-3cm 2-IOcm Nuclei Small, pyknotic Large, vescicular Nucleoli No Yes Sheets No Yes Spindling No Yes, some Necrosis No Yes, so01e Mitoses No Yes, rare; nearly any (eg., 1120 hpf) suspicious

"Suspicious for malignancy" will caus~ proper excision, search for local nodal involven1ent.

Armin A., Connelly E.M .. Rowden G. An immunoperoxidase investigation of S 100 protein in granular cell tl)yoblastomas: Evidence for Schwann cell derivation. Am. J. Clin. Pathol. 79: 37-44, 1983. Dhillon A.P., Rode, J. Immunohistochemical studies of S £00 protein and other neural characteristics expressed by granular cell tumor. Diagnostic Histopathol. 6: 23-28, 1983. Enzinger F .. Weiss S. Soft Tissue Tumors. C.V. Mosb}' Co., St. Louis. 1995. Finkel G., Lane B. Granular cell variant of neurofibromatosis: Ultrastructure of benign and malignant tumors. Hum. Pathol. 13:959-963, 1982. Matthews J., Mason G. Granular cell myoblastoma: An immunoperoxidase study using a variety of antisera to human carcinoembryonic antigen. Histopathology 7:77-82, 1983. McWilliams L.J., Harris M. Granular ·cell angiosarcoma.(}[ the skin: histology, electron microscopy and immunohistochemistry of a newly recognized tumor. Histopathology 9:1205-1216, 1985. Mukai M. Immunohistochemical localization of SJOO protein and peripheral nere proteins (P2 proiein, PO protein) in granular cell tumors. Am. J. Pathol. 112: 139-146, 1983. Naka.uuo Y., lshizeki.J., Takahashi K .. Yamaguchi H. Immunohistochemical localization of SIOO protein in granular cellmyoblastoma. Cancer 49: 1624-1628, 1982. Ravich A., Stout A.P.. Ravich R.A. Malignant g~anular cell myoblastoma involving the urinary bladder. Annals of Surg. 121:361-372, 1945. RobertSon A.J., Mcintosh W., Lamont P .• Guthrie W. M"'lignant granular cell tumor (myoblastoma) of the vulva: report of a case and review of the literature. Histopathology 5:69-79. 1981. Shimamura K .• Osamura R.Y., Ueyama Y., et at. Malignant granular cell tumor of the right sciatic nerve. Report of an autopsy case with electron microscopic, immunorustochemichl, and enzyme histochemical studies. Cancer 53: 524-529, 1984. Stefansson K., Wollman R.L. SIOO protein in granular cell tumors (granular cell myoblastomas). Cancer 49: 1834- 1838, 1982. Steffelaar J.W ., Nap M., v. Haelst U.J.G.M. Malignant granular cell tumor. Report ofa case with special reference. to carcinoembryonic antigen. Am. J. Surg. Pathol. 6: 665-672, 1982. 1993-1996: G ra nular Cell tumors Mentzel T, Wadden C. FletcHer COM: Granular cell change in smooth muscle tumours of skin and soft tissue. Histopathology 24:223-231. 1994. Sobel HJ: Epithelioid leiomyoma of the breast with granutiar cell change. Hum Pathol25:625, 1994. Pi ana S. Roncaroli F: Epithelioid leiomyosarcoma of retrOperitoneum with granufar cell change. Histopathology 25:90· 93, 1994. . Nikkels AF. Arrese Estrada J, Pierard·Franchimont C, Pierard GE: CD68 and factor XIIIa expressions in granular·cell tumor of the skin. Dermatology 186:106-108, 1993. Kunin PJ, Bonin OM: Immunohistochemical demonstration of the lysosome-associated glycoprotein CD68 (KP-1) in granular cell tumors and Schwannomas. Hum P.athol 25:1 I 72- 1178, 1994. Lee J. Bhawan J, Wax F, Farber J: Plexiform granular cell tumor. A report of two cases. American Journal of Dermatopathology 16:537-541, 1994. Parayno PP, August CZ: Malignant granular cell tumor- Report of a case with DNA ploidy analysis. Arch Pathol Lab Med 120:296·300, 1996. CASE 14. 25806 Malignant Peripheral Nerve Sheath Tumor in Neurofibromatosis HISTORY: A 53-year-old female presented with pain in her right leg, down the posterior aspect, and then onto the anterior aspect. Physical exam disclosed a mass in the right pelvic area. Pelvic ultrasound revealed the mass to be 7 em in the right pelvis; a barium enema showed no involvement of colon; and an I'VP revealed no compression of the ureters or kldney involvement. The specimen consisted of a lobulated firm mass which measured 11 x 10 x 5 em and weighted 280 grams. The outer surface was partially bossilated and nodular, partially irregular and disrupted. Cut sectioning revealed fmn, fleshy, glistening tan tissue. Approximately one-third of the tumor was hemorrhagic, necrotic and friable. An additional specimen consisted of an 11 x 8 x 3.3 em ovoid, flattened fragment of rubbery tissue which weighted 100 grams. The external surface of the tissue was partially invested by a thin, semi-translucent membrane. The was a dismption leading into a flattened cyst which measured 8.0 x 7.0 em. The internal surface of the cyst was irregular, wrinkled and varied from gray­ tan to hemorrrbagic and red-purple. Protruding from one end of the specimen was a 2.5 em long x 1.5 em wide rubbery, gray-tan, cord-like st11,1cture. possibly representing a nerve. Further sectioning of the wall of the tumor revealed rubbery, gray-tan to slightly softer, yellow-tan tissue throughout the areas of yellow softening and necrosis. The wall of the tumor ranged from .2 to 1.8 em thick. Past medical history was significant for previous hysterectomy with removal of her right tube and ovary, and von Recklinghausen's disease, having multiple neurofibromas throughout her body externally. · Differential Diagnosis Synovial sarcoma Fibrosarcoma MPNST, focal epithelioid Leiomyosarcoma MPNST, focal RMS (friton) MFH Immunohistochemical Results Desmin SIOO CD34 - HHF35 HMB45 CD31 SMActiri Fl3a FVDI Myoglob. CD68 EMA - Viment. MIC2 CK-AE Leu 7 CD57 ++ Chromog CK-CAM MPNST: As many authors state, MPNST can be diagnosed on histologic grounds alone in the absence of a clear cut origin from a nerve. Such a nerve origin is by no means always demonstrated and may be difficult to do so. Therefore, careful attention to pattern and nuclear shape as well as other features are stressed. The cells of MPNST show indistinct cytoplasm with small elongated nuclei - wavy or "comma-shaped", quite unlike the nuclei found in fibrous or smooth muscle tumors. Quite commonly, the nucleus is bullet or torpedo-shaped, with one end blunt and the other tapered or pointed. Concerning pattern, MPNST occur in sweeping fascicles which occasionally take on a herringbone appearance. Overall, the pattern of many tumors shows alternating hypercellular fascicular areas with hypocellular myxoid zones (hypo/hypercellular pattern). This is somewhat reminiscent of the Antoni A - Antoni B pattern found in benign schwannomas. Other features, if found, are quite helpful; these include prominent nuclear palisading, so-called tactoid differentiation (where whorls of cells resemble small nerves) and the presence of heterologous elements (see below). Less specific findings are hyaline bands within the tumor, intraneural spread, and spread under endothelial cells into vascular lumens. MPNST is an underdiagnosed tumor. This is due to the fact that not all cases will show definite origin from a nerve and that the histology may resemble fibrosarcoma. The presence of heterologous elements, eg. rhabdomyosarcomatous elements in a spindle cell sarcoma practically identifies the spindle cell element as nerve sheath in origin. Such muscle differentiation is often found at the junction between hypercellular and hypocellular regions. MfNST: Criteria for Diaenosis I. Origin from nerve, consistent histology. II. Presence of Neurofibromatosis, consistent histology. ill. No relationship to nerve: Patterns Fibrosarcoma-like, Alternating hypo- hyper-cellularity Cytology Thin pointed wavy nuclei Fibrillar background Other Nerve-like whorls Thick walled vasculature Heterologous elements MPNST: Subtypes l. Neurofibroma-like 4. Pleomorphic (VRN cases) 2. Fibrosarcoma-like 5a Epithelioid type (5%) 3. Usual spindle cell type 5b Superficial epithelioid type 6. Heterotopic elements (VRN cases)

Occasional tumors more closely resemble neurofibromas with increased cellularity, pleomorphism and mitoses. These have been called malignant neurofibroma although the term neurofibrosarcoma has also been applied; this latter term should be avoided since it is also used, inaccurately for the ordinary spindle cell MPNST. In this subtype, one must ignore bizarre nuclear changes in assessing malignancy, and instead search for mitotic figures. Mitoses are important: they are not identified in benign lesions, and any significant mitotic rate ( 1/20 hpf) can be construed as evidence for a potential malignant behavior. Although definitive criteria have not been systematically studied, such a low rate should act as an overall guide since such rumors can definitely kill the patienL It is perhaps more important in this regard to err on the side of calling a lesion a low grade MPNST to affect a wider local excision and possibly prevent further biologic aggressiveness. One other hint for the diagnosis of malignancy in a neurofibroma-like rumor is the presence of focal densely cellular regions. Other cases have a distinctly epjtbel!ojd appearance. These cases account for about 5% of all MPNST, and may be deep or superficial. The superficial tumors have a more favourable prognosis than the deep ones, although they can metastasize, and large tumors are worse. Heterotopic Elements or Divergent Differentiation Glandular differentiation as described by Woodruff (see below),and rhabdomyosarcoma elements (malignant Triton tumor), cartilage or chondrosarcoma, and osteoid or osteosarcoma might be found; angiosarcoma and liposarcoma have all been described. These tumors with divergent differentiation (found in 16% of cases -Ducatman) occur more frequently in VRN, the group with the worst prognosis of aU MPNST. This ability of nerve sheath tumors to exhibit so-called heterotopic elements is imparted by its neural crest origin, where the mesenchymal tissue is pluripotent and forms the entire soft tissue of the head. Malignant Triton Tumor Tumors with neural and skeletal muscle differentiation include: neuromuscular hamartoma, medulloblastoma with rhabdomyosarcoma, rhabdomyosarcoma with ganglion cells (ectomesenchymoma), and malignant scbwannoma with rhabdomyosarcoma (Triton, first described by Masson in 1932). About 70% (mostly male, in head and neck) occur in von Recklinghausen's neurofibromatosis. 5 year survival is very poor at about' 12%. Glandular malignant schwannoma. First described by Garre (1892), involving the sciatic nerve, only around two dozen subsequent cases have been reported-, mostly in von Recklingbausen's neurofibromatosis, and in major nerves: sciatic, median, brachial plexus, spinal nerves. They have a spindled background and may have other heterotopic elements such as cartilage or osteoid. The glands are well differentiated nonciliated cuboidal or columnar cells with clear cytoplasm, occasional goblets, and neuroendocrine cell differentiation (demonstrable by chromogranin, etc) (Christensen et al, 1988; Woodruff & Christensen 1993). While essentially all benign nerve sheath tumors containS 100 antigen, only 50-70% ofMPNST (including the epithelioid type) exhibit this marker. It is often seen in more differentiated, loose, wavy areas.

Malignant Schwannoma: Natural History* & Prognostic Factors YRN Solitacy I Unfavorable LR >50% >50% I Size (>7 cm)(>5a) Mets 84% 52% I Location (central) Surv 12 mo 34 mo I Mitotic count (>6/10 hpf) Surv (5 yr) 10-23% 25-47% I Presence ofVRN *Mayo Oinic, 1963; AFIP,I979; Memorial, 1981 a Ducatman et al: no relation to grade, mitoses

Natural History & Prognostic Factors: Concerning the variant types (including the epithelioid malignant schwannoma), there is no evidence to suggest that patients with such rumors fare any differently from the usual MPNST. However, patients with tumors showing heterotopic elements , particularly Triton tumors, whether or not they occur in association with VRN, do appear to have a worse prognosis; perhaps this is due to the usually high grade histology. Secondly, patients with MPNST in association with VRN do worse. While sporadic MPNST show a five year survival rate of 40-70%, VRN cases for the most pact display lower five year survival rates of 15-30%. This difference is usually explained by the fact that more VRN cases occur in central unresectable areas; however, in a recent study Ducatrnan et a! were unable to conf1I1ll. this. MPNST as a rule tend to have a high rate of local recurrence, >50%; this is even higher (and earlier) in patients with VRN. Although there seems to be an overall correlation of prognosis with grade, individual cases with very low mitotic rates (<1/lOhpf) nonetheless are fatal. Also, <:ases with mitotic rates of >6/lOhpf do worse on the average. Again, Ducatman eta! recently noted no correlation between survival and grade or mitotic rate. Other poor prognostic signs are central location. and size > 5 em.

Bojsen-Moller M, Myhre-Jcnsen 0 . A consecutive series of30 mnlignant schwannomas. Survival in relation to clinico­ pathological parameters and treatment. Acta Path Microbiol Immunol Scand 1984; 92: 147-155. Brasfield R, Oas Gupta T. Von Reckli nghausen's disease: A clinicopathologic study. Ann Surg 19n; 175:86-104 .. D'Agostino A. Soule E, Miller R. Sarcomas of the peripheral nerves and somatic soft tissues associated with multiple neurofibromatosis (von Recklinghauseo's disease). Cancer 1963; 16: 1015-1027. D'Agostino AN, Soule EH , Miller RH. Primary malignant neoplasms of nerves (malignant neurilemmomas) in patienrs without manifestations of multiple neurofibromatosis (Von Recklinghausen's Disease). Cancer 1963; 16; 1003.-1014. Daimaru Y. Hashimoto H. Enjoji M. (1985). Malignant peripheral nerve sheath tumors (malignant scbwannomas): an immunohistochemical study of 29 cases. Am J Surg Patbol 1985; 9: 434-444. Oucatman BS, Scheithauer BW. Piepgras DG. Reiman HM, Dstrup OM. Malignant peripheral nerve sheath tumors- a clinicopathologic study of 120 cases. Cancer 1986; 57; 2006-2021. Ducaunan BS. Scheithauer BW. Postirrodiation neurofibrosarcoma. Cancer 1983; 51; 1028-1033. Erlandson RA. Woodruff JM. Peripheral nerve sheath tumors. An electron microscopic study of 43 cases. Cancer 1989; 49; 273-287. Fisher C, Carter RL, Ramachandra S, Thomas DM. Peripheral nerve sheath differentiation in malignant soft tissue tumours: an ultrastructural and immunohistochemical study. Histopathology 1992; 20; 115-1 26. Fisher C. The value of electron microscopy and immunohistochemistry in the diagnosis of soft tissue san:omas: a study of 200 cases. Histopathology 1990; 16; 441 -454. Giangaspero F. Fratamico FCM, Ceccarelli C, Brisigotti M. Malignant peripheral nerve sheath tumors and spindle cell sarcomas: an immunohistochemical analysis of multiple markers. Appl Patbol1989; 7; 134-144. Guccion J, Enzinger F. Malignant schwannoma associated with von Recklinghausen's neurofibromatosis. Virchows Arch (Path Anat Histol) 1979; 383:43-57. Harkin JC. Reed RJ. Tumors of the peripheral nervous system. Atlas of tumor pathology. 2nd series. fasc 3. Washington DC. Armed Forces Institute of Pathology, 1969. Hajdu SI. Peripheral nerve sheath tumors. Histogenesis, classification and prognosis. Cancer 1993; 72: 3549-3552 Herrera GA. Reimann BEF, Salinas I A. Malignant schwannomns presenting as malignant fibrous histiocytomas. Ultr.lStruCtural Pathol 1982; 3; 2.53-261. Hirose T, Sumitomo M, Kudo E. Hasegawa T, Teramae T, Murase M, Higasa Y, Ikat.a T, Hizawa K. Malignant peripheral nerve sheath tumor (MPNST) showing perineurial cell differentiation. Ami Surg Patholl989: 13: 613-620. . Johnson TL, Lee MW, Meis JM, Zarbo RJ, Crissman JD Immunohistochemical characterization of malignant peripheral nerve sheath tumors. Surg Pa!.hol 1991: 4; 121-135 Matsunou H; Shimoda T, Kakimota S, Yamaslllta H, Ishikawa E, Mukai M. Histopathologic and immunohistochemical study of malignant tumors of peripheral nerve sheath (malignant Schwannoma). Cancer 1985: 56: 2269-2279. Miettinen M, Saari A. Phreochromocytoma combined with malignant schwannoma: unusual neoplasm of !.he adrenal medulla. Ultrastructural Pathol1988; 12: 513-527 Riccardi V. Von Recklingbausen's neurofibromatosis. NEngiJMed 1981; 305: 1617-1626. Robey SS, deMent SH, Eaton KK, Aoun H. Malignant epithelioid peripheral nerve sheath tumor arising in a benign schwannoma. Surg Neurol 1987; 28; 441-446. Storm F, Eilber F, Mirra J, Morton D. Neurofibrosarcoma. Cancer 45:126-129,1980. Stout AP. Tumors of !.he peripheral nervous system; Atlas of Tumor Pathology Sect 2, Fasc 6, Waslllngton DC, Armed Forces lnstitute of Pathology, !949. Swanson PE, Manive1 JC, Wick MR. Immunoreactivity ror Leu-7 in neurofibrosarcoma and other spindle cell. sarcomas of soft tissue. Am J Pa!.hol 1987: 126; 546-5,60. Taxy JB, Banifora H. Trujillo Y, Dorfman HD. Electron microscopy in !.he diagnosis of malignant schwannoma. Cancer 1981; 48; 1381-1391. Trojanowski JQ, Kleinman GM , Proppe KH. Malignant tumors of nerve sheath origin. Cancer 1980; 46: 1202-1212. Tsuneyosbi M, Enjoji M. Primary malignant peripheral nerve tumors (malignant scltwannomas).A clinicopathologic and electron microscopic study. Acta Pa!.hol Jpn 1979; 29; 363-375. White H. Survival in malignant scltwannoma. An eighteen year study. Cancer 1971; 27:720-729. Wick MR, Swanson PE, Scheithauer BW, Manivel JC. Malignant peripheral nerve sheath tumor; an immunohistochemical study of 62 cases. Am 1 Clin Pathol; !987; 87: 425-433. Woodruff JM. Arthur Purdy Stout and the evolution of modem concepts regarding peripheral nerve sheath tumors . .tuner J Surg Pathol 1986; 10:63-67. Woodruff JM, Selig AM. Crowley K, Allen PW. Schwannom.a (neurilemoma) with malignant transfonnation. A rare. distinctive peripheral nerve tumor. Am J Surg Pathol 1994: 18: 882-895. Epithelioid Variant of MS/MPNST Alvara M, Mandy bur T, Menefee M. Light microscopic and ultrastructural observations of a metaStasizing malignant epithelioid schwannoma. Cancer 38:1977-1982. 1976. Dabski C, Reiman HM Jr, Muller SA. Neurofibrosarcoma of skin and subcutaneous tissues. Mayo Clin Proc 1990; 65:164-172. DiCarlo EF, Woodruff JM, Bansal M, Erlandson RA. The purely epithelioid malignant peripheral nerve sheath tumor. Amer J Surg Patbol 10:478-490, 1986'. L.askin WB, Weiss SW, Brat!.hauer GL. Epithelioid variant of malignant peripheral nerve sheath tumor (malignant epithelioid schwannoma). Am J Surg Pathol 1991; ~5; 1136- L145 . .Lodding P, K.indblom .LG, Angervall L Epithelioid malignant schwannoma. A study of 14 cases. Virchows Arch [A] 1986; 409:433-451. Reed R, Leonard D. Neurotropic melanoma: a variant of desmoplastic melanoma. Am J Surg·Pathol 1979; 3: 301-31 1. Yousem SA, Colby TV, Urich H. Malignant epithelioid schwannoma arising in a benign schwannoma. A case report. Cancer 57:2799-2803, 1985. Malignant Triton Tumor Brooks J, Freeman M, Enterline H. Malignant "Triton" tumors: Natural history and immunohistochemistry of nine new cases with literature review. Cancer 55:2543-2549, 1985. Brooks JJ. Malignant Peripheral Nerve Sheath Tumors with Divergent Differentiation including Malignant ''Triton" Tumors. In Textbook of Uncommon Cancer, ed. Williams.CJ, Krikorian JG, Green MR. and Raghavan D, John Wiley & Sons, LTD, Sussex, England, 1988. Ducatman B, Scheithauer B. Malignant peripheral nerve sheath tumors with divergent differentiation. Cancer 54:1049- 1057, 1984. Woodruff J, Chemik N, Smith M, Millet W, Foote F. Peripheral nerve tumors with rhabdomyosarcomatous differentiation (malignant "Triton" tumors). Cancer 1973:32:426-439. Glandular malignant Schwannoma Christensen WN, Strong EW, Bains MS, Woodruff 1M Neuroendocrine differentiation in !.he glandular peripheral nerve sheath tumor. Am J of Surg Path 1988; 12; 417-426. Wong SY, Teh M, Tan YO, Best PV Malignant glandular triton tumor. Cance.r 1991; 67; 1076-1083. Woodruff]. Peripheral nerve tumor showing glandular differentiation (glandularschwannomas) Cancer 1976: 37:2399- 2413. Cellular schwannoma is a variant of schwannoma with encapsulation and a predominantly cellular growth pattern but no Verocay bodies. This is most frequent in middle aged females, usually solitary (but occasionally multinodular or plexiform) and only rarely associated with VRN. Most commonly it is found paravertebrally in the retroperitoneum, pelvis or mediastinum. Well­ encapsulated, with a related nerve of origin in over 40% of cases, they have a smooth surface and a tan-yellow cut face. Histologically, they are composed of thin tapered spindle cells, occasionally palisaded, with whorls and storiform areas. The cytoplasm is eosinophilic with indistinct cell boundaries. A few have Antoni B areas. Over 90% are S I 00-protein positive. The rumors can be quite large (up to 19 em in diameter) and there may be nuclear atypia and mitotic activity (not usually exceeding 4/!0hpf, although higher counts can be found in small foci). Necrosis is unusual but recorded, as a discrete circumscribed area without a rim of crowded atypical cells as might be expected for MPNST. A few cellular scbwannomas locally recur, but none has metastasized. Granular cell change in a cellular schwannoma bas been described (Carpenter et al, 1992). Co.rpenter PM. Grafe MR. Varki NM. Granular eclls in a cellular neurilemmoma. Arch Pathol Lnb Med 1992; 116: 1083-1085 Casadei GP, Scheitbauer BW, Hirose T, Manfrini M, Van Houton C, Wood MB. Cellular scllwannoma. A clinicopathologic. DNA now cytometric, and proliferation marker study of70 patientS. Cancer 1995; 75:1109- 1119 Dcrui!Z JP, Janzer RC, Costa J. Cellular scbwannomas of the intracranial and intraspinal compartment: morphological and immunological characteristics compared with classical benign schwannomas. J Ncuropathol Exp Ncurol 1993; 52: 114-118. Fletcher COM. Davies SE. McKee PH. Cellular schwannoma: a distinct pseudosarcomatous entity. Histo11athology 1987; 11: 21- Lodding P, Kindblom l..Q, Angervall L. Stenman G. Cellular schwannoma. A clinicopathologic study of29 cases. Vircbows Arch [AI 1990; 416:237-248. White W, Shui MH, Rosenblum MK, Erlandson RA. Woodruff JM Cellular schwannoma. A clinicopathologic study of 57 patients and 58 tumors. Cancer 1990; 66; 1266-1275. Woodruff JM, Godwin TA. Erlandson RA, Susin M, Martini N. Cellular schwannoma: a vnriety of schwannoma sometimes mistaken for a malignant tumor. Am J Surg Pathol 1981; 5:733-744. CASE 15. 26060 Leiomyosarcoma, myxoid, of Soft Tissue

IDS TORY: A 67-year-old white female noted gradual ··swelling" of the left hip for a 5 month duration. A cr revealed a mass involving the left anterior thigh. A needle biopsy was performed, foUowed by definitive resection. On gross exam, the specimen consisted of a 600 gram, 17 x 17 x 6.5 em mass composed over 90% of adherent tumor nodules, and rare identifiable strucrures, including fascia and skeletal muscle. Tumor nodules varied from myxoid to firm, white-tan and were separated by thin fibrous septae. Fascia bounded the tumor inferiorly. Skeletal muscle was present in a thin rim along one edge. A separate mass of tumor weighing 30 grams and measuring 4.5 x 4.0 x 2.0 em was also submitted. Tbe rumor grossly involved the deep and lateral margins of resection, with only a thin band of fibrous tissue surrounding it. Post-operatively, the patient received irradiation for 5 weeks. Because of a past history of congestive heart failure, chemotherapy with adriamycin was not used.

Differential Diagnosis MyxoidMFH Myxoid Leiomyosarcoma Myxoid MPNST Nodular fasciitis

Immunohistochemical R esults • this case Desmin SlOO CD34 HHF35 + HMB45 CD31 SMActin + Fl3a FVID Myoglob. CD68 El\1A Viment. MIC2 CK-AE Smooth muscle tumors of soft tissue account for approximately 7% of aJl soft tissue neoplasms. They may be divided into three groups which will be discussed separately with emphasis on leiomyosarcoma. Benign soft tissue smooth muscle tumors or leiomyomas occur mainly in the skin; all deeper tumors should be viewed with skepticism. This has been recently re­ inforced by Fletcher et al who, having reported on deep leiomyomas, later related metastases on some of those cases. A. Retroperitoneal. Intra-abdominal: This is the most common group of smooth muscle tumors in soft tissue. Tumors occur at an average age of 60 and the majority of patients are female (66% ). Patients complain of a mass or swelling and weight loss. Often these tumors are huge, involving other strucrures and thus unressectable. Occasional prominent cyst formation may cause confusion with a cystic neurolemmoma. In over 80% of cases, the mitotic rate will be greater than 5110 hpf. However, cases with a mitotic rate of 1-4110 bpf should also be considered malignant especially if tumors are greater than 7.5 em and necrosis is present. As a rule, tumo.rs in this group are highly aggressive with a 29% five year survival rate. B. Skin and Subcutaneous Tissue: Unlike the other two groups, males predominate in this category (2-311 MIF). They occur most commonly between the 5th and 7th decade and are found predominantly on the extremities in the hair-bearing regions. The cutaneous lesions are small (2 em) and can contain discoloration and ulceration. Subcutaneous lesions are larger and without such skin changes. Pain is a common fearure in both types. Concerning mitotic rate, over 80% will have greater than 2110 hpf. Occasional leiomyosarcomas will demonstrate mitotic rates of about 1/10 hpf. Basically, throughout these three groups (A,B,C), any significant (1110 hpf) mitotic rate should be considered highly suspicious. As a general rule, leiomyosarcomas of the skin and subcutaneous tissue have a better prognosis due to their superficial location. Dermal rumors rarely metastasize (0-10%), but subcutaneous rumors metastas1ze in 30-40% of cases. Local recurrence of dermal rumors does not necessarily lead to metastatic disease. C. Vascular Origin: Leiomyosarcomas may arise from medium or large veins such as the inferior vena cava. Of these three groups, these are the least common. Within the inferior vena cava (IVC) group, a marked female predominance is noted (80-90% ). Tumors may be of the upper third IVC (with jaundice, Budd-Chiari syndrome, ascites); middle third NC (with RUQ pain mimicking biliary diseas.e); or the lower third NC (with leg edema). In tumors of other arteries or veins, the sex ratio is about equal. The occurrence of true benign leiomyomas arising from vessels is rare (this statement does not refer to the so-called vascular leiomyoma). Microscopic Features: Leiomyosarcomas are composed of spindle cells with eosinophilic cytoplasm having the classic "cigar-shaped" nucleus. Occasional nuclei will show a vacuole at one end of the nucleous. On trichrome stain, the cytoplasm is deep red and on PTAH stain purple-blue. Glycogen can usually be found within leiomyosarcomas. Many tumors contain large areas of hyalinization; necrosis and hemorrhage can also be found. Nuclear pleomorphism should alert one to search for mitoses, but should be disregarded for diagnostic purposes; it is mainly useful in grading a known smootlimuscle malignancy. Smooth Muscle Tumors: Subtypes & Variable Patterns I. Usual Spindle Cell type (B&M) I -Alternating 2. Pleomorphic (B&M) I Bundles 3. Epithelioid (B&M) I -Vacuoles* 4. Myxoid throughout (lvl) I 4. Dedifferentiated (M) I -Myxoid areas *"Leiomyoblastomas" are vacuolated epithelioid SMT, mostly benign; they must be evaluated by mitotic rate and may be malignant; the term should be abandoned. Subtypes!V ariants: Occasional smooth muscle tumors exhibit an epithelioid appearance. Most of these tumors contain eosinophilic cytoplasm and occur in any site although they are more . common in the uterus and stomach. The epithelioid nature does not imply malignancy; these tumors shm!ld be evaluated on the basis of mitotic rate as described above. Occasional epithelioid smooth muscle tumors may contain very prominent clear or vacuolated cytoplasm, which were originally termed "leinmyoblastomas". However, this feature is not noted on frozen section or ultrastructurally, anc! has been found to be due to formalin fixation; like Evans, I and many others believe this term should be abandoned. This phenomenon may be the cause of the "clear cell" variant described by Hasliimotn et al. With some smooth muscle tumors, focal myxoid changes can be seen and rarely such changes will be present throughout the neoplasm. If myxoid thl'oughout, the lesion may behave aggressively and indeed the number of mitoses may not be a reliable way of predicting the biologic behavior of this variant (Salm et al). Beware of the myxoid smooth muscle tumor. The pleomorphic type still retains its fascicular pattern and thus can be.distinguished from MPH; this is an example of what I call "pleomorphism within a phenotype". · Natul'al History: The course of non-uterine leiomyosarcomas, like their uterine counterparts, is uniformly deadly when metastases develop. Except for GI cases, specific data concerning ftve year survival rates is not reported due to the rarity of these neoplasms. The five year survival rate of retroperitoneal leiomyosarcomas is 30%. The local recurrence rate of skin and subcutaneous tumors is 42%; and Hashimoto et al report a 61% 5-year survival for soft tissue leiomyosarcomas. From ECOG data, the 5-year survival of metastatic leiomyosarcoma is 19% from initia:l diagnosis. Prognostic Factors: Although leiomyosarcomas are ·graded in a stepwise fashion (I, II, ill) based on nuclear pleomorphism, necrosis, and mitotic rate; the grade may not be totally predictive in an individual case. Thus, regardless of site, perhaps the single most important prognostic factor is resectibility. This explains the good prognosis of the superficial skin and subcutaneous tumors.

MITOTIC COUNT AND MALIGNANCY IN SMOOTH MUSCLE TUMORS SITE BENIGN BORDERLINE MALIGNANT MA!.IGNANT FEATIJRES Uterine 1-4110 hpf 5-9110 hpf" 10110 ~pf" GI tract 0/10 hpf 1110 hpf, if consistent size > 5-6 ·cm 5110 hpf =definite necrosis pleomorphism Skin/Sub- 0110 lipf " 1110 hpf, if consistent cumneous 2110 hpf; definite Retro- 1-4110 hpf size> 7.5 em peritoneum 0110 hpf 5110 hpf; definite necrosis Vascular 0110 Iipf 1-4110 hpf large size necrosis Soft Tissue 1-2/1 0 hpf (depth important) *Criteria are applicable mainly to spindled tumors without significant atypia or epithelioid morphology.

Adeyemi E, Scejbal V. Leiomyosarcoma of the inferior vena cava. A case report with review of the literature. Post Grad Med J 58:515-519, 1982. Bailey R, Stribling J, Whitzner S, Hardy J. Leiomyosarcoma of the inferior vena cava: Report of a case and review of the literature. Ann Surg 184:169-173. 1976. . Brennan GE, Johnson DE, Eady JL. Leiomyosarcoma of the hand and wrist. J Bone and Joint Surg. 68A: 139-142, 1986. Chen K, Hafez G, Gilbert E. Myxoid variant of epiihelioid smooth muscle tumor. Am J Clio Pathol 74:350-353, 1980. Dahl I, Angervall L. Cutaneous and subcutaneous leiomyosarcoma-A clinicopathologic study of 47 patients. Pathologic a Europaea 9:307, 1974. Donhuijsen K. Mitosis counts: reproducibility and significance in grading of malignancy .. Hum Pathol 17: 1122-1125, 1986. Ellis P, Whitehead R. Mitosis counting-a need for reappraisal. Hum Pathol12:3-4, 1981. Enzinger F, Weiss S. Leiomyosarcoma (Chapter 12) in Soft Tissue Tumors. C. V. Mosby Co. 1983. Fields J, Helwig.E. Leiomyosarcoma of the skin and subcutaneous tissue. Cancer 47:156-169, 1981. Gustafson P, Willen H, Baldetorp 13, PernOM, Akennan M, Rydholm A: Soft tissue leiomyosarcoma: A population­ based epidemiologic and prognostic study of 48 patients, including cellular DNA content. Cancer 70: 114-119, 1992. Hashimoto H. Daimaru Y. Tsuneyoshi M, Enjoji M. Leiomyosarcoma of the external soft tissues. A clinic:opathologic, immunohistochemical and electron microscopic study. Cancer 57:2077-2088, 1986. Kilpatrick SE, Mentzel T, Aetcher CDM: "Leiomyoma of deep soft tissue: Clinicopathologic analysis of a series. Am J Surg Pathol 18:576-582, 1994. Leu HJ, Makek M. Intramural venous leiomyosarcomas. Cancer 57:1395-1400,1986. Matthews TJ, Fisher C: Leiomyosarcoma of soft tissue and pulmonary metastasis, both with osteoclast-like giant cells. J Clin Pathol 47:370-371, 1994. McClain KL, Leach CT. Jenson HB, Joshi VV, Pollock BH, Parmley RT, DiCarlo FJ, Chadwick EG, Murphy SB: Association of Epstein-Barr virus with leiomyosarcomas in young people with AIDS. N Eng! J Med 332:12-18, 1995. Mentzel T, Calonje E. Aetcher COM: Leiomyosarcoma with prominent osteoclast-like giant cells: Analysis of eight cases closely mimicking the so-<:alled giant cell variant of malignant fibrous histiocytoma. Am J Surg Pathol 18:258-265, 1994. Salm R, Evans OJ. Myxoid leiomyosarcoma. Histopathology 9:159-169, 1985. Schmooklcr B, Lauer D. Retroperitoneal leiomyosarcomas. A clinicopathogic analysis of 36 cases. Am J Surg Pathol: 269-280. 1983. Suster S: Epithelioid leiomyosarcoma of the skin and subcutaneous tissue: Clinicopathologic, immunohistochemical, and ultrastructural study of five cases. Am J Surg Pathol 18:232-240, 1994. Swanson PE, Wick MR, Dehner LP: Leiomyosarcoma of somatic soft tissues in childhood: An immunohistochemical analysis of six cases with ultrastroctural correlation. Hum Patl)ol22:569-577, 1991. Varella Duran J, Oliva H, Rosai J. Vascular leiomyosarcoma. The malignant C!)Unterpan of vascular leiomyoma. Cancer 44:1684-1691, 1979. Wile A, Evans H, Romsdahl M. Leiomyosarcoma of soft tissue: A clinicopathologic study. Cancer 48:1022-1032, 1981. CASE 16. 27941 Sarcoma suspicious for Endometrial Stromal Sarcoma

IDSTORY: A 75-year-old. female presented with acute abdominal catastrophe. bleeding intraperitoneally with increasing abdominal size. Her hemoglobin was 6.8 on admission, with a low blood pressure. CT scan revealed a 20 em mass in her left lower quadrant. An exploratory laparoromy, sigmoid colectomy with primary anastomosis, and gastrostomy rube placement were performed. The specimen of sigmoid colon and mesentery contained a large hemorrhagic soft tan and mostly necrotic tumor located in the mesenteric fat, in aggregate measuring 15 x 15 x 10 em. The rumor extended through the mesenteric fat to the serosal surface. The colonic mucosa had a normal mucosal pattern. Further seetions showed a predominantly gelatinous mass of tissue. No discrete lymph nodes were identified in the pericolonic fatty tissue. Differential Diagnosis Synovial sarcoma Ewing's sarcoma/PNET Desmoplastic small round cell tumor (SRCT) Histiocytic malignancy Hemangiopericytoma Other- stromal sarcoma

In this highly cellular tumor, all of the above can be considered. Mocphologically, the cells were incredibly uniform, and there were also areas of slight clumping ofcells. Only a handful of soft tissue sarcomas have an exactly uniform histologically. As one looks at the cells at high power, they had a slightly rounded or "epithelioid" histo1ogically when looser areas are visualized. There were no. rosettes, nor were there the typical fibrous bands of Ewing's sarcoma. Against synovial sarcoma was the lack of overlapping nuclei, although this is weak evidence. Without desmoplasia, the desmoplastic SRCT would be highly unlikely; there are rare non-desmoplastic variants but they still have a nesting pattern not seen here. Histiocytic malignancy - true histiocytic lymphoma or Langerhans histiocytosis -have different nuclei, bent and grooved respectively. Of importance here is the occasional presence of a cording pattern, the presence of significant cytoplasm (against PNET), the low mitotic rate and lack of much apoptosis (against PNET), and the similarity in appearance to endometrial stromal cells in edematous areas. Immunohistochemical Results - this case Desmin + SlOO CD34 - HHF35 HMB45 CD31 ·SMActin F 13a FVlli Myoglob. CD68 EMA Viment. MIC2 + CK-AE NSE + Chromog CK-CAM And positive Estrogen & Progesterone receptors!! Note tbe presence of desm.in which would be rare in Ewing's or PNET although focal ractions have been reported. The presence of NSE is non-specific. The lack of epithelial markers excludes synovial sarcoma and desmoplastic SRCT. Hemangiopericytoma is a diagnosis of exclusion and the case was CD34 negative. The MIC2 reaction was cytoplasmic and not membrane- again non-specific. The key fiQding was the marked estrogen and progesterone receptor content.

Lessons: This case illustrates several lessons to be constantly remembered when d~aling with a potenti3:! soft tissue tumor. First, the lack of proper history is so common in dealing with any case in surgical pathology including sarcomas. In this case. it is unknown whether or not the patient had a prior lesion, but it is now worth checking. Secondly, when viewing a potential soft tissue tumor, if the pattern is unusual, it is my belief that one sbould begin to think of other possibilities of non-soft tissue origin which would include GI stromal tumors, endometrial stromal sarcoma, and mesothelioma, and the like. Third, immunohistochemical stains can be of immense value, within a given differential diagnosis. Here, the use of estrogen receptor and progesterone receptor on tbe paraffin tissue allowed for a rather frrm and confident diagnosis as there are only a handful of tumors in the body with extensive expression of these hormone receptors. As a personal note, I always consider stromal sarcoma in a lung or abdominal lesion I can't otherwise explain fully, in which case I order the hormone stains.

Abrams J, Talcott J, Corson JM: Pulmonary metastases in patients with low grade endometrial stromal sarcoma: clinicopathologic findings with immunohistochemical characterization. Am J Surg Pathol!3:!3:i-!40, 1989. Chang KL, Crabtree GS, Lim-Tan SK. Kempson RL, Hendrickson MR: Primary uterine endometrial stromal neoplasms: A clinicopathologic study of I 17 cases. Am J Surg Patholl4:415-438. !990. Babbs OJ, Silverman JF, Geisinger KR: Immunohistochemical study of uterine stromal sarcoma and rhabdomyosarcoma. Arch Pathol Lab Med 113:1151 -1154, 1989. El-Naggar AK, Abdul-Karim FW, Silva EG, McLem9re D. Garnsey L: Uterine stromal neoplasms: A clinicopathologic and DNA flow cytometric correlation. Hum Pathol22:897-903. 1991. Farhood AI, Abrams J: Immunohistochemistry of endometrial stromal sarcoma. Hum Patbol22:224-230, 1991. Franquemont OW, Frierson HF,Jr., Mills SE: An immunohistochemical study of normal endometrial stroma and endometrial stromal neoplasms: Evidence for smooth muscle differentiation. Am J Surg Pathol 15:86!-870, 1991. Lillemoe TJ, Perrone T, Norris HJ, Dehner LP: Myogenous phenotype of epithelial-like areas in endometrial stromal sarcomas. Arch Pathol Lab Med 115:215-219, 1991. Navarro D, Cabrera JJ, Le6n L, Chirino R, Fem6ndez L, L6pez A, Rivero JF, Fernandez P, Falc6n·O, Jimenez P, Pestano J, Diaz-Chico JC, Diaz·Chico BN: Endometrial stromal sarcoma expression of estrogen receptors, progesterone receptors and estrogen-induced srp27 (24K) suggests hormone responsiveness. J Steroid Biochem Mol Bioi 41:589-596, 1992. Rizcq .MN. Van de Rijn M, Hendrickson MR, Rouse RV: A comparative immunohistochemical study of uterine smooth muscle neoplasms with emphasis on the epithelioid variant. Human Pathology 25:671-677, 1994. Sabini G, Chumas JC. Mann WJ: Steroid hormone receptors in endometrial stromal sarcomas: A biochemical and immunohistochemical study. Am J Cl.in Pathol 97.:381-386, 1992. Suzuki M, Aizawa S. Ushigome S: Endometrial str.omal sarcoma oflow-grade malignancy. Immunohistochemical and three-dimensional reconstruction study with special emphasis on the inadequate terminology of endolymphatic stromal myosis. Acta Pathol Jpn 39:260-265, !989. CASE 17. 26417 Rhabdomyosarcoma, embryonal with pleomorphic areas HISTORY: A 27-year-old Hispanic male initially presented with a large deformity of the mandible, especially on the right side. He had previously undergone antibiotic treatment of what was thought to be an abscess while living in Mexico. He was reevaluated in this country and an oral surgeon did a biopsy, which confmned malignancy. Physical examination of the oral cavity revealed a large mass which was arising from the floor of the mouth and pushing the tongue up and backwards. The mass was involving the entire mandible and floor of the mouth. The specimen weighed 316 grams, and showed an overall .dimension of 12 x 9 x 7 em. The specimen included mandible with molar teeth, and showed a large fungating tumor mass which occupied the mid-portion of the specimen, including the entire area between the symphysjs of the mandible. In the mid-portion, at the superior surface, the specimen was ulcerated and showed a 2.0 x 1..5 q.n grayish-red protruding area. Sectioning through the tumor itself showed a lobulated grayish­ white appearance. The tumor mass was quite extensive, and in the midline, near the fungating nodule, there were zones of mahogany red blo.oclclot and reddish-tan hemorrhage. A yellow soft grumous area of necrosis was also noted grossly. · Differential Diagnosis Leiomyosarcoma Rhabdomyosarcoma, spindle cell MFH RMS, embryonal/pleomorphic MPNST The fibrillar character of the cytoplasm is evidence against leiomyosarcoma, MPNST, and MFH. One question this case raises is whether the lesion arose in soft tissue or bone; there are rare pr:imary RMS of bone (see references). Immunohistochemical Results -this case Des min + SlOO CD34 - HHF35 + HMB45 CD31 SMActin Fl3a FVIII Myoglob. +f CD68 EMA Vjment. MIC2 +f CK-AE NSE +f Chromog CK-CAM Nme that while the results confirm a skeletal muscle differentiation, there is also MIC2 reactivity which has been reported in RMS. Note also the weak NSE reaction which can occur occasionally. Rhal)domyosarcomll (RMS) The vast majority of RMS do not occur in the extremities, where the bulk of the skeletal muscle resides. Rather, there are a host of claSsic locations, each with its own typiCal histology and Dfltural history. Though the. vast majority of cases occur in the first decade, this js_no t true for the paratesticular apd extremity cases, both of which are found in adolescence. Rarely, cases occur congenitally or in adults over 40 years of age. The majoricy ofadult pleomorphic RMS, as

Copeland U, Sneige N, Suinger CA. Gershenson OM, Saul PB, Kavanagh JJ. Alveolar rhabdomyosarcoma of the female genitalia. Cancer 1985;56:849-855. Crist WM, Raney RB, Tefft M, Heyn R. Hays DM, Newton W, Beltangady M. Maurer HM. Soft tissue sarcomas arising in the retroperitoneal space in children. A report from the Intergroup Rhabdomyosnrcoma Study (IRS) Committee. Canctr 1985;56:2125-2132. Enzin~r FM. Shlraki M. Alveolar rhabdomyosnrcoma. An analysis of 110 cases. Cancer 1969;24: 18-31. Fitzmaurice RJ, Tobnson PRE. Liu Yin JA, Freemon! AJ. Rhabdomyosarcoma presenting as ·acute leukaemia'. Histopathology 1991; 18: 173-175. Flamant F, Hill C. The improvement and survival associated with combining chemotherapy and childhood rhabdomyosarcoma. A historical comparison of 345 patients in the same center. Cancer 1984;53:2417-2421. Oonazlez Crussi F, Black Schaffer S. Rhabdomyosarcoma of infancy and childhood. Problems of morphologic classification. Am J Surg Pmho/1919;3: 157-171. Heyn R, Ragab A, Raney RB. Ruymann F, Tefft M. Lawrence W, Soule E, Maurer HM. Late effects of therapy in orbital rhabdomyosarcoma in children. Cancer 1986;57: 1738-1743. Hom R. Enterline HT. Rhabdomyosarcoma. A clinico-pathological study and classification of 39 cases. Cancer 1958;11:181-199. Miettinen M. Rhabdomyosarcoma in patients older than 40 years of age. Cancer 1988;62:2060-2065. Molenaar WM, Oosterhuis AM. Ramaekers FCS . The rarity of rhabdomyosarcomas in the adult: a morphologic and immunohistochemicnl study. Pathol Res Pract 1985;180:400-404. Newton WA, Soule EH, Hamoudi AB, Reiman HM, Shimada H, Beltangady M. Maurer H. Histopathology of childhood sarcomas, Intergroup Rhabdomyosarcoma Studies I and 11; clinicopathologic correlation. J Clin Oncol 1988;6:67-75. Parham OM, Webber B, Holt H. Williams WK. Maurer H. Immunohistochemical study ofchildhood rhabdomyosarcomas and related neoplasms: Results of an Intergroup Rhabdomyosarcoma Study projecL Cancer I 991;67 :3072-3080. Raney RB, Hays OM. Lawrence W, Soule EH, Tefft M, Donaldson MH. Paratesticular rhabdomyosarcoma in childhood. Car~cer 1978;42:729-736. Reboui-Many J, Quintana E. Mosseri V, Flamanl F, Assclain B, Rodary C. Zucker JM. Prognostic factors of alveolar rhabdomyosarcoma in childhood: An Intcmntional Society ofPediallic Oncology study. Cancer 1991;68:493- 498. Ruymann F, Heyn R. Ragab A, Hayes D, Newton W, Palmer N, Foulkes M. Completely resected rhi>bdomyosarcoma: the effect of unfavorable histology on survival. Proc Am Soc Clin Oneal 1984;Absttnct C-334:86. Seidal T, Kindblom LG, Angervall L. Rhabdomyosarcoma in middle-aged and elderly individuals. APMIS 1989;97:236- 248. Soule EH, Geitz M, Henderson ED. Embryon31 rhabdomyosarcoma of the limbs and limb-girdles. A clinicopathologic study of 61 cases. Cancer 1969;23: 1336·1 346. Tsokos M, Webber B. Parham D. Wesley R. Miser A, Miser JS, Etcubanas E. Kinsella T, Grayson J. Glatstein E. Piuo PA, Triche TJ. Rhabdomyosarcoma: a new classification scheme related to prognosis. Arch Pathol Lab Med 1992; 116: 847-855. Primary RMS of Bone Lucas OR. Ryan JR. Zalupski MM. Gross ML. Ravindranath Y, Ortman B: Primary embryonal rhabdomyosarcoma of long bone - Case report and review of the literature. Am J Surg Pathol 20:239-244, 1996. Oda Y, Tsuneyoshi M, Hashimoto H, !washita T. Usbijima M. Masuda S, Iwamoto Y, Sugioka Y: Primary rhabdomyosarcoma of the iliac bone in an adult: A case mimicking fibrosarcOma. Virchows Arch A Pathol Anat Histopatbol423:6S-69, 1993. Reith JO, Bauer TW, Fischler OF, Joyce MJ, Marks KE: Dedifferentiated chondrosarcoma with rhabdomyosnrcomatous differentiation. Am J Surg Pathol 20:293-298. 1996. Shapeero LG, Couanet D, Vane! D, Ackerman LV. Terrier-Lacombe M·J. Flarnant F, Contesso G, Lumbroso J: Bone metastases as the presenting mnnifestation of rhabdomyosarcoma in childhood. Skeletal Radiol22:433-438, 1993. CASE 18. 27639 Spindle Cell Lipoma, myxoid HISTORY: This 42-year-old male presented with an occipital mass. The specimen consisted of a soft tan mass which measured 2.5 em in diameter. Differential Diagnosis Neurofibroma Fibrous histiocytoma Spindle cell lipoma Solitary fibrous rumor The haphazard arrangement of the nuclei in a neurofibroma together with the different type of fibrillar background, allow neurofibroma to be excluded in this case. Here, the nuclei here are oriented one to another and seemed to flow in a stream. Fibromatosis also has a different collagenized background, being a continuous bed of collagen with only scattered thicker collagen bundles, such as keloidal collagen. Also, the cells are dispersed singly and the nuclei are not closely opposed as in this lesion. A fibrous histiocvtoma bas a storiform pauem, even when infiltrating a fat lobule. Imrnu.nohistochemical Results - this case Des min SlOO CD34 ++ HHF35 HMB45 CD3 1 SMActin Fl3a FVill Myoglob. CD68 ElviA Spindle Cell Lipoma The name of this benign rumor betrays its content: an ordinary lipoma with a variable content of bland spindle cells. Absent are the lipoblasts and capillary network of liposarcoma The spindle cells morphologically remind one of those seen in neurofibroma - the nuclei may be wavy but bland. In fact, distinction between a neurofibroma or a fibrous histiocy10ma deep within fat can be difficult in those cases where s11indle cells predominate. The spindle cell lipoma however fails to exhibit a storifonn pattern and IS frequently more cellular than the usual neurofibroma. Its clinical presentation is highly typical with the vast majority oflesions occurring in elderly males on the back of the neck or shoulder. It is unusual for the tumor to recur and the spindle cell element is SlOO negative. The presence of the thin collagen bands, often in parallel array, is very typical and contrasts with the collagen found in the other lesions. Spindle cell lipoma is likely related to pleomorphic lipoma, as a number of the latter have a population of bland spindle cells and appear to conbine fearures of both lesions. Recently, Brooks et al have proposed that there may be 2 subtypes of SCL (regular and myxoid) and that the regular type may be related to soliwy fibrous rumor (SFT). Spindle cell lipoma- Characteristic findings Bland spindle cells, palisading occasionally, wavy nuclei in some C.ollagen bands= thio, 8arallel No thrombi, haphazard nuclei, storifonn pattern Muscle marker & S 10 negative. CD34 positive!

Angervall L, Dahl!, Kindblom L. Save-Soderbenb J. Spindle Cell Lipoma. Acta Path. Microbial. Scand. 1976: A,84: 477-487. Auopardi J,locco J. Salm R. Pleomorphic lipoma: a tumour simulating liposarcoma. Histopathol t983; 7: 511 -523. Beham A, Schmid C, Hoot S. Fletcher COM. Spindle cell and pleomorphic lipoma: An immunohistochemical study and histogenetic analysis. J Patho/1989;158:'119-222. Enzinger F, Harvey D. Spindle cell lipoma. Cancer 1975; 36: 1852-1859. Fletcher C, Mllftin-Bates E. Spindle cell lipoma: a clinicopathological study with some original observations. Histopathology 1987; II: 803-817. Levy FE, Goding GS.Jr.. Spindle-cell lipoma: An unusual oral presenllltion. Otol

Cytogen~ t~cs of Rou~d Cell Lip?sar~oma & Theories of Origin In myxojd liposarcoma a ~haractensuc translocauon bas been 1dentJfied (t(l2; 16)]. In this location the CHOP gene bas been tdenufied and ther~ may be a probe for this gene in t~e fu~re for potential diagnostic use. Recently. a case of round cell hposarcoma was found to have an 1dent1cal translocation. The cytogenetics of the cas ~ presented were interesting: there was an insertion--46XX ins(12;16)(ql3; pll,p l3), a fmding which has not been reported before, although this is a variation on the t(l2;16) translocation of myxoid liposarcoma and would likely result in a similar molecular effect.

M:yxoid liposarcoma Molecular Biology CHOP, at 12q 13, encodes nuclear inhibitor of C/EBP CIEBP (CCAAT/enhancer binding) transcription factors high levels in normal fat adipocytic differentiation of fibroblasts cytokine induced de-differentiation, adipocytes growth arrest of differential adipocytes Rearrangement in myx lipos, not in other tumors with similar breakpoints (lipoma, leiomyoma, clear cell) Abnormally long transcript and protein Fusion with TLS, nuclear RNA binding like EWS Round Cell Liposarcoma (RCLS) The overall incidence of RCLS is estimated at 8-20% of all liposarcomas. Round cell liposarcomas occur in the deep soft tissues of the thigh and retroperitooeum most commonly. They occur at a slightly younger group than myxoid or well differentiated liposarcomas. The typical tumor is quite large and displays areas of hemorrhage and necrosis. As a rule, they are highly cellular rumors composed of polygonal cells with single round to oval nuclei. Lipoblasts may be seen throughout or only focally. The vascularity of the tumor may be difficult to see due to the high degree of cellularity. Ultrastructurally round cell liposarcoma is similar to myxoid liposarcoma in baving a dilated rough endoplasmic reticulum, an external lamina, and variably sized membrane-bound vacuoles containing electron dense material. Some cells have a few large lipid droplets. Relationship to Myxoid Type RCLS appears to be part of a spectrum with myxoid liposarcomas at one end and the more highly cellular variant at the other. Round cell liposarcoma has come to be regarded therefore as the more poorly differe.ntiated form of myxoid liposarcoma and histologically the two patterns may be seen in association in a fair number of cases. Pure round cell liposarcoma is rare. Long ago Enterline called round cell liposarcomas "poorly differentiated myxoid liposarcoma". Now there is a return to that type of designation. Indeed in the new WHO classification, round cell liposarcoma is considered a poorly differentiated myxoid type. Most recently. Evans has proposed that previously diagnosed RCLS be called "cellular myxoid liposarcoma" when the tumor contains more than 25% of highly cellular tissue. Thus, liposarcomas may now be divided into two groups: l) the well differentiated/pleomorphic liposarcoma group including dedifferentiated liposarcoma (MPH-like morphology) and pleomorphic liposarcoma; and 2) the myxoid/round cell liposarcoma spectrum. When to Diagnose RCLS Round cell llposarcoma is diagnosable when any lipocytic tumor, myxoid or not, contains a greater than 25% of the round cell morphology (mixed myxoid/round cell histology), according to the Evans criteria. Highly cellular areas of a myxoid liposarcoma can be considered round cell morphology. However, caution is recommended since myxoid liposarcomas may have increased cellularity at the periphery of lobules and therefore mimic round cell liposarcoma; ifjust in this location, this is !lQl round cell liposarcoma. A round cell liposarcoma must have at least a broad sheet of cells comprising several low power microscopic fields in order to indicate a true round cell morphology and metastatic capability. Recently, Smith eta! have studied the quantity of round cell morphology on survival and showed a decreased survival with increasing content. When to diagnose Grade II Myxoid Liposarcoma If the cellular area is small and limited to a portion of. one slide in a typical myxoid liposarcoma, one may use the designation "myxoid liposarcoma with focal round cell morphology". Such an area in a myxoid liposarcoma would be cause to up the grade from Grade I to Grade II. A larger area of at least 25% of the rumor would cause the tumor to be designated round cell liposarcoma (Grade III). Does RCLS exist? Evans has declared that RCLS does not exist because it is really cellular myxoid liposarcoma However, clinicians are familiar with this term, and there is a body of literature utilizing this term for many years. Therefore, it is recommended that the terminology continue to be used despite the fact that it clearly does represent the most cellular end of the myxoid liposarcoma spectrum. STT: Mole·cular Biology Cytogenetic findings key Common mechanism for tumor formation in 4 rumors Ewing's/PNET EWSIFLil transcription factor Alveolar RMS PAX3/ transcription factor Myxoid LS CHOPrrLS transcription factor Clear cell sa EWS/A TF 1 transcription factor Myxoid MFH versus Myxoid LS These tumors differ both in cell type and in vascularity. First of all, at medium power, one immediately notices prominent nuclear variation in NIFH (pleomorphism in my mind is defined at this power), whereas myxoid liposarcoma tends to be a uniform rumor in a vast majority of cases. The cells at high power also differ: MFH cells tend to be elongated and spindly, even though occurring singly. They often show a stellate shape. Myxoid liposarcoma cells tend to be small, slightly oval or at the most, minimally spindled. The vasculature in myxoid MFH is prominent but different: the vessels appear pinker and thicker, and they have a widely arcing formation, in contrast to myxoid liposarcoma where the vessels are thin capillaries with more shonened arcs and right angle branching (i.e., the so-called "capillary network"). MFH myxoid type is often subcutaneous - also a help, since most myxoid liposarcomas are deeper rumors. Other myxoid rumors should be considered in the differential diagnosis and include myxoid chondrosarcoma (neaily avascular), recurrent myxoid dermatofibrosarc.oma protuberans (recurrence would likely place a tumor in the subcutaneous region without a dermal component; this lacks pleomorphism), myxoid leiomyosarcoma (nuclei differ, also groups of cells form separated bundles), myxoid malignant nerve sheath rumor, myxoid melanoma (why an S 100 stain should always be performed when MFH is a possibility), low grade myxofibrosarcoma (perhaps the grade 0-1 end of the myxoid MFH spectrum), and Evans low grade fibromyxoid sarcoma.

Allen PW: Myxoid rumors of soft tissues. Pathol Annu 15:133-192. 1980. Azumi N, Cunis J, Kempson R. Hendrickson M. Atypical and malignant neoplasms showing lipomatous differentiation: A study of Ill cases. Am I Surg Pathol 1987: II: 161 -183 Btltone MV, Crozat A. Tabaee A. Philipson L, Ron 0: CHOP (GADD 153) and i!S oncogenic variant, TLS•CHOP, have opposing effec!S on the induction of G1/S arrest. Genes Dev 8:453-464, 1994. Eneroth M, Mandahl N, Heim S, Will~n H. Rydholm A, Alber!S KA, Mitelman F: Localization of the chromosomal breakpoints of the t( 12;16) in liposnrcoma to subbands l2q 13.3 and 16pl t .2. Cancer Genet Cy10genet 48:101- 107, 1990. Enterline H. Culberson J. Rochlin D. Brady L. Liposarcoma- A clinical and Pathologic study of 53 cases. Cancer 1960; 13: 932-950 Enzingcr F. Winslow D. Liposarcoma: 1\ study of 103 cases. Virchows Arch (Pathol Anat) 1962; 335:367 Hashimoto H, Daimaru Y, EnjojfM. S-100 protein distribution in liposarcoma. An immunoperoxidase study with special reference to (he 'distinction of liposarcoma from myxoid malignant fibrous histiocytoma. Virch Arch (Pathol Anat) 1984; 4{)5: 1-10. Hashimoto H, Daimaru Y, Enjoji M: S-1.00 protein distribution in liposarcoma. An immunoperoxidase study with special reference to the aistinction of lfposarcoma from myxoid malignant fibrous histiocytoma. Virchows Arch [A]405:l-JO, 1984. Kindblom L-G, Angervall L, Svendsen P. Liposarcoma. A clinicopathologic radiographic and prognostic study. Acta Pathol Microbial Scand (A) (Supp) 1975; 253; 3-71 Patel SR. Burgess MA, Plager C, Papadopoulos NE. Linke KA, Benjamin RS: Myxoid liposarcoma: Experience with chemotherapy. Cancer 74:1265-1269, 1994. Paulien S. Turc-Carel C. Cin PD. Jani-Sait S, Sreekantaiah C, Leong SPL, Vogelstein B, Kinzler KW, Sandberg AA, Gemmill RM: Myxoid liposarcoma with t(l2; 16) (q 13;p 11) contains site-specific differences in methylation patterns surrounding a zinc--finger gene mapped to the breakpoint region on chromosome 12. Cancer Res 50:7902-7907, 1990. Reszel PA. Soule EH. Coventry MB: Liposarcoma of the extremities and limb girdles. A study of two hundred twenty-_ two cases. J Bone Joint Surg [Am] 48:229-244, 1966. Smith TA, Easley KA. Goldblum JR: Myxoid/round cell liposarcoma of the extremities- A clinicopathologic study of 29 cases with particular attention to extent of round cell liposarcoma. Am J Surg Pathol 20:171-180, 1996. Tsuneyoshi M, Hashimoto H, Enjoji M: Myxoid malignant fibrous histiocytoma versus myxoid liposarcoma. A comparative ultrastructural study. Virchows Arch [A]400:187-199, 1983. Chondroid Lipoma & Lipoblastoma Meis JM, Enzinger FM: Chondroid lipoma: A unique tumor simulating liposarcoma and myxoid chondrosarcoma. Am J Surg Pathol 17:1103-1112, 1993. Mentzel T. Calonje E. Fle-tcher COM: Lipoblas.toma and lipoblastomatosis: A clinicopathological study of 14 cases. Histopathology 23:527-533, 1993. CASE 20. 27720 Liposarcoma, dedifferentiated, grade 3 ffiSTORY: A 62 year old man had a 5 year history of increasing right scrotal swelling. There was no prior history of cancer. The right pararesticular mass was resected. The en block resection weighted 1070 grams and included spermatic cord, testicle and soft tissue overlying a large bosselated mass. The distal spermatic cord was without gross abnormalities. More proximally, the spermatic cord was enveloped by the mass and difficult to identify. TI1e bosselated mass measured 18 x 7 x 17 em and did not grossly perforate the surrounding soft tissue nor did it involve the testicle or head of the epididymis. On sectioning, the mass consisted of multiple nodules of a variegated appearance, ranging from translucent and myxoid (10%) to fum, medium pink-tan with areas of white fibrosis (60%) and a gritty texrure on cut section. These nodules ranged up to 7 em in diameter and in many areas were confluent. The surrounding tissue was pale yellow lobulated adipose tissue of variable thickness. The inked soft tissue margin juxtaposed adipose tissue, in no areas directly overlying the firm rumor nodules. The gross estimate of necrosis volume was less than 5%. Differential Diagnosis MPH, storiform/pleomorphic Liposarcoma, pleomorphic Dedifferentiated sarcoma Liposarcoma, spindle cell Leiomyosarcoma Liposarcoma, fibrous areas Liposarcoma, well diff. (WDLS) Grade 1 dediff.

The differential diagnosis in this case is listed above. MFH may be excluded on the basis of any other type of differentiation. No Jeiomyomatous areas were noted here. Pleomorphic liposarcoma may not have any low grade areas and basically resembles an MFH in which there are noticeable lipoblastS, both small and pleomorphic. Spindle cell liposarcoma is a recently described but controversial lesion with a fibrosarcomatous appearance to some areas; definitive WDLS is or must be visible. Some doubt that it deserves a separate designation as it has been known for some time that primary or recurrent liposarcoma may take on such an appearance. The fibrou~ areas of WDLS re~em b l e fibromatosis except that there js wjdely scattered pleomorphism visible at low power; it is not a cellular tumor. However, I believe one can make a diagnosis of WDLS on the basis of the fibrous nodules only, particularly when these are the only component removed- as in a groin tumor [i.e., the surgeon removes only the firm areas leaving the fatty regions behind]. Immunohistochemical Results - this case Desmin s 100 +* CD34 + HHF35 HMB45 CD31 SMActin Fl3a + FVill Myoglob. CD68 EMA Viment. MIC2 CK-AE These results confirm the presence ofrare lipoblastic cells (SlOO positive); the CD34 is also commonly found in the fibrous areas of WDLS. Atypical Lipoma (Lipomatous Tumor); Well Differentiated Liposarcoma (WDLS) and Dedifferentiated Liposarcoma About one third of all liposarcomas, these are rumors of the middle-aged and elderly, with a 60-70 peak, and a slight male predominance, and are most frequent (and often very large) in the retroperitoneum followed by lower limb including inguinal region. In the limbs they are deep to deep fascia and can be intramuscular. Another typical site is paratesticular, where there are about 90 reported cases. Grossly, they are yeUow fatty tumors perhaps focally myxoid but without hemorrhage and necrosis. Histologically. lipoma-like, sclerosing and inflammatory subtypes are recognised. The first two (and sometimes all three) may coexist and represent variations of the same tumour, although they can also appear separately. In lipoma-like liposarcoma, large areas may resemble lipoma, indicating the need for extensive sampling (at least one block per em of diameter), particularly of greyish fibrous­ looking areas. An irregularity in size of far cells is a clue, and cells with atypical irregular nuclei are also frequently seen, particularly in fibrous areas which, in sclerosing liposarcoma, appear as broad bands of focally myxoid, variably cellular or densely fibrous tissue (sclerosing liposarcoma has been likened to hypocellular fibrosarcoma inftltrating ran. The diagnostic feature is the presence in this context of cells with distinctly atypical and pleomorphic hyperchromatic nuclei, including lipoblasts with one or multiple lipid vacuoles. They are often less numerous than the non-lipoblastic·atypical cells, sight of which should prompt a search for atypicallipoblasts to substanUate the diagnosis and rule out other sarcomas infiltrating fat. In all types, mitoses are Tare. Pleomorphic areas are also very occasionally found, but dedifferentiation ,is more likely in recurrent \\TI)LS. The vasculature is not prominent, although occasional myxoid liposarcoma-like areas can be seen, as can haemangiopericytomatous patterns. Stromal findings can include metaplastic bone (±osteoclast-like giant cells), inftltrates of lymphocytes, etc inflammatory liposarcoma (see below). Smooth muscle has been reported in three cases (Evans, 1990). Atypical Lipomatous Tumor or Atypical Lipoma is the suggested term for a rumor with the morphology of well-differentiated liposarcoma, ie differentiated fatty tumour containing atypical cells and/or lipoblastg, occurring in the deep soft tissues of extremities. The concept is proposed because clinically lipoma-like and sclerosing WDL in the soft tissues of the limbs and girdles do not metastasize, and indeed rarely recur if completely excised. Evans has suggested that all these, arid subcutaneous pleomorphic lipoma, be included in the category atypical lipomatous tumour; Azumi et al point out tha.t for "superficial differentiated fatty neoplasms containing atypical c.ells" the term atypical lipoma implies only a peculiar morphology, but. that for ileep- and intramuscular ones, the same term draws attention both to the morphology and to the tendency to recur. The pathology report should state the likely behaviour to avoid ambiguity. On the other hand, histologically identical retroperitoneal tumors recur in 60-100% of cases, can be fatal by local growth, metastasise in up to 18% (Kindblom, 1975) and dedifferentiate more often. For these, the term WD liposarcoma is retained, although in a recent I0 year follow up study Evans (1988) has suggested that the term atypical lipomatous tumor should actually include those of retroperitoneum since, in spite of uncontrolled recurrence, none metastasised. They may, however, dedifferentiate and then metastasize. Dedifferentiation is most likely in retroperitoneal tumors but has also been occasionally described in limb tumours (Brooks & Connor, 1990). This signifies the potential for metastatic disease occurring from such cases, although without metastasis as yet. It should where possible receive adequate local excision but, because of the extreme unlikelihood of malignancy, not aggressive or mutilating surgery, or irradiation. Dedifferentiation This was defined specifically by Evans as bi!!h!v cellular areas which also must have a mitotic rate of at least 5/10 hpf. (Grade 3) This case certainly meets those criteria. However, there have been a few recent studies which re-defme this and allow for less cellularity and fewer mitoses (in other words·allowing for both Grade 2 as well as Grade 3 dedifferentiation). Neither the amount of dedifferentiation -size - nor the Grade have been predictive of the time to recurrence·or metastases, or the overall survival. Pleomorphic Lipoma: Occasionally, the differential diagnosis can be between a pleomorphic lipoma and an atypical lipoma (or well differentiated liposarcoma). Both may have florette cells, scattered collagen bundles, and nuclear atypia (see table). Differential ])jagnosis: Pleomorphic lipoma vs AL T/WDLS P!eomowbic lipoma Atypical lipoma {W])LS. extremitv) Spindle cells + + Collagen bands + + Sclerosis +1- + Broad fibrous septa + Floret ceUs ++ +1- Lipoblasts +1- + Bizarre nuclei + Location superficial deep Usually, in an atypical lipoma there are broad fibrous septa dissecting the lesion. Here one has the combination of iloret cells, large bizarre nuclei as well as scattered lipoblasts. Lipoblasts may also be seen in pleomorphic lipoma, although to· a lesser extent. The overall circumscription, while not actually being a true capsule, can be seen in either lesion. Does such a distinction matter? Actually, the recurrence rates for these two tumors are similar although typical lipoma can be expected to recur at a higher rate if not completely excised. Neither lesion has the capability of metastasis ani! both do require a true excision. the importance of such a distinction woulil be in the possible occurrence of dedifferentiation in an atypical lipoma, if not in the primary tumor, then subsequently in a recurrence. In any case, the clinical management of these two lesjons js·nearlv equjva!ent.

Allen, 1'. Tumors and Froliferntions of Adipose TisSue. Masson Publishing Co, USA, New York, 1981. Atumi. N, Curtis, J, Kempson, R, Hendrickson, M. Atypical and malignant neQplasms showing lipomatous aifferentiation: A study of 111 cases. Am J s~rg Pathol 1987; II: 16l-l83. Dei Tos AP, Mentzel T, Newman PL, Fletcher COM: Spindle cell liposarcoma, a hitherto unrecognized variant of liposarcoma: Analysis of.six cases. Am J Surg Pa.thol 18:913-921, L994. Enterline H, Culberson J, Rochlin D, Brady L Liposarcoma - A clinical and pathologic stUdY of 53 cases. Cancer 1960; 13:932-950. Enzioger F, Winslow b. Liposarcoma: A study ofl03 cases. Virchows Arch (Pathol Anat) 1962; 335:367. Evans-H. Liposarcoma. A study of 55 cases with reassessment of its classification. Am J Surg Patho11979; 3:507- 523. Evans H. Liposarcomas and atypical lipomatous tumors: a study of 66 cases followed for a minimum of I 0 years. Surg Pathol l: 41-54, 1988. Evans HL, Soule EH, Winkelmann RK: Atypical lipoma, atypical iniramuscular lipoma, and well differentiated retroperitoneal liposarcoma: a reappraisal·of 30 cases formerly classified as well differentiated li):>osarcoma. Cancer 43:574~584, 1979. Evans HL: Smooth muscle in atypical lipomatous tumors: A report of three cases. Am J Surg Pathol 14:714-718, 1990. Gustafson P, Rydholm A, Willen H, Baldetorp B, Ferno M. Akerman M: Liposarcoma: A population-based epidemiologic and prognostic study of features of 43 patients, including tumor DNA content. lnt J Cancer 55:541-546, 1993. Lazarus SS, Trombetta LD. Ultn>structural and histochemical identification of sclerosing liposarcoma. Histopathology 5:223-235, 198 I. Lucas DR, Nascimento AG. Sanjay BKS, Rock MG:· Well-differentiated liposarcoma: The Mayo Clinic experience with 58 cases. Am J Clin Pathol102:.677-683, 1994. Reszel P, Soule E, Coventry M. Liposarcoma of the extremities and limb girdles: A srt!dy of 222 cases. J. Bone Joint Surg 1966; 48A:229-244, Shmookler B, Enzinger F. Pleomorphic lipoma: a benign tumor simulating liposarcoma: a clinicopathologic analysis of 48cases. Cancer 1981; 47: 126-133. Snover D, Sumner H, Dehner L: Variability of histologic pal!em in recurrent soft tissue sarcomas originally diagnosed as liposarcoma. Cancer 49:1005-1015, 1982. Atypical Lipoma • dedifferentiation in Brool

Myxoid MFH: This is defined as an MFHcontaining greater than 50% myxoid histology. In practically every instance, histologic-features resembling the usual .tviFH can be found. The myxoid areas are composed of spindle shaped cells with scattered pleomoll?hic cells upon a myxoid background. This may cause confusion with myxoid liposarcomas; however, both the cells and the background contain hyaluronidase-sensitive mucopolysaccharide. In addition, the myxoid areas rarely display the prominent thin capillary vascular structure characteristic of liposarcoma. Tumors display vascularity but often have cells clustered against the vessels giving a thicker appearance than the capillary network of liposarcoma. The importance of defining this type is its more favorable natural history; although the recurrence rate is high, the metastatic rate (23%) is much lower than the usual type. Interestingly, because Myxoid .tviFH is related to the storiforrn pleomorphic type by virtue of containing morphologically identical areas in most cases, Dr. Brooks believes that this is the most specific type or representative of MFH and it offers the key to the cell of origin; after all, the diagnosis of SIP MFH is complicated as it may be mimicked by many other tumors. Study of the myxoid type may prove fruitful in establishing histogenesis. Dedifferentiation & the Final Common Pathway: Most sarcomas have a single histologic pattern and retain it within metastases (if present). It has become apparent that there are a number of primary sarcomas with two different patterns -­ namely, one pattern of an identifiable phenotype such as leiomyosarcoma, and another pattern which often is .tviFH-like in appearance. When immunohistochemical markers are performed on such cases, the original phenotypic pattern usually marks in the appropriate way but the .tviFH-like area (or dedifferentiated portion) may either lose·antigenic expression or occasionally retain the expression of the differentiated phenotype. In. any case, it appears as if this phenomenon of "dedifferentiation" is nonrandom, since the MFH-like pattern is practically always the second pattern noted. Dedifferentiation may alternatively be noted onlyin subsequent metastatic disease. It might be mentioned that the designation "dedifferentiation" is incorrect: This actually represents a form ofmmor progression wherein a more primitive type of cell obtains a growth advantage and begins to occupy the majority of the tumor. Due to this phenomenon, it has been proposed that MFH is actually a final common pathway ill soft tissue pathology. There are several implications of this hypothesis. First of all, when one encounters a potential MFH lesion, one should look at the periphery of the tumor for the possibility of identifying a more differentiated phenotype, such as leiomyosarcoma. In other words, an MFH may be a dedifferentiated tumor of another type in disguise. Secondly, if one is faced with a metastatio lesion in the lung, for example, such a lesion may well arise not only from a primary MFH, but also from a variety of soft tissue tumors which undergo dedifferentiation to the .tviFH pattern. Thus, examination of the-metastatic lesion may not be indicative of the pathology of the primary. The third implication of this hypothesis has to do with pathways in mesenchymal differentiation. If it is true that dedifferentiation would retrace the steps of differentiation in mesenchymal development, then the fact that the MFH phenotype is usually the dedifferentiated portion means that the .tviFH cell is more primitive than most other soft tissue phenotypes. Prognostic Factors: Size: There is a direct correlation between the size,_depth of tumor, and th~ metastatic rate; Rydholm eta! also report a correlation with grade (deeper= higher grade). Recently, in a study of extremity cases, Bertoni eta! show a poorer prognosis with size >5 em. Superficial tumors: (subcutaneous and superficial fascia) These fair much better than patients harboring deeper tumors (intramuscular and retroperitoneal). Histologic type: As mentioned above, the myxoid and angiomatoid subtypes are the most favorable and the inflammatory variety the least favorable histology. Location: On extremities, more distal tumors tend to be more resectable and carry a more favorable prognosis. Inflammation: Tumors with a prominent inflammatory component have a more favorable outlook as far as metastatic potential. (Unlike Inflammatory .tviFH, the host response here is lymphoplasmacytic, not neutrophilic). Malignant Fibrous Histiocytoma. (MFH) General Ozello L, Stout A, Murray M. Cultural characteristics of malignant histiocytomas and fibrous xanthomas. Cancer 1963; 16: 331. Weiss S, Enzinger F. Malignant fibrous histiocytoma: An analysis of 200 cases. Cancer 1978; 41: 2250-2266. Bhagavan B, Dorfman H. The significance o{ bone and cartilage formation in malignant fibrous histiocytoma of soft tissue. Cancer 1982; 49:480-488. Kearney M, Soule E, Ivins J. Malignant fibrous histiocytoma. A retrospective study of 167 cases. Cancer 1980; 45:167- 178. Hashimoto H, Enjoji M. Recurrent malignant fibrous histiocytoma. A histologic analysis of 50 cases. Am J Surg Pathol 1981; 5:753-760. Rydholm A. Syk I. Malignant fibrous histiocytoma of soft tissue. Correlation between clinical variables and histologic malignancy grade. Cancer 1986; 57:2323-2324. Bertoni F, Capanoa R. J;liagini R, Bacchini P, Guerra A, Ruggieri P. Present D. CampanacciM. Malignant fibrous histiocytoma of soft tissue. An analysis of 78 cases located and deeply seated in the extremities. Cancer 1985; 56: 356-367. Enzinger FM. Malignant fib rous histiocytoma 20 years after Stout. Am 1 Surg Pathol 1986; I0 : 43-53. Soul~ .E, Enriquez P. Atypical fibrous histiocytoma, malignant fibrous histiocytoma, malignant histiocytoma. and epithelioid sarcoma: a comparative study of 65 tumors. Cancer 1972; 30: ·128 -143. Enjoji M. Hasbimoto H. Tsuneyoshi M.Iwasaki H. Malignant fibrous histiocytoma: a clinicopathologic study of 130 cases. Acta Pathol Jpn 1980; 3Q(5): 727-741. Enjoji M, Hashimoto H. Diagnosis of Soft Tissue Sarcomas. Path Res Prac 178: 215-226,1984. Reddick R, Michelitch .H, Triche T. Malignant soft tissue tumors·(maljgnant fibrous histiocytoma, pleomorphic liposarcoma. and pleomorphic rhabdomyosarcoma): an electron microscopic study. Human Pathol 1979; 10: 327-343. Jabi M, Jeans D, Dardick I. Ultrastructural Heterogeneity in Malignant Fibrous Histiocytoma of Soft Tissue. Ultrastructural Pathology 11 :583-582, 1987. Dehner LP. Malignant Fibrous Histiocytoma: ·Nonspecific Morphologic Pattern, Specific Pathologic Entity, or Both? Arch Pathol Lab Med 112: 236-237, 1988. Meister P. Malignant Fibrous Histiocytoma: History, Histology and Histogenesis. Pathol Res Pract 183: I, 1988. Raney RB, Allen A, O'Neill J, Handler SO, Uri A, Littman P. Malignant tibrolis histiocytoma of soft tissue in childhood. Cancer 57:2198-2201. 1986. Fletcher COM. Soft Tiss.ue Sarcomas Apparently Arising in Chronjc Tropical Ulcers. Histopathology 11: 501-510. 1987. Abdul-Karim FW, Ayala AG, Chawla SP, Jing.BS, Goepfert H. Malignant fibrous histiocytoma of jaws. A clinicopathologic study of 11 cases. Cancer 56: 1590-1596, 1985. MFH - origin · Fletcher COM: Pleomorp!lic o:>alignant fibrous histiocyton:>a: Fact or fiction? A critical reappraisal based on 159 tumors diagnosed as pleomorphic sarcoma. Am J Surg Pathol 16:213-228, 1992. Brooks JJ: Fact or fiction: Malignant fibrous histiocytoma. Am J Surg Pathol 16:1023, 1992. Fletcher COM: Fact or fiction: Malignant fibrous histiocytoma. Response. Am J Surg Pathol 16:1023-1024, 1992. Brooks JJ, Hergan R, Ryan L: Malignant fibrous histiocytoma (MFH): prognostic value of HLA-Dr paraffin immunoreactivity. Mod Pathol 5:4A, 1992. MFH • Dedifferentiation & Final Common Pathway: Brooks J. The significance of double phenotypic paucms and markers in sarcomas: A new model of mesenchymal differentiation. Am J Patltol 1986; 125: 113-123. Wick MR. Siegal GP, Mills SE, Thimpson RC. Sawhney D. Fechner RE. Dedifferentiated Chondrosarcoma of !;lone: An Immunohistochemical and Lectin-Histochemical Study. Virchows Arch A 411 : 23-32, 1987. Costa MJ: Malignant fibrous histiocytoma phenotype in pleomorphic sarcoma differentiation in recurrent disease. Arch PathoiLab Med 118:160-164, !994. ·

Pleomofphic byalioiziog angiectatic tumor Smith MEF; Fisher C, Weiss SW: Pleomorphic hyalinizing angiectatic tumor of soft parts- A low-grade neoplasm resembling neurilemoma. Am J Surg Pathol 20:21-29, 1996. CaJifornia Tumor Tissue Registry: Semi-Annual Cancer Seminars

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