CASE HISTORIES

MINNESOTA SOCIETY OF CLINICAL PATHOLOGISTS

FALL SEMINAR

NOVEMBER 7, 1987

HECTOR BATTIFORA, M.D.

Chairman, Division of Pathology

City of Hope National Medical Center

Duar te, Cali forni a

1987 MSCP FALL SEMINAR CASE HISTORIES

Case 1

An 8-year-old male presented with a 72 hour history of fever and left back pain over the scapular region. Physical examinat ion was basically normal except for feve r (102-104°). A chest x-ray showed consolidat ion of the lef t upper lobe and a pleural effusion. He was admi tted to the hospital where cultures were obtained and antibioti c therapy was initiated. His fever, pain and effusion resolved with therapy. ACT scan reveal ed a mass versus abscess i n the left chest and a needle biopsy was performed showing a ''small blue cell tumor". At surgery, a pleural-based mass was ''shelled out" of the lung and resected from the pleura. The ribs in the area were seemingly uninvolved . (Contributed by Margaret Heisel, M. D. and Susan Simonton, M.D. , Minneapo lis, MN)

Case 2

A 60-year-old woman presented with the recent onset of right upper quadrant pain suspected as representing acute cho lecystiti s. A cholecystectomy revealed cholelithiasis and an incidental t umor in the duodenal wall . A transduodenal biopsy was performed, and the mass was resected. The patient had no known biochemical abnormal iti es. (Contr ibuted by Bernd -Scheithauer, M. D. , Rochester, MN )

Case 3

A 71-year-old male presented with a 7-week history of rectal bleeding. Colonoscopy revealed two fri able rectal polyps at 7 em . which meas ured 1.5 em . and 1.0 em. These were biopsied but not entirely removed. A repeat examination including colonoscopy three weeks l ater showed no other les ions in the colon, rectum or anus . The patient had no other signif icant complaints or cli ni cal findings . An abdomi nal - perineal resecti on was performed a week l ater . The section is from that specimen. (Contribu ted by David Cherwitz, M. D. , Minneapolis, MN)

Case 4

A 62-year-old woman was found to have a pelvic mass upon bimanual gynecolo­gical examination. A laparotomy revealed the presence of a well de limited, spherical mass, 11 em. in diameter attached to the pelvic retroperitoneum, with no obvious connection with internal genitalia (which appeared normal to the surgeon). No renal or suprarenal masses were seen. The tumor had a dense fibrous capsule wh ich was focally calcified . The cut surface showed a yel low­gray soft tumor tissue with areas of hemorrhage and degeneration. (Contributed ~Hector Battifora , M. D. , Duarte, CA)

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Case 5

A 66-year-old male underwent biopsy of a soft tissue mass which was centered over, and had destroyed the right scapula. The right shoulder was reported to have been painful for the past year, and a mass had been present for the last six months. Past history was remarkable for adenocarcinoma of the prostate, Gleason's grade 2/2 discovered one year earlier in prostate chips removed for relief of obstructive symptoms. (Contributed by Steve Ewing, M. D., Minneapolis, MN)

Case 6

A 38-year-old female was found to have an asymptomatic mass in the right neck. Thyroid function studies were normal . On ultrasound examination, a solid mass in the right lobe of the thyroid was found . Fine needle aspiration biopsy showed cells with nuclear features which were suspicious for papillary car­cinoma. The lobectomy contained a well-circumscribed, firm, light-grey mass measuring 3. 5 x 1.5 x 1 em. (Contributed by J. Aidan Carney, M.D. , Rochester, MN)

Case 7

A 30-year-old female presented with nasal stuffiness and episodic epistaxis for several months. A mass was discovered in the region of the nasal septum and was locally resected irr'1972 . At that time, there was no evidence of tumor out­side of the head and neck region. (Contributed by Charles Horwitz, M.D. , Minneapolis, MN)

Case 8

A 66-year-old man, retired asbestos worker, presented with a history of a dry cough for approximately one month and no other symptoms . Chest x-rays showed opacification of the left lung. A thickened, leathery pleura was decor­ticated. (Contributed by Hector Battifora, M.D., Duarte, CA)

Case 9

A 61-year-old woman had a skin tumor on the ulnar surface of the right forearm which was biopsied by a dermatologist, interpreted as basal cell car­cinoma and excised . A local recurrence was treated with injections of cor­tisone. Six months later she presehted with ipsi lateral lymphadenopathy . An axillary lymph node dissection was done. Material submitted is from the lymph node dissection . (Contributed by Hector Battifora, M.D., Duarte, CA)

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Case 10

A 48-year-old general practitioner fell while skiing and fractured his arm. Roentgenograms showed a fracture through a lytic lesion involving the distal radius. (Contributed by K. K. Unni, M.D . , Rochester, MN)

Case 11

A 51-year-old woman presented with a deep subcutaneous mass, approximately 4 em. in diameter, in the mid-anterior area of the left thigh. A relatively well circumscribed ovoid, pale pink mass was excised. (Contributed by Hector Battifora, M.D., Duarte, CAl

Case 12

A 73-year-old man had a keratotic lesion on his left nostril and a somewhat thickened and indurated, tender, left nasal ala. A biopsy was followed by wide resection. (Contributed by Hector Battifora, M. D. , Duarte, CAl

Case 13

A 74-year-old mal e developed obstructive bladder symptoms and had a TURP (8 grams) . An anterior exenteration was performed and an ileal conduit was established. Three months the1·eafter he had a recurrent mass in the pe 1 vis and underwent radiotherapy. (Contributed by John R. Gellner, M. D., Rochester, MN)

Case 14

A 25-year-old white female presented with a painless lesion in the dorsum of her right forearm . The lesion was excised . One year later a walnut- sized ncurrence was identified in this region. At this time she had pain and numb­ness and tingling in the region of the forearm and an inability to fully extend ~me of her fingers. The patient had no other abnormalities on physical exami­nation and her past medica 1 hi story was otherwise unremarkable . The tissue sub­lilt ted for evaluation is from the re-excision specimen. (Contributed by Les Wold, M.D . , Rochester, MN )

Case 15

A 36-year-old man deve loped acute peritoneal symptoms due to perforation of a tumor mass involving the duodenum. At laparotomy tumor was found involving ~e mesentery, and several foci i n the jejunum and i leum. Biops i es of several -these revealed a similar neoplasm. (Contributed by Hector Battifora, M.D., Duarte, CA)

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Case 16

A 73-year-old woman developed progressively worsening dysphagia and lost 40 lbs. in 1.5 years. Chest x-ray revealed a posterior, mid-mediastinal mass in yo 1 vi ng :{~e esophagus. An esophagectomy was performed. (Contributed by Hector Bat~fora, M. D., Duarte, CA)

Case 17

A 6-year-oJd boy in previous good health presented with sudden shortness of breath . A chest x-ray showed complete opacification of the left thorax . Tumor cells were present in the pleural fluid . At thoracotomy, a large mass was attached to the diaphragm. (Contributed by Jan Ophoven, M.D. and John Priest, M.D., St. Paul, MN)

Case 18

A 58-year~old woman presented with a pelvic mass which was suspected as representing uterine fibroids . The uterus contained several unremarkable leiomyomas and a large, partially necrotic mass . The section is taken from the necrotic portion of the tumor . (Contributed by T. Akhavan, M.D., Alexandria, MN) -

Case 19

A 20-year-old male presented with progressive visual disturbances over the past 3-4 months requiring a change in his glasses but without any noticeable improvement . Ophthalmologic examination revealed bilateral papilledema and optic nerve atrophy . A MRI scan showed a large left frontal lobe mass. At surgery, a large extra- axial tumor was attached to the falx cerebri. (Contributed by Joe Ho Sung, M.D., Minneapolis, MN)

Case 20

A 34-year-old female presented with abdominal distention and palpable intra­abdominal masses. Laparotomy revealed peritoneal and subdiaphragmatic implants. The ovaries were described as gross ly normal . (Contributed by Hector Battifora, M. 0., Duarte, CA)

MINNESOTA SOCIETY OF CLINICAL PATHOLOGISTS

FALL SEMINAR

NOVEMBER 7, 1987

HECTOR BA TTIFORA, M.D.

Chairman, Division of Pathology

City of Hope National Medical Center

1500 Duarte Road

Duarte, CA 91010

MSCP 1987 FALL SEMINAR- PAGE 1

1987 MSCP FALL SEMINAR CASE HISTORIES

Case 1

An 8-year-old male presented with a 72 hour history of fever and left back pain over the scapular region. Physical examination was basically nor­mal except for fever (102-104°). A chest x-ray showed consolidation of the left upper lobe and a pleural effusion. He was admitted to the hospital where cuftures were obtained and antibiotic therapy was initiated. His fever, pain and effusion resolved with therapy. A CT scan revealed a mass versus abscess in the left chest and a needle biopsy was performed showing a "small blue cell tumor". 'At surgery, a pleural-based mass was "shelled out" of the lung andre­sected from the pleura. The ribs in the area were seemingly uninvolved. (Contributed by Margaret Heisel, M.D. and Susan Simonton, M.D., Minneapolis, MN)

Case 2

A 60-year-old woman presented with the recent onset of right upper quadrant pain suspected as representin$ acute cholecystitis. A cholecystec­tomy revealed cholelithiasis and an inctdental tumor in the duodenal wall. A transduodeoal biopsy was performed, and the mass was resected. The patient had no known biochemical abnormalities. (Contributed by Bernd Scheithauer, M.D., Rochester, MN) -

Case 3

A 71-year-old male presented with a 7-week history of rectal bleeding. Colonoscopy revealed two friable rectal polyps at 7 em. which measured 15 em. and 1.0 em. These were biopsied but not entirely removed. A repeat examination including colonoscopy three weeks later showed no other lesions in the colon, rectum or anus. The patient had no other significant complaints or clinical findings. An abdominal-perineal resection was performed a week later. The section is from that spectmen. (Contributed by David Cherwitz, M.D., Minneapolis, MN)

Case 4

A 62-year-old woman was found to have a pelvic mass upon bimanual gynecological examination. A laparotomy revealed the presence of a well delimited, spherical mass, 11 em. in diameter attached to the pelvic retroperi­toneum, with no obvious connection with internal genitalia {which appeared normal to the surgeon). No renal or suprarenal masses were seen. The tumor had a dense fibrous capsule which was focally calcified. The cut surface showed a yellow-gray soft tumor tissue with areas of hemorrhage and degeneratJOn. (Contributed by Hector Battifora, M.D., Duarte, CA)

Case 5

A 66-year-old male underwent biopsy of a soft tissue mass which was centered over, and had destroyed the right scapula. The right shoulder was reported to have been painful for the past year, and a mass had been present for the last six months. Past history was remarkable for adenocarcinoma of

MSCP 1987 FALL SEMINAR · PAOE 2

the prostate, Gleason's grade 2/2 discovered one year earlier in prostate chips removed for relief of obstructive symptoms. (Contributed by Steve Ewing, M.D., Minneapolis, MN)

Case6

A 38-year-old female was found to have an asymptomatic mass in the right neck. Thyroid function studies were notmal. On ultrasound examina­tion, a solid mass in the right lobe of the thyroid was found. Fine needle aspi­ration biopsy showed cells with nuclear features which were susP.icious for papillary carcinoma. The lobectomy contained a well-circumscnbed, firm, light-grey mass measuring 35 x 15 x 1 em. (Contributed by J. Aidan Carney, M.D., Rochester, MN)

Case 7

A 30-year-old female presented with nasal stuffiness and episodic epistaxis for several months. A mass was discovered in the region of the nasal septum and was locally resected in 1972. At that time, there was no evidence of tumor outside of the head and neck region. (Contributed by Charles Horwitz, MD., Minneapolis, MN)

Case 8

A 66-year-old mao, retired asbestos worker, presented with a history of a dry cough for approximately one month and no other symptoms. Chest x­rays showed opacification of the left lung. A thickened, leathery pleura was decorticated. {Contributed by Hector Battifora, M.D., Duarte, CA)

Case9

A 61-year-old woman had a skin tumor on the ulnar surface of the right forearm which was biopsied by a dermatologist, interpreted as basal cell car­cinoma and excised. A local recurrence was treated with injections of corti­sone. Six months later she presented with ipsilateral lymphadenopathy. An axillary lymph node dissection was done. Material submitted is from the lymph node dissection. (Contributed by Hector Battifora, M.D., Duarte, CA)

Case 10

A 48-year-old general practitioner fell while skiing and fractured his arm. Roentgenograms showed a fracture through a lytic lesion involving the distal radius. (Contributed by K. K. Unni, M.D., Rochester, MN)

Case 11

A 51-year-old woman presented with a deep subcutaneous mass, approximately 4 em. in diameter, in the mid-anterior area of the left thigh. A refatively well circumscribed ovoid, pale pink mass was excised. (Contributed by Hector Battifora, M.D., Duarte, CA)

MSCP 1987 FALL SEMINAR- PAGE 3

Case 12

A 73-year-old man had a keratotic lesion on his left nostril and a somewhat thickened and indurated, tender, left nasal ala. A biopsy was followed by wide resection. (Contributed by Hector Battifora, M.D., Duarte, CA)

Case 13

A 73-year-old male developed obstructive bladder symptoms and had a TURP (8 grams). An anterior exenteration was performed and an ileal conduit was established. Three months thereafter he had a recurrent mass in the pe-lvis and underwent radiotherapy. (Contributed by John R. Goellner, M.D., Rochester, MN)

Case 14

A 25-year-old white female presented with a painless lesion in the dorsum of her right forearm. The lesion was excised. One year later a walnut-sized recurrence was identified in this region. At this time she had pain and. numbness and tingling in the region of the forearm and an inability to fully extend some of her fingers. The patient had no other abnormalities on physical examination and her past medical history was otherwise unre­markable. The tissue submitted for evaluation is from the re-excision specimen. (Contributed by Les Wold, M.D., Rochester, MN)

Case 15

A 36-year-old man developed acute peritoneal symptoms due to per­formation of a tumor mass involving the duodenum. At laparotomy tumor was found involving the mesentery, and several foci in the jejunum and ileum. Biopsies of several of these revealed a similar neoplasm. (Contributed by Hector Battifora, M.D., Duarte, CA)

Case 16

. A 73-year-old woman developed progressively worsening dysphagia and lost 40 lbs. in 15 years. Chest x-ray revealed a posterior, mid-med1astinal mass involving the esophagus. An esophagectomy was performed. (Contributed by Hector Battifora, M.D., Duarte, CA)

Case 17

A 6-year-old boy in previous good health presented with sudden short­ness of breath. A chest x-ray showed complete opacification of the left thorax. Tumor cells were present in the pleural fluid. At thoracotomy, a large mass was attached to the diaphragm. (Contributed by Jan Ophoven, M.D. and John Priest, M.D., St. Paul, MN)

Case 18

A 58-year-old woman presented with a pelvic mass which was suspected as representing uterine fibroids. The uterus contained several unremarkable leiomyomas and a large, partially necrotic mass. The section is taken from

MSCP 1987 FALL SEMINAR- PAGE 4

the necrotic portion of the tumor. (Contributed by T. Akhavan, M.D., Alexandria, MN)

Case 19

A 20-year-old male presented with progressive visual disturbances over the past 3-4 months requinng a change in his glasses but without any noticeable improvement. Ophthalmologic examination revealed bilateral papilledema and optic nerve atrophy. A MRI scan showed a large left frontal lobe mass. At surgery, a large extra-axial tumor was attached to the falx cerebri. (Contributed by Joo Ho Sung, M.D., Minneapolis, MN)

Case 20

A 34-year-old female presented with abdominal distention and palpable intra-abdominal masses. Laparotomy revealed peritoneal and sub­diaphragmatic implants. The ovaries were described as grossly normal. (Contributed by Hector Battifora, M.D., Duarte, CA)

MSCP 1987 FALL SEMINAR· PAGE 5

CASE 1 - SOFf TISSUE - MALIGNANT SMALL CELL ruMOR OF THE THORACOPULMONARY REGION IN CHILDHOOD (ASKIN TUMOR)

Clinically, as well as histologically, this is a neoplasm which fits well into the clinicopathologic entity described by Askin1 et aL The subtitle: "A distinctive clintcor.athologic entity of uncertain histogenesis" was used to reflect the authors difficulty in establishing the cell of origin of this type of "small blue cell tumor".

Twenty five percent of the cases in the original series by Askin presented with a febrile episode, as did this child. A pleural based mass with variable involvement of the chest wall was seen in 45% of these cases. Pulmonary parenchymal disease was present in 25% of the cases. Bone (rib) involvement was present in 25%. The disease was more common in females (75%) and presented at an average age of 14.5 years. However the range was from 6 months to 20 years. Histopathologically, compact sheets of cells, a nestin~ arrangement of cells with an intervenmg fibrovascular stroma and serpigmous bands of cells were the three basic microscopic patterns of tumor appreciable at low magnification. The peripheral margms of the tumor appear to be pushing, rather than infiltrating. Perhaps this is why the present tumor was capable of being "enucleated" by the surgeon. The differenttal diagnosis in such cases involves Ewing's sarcoma, lymphoma, rhabdomyosar­coma and peripheral neuroepithelial tumor (PNET). This neoplasm closely resembles Ewing's sarcoma. A diagnosis of extraosseous Ewing's sarcoma could thus be made in this case. However, the absence of glycogen militates against this possibility. In Askin's series none of the cases was dP AS positive (in fact, PAS positivity was an exclusionary feature in Askin's series). The point could be made that PAS negative does not exclude Ewing's sarcoma since absence of staining may be caused by improper fixation. Schajowicz3

emphasized the use of Carnoy's fixative to better bring out this helpful feature of Ewing's sarcoma. The clinical behavior, however, is unlike Ewing's sarcoma .because of absence of the widespread involvement of bones seen in Ewing's sarcoma. Recent immunohistologic studies of Ewing's sarcoma have shown focal expression of keratins and neurofilament, coexpressed with vimentin. This led to the speculation that Ewing's sarcoma is a tumor derived from a pluripotential cell capable of mesenchymal and epithelial, and even neural differentiation, thus suggesting that this tumor should be classified as a "blastoma" rather than as a true sarcoma.2 In the case under discussion, a hematopoietic histo~enesis was readily excluded because of the absence of leukocyte markers, m particular leukocyte common antigen. Rhabdomyosarcoma is unlikely because of the absence of detectable rhabdomyoblasts and of the characteristic focally myxoid stroma of Rhabdomyosarcoma. Nowadays it is easy to exclude rhabdomyosarcoma on the basis of the immunohistological study with antibodies to desmin and, bet ter yet, with the monoclonal antibody to muscle-specific actin designated as HHF35.4 Neuroblastoma appears unhkely on cytologic grounds. H owever, electron microscopy may be needed to completely exclude this possibility. In this case we found absence of neuron-specific enolase, neurofilament and chromogranin with the use of monoclonal antibodies. Although these findings militate against classical neuroblastoma, they do not totally exclude it because they are relatively insensitive markers for neuroblastoma. A primitive peripheral neuroectodermal tumor may also be postulated. This is an exceptionally rare neoplasmand most such cases reported in the early literature turned out to be cases of Merkel cell tumors (see case 9). However,

MSCP 1987 FALL SEMINAR- PAGE 6

none of the cases in Askin's original series showed true Bomer Wright pseudorosettes but in half the cases the cellular profiles were arranged about a central acidophilic focus. These differed from classical Homer Wright pseudorosettes in that their centers were hyaline rather than fibrillary. We have in our files two examples of PNET with characteristic Homer Wright pseudorosettes. ·In both of these the ultrastructural study confirmed the neuronal differentiation of the neoplasm and the immunocytochemistry revealed presence of neurofilament and neuron-specific enolase in many of the tumor cells, in contrast with the I)egativity exhibited by the present tumor.

Thus, the "histogenesis" of this neoplasm remains undetermined (at least to me), nearly a decade after its inittal description. However, qtany refer to this tumor as peripheral neuroepithelioma of the chest wall. I am reluc­t~nt to u~e ~his term because of the ,paucity .of ev~dence for nc::ur?eJ?ithelial dtfferentlatton. However, my expenence wtth thts neoplasm tS hmtted and I am open minded about this issue.

REFERENCES

1. Askin FB, Rosai J, Sibley RK, Dehner LP, and McAlister H~ Malignant small cell tumor of the thoracopulmonary region in child­hood. A distinctive clinicopathologic entity of uncertain histogenesis. Cancer 43:2438, 1979.

2. Moll R, Lee I, Gould VE, Berndt R, Roessner A, and Franke WW ~ Immunocytochemical analysis of Ewing's tumors. Patterns of expres­sion of intermediate filaments and desmosomal proteins indicate cell type heterogeneity and pluripotential differentiation. Am J Pathol 127:288, 1987.

3. Schajowicz F.: Ewing's sarcoma and reticulum cell sarcoma of bone: With SJ?ecial reference to the histochemical demonstration of glycogen as an atd to differential diagnosis. J Bone Joint Surg 41A:185, 1%9.

4. · Tsukada T, McNutt MA, Ross Rand Gown AM~ HHF35, a muscle actin-specific monoclonal antibody. II. Reactivity in normal, reactive, and neoplastic human tissues. Am J Pathol127:389, 1987.

CASE 2 - DUODENUM - CALCIFYING SOMATOSTATINOMA

This is a tumor with histopathological features suggestive of a carci­noid tumor. However, there are many areas in which calcification in the form of psammoma bodies has taken place. This is unusual in carcinoids and should alert us to the possibility of a somatostatinoma, where it has been often noted. It shoulcf also not be mistaken for other, non neuroendocrine epithelial neoplasms featuring microcalcifications. The majority of the cases of calcifying somatostatinomas in the literature have originated in the duodedum, near the ampulla of Vater.6 Somatostatin is a product of the D type endocrine cells of the pancreas where most somatostatinomas originate. Curiously, pancreatic somatostatinomas do not show calcification.1 Some somatostatmomas have been associated with Von Recklinh.ausen disease. 2•

4

MSCP 1987 FALL SEMINAR -PAGE 7

Whereas expression of multiple hormones is common in neuroendocrine tumors, calc1fying somatostatinoma seems to exclusively express somatostatin (as confirmed by immunohistochemistry in the present case). Mucin production is common, which was evident in the present case with the mucicarmine stain. Grimelius stains have been often reported as negative and we obtained equivocal to negative results in our sample. On the other hand, a monoclonal antibody to chromogranin gave intense immunoreactivity in many of the neoplastic cells and with a characteristic granular cytoplasmic distribution. In our experience and that of many others, chromogranin is a reliable marker for neuroendocrine differentiatiOn, particularly when complied with a positive immunostain for keratin and, in our hands, it has turned out to be more reliable than the Grimelius, not only in specificity but sensitivity. Relatively intense stainin~ for somatostatin was seen with a commerc1ally available antiserum whtch, considering the fact that the tissue had in all probability, been overfixed in formalin, indicates a high content of this substance. Incidentally, I think the tissue was overfixed because it took three hours of trypsinization to obtain positive keratin immunostaining (six times the normal time). Although I have not seen electron micrographs m this case, one can predict that there would be many electron-dense, membrane bound granules w1thin the neoplastic cells.

This patient had no biochemical evidence of elevation of somatostatin in serum. That often appears to be the case for this type of tumor. The so­called somatostatin syndrome, characterized by diabetes and fatty diarrhea, features which may be reproduced by prolonged- somatostatin infusion,~ is more commonly associated with pancreatic somatostatinomas.3 In fact, it has been suggested that the term somatostatinoma be reserved to tumors having biochemical manifestations of hypersecretion of somatostatin.

REFERENCES

1. Dayal Y, Nunnemacher G, Doos WG, DeLellis RA, O'Brien MJ, and Wolfe HJ; Psammomatous somatostatinomas of the duodenum. Am J Surg Pathol 7:653, 1983.

2. Dayal Y, Tallberg KA, Nunnemacher G, DeLellis R, and Wolfe HJ; Duodenal carcinoids in patients with and without neurofibromatosis. Am J Surg Pathol 10:348, 1986.

3. Ganda Om P, Weir GC, Soeldner JS, Legg MA, et al~ "Somatostatinoma'': a somatostatin-containing tumor of the endocrine pancreas. N Engl J Med 296963, 1977.

4. Griffiths DFR, Jasani B, Newman GR, Williams ED, and W illiams GT.: Glandular duodenal carcinoid-a somatostatin rich tumour with neuroendocrine associations. J Clin Pathol 37:163, 1984.

5. Krejs GJ, Orci L, Conlon J, Ravazzola M, et al; Somatostatin om a syndrome. Biochemical, morphologic and clinical features. N Engl J Med 301:285, 1979.

6. Stammer PE, Stolte M, and Seifert E; Somatostatinoma o:f Vater's Papilla and of the Minor Papilla. Cancer 60:232, 1987.

MSCP 1987 FALL SEMlNAR- PAGE 8

CASE 3 • RECTIJM • MALIGNANT MELANOMA. PROBABLY PRIMARY

There is no difficulty in establishing a diagnosis of melanoma in this case. The histologic appearance and the ample evidence of melanin production give the dtagnosis away. The problem, however, lies with the unusual clinical presentation. Melanoma of the anus and anorectal junction, albeit rare, is a well documented entity. Primary melanoma of the rectum and large intestine is, on the other hand, exceedmgly rare and more difficult to document as a true primary. The best evidence is a cure after appropriate therapy.

The immunohistochemistry is confirmatory as the cells were keratin negative, vimentin positive, SlOO protein3.4 and HMB45 positive. This is, of course, the expected phenotype for melanoma. The presence of SlOO protein by itself is not necessarily dtagnostic of melanoma. It is now well known that many carcinomas may be S100 protein positive. For example, about 10% of breast carcinomas may show this marker. This is not a problem if one considers that 100% of breast cancers are keratin positive and melanomas do not express keratins (with rare, and debatable, exceptions). Thus, a sensitive antibody (or cocktail) to low-molecular-weight keratin should always be used in tandem with antisera to SlOO protein.1 The addition of the monoclonal antibody HMB452 to our armamentarium of diagnostic reagents has increased the specificity of the diagnostic panel for melanoma. In our experience, nearly 80% of amelanotic melanomas are HMB45 positive, whereas no carcinoma was ever found to stain with it. Tlris antibody may be particularly helpful in the rare example of melanoma staining with antibodies to keratin. I t is not clear whether the latter represent true examples of expression of keratins by melanoma. In most instances only very few cells stain and usually with one or two monoclonal antibodies. It is possible that these are examples of sharing of the keratin epitope with an unrelated molecule but, nevertheless may pose diagnostic problems. The diagnostic approach, using a panel to several markers solves most of these infrequent cases.

If it were not for the abundance of melanin production in this case, one would have to consider malignant lymphoma in the differential diagnosis, particularly since lymphoma of the rectum is a lot more common than melanoma. If so, the IHC results would have been negative to all markers, with the possible exception of vimentin. The panel would, of course, have included leukocyte common antigen which, in most cases of lymphoma, is positive.

1.

2.

3.

REFERENCES

Battifora H: Recent progress in the immunohistochemistry of solid tumors. Sem Diag Pathol 4:251, 1984.

Gown AM, Vogel AM, Hoak D, Gough F, and McNutt MA~ Monoclonal antibodies specific for melanocytic tumors distinguish subpopulations of melanocyte&. Am J Pathol 123:195, 1986.

Kahn HJ, Marks A, Thorn H, et al: Role of antibody to SlOO protein in diagnostic pathology. Am J Clio Pathol 79-.341, 1983.

,

MSCP 1987 FALL SEMINAR- PAGE 9

4. Nakajima IT, Watanabe S, Sato T, et al: Immunohistochemical demonstration of SlOO protein in malignant melanoma and pigmented nevus, and its diagnost1c application. Cancer 5:912, 1982.

CASE 4 - RETROPERITONEUM - MALIGNANT MELANOMA ys MELANOTIC MALIGNANT SCHWANNOMA

This is another unusual example of malignant melanoma arising in a bizarre site and with some peculiar features such as abundant glycogen, fat and a calcified fibrous capsule. I am sure that if it were not for the fact that the neoplastic cells are obviously making melanin (some slides have a few melanin-containing cells), the diagnosis of melanoma would not even cross our minds. In fact, the majority of observers would consider a renal cell carci­noma or a carcinoma of the adrenal, given this histologic picture and clinical presentation. Both of these epithelial tumors would be keratin positive when tested under appropriate conditions with one or several monoclonal antibod­ies to low-molecular-weight keratins. This was done in this case with negative results. Other epithelial markers such as EMA also were negative. On the other hand, most of the tumor cells reacted strongly and with nuclear and cytoplasmic staining, with antisera to 8100 protein. Antibody HMB45 which recognizes a relatively specific melanoma antisen, probably a molecule needed for the production of melanin1 also stamed most tumor cells. Although these immunohistochemical results-are virtually diagnostic of melanoma, some melanin-producing schwannomas could express a similar phenotype. The only schwannoma which could be histologically compatible with the present tumor would be the so-called epithelioid schwannoma.2

Indeed, htstologic and immunohistochemical overlap between schwannoma and melanoma are frequent and explainable on account of their shared neural crest derivation. Abundant production of collagen type IV is common in well differentiated examples of schwannoma and can be demonstrated with appropriate antibodies or wtth the electron microscope. 4 In this case monoclonal antibodies to collagen type IV showed, afbeit only focally, the presence of basal lamina material surrounding individual tumor cells in support of schwannoma. However the presence of numerous cell processes, as commonly seen in schwannoma, was not noted by electron microscopy. Abundant lipid vacuoles and glycogen granules within most of the neoplastic cells was confirmed by the EM study. Most importantly, numerous typtcal premelanosomes were found without difficulty within the neoplastic cells.

This is a neoplasm which defies precise classification. It clearly has ultrastructural and phenotypic features which could warrant a diagnosis of malignant melanoma, but some. features which suggest Schwannian differentiation. The latter is not surprising give!) the histogenetic kinship of melanocytes and schwann cells. Ultrastructural overlapping features between schwannoma and melanoma were reported by Mazur and Katzenstein in a study of more than 20 amelanotic melanomas.3 The tumor location, and the fact that it was surrounded by a fibrous, ossified capsule, suggests that the lesion had been there a long time and perhaps is ansing over a pre-existent benign tumor (perhaps a solitary benign schwannoma). A malignant epithelioid s7hwanno~a with ~elan.in production could als<;> ~e supported by some of the tmmunohtstochemtcal fmdmgs as well as the chmcal appearance. Despite these difficulties, however, the differential diagnosis was considerably

MSCP 1987 FALL SEMINAR- PAGE 10

narrowed by the special studies. At any rate the neoplasm behaved in a malignant fashion. The patient died in less than a year with disseminated metastasis.

REFERENCES

(Also see previous case)

1 Gown AM, Vogel AM, Hoak D, et al: Monoclonal antibodies specific for melanocytic tumors distinguish subpopulations of melanocytes. AM J Pathol123:195, 1986.

2. DiCarlo EF, Woodruff JM, Bansal M, Erlandson RA: The purely epithelioid malignant peripheral nerve sheath tumor. Amer J Surg Pathol10:278, 1986.

3. Mazur MT, and Katzenstein A-L A: Metastatic melanoma: The spec­trum of ultrastructural morphology. Ultrastruct Patholl:337, 1980.

4. Taxy JB, Battifora HB: Epithelioid schwannoma: Diagnosis by electron microscopy. Ultrastruct Pathol 2:19, 1981

CASE 5 • SOFf TISSUE - UNPIFFERENTitUED CARCINOMA OF PROBABLE SWEAT GLAND ORIGIN

The architectural features of this undifferentiated neoplasm suggest epithelial origin. However, cytologically one must also consider melanoma, lymphoma, and although less likely, a sarcoma. The IHC revealed a characteristic epithelial phenotype. A large proportion of the tumor cells stained heavily with a cocktail of monoclonal antikeratin antibodies and failed to stain with a monoclonal antibody to vimentin and an antiserum to S100 protein. Leukocyte common antigen could not be demonstrated. These findin~s, along with the histological appearance, warrant a diagnosis of undi f­ferentiated carcinoma. The problem, g1ven the clinical history, is whether this is a metastasis from his prostatic carcinoma. The answer is most probably not, in view of the uncharacteristic cytologic and architectural appearance of the neoplasm and because neither prostatic-specific antigen nor prostatic acid phosphatase could be demonstrated with appropriate immunostains, although these markers may be absent in undifferentiated carcinoma of the prostate. 1 H owever, his prostatic carcinoma had been reported as being Gleason 2/2. It is improbably that his prostatic cancer has transformed to such a degree. Furthermore, the fact that apparently the scapular lesion was present there for at least six months, with no evidence of metastases elsewhere also militates against metastatic carcinoma. Assuming that a thorough study failed to reveal presence of a primary tumor in the usual sites: lung, pancreas, upper G.I. tract, etc., one has to postulate the possibility that this is a primary carcinoma arising in sweat gland and treat the patient accordingly. The absence of features of eccrine or apocrine differentiation, at least in the material available to me, does not permit a more firm diagnosis. While the IHC workup was useful in ruling out several possibilities, it does not offer clues as to the histogenesis of the neoplastic cells. CEA bas been reported to be present in sweat gland carcinoma3. In the present case, we failed to detect

I

MSCP 1987 FALL SEMINAR- PAGE 11

CEA with a reliable monoclonal antibody. Lastly, one must not confuse sweat gland carcinoma with the so called trabecular carcinoma of the skin5 as it happens to be the case in some textbooks. We now know that the tumor described by Taker belongs in the category of neuroendocrine carcinoma (see case 9, this seminar).

Prognosis for sweat gland carcinoma, depends on the histologic type.2•4

In this case, given the marked degree of anaplasia and high mitotic acttvity, one may expect a metastatic potential for thts neoplasm, although _erecise classification beyond the group of "high maHgnant potential'14 is difficult in this case.

2.

3.

4.

5.

REFERENCES

Battifora H~ Immunohistologic applications of antibodies to _erostate­specific anti~en: A comparison of antiserum to prostate-spectfic antigen, antiserum to prostatic acid phosphatase, and three monoclonal antibodies to prostate-specific antigen. In Symposium Proceedings: Tumor Markers in Prostate Cancer. P.H. Lange Ed, Excerpta Medica, Princeton, N.J. pp 2, 1986.

Dissanayake RV, and Salm R~ Sweat gland carcinomas: Prognosis related to histological type. Histopathology 4:445, 1980.

Penneys NS, Nadji M, Siegels-Weissmali'J, Ketabchi M, Morales AR~ Carcinoembryomc antigen in sweat gland carcinomas. Cancer 50:1608, 1982. '

Santa Cruz D: Sweat gland carcinomas: A comprehensive review. Seminars Diag Pathol 4:38, 1987.

Toker C: Trabecular carcinomas of the skin. Arch Dermatol105:107, 1972.

CASE 6 • THYROID • HYALINIZING TRABECULAR ADENOMA

This is probably case 7 of the series of 11 cases of a peculiar adenoma of the thyroid recently reported by Carney et al.1 Their cases often were mistaken for medullary or papillary carcinoma because they shared many morphological features with these neoplasms. Their patients ranged from 27 to 63 years of age and, interestingly, all were women. The tumors ranged in diameter from 0.3 to 4 ems but the majority measured less than 2 em. All were well circumscribed and an intact capsule was noticed in 9 of them. The tumor cells formed solid masses, variably sized lobules separated by varying amounts of stroma. They were medium sized, polygonal, oval and elongated and with acidophilic, amphophilic or clear and finely granular cytoplasm and scant mitosis. Diastase resistant, PAS positive granularity was .Present. IHC showed presence of keratin and thyroglobulin but not calcitonm. Grimelius stains were negative and electron microscopy failed to reveal presence of neurosecretory granules. A characteristic trabecular pattern of growth, suggesting a neuroendocrine neoplasm and often associated with hyalinized stroma contributed to its medullary carcinoma mimickery.

MSCP 1987 FALL SEMINAR- PAGE 12

IHC done in my laboratory confirmed the expression of thyroglobulin but not calcitonin by the tumor cells, in agreement with the Carney's results.2

Failure to immunostain for calcitonin can be safely interpreted as ruling out medullary carcinoma because this marker is demonstrable without difficulty in all cases . 5 As is the case with many neuroendocrine tumors featuring good differentiation, chromogranin is, in my experience positive in all cases of medullary carcinoma of the thyroid4 and 1s superior in sensitivity and specificity to the Grimelius method. Expectedly, neither NSE nor chromogranin were expressed by the tumor cells, thus providing additional evidence to rule out medullary carcinoma. Also expectedly, coexpression of keratin and vimentin was exhibited by virtually every neoplastic cell as is the case in vir tually all thyroid neoplasms.l,.3·6

1.

2.

3.

4.

5.

6.

REFERENCES

Azumi N, and Battifora H~ The distribution of vimentin and keratin in epithelial and non-epithelial neoplasms. A comprehensive immuno­histochemical study on formalin- and alcohol-fixed tissues. Am J Clin Pathol88:286,1987.

Carney JA, Ryan J, and Goellner JR~ Hyalinizing trabecular adenoma of the thyroid gland. Am J Surg Patholll:583, 1987.

Miettinen M, Franssila K, Lehto V-P, Paasivuo R, and Virtanen I: Expression of intermediate filament proteins in thyroid gland and thyroid tumors. Lab Invest 50:262, 1984.

Schmid KW, Fisher-Colbrie R, Hagn C, et al: Chromogranin A and B and secretogranin II in medullary carcinomas of the thyroid. Am J Surg Patholll:551, 1987.

Sikri KL, Varndell IM, Hamid QA, et al: Medullary carcinoma of the thyroid. An immunocytochemical and histochemical study of 25 cases usmg eight separate markers. Cancer 56:2481, 1985.

Uribe M, Grimes M, Fenoglio-Preiser CM, and Feind C: Medullary carcinoma of the thyroid gland. Clinical, pathological, and immunohis­tochemical features with review of the literature. Am J Surg Pathol 9'577, 1985.

CASE 7 - INTRANASAL LESION - OLFACTORY NEUROBLASTOMA

This case represents a neoplasm with neuronal differentiation which has been variously designated as esthesioneuroblastoma, olfactory neu­roblastoma, esthesioneuroe_£ithelioma, or olfactory placode tumor. The term "olfactory neuroblastoma" (ONB) appears to have acquired wide acceptance and will be used here. It is a rare neoplasm which may be seen in patients of any age. It arises from the olfactory epithelium of the upper nasal passages and infrequently from other regions such as the turbinates or nasal sinuses, but often mvolves these structures secondarily.3

MSCP 1.987 FALL SEMINAR· PAGE 13

Diagnosis is frequently a problem, especially because, in many cases, ONB may be poorly differentiated and diff1cult to distinguish from other round cell tumors common in the nasal region, such as undifferentiated carci­noma, large cell lymphoma, and rhabdomyosarcoma. Well and moderately differentiated cases can be recognized without much difficulty because of the abundant fibrillary background, the presence of occasional Homer-Wright rosettes, and a lobular type of architecture. Less differentiated cases may re­quire ancillary procedures such as electron microscopy and immunohisto­chemistry for elimination of other possibilities.

The demonstration of neuronal differentiation is essential in confirming the diagnosis of ONB and for this purpose, the electron microscol'e continues to be a very useful adjunct which, even in poorly differentiated cases such as the present one, may show the presence of neurites containing neurotubules and neurosecretor)' granules. The latter, in the absence of neuronal processes are less reliable, smce they are also seen in neuroendocrine neoplas~s.9

Immunohistochemical findings are also of value in the diagnosis of ONB. In my experience, keratins are not expressed by the neoplastic cells of ONB but rare associated or residual supportive epithelial cells may do so. However, Taxy et al. have reported cases of olfactory neural tumors expressing keratins.10 The demonstration of keratins in a lar~e proportion of neoplastic cells rules out ONB in favor of undifferentiated carcmoma. With ~ood technique, it is possible to stain for keratins virtually all neoplastic cells m cases of undifferentiated carcinoma of the nasopharynx. Lymphoma can readily be excluded with antibodies to leukocyte common antigen if adequately fixed material is available. In our experience, 90% of formalin­fixed large cell lymphomas stain with the antibody cocktail LCA (DAKO) to leukocyte common antigen, and virtually all show staining on frozen sectJOns on absolute-ethanol or BS-fixed paraffin-embedded samples. Rhabdomyosarcomas, even if poorly differentiated, will display at least focal expression of muscle-specific actin with Mab HHF35. Neuron-specific enolase (NSE) is also diagnostically helpful since most neuroblastomas are NSE positive.12 It is important, however, to bear in mind that many neu­roendocrine neoplasms are also NSE positive. These, however, will also express keratin. A problem with NSE is that most available antisera will stain a variable (but sometimes large) proportion of non-neural and non­neuroendocrine tumors. Better specificity can be attained with the use of Mabs to NSE.U Neurofilament (NF) may be expressed by both ONB7

•8 and neuroendocrine tumors. The latter however, coexpresses NF and keratins.1•

13

SlOO protein can be very useful, even in poorly differentiated ONBs. Electron microscopy of ONB demonstrates satellite (Schwann) cells, whose cytoplasmic processes envelope the neoplastic cells.9 These satellite cells are strongly SlOO protein-positive and are seen to surround the clusters of SlOO protein-negative neoplastic cells in a characteristic and diagnostically useful pattern.2

Neuroendocrine carcinomas are most commonly SlOO protein negative, and the few positive cells do not show the satellite pattern of ONB.

The current case shows sheets of round or elongated neoplastic cells with vesicular chromatin, inconspicuous or small nucleoli, and small or indis­tinct amounts of cytoplasm. Thin fibrovascular septae separate some of the larger clusters. A finely fibrillary, eosinophilic matrix, absent over wide areas is seen in some spaces between groups of cells giving a faint suggestion of

MSCP 1987 FALL SEMINAR- PAOE 14

pseudo-rosettes. In this case, IHC helped in ruling out rhabdomyosarcoma and undifferentiated carcinoma, as neither muscle-specific actin nor keratins· could be demonstrated. Lymphoma was ruled out by the absence of leukocyte-common antigen and the inconsistent cytologic appearance. However, no neurofilament expression could be detected, although we used several monoclonal antibodies to the various molecular weight classes of NF. This is consistent with our experience with the poorly differentiated neuroblastomas. Similarly, no NSE could be found with a monoclonal antibody which in our. hands has proven to be more specific than commercially available antisera.U However, both NSE and chromogranin are relatively insensitive markers in poorly differentiated neuroblastomas and in this case both failed to give posittve results.

Rarely, soft-tissue neoplasms, mimicking neuroblastoma have been found in adults. On close examination, however, many of these afpear to be neuroendocrine carcinomas; in particular, cutaneous (Merkel cell neuroen­docrine carcinoma.5 At any rate, there is little doubt that tumors with fea­tures of neuronal c:lifferentiation (peripheral neuroblastoma) do exist.4

The value of grading ONB is, however, somewhat controversial. Completeness of excision at the initial procedure appears to be the best prognostic indicator.6

1

2.

3.

4.

5.

6.

7.

REFEREN~ES

Battifora H, and Silva E: The use of antikeratin antibodies in the immunohistochemical distinction between neuroendocrine (Merkel cell) carcinoma of the skin, lymphoma and oat cell carcinoma. Cancer 58:1040, 1986.

Choi HS, and Anderson PJ: Immunohistochemical diagnosis of olfactory neuroblastoma. J Neuropathol Exp Neural 44:18, 1985.

Gerard-Marchant R, Micheau C: Microscopic diagnosis of olfactory esthesioneuromas: General review and report ·of five cases. J Natl Cancer Inst 35:75, 1965.

Hashimoto H, Enjoji M, Nakajima T, Kiryu H, Daimaru Y: Malignant neuroepithelioma (peripheral neuroblastoma). A clinicopathologic study of 15 cases. Am J Surg Pathol 7-309, 1983.

Mackay B, Luna MA, and Butler JJ: Adult neuroblastoma. Electron microscopic observations in nine cases. Cancer 371334, 1976.

Mills SE, and Frierson HF: Olfactory neuroblastoma. A clinicopathologic study of 21 cases. Am J Surg Pathol 9: 317, 1985.

Mukai M, Torikata C, Iri H, Morikawa Y, Shimizu K, Shimada T, Nukina N, Ihara Y, and Kageyama K: Expression of neurofilament triplet proteins in human neural tumors. An immunohistochemical study of paraganglioma, ganglioneuroma, ganglioneuroblastoma, and neuroblastoma. Am J Pathol122:28, 1986.

'

MSCP 1987 FALL SEMINAR . PAGE 15

8. Osborn M, Dirk T, Kaser H, Weber K, and Altmannsberger M: Immunohistochemical localization of neurofilaments and neuron­specific enolase in 29 cases of neuroblastoma. Am J Pathol122:433, 1986.

9. Taxy JB, and Hidvegi DF: Olfactory neuroblastoma: An ultrastructural study. Cancer 39:131, 1CJ77.

10. Taxy JB, Bharani NK, Mills SE, Friersop HF, and Gould VE: The spectrum of olfactory neural tumors: A light-microscopic immunohistochemical and ultrastructural analysis. Am J Surg Pathol 10:687, 1986.

11. Thomas P, Battifora H, and Manderino G: Is neuron-specific enolase specific? An immunohistochemical comP.arison of a monoclonal and a polyclonal antibody against neuron-spectfic enolase. Am J Clin Pathol 88:146, 1987.

12. Tsokos M. Linnoila RI, Chandra RS, and Triche TJ: Neuron-specific enolase in the diagnosis of neuroblastoma and other small, round-cell tumors in children. Hum Pathol15:575, 1984.

13. Van Muijen GNP, Ruiter DJ, Van Leeuwen C, Prins FA, Rietsema K, and Warnaar SO: Cytokeratin and neurofilament in lung carcinomas. Am J Pathol116:363, 1984.

CASE 8 - PLEURA - MALIGNANT FIBROUS MESOTHELIOMA

This case was chosen to discuss the diagnostic spectrum posed by the various histologic forms of malignant mesothelioma. Accurate diagnosis in these cases often demands the use of special methods, including electron microscopy, quantitation of hyaluronic acid in effusion fluid or tumor ho­mogenates, and immunohistochemical study. Diagnostic precision is necessary, not so much because of a possible impact on current therapy, but because a large number of these cases may lead to litigation, especially when there is a history of occupational exposure to asbestos.

Three histologic types of diffuse, malignant mesothelioma can be rec­ognized: epithelial, biphasic, and sarcomatoid. The first type, which is the most common, is a purely epithelial tumor in which a tubulopapillary pattern of growth predominates, if sufficiently well differentiated. Such cases are notoriously difficult to distinguish from adenocarcinoma metastatic to the pleural or peritoneal surface. Electron microscopy is one of the most helpful tools for this differential diagnosis as, in most of these mesotheliomas, it will reveal characteristic, abundant4 thin~ bushy microvilli covering the free surfaces of the neoplastic cells. ·12

•14

•1 These microvilli are readily

distinguished from the short, stubby ones which adenocarcinomas may display. However, there are many cases of bonafide epithelial mesotheliomas lacking these features.

Recently, several marker substances which are often expressed by ade­nocarcinoma, but seldom by mesothelioma, have been identified.1•10•13•16 A specific marker for mesothelial cells is, unfortunately, not available, although

'

MSCP 1987 FALL SEMINAR- PAOE 16

an antiserum claimed to be specific for mesothelium was prepared by Singh11

and more recently by Donna et al.5 Both mesothelioma and adenocarcinoma express keratins, but there is evidence, mostly from studies based on gel elec-· trophoresis, that some keratin subtypes differ in the two tumors.2 However, overlaps in the expression of the various keratins by these two neoplasms, as well as insufficient specificity of ·available antibodies, do not currently permit immunohistochemical application of this knowledge to the differential diag­nosis between mesothelioma and adenocarcinoma. It is, however, likely that the rapid development of libraries of monoclonal antikeratin antibodies may result in sufficient numbers of reliable antibodies allowing for immunopheno­typing of keratins. Whether this immunophenotyping would be helpful in the separation between mesothelioma and adenocarcinoma remains, at present, moot.

Mesothelioma may also present a biphasic, epithelial-sarcomatoid pat­tern. This mixed type of mesothelioma is the easiest one to diagnose histolog­ically, since few neoplasms with a similar appearance and involving serous membranes are to be found. This biphasic rattern has led some to postulate a histogenetic relationship between mesothelioma and synovial sarcoma (SS); however, there are many differences between these two neoplasms which cast some doubt on such a relationship. The separation between the two compo­nents is demarcated less sharply m mesothelioma than in SS. Formation of cystic spaces, calcification, and production of neutral mucin, so common in SS, are exceptional in mesothelioma. _

Ultrastructurally, the epithelial component of SS resembles adenocarci­noma in that it has sparse and short stubby Il)icrovilli, in contrast t0 the long, abundant, and thin ones of epithelial mesothelioma. There ate also important immunophenotypic differences between SS and biphasic mesothelioma. We have studied nearly 30 cases of biphasic mesothelioma with several mono­clonal antibodies to keratins. In every sample, the cells in the sarcomatoid phase strongly. and diffusely expressed keratins. In SS, on the other hand, ker­atins were always focally expressed in the spindle cell phase. Vimentin was found in the spindle cells in both neoplasms but usually the immunostains were more intense in SS. There are also immunophenotypic differences in the epithelial components of these two neoplasms. In keeping with the ultrastructural findings, most of the markers which are present in adenocarcinoma, but not in mesothelioma, were expressed in the cells of the epithelial phase of SS. In other words, the epithelial phase of SS is more true epithelial tadenocarcinoma-like) than mesothe.lial-like.

Sarcoma-like mesothelioma is a type of diffuse, malignant mesothe­lioma in which the spindle cell component dominates or is exclusively present. This is another group of mesotheliomas in which histologic diagnosis is diffi­cult. _Such cases must be differentiated fron:t a variety.of spindle cell ~a.rcomas that mvolve the chest wall or that secondanly extend into serosal cavities. An accurate diagnosis of sarcoma-like mesothelioma may not be possible without specialized procedures. In our hands, the most useful of these is immunohistochemical testing for keratins. To date we have studied 15 examples of pure sarcomatous mesothelioma (unpublished observations), and in every case we had no difficulty i~ demonstratmg the ex:pression of keratins by most of the neoplastic cells, Similar results have been reported by others.'·8

If spindle cell carcmoma and sarcoma-like renal cell carcinoma can be excluded, the diagnosis of mesothelioma is virtually assured. Spindle cell

MSCP 1987 FALL SEMINAR- PAGE 17

carcinoma and sarcomatoid renal cell carcinoma may have a similar immunophenotype. However, these t~o neoP,lasms usually .c~n b.e ruled out on clinical grounds alone. Monophastc synovtal sarcoma ansmg m the chest waU would have fewer keratin-positive cells and is unlikely to present as a tumor involving the pleural or peritoneal surfaces.

Sub-mesothelial spindle cells that are indistinguishable from fibroblasts on conventional histologic examination, may express readily detectable ker­atins under certain conditions. We (unpubhshed observations) and others3

have observed this phenomenon in pleural and peritoneal tissues in the pres­ence of a variety of mechanical, chemical, and bacterial irritants. In these cases, the cells do not have cytologic features of malignancy, tend to have their long axes parallel to the mesothelial surface, and are, as a rule, sharply demarcated from the underlying, keratin-negative tissue, which they do not seem to invade. In sarcomatous mesothelioma, on the other hand, the cells usually are atypical, are arranged haphazardly, and display invasive proper­ties that can best be revealed by immunohistochemical study with antibodies to low-molecular-weight keratins. Nevertheless, especially when one is dealing with small biopsies, these features may not be apparent; therefore, the presence of keratin-containing spindle cells should not be interpreted as diagnostic of sarcomatous mesothelioma. In other words, whether the spindle cells are malignant or benign should be determined by conventional cytologic and/or histologic criteria.6

We have seen diffuse pleural neoplasms made up of bland, fibroblast­like cells, with abundant fibrous stroma, mimicking fibromatosis (desmoplastic mesothelioma). In these, the demonstration of frank invasion of the lung and chest wall by keratin-containin~ spindle cells permitted a diagnosis of malignant mesothelioma. The climca] behavior was typically malignant in both cases.

Localized "mesotheliomas", on the other hand, are consistently keratin­negative, confirming electron-microscopic studies that suggest that these neo­plasms are made up of sub-mesothelial fibroblasts rather than mesothelial cells.9

In this case, a large firm, white-gray tumor covered the surface of the lung, according to the pathologist who contributed the case. The clinical his­tory, as well as the gross appearance and the presence of abundant fer­ruginous bodies within the adjacent pulmonary tissue, suggested malignant mesothelioma. However, the neoplasm had a sarcoma-like appearance. In many places, a frank storiform pattern was noticed, and thus a true sarcoma, possible a malignant fibrous histiocytoma, involving the pleura secondarily, could not be excluded with confidence. Strong expression of keratins by the neoplastic cells was readily demonstrable in the present case. Together with the history of asbestos exrosure and presence of asbestos bodies in the adjacent lung, the clinica findings and ~ross appearance of the neoplasm are strong evidence supporting our diagnosiS of sarcoma-like mesothelioma.

REFERENCES

1 Battifora H, and Kopinski M: Distinction of mesothelioma from adenocarcinoma. An immunohistochemical approach. Cancer 55:1679, 1985.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

MSCP 1987 FALL SEMINAR- PAGE 18

Blobel GA, Moll R, Franke WW, Kayser KW, and Gould VE: The intermediate filament cytoskeleton of malignant mesotheliomas and its diagnostic significance. Am J Patho112:235, 1985.

Bolen JW, Hammar SP, and McNutt MA: Reactive and neoplastic serosal tissue. A light-microscopic, ultrastructural, and immunocytochemical study. Am J Surg Pathol10:34, 1986.

Davis JMG: Ultrastructure of human mesotheliomas. J Natl Cancer Inst 52:1715, 1974.

Donna A, Betta PG, Bellingeri D, and Marchesioi: New marker for mesothelioma: An immunoperoxidase study. J Clin Pathol 39:961, 1986.

Epstein Jl, and Budin RE: Keratin and epithelial membrane antigen immunoreactivity in nonneoplastic fibrous pleural lesions: Implications for the diagnosis of desmoplastic mesothelioma. Hum Pathol17:514, 1986.

Erlandson RA, Cordon-Cardo C, and Melamed MR: Proposed classification of pleural neoplasms. Lab Invest 54:19A, 1986 (Abstract).

Montag AG, Pinkus GS, and Corson JM: Immunoreactivity for keratin proteins in sarcomatoid diffuse malignant mesotheliomas: A diagnostic discriminant among malignant spindle cell tumors. Lab Invest 52:42A, 1985 (Abstract).

Said JW, Nash G, Banks-Schlegel S, Sassoon AF, and Shintaku PI: Localized fibrous mesothelioma: An immunohistochemical and electron microscopic study. Hum Pathol15:440, 1984.

Sheibani K, Battifora H, and Burke J: Antigenic phenotype of malignant mesotheliomas and pulmonary adenocarcinomas. An immunohistologic analysis demonstrating the value of Leu M1 antigen. Am J Pathol123:212, 1986.

Singh G, Whiteside TL, and Dekker A: Immunodiagnosis of mesothelioma: Use of antimesothelial cell serum in an indirect immunofluorescence assay. Cancer 43:2288, 1979.

Stoebner P, Bernaudin JF, Nebut M, and Basset F: Contribution of electron microscopy to the diagnosis of pleural mesothelioma. Ann NY Acad Sci 330:751, 1979.

Szpak CA, Johnston WW Roggli V, Kolbeck J1 Lottich SC, Vollmer R, Thor A, and Schlom J: The diagnostic distinctiOn between malignant mesothelioma of the pleura and adenocarcinoma of the lung as defined by a monoclonal antibody (B72.3). Am J Pathol122:252, 1986.

Wang N: Electron microscopy in the diagnosis of pleural mesothelioma. Cancer 31:1046, 1973.

I

MSCP 1987 FALL SEMINAR- PAGE 19

15. Warhol MJ, Hickey WF, and Corson JM: Malignant mesothelioma: Ultrastructural distinction from adenocarcinoma. Am J Surg Pathol 6:307' 1982.

16. Whitaker D, Sterrett GF, and Shilkin KB: Detection of tissue CEA­like substance as an aid in the differential diagnosis of malignant mesothelioma. Pathology 14:255, 1982.

CASE 9 - SKIN - CUTANEOUS NEUROENPOCRINE CARCINOMA (MERKEL CELLTUMORl

This is a typical case of cutaneous neuroendocrine carcinoma; the initial diagnostic difficulty is difficult to explain. A more common diagnostic problem is posed by the intermediate tyP.e in Gould's classification because of 1ts resemblance to malignant lymphoma.8 Six of 35 of these tumors in our series had been misdiagnosed as lymphoma.

Electron microscopy or immunohistochemistr); are capable of establish­ing the correct diagnosis in virtually every instance. ·6•

7 With the electron mi­croscope it is possible to demonstrate the presence of characteristic dense core bodies often located preferentially beneath the cell membrane.6 However, it should be emphasized that sometimes only a few cells display these structures and painstakmg search may then become necessary. Cell attachment sites, although not specific, can be often found in NEC and although they do not confirm the diagnosis they are helpful to rule out lymphoma.

By immunohistochemistry, several markers can be detected in NEC which are not present in lymphoma; these include a number of neuropeptides as well as neuron specific enolase. Most useful, however, is the fact that the vast majority of NEC of the skin that we have studied express keratin and frequently with a characteristic pattcrn.3 The demonstration of keratin by immunohistochemical methods readily rules out lymphoma. Additionally, there are now numerous antibodies to lymphocyte markers which can be helpful in the differential diagnosis between lymphoma and other round cell non hematopoietic tumors. Some of these antibodies are widely specific against hematopoietic cells and LCA.l,5·9•1o

Only one of 35 neuroendocrine carcinomas of the skin which we have, to date, studied with a battery of monoclonal antibodies to keratins has failed to give positive results.3 A step of trypsinization, adjusted to the duration of fixation is however imperative if the tissue was fixed in formalin.2 From a practical diagnostic standpoint, therefore, keratins constitute the most reliable marker to use in the differential diagnosis between NEC and lymphoma. In many cases of NEC of the skin the keratin distribu tion has a characteristic inclusion-like pattern which, in itself, is hi~hly supportive of the diagnosis. Interestingly, a small proportion of NEC, m our experience, coexpress neurofilament with keratin. In those cases (and the present one is an example of them) the distribution of the neurofilament apP.ears to be exclusively ball-like whereas the keratin shows a mixed, ball-hke and perinuclear pattern. Other substances such as VIP, calcitonin, NSE, etc. are less frequently positive. If present, however, they give fu rther evidence of the neuroendocrine nature of the tumor.

MSCP 1987 FALL SEMINAR- PAOE 20

REFERENCES

1. A ndres TL and Kadin ME: Immunologic markers in the differential diagnosis of small round cell tumors from lymphocytic lymphoma and leukemia. Am J Clin Pathol 79'546,1983.

2. Battifora H, and Kopinski MI: The influence of protease digestion and duration of fixation on the immunostaining of keratins. A comparison of formalin and ethanol fixation. J H istochem Cytochem 34:1095, 1986.

3. Battifora H , and Silva EG: The use of antikeratin antibodies in the im­munohistochemical distinction between neuroendocrine (Merkel Cell) carcinoma of the skin, lymphoma and oat cell carcinoma. Cancer:58:1040, 1986.

4. Battifora, Hand Trowbridge IS: A monoclonal antibody useful for the differential diagnosis between malignant lymphoma and nonhematopoietic neoplasms. Cancer 51:816,1983.

5. Borowitz MJ and Stein RB: Diagnostic applications of monoclonal antibodies to human cancer. Arch Pathol Lab Med, 108:101, 1984.

6. Gould VE, Moll R , Moll I , Lee I and Franke WW: Neuroendocrine (Merkel) Cells of the skin: Hyperpla$jas, dysplasias and neoplasms. Lab Invest 52:334, 1985.

7. Sibley RK, Dahl D: Primary neuroendocrine (Merkel cell?) carcinoma of the skin. II. An immunocytochemical study of 21 cases. Am J Surg Pathol 9'109, 1985.

8. Sibley RK, Dehner LP and Rosai J: Primary neuroendocrine (Merkel cell?) carcinoma of the skin. 1 A clinicopathologic and ultrastructural study of 43 cases. Am J Surg Pathol 9:95, 1985.

9. Warnke RA, Gatter KC, Falini B, et a l: Diagnosis of human lymphoma with monoclonal antileukocyte antibodies. NEJM 309-1275, 1983.

10. Wood GS, Link DM, Warnke R, eta!: Pan-leukocyte monoclonal antibody L3B12: Characterization and application to research and diagnostic problems. Am J Clio Pathol 81:176, 1984.

CASE 10- DISTAL RADIUS - XANTHQGRANPWMA

The radiolo~ical appearance of this patient's osteolytic lesion in the distal radius is entirely compatible with a giant cell tumor (GCT), a diagnosis that would be favored by the majority of radiologists and bone pathologists examining the x-rays. In fact, th1s lesion could have started as gian t cell tumor which has n ow been totally replaced by a xanthogranulomatous process, an interpretation I favor. I am, of course, assuming that the material I had to examine was representative of the histological appearance of the entire lesion. Xanthogranulomatous areas are common in GCT and other benign osseous lesions such as fibrous dysplasia, nonosteogenic fibroma and

,

MSCP 1987 FALL SEMINAR- PAGE 21

fibrous histiocytomas. Xanthoma-like areas may also be seen in malignant bone tumors, especially in malignant fibrous histiocytoma. Thus, as in the case of most bone tumors, careful attention to the clinical picture, site and x­ray appears to be essential for diagnosis.

The majority of so called xanthoma of bone are examples of monuments to the previous existence of a GCT. Indeed, I have seen examples of GCT in which over 90% of the lesion was composed of xanthogranuloma, indistingishable from the present case. According to Dahlin, "xanthoma" of bone is always a secondary phenomenon occurring over some pre-existing process. They are benign in their majority and should receive conservative surgical treatment.1

REFERENCE

1. Dahlin DC: Bone tumors. General aspects and data on 6,221 cases. Third edition. Chas. Thomas, Springf1eld II. Eds. 1978.

CASE 11 - SOFT TISSUE - LEIOMYOSARCOMA

This tumor was sent to me in consultation with a diagnosis of poorly differentiated malignant neoplasm. Although mali~nant schwannoma was favored, even metastatic carcmoma was conside~d m the differential diagnosis, undoubtedly because of the presence of epithelioid areas.

Although cytologically poorly differentiated, at least by conventional stains, this is a relatively well differentiated leiomyosarcoma from the immunophenotypic and ultrastructural vantage points. Practically all the neoplastic cells stained with monoclonal antibody HHF35 (to muscle-specific actin) and with relatively high intensity. This finding is enough to establish muscle differentiation. Myofibroblasts may also be positive but usually with lesser intensity. Besides, the cytological features are against a myofibroblastic lesion. Rhabdomyosarcoma (RMS) will also be positive with this monoclonal antibody. However, in RMS, the staining is usually quite focal; some cells staining quite intensely and others not at all. In the present case the staining is rather generalized and the histopathologic features do not support RMS. Additional confirmatory evidence was provided by immunostains with a monoclonal antibody to collagen type IV.2 This antibody identifies the major component of basal lamina and is very useful in all instances where demonstration of basal lamina is diagnostically helpful. Here we can extrapolate much of the ultrastructural data of the past couple of decades. In this case, most tumor cells were surrounded by a layer of collasen type IV, as one would expect of normal smooth muscle and well differentiated leiomyosarcoma. The distribution of collagen type IV in soft tissue tumors can be useful in their differential diagnosis1 Interestingly, we failed to demostrate presence of desmin, the intermediate filament of muscle cells despite the use of two different monoclonal antibodies to this IF. Because the tissue was adequately fixed, this probably represents true negativity due to absence of expression of this molecule by the neoplasm. Furthermore, immunostainmg for muscle-specific antigen is, as a rule, more intense than that of desmin, even when both markers are expressed. Whether this is the result of better preservation of the actin epitope or greater expression of this

MSCP 1987 FALL SEMINAR - PAOE 22

molecule by muscle tumors is not yet clear but the latter aJ?pears probable. From a practical viewpoint, HHF35 is a better, more sensittve reagent than all antisera and monoclonal antibodies to desmin that I have tested to date. · HHF35 has an added advantage over antibodies to desmin because it performs well on formalin-fixed tissue whereas the latter often requires special fixatives or a protease digestion step. The remaining immunophenotype of this neoplasm was consistent with leiomyosarcoma. The neoplastic cells expressed vimentin but not SlOO protein.

Electron microscopy revealed the characteristic features of smooth muscle in a large proportion of the neoplastic cells. These were the presence of a basal lamina enveloping much of the cell membrane, marked pinocytotic activity of the plasmalemma, presence of subplasmalemmal dense bodies and abundance of thin filaments.

Leiomyosarcoma of the deep soft tissues of the extremities is an uncommonly recognized tumor. It is possible that some of these, like the present case, are misdiagnosed as malignant fibrous histiocytoma or as some other type of sarcoma. Most recognized leiomyosarcomas of the deep tissues of the extremities appear to arise from large veins. It is possible that tumors like the present one arise from smaller vessels which quickly become incorporated in the tumor mass. Obviously these tumors could just as readily originate from multipotential mesenchymal cells whether associated with blood vessels or not.

REFERENCES

1. O~awa K, Oguchi M, Yamabe H, Nakashima Y, and Hamashima Y: Distribution of collagen type IV in soft tissue tumors. An immunohistochemical study. Cancer 58:269, 1986.

2. Sakai LY, Engvall E, Hollister DW, and Burgeson RE: Production and characterization of a monoclonal antibody to human type IV collagen. Am J Pathol108:310, 1982:

CASE 12 - NOSE - DESMOPLASTIC MALIGNANT MELANOMA

Spindle cell tumors of the skin of diverse histo~enesis may present with clinical and histopathologic features so similar that dtstinction between the v~rious subtypes may be exceedingly difficult without the benefit of special methods. Atypical fibrous xanthoma (AFX), spindle cell malignant melanoma (SCM) and spindle cell carcinoma (SCC) are tlle most frequent ex­amples of tumors entenng the differential dia~nosis in such instances.1 All three predilect the sun-exposed areas of the skm of the elderly. Atypical fi­brous xanthoma, despite its alarming histologic appearance, carries an excel­lent prognosis and requires conservative management. On the other hand SCM and SCC may show locally aggressive behavior and/or metastasize. The need to accurately classify these neoplasms is therefore obvious. One cannot find much help from the literature because the overlap of clinical and histo­logic appearances raises the question of the possible lack of homegeneity of some of the series reported based on routine histologic study. To quote Rosai: "One cannot help wondering whether at least some of the tumors presently

J

MSCP 1987 FALL SEMINAR· PAOE 23

designated as atypical fibroxanthomas may not actually be carcinomas or melanomas in disguise" (Ackerman's Surgical Pathology, 6th edition, page 134). The case we are currently discussing is a good example of the problem. The original diagnosis on the initial biopsy was sec, a dJagnosis wnich was con­sidered to be supported by the ultrastructural findings. Other consultants who viewed the case preferred to consider it a sarcoma, possibly of smooth muscle origin while some favored atypical fibrous xanthoma.

Electron microscopy showed nests of tumor cells which appeared to be bound by amorphous material resembling basal lamina. The cells had fre­quent, slender cytoplasmic processes and, despite the presence of numerous s1tes of cell to cell contact, few attachment sites and no convincing desmo­somes were found. The cytoplasm contained variable amounts of rough endo­plasmic reticulum, but no organelles permitting us to identify a differentiation pathway. Specifically, myofilaments, dense bodies and melanosomes were not seen within tumor cells. Some electron micrographs illustrated elongated cells in clusters associated by well developed desmosomes and containing clearly identifiable tonofilaments. There was, however, doubts about whether these represented tumor cells or entrapped skin adnexal cells.

Immunohistochemistry helped to answer the questions raised by the electron microscopy and provided information which cleared up the diag­nostic problem. The two most useful antibodies in these cases are: antiserum to protein SlOO and monoclonal antibody to low molecular weight keratins such as AE1.2•8 These showed that the tumor cells expressed protein SlOO and not keratins. Thus a diagnosis of SCM was rendered. The clmical evolution was confirmatory as one year later the patient expired with massive involvement of face and most of the cranium.

We have examined 25 examples of clinically proven. malignant melanoma of the spindle cell type and found expression of l'rotein SlOO in all of them. In the present case there was strong immunoreacttvity of cytoplasm and some nuclei of the vast majority of the tumor cells with two (Dako, Mallinckrodt) antisera to protem SlOO. These results were reinforced by the absence of keratin expression with AEl (as well as several other antikeratin moabs and antisera). However occasional, entrapped, keratin positive, skin adnexal structures could be found among the tumor cells, a finding that correlates with, and explains the ultrastructural findings. The results of these tests, I felt, warranted a diagnosis of spindle cell malignant melanoma. It is important to reiterate that a positive SlOO protein immunostain is insufficient ev1dence for melanoma. Other tumors of the skin may also be SlOO positive.2 A reliably ne~ative keratin immunostain is therefore essential. A strong staining for v1mentin is also helpful to complete the immunophenotype of melanoma2,8 It is also imJ?Ortant to keep in mind that some antisera and even some monoclonal antibodies to keratins (PKKl and 2 for example)4,5 may show partial cross reactivity with epitopes shared with vimentin. Some of the few reports in the literature of keratm-positive melanoma are probably due to use of such antibodies.4

We have found several examples of spindle cell carcinoma (SCC) in which virtually every cell stained strongly with AEl and some in which only a few of the spindle cells expressed keratms detectable with currently avail­able antikeratin antibodies. Is it possible that some, or all, so called AFX are examples of SCC with loss of the1r capacity to express keratins? We cannot

MSCP 1987 FALL SEMINAR- PAOE 24

answer this question with any confidence at the present time. We are currently conducting a prospective study with Dr. Ronald Barr (Dept. of Dermatology and Pathology, UC Davis) with several immunohistochemical procedures. We have found that most tumors suspected of bein~ AFX ex-. press neither SlOO protein nor keratins. Furthermore the detectiOn of SlOO protein in the absence of keratins most certainly indicates malignant melanoma, as follow-up of these cases seems to substantiate.

On the other hand, a small number of cases initially suspected to be AFX contained keratins and were, by convention, reclassified as SCC. Follow­up study of these cases is needed to ascertain the clinical impact of this finding. However it may be significant that a retrospective study of two cases from my files, initially diagnosed as AFX, but that had aggressive clinical behavior, demonstrated presence of keratin within the neoplastic cells. Thus, for the time being, an immunophenotype in which neither SlOO protein nor keratins are found in a cytologically malisnant spindle cell neoplasm supports AFX and hence, portends a benign behav10r.

The electron microscope plays a less important role in the differential diagnosis of spindle cell tumors of the skin. Identification of premelanosomes in SCM by ultrastructural study is often unrewarding. Interestingly, as in the case of SCC, the electron microscopic study of cases of SCM have suggested that the desmoplasia observed in desmoplastic malignant melanoma may be the result of fibroplasia of neoplastic melanocytes rather than by stimulation of stromal fibroblasts.3•6 This should not be surprising since collagen produc­tion by schwannoma, an histogenetically related neoplasm, is a well recog­nized fact.

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REFERENCES

Conley J, Lattes R, and Orr W: Desmoplastic malignant melanoma (a rare variant of spindle cell melanoma). Cancer 28:913, 1971

Eusebi V, Ceccarelli C, Piscioli F, Cristofolini M, and Azzopardi JG: Spindle cell tumours of the skin of debatable origin. An immunocytochemical study. J Pathol144:189, 1984.

From L, Hanna W, Kahn HJ, et al: Origin of the desmoplasia in desmoplastic malignant melanoma. Hum Pathol14:1072, 1983.

Gatter KC, Ralfkiaer E, Skinner J, et al: An immunocytochemical study of malignant melanoma and its differential diagnosis from other malignant tumours. J Clio Pathol 38:1353, 1985.

Huitfeldt HS, and Brandtzaeg P: Various keratin antibodies produce immunohistochemical staining of human myocardium and · myometrium. Histochemistry 83:381, 1985.

Ramaekers FCS, Puts JJG, Kant A1 et a l: Intermediate filaments in malignant melanomas. IdentificatiOn and use as marker in surgical pathology. J Clio Invest 71:635, 1983. .

Valensi QJ: Desmoplastic malignant melanoma. A light and electron microscopic study of two cases. Cancer 43:1148, 1979.

MSCP 1987 FALL SEMINAR- PAGE 2S

8. Warner TFCS, Lloyd RV, Hafez GR, and Angevine JM: Immunocytochemistry of neurotropic melanoma. Cancer 53:254, 1984.

CASE 13- PROSTATE- CARCINOSARCOMA

This is a remarkable example of a most. rare neoplasm anywhere, and even more rare in the prostate. One portion of the resection specimen contains classical adenocarcinoma of the prostate, the other a high grade neoplasm characterized by an admixture of spindle-shaped cells, round or polygonal cells within a variable amount of stroma. Where the cells round up the stroma is h>;aline and reminiscent of cartilage. Indeed areas of ty~;>ical neoplastic cartilage are also discernible in this sample. This combination of carcinoma and sarcoma are responsible for the term carcinosarcoma. However, is this really two different neoplasms occurring in the same area- a true collision tumor? Or, as is more often the case, coulcf it not be that the sarcomatous component derives by a process of transformation (metaplasia) from a common epithelial origin? This issue has been debated fiercely at the light and electron microscopic level. Some people show convincing evidence for the dual origin; others, including yours truly, finding evidence for a common, epithelial origin. Now the argument continues at the immunohistochemical level.

Ordonez et al4 studied a case of so-called-carcinosarcoma of the prostate by IHC and they found expression of prostatic acid phosphatase in both the sarcomatoid element, as well as the area of well-differentiated carcinoma, which, in their opinion, confirmed the epithelial origin of both components. Electron microscopy further confirmed those findings b:l demonstrating desmosomes in the sarcomatoid areas. Hokamura et al studied another example and found prostatic acid phosphatase only in the epithelial component. A few other cases in the literature have not been studied with prostatic markers.

Immunohistochemistry in the present case showed intense staining of the well-differentiated adenocarcinoma for prostatic acid phosphatase as well as for prostate-specific antigen. However no cell in the sarcomatous area stained for any of these markers. More helpful, because of its superior sensitivity to detect evidence of epithelial differentiation in the sarcoma area, is the use of cocktails of monoclonal antibodies to low-molecular-weight keratins. In the present case such study was done in my laboratory. We failed to detect keratins in any of the cells of the sarcomatous area. We also failed to detect any evidence of differentiation of the sarcoma-like cells and the only intermediate filament detectable was vimentin. My experience with four carcinosarcomas from other regions (pancreas, gallbladder, urinary bladder and kidney) is an even tie. In two of these cases the sarcomatous regions of the neoplasms had focal expression of keratins; in the other two it did not. These results could be interpreted two ways: there is such a thing as true carcinosarcomas, to be distinguished from carcinomas with pseudosarcomatous metaplasia or, alternatively, all such tumors are truly carcinomas with sarcomatous metaplasia but our methods are not sensitive enough to prove it. I favor the second choice.

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MSCP 1987 FALL SEMINAR· PAOE 26

REFERENCES

Ginesin Y, Bolkier M, Moskovitz B, Lichtig C, and Levin DR: Carcinosarcoma of the prostate. Eur Urol12:441, 1986

Hokamura K, Kurozomi T, Tanaka K, and Yamaguchi A: Carcinosarcoma of the prostate. Acta Pathol Jpn 35:481, 1985.

Krastanova LJ, Addonizio JC: Carcinosarcoma of prostate. Urology 18:85, 1981.

Ordonez NG, Ayala AG, von Eschenbach AC, Mackay B, Hanssen G: Immunoperoxidase localization of prostatic acid phosphatase in prostatic carcinoma with sarcomatoid changes. Urology 19:210, 1982.

CASE 14 - SOFT TISSUE - CLEAR CELL SARCOMA (MALIGNANT MELANOMA OF THE SOFT PARTS)

This is a clear example of the entity described by Enzinger in 19651

under the name clear cell sarcoma of tendons and aponeuroses. Since the original description, numerous additional cases have been reported. The neoplasm has gained recognition as a disc.tcte clinicopathologic entity and its "histogenesis" has been established by ultrastructural and immunohistochemical studies.

As originally described, this is a distinctive tumor, originating near tendons and aponeuroses, predominantly in young adults :and women, with a proclivity for local recurrence and late metastasis. The tumors were slow growing and painless and many had been present for many years before treatment was SQught. Characteristically, D:ests of round or fusiform, pale staining cells with prominent nucleoli and marked uniformity are seen. In about a third of the cases the cytoplasm is not clear but rather finely granular and eosinophilic. However, the nuclear features are uniform. No evidence of biphasic growth was found in any of the original cases. Interestingly, in the onginal series no melanin production was noted although Fontana stains were done in 15 of them. Publications from several laboratories soon appeared showing the frequent occurrence of melanin production by the neoplastic cells. Mukai et al2 studied 8 cases, some melanotic some aroelanotic by enzyme histochemical and immunohistochemical (SlOO protein). He found no evidence of differences between the two ~roups and concluded that clear cell sarcoma was a tumor of neural crest origm. Currently this tumor is accepted by most as belonging to the melanoma family, although a weak case could be made for schwannoma with melanin production.

Our immunohistochemistry confirmed the diagnosis, as SlOO and HMB45 gave intensive immunostaining. Incidentally, we have found HMB45 to be positive in every one of the 6 clear cell sarcomas that we have studied to date.

MSCP 1987 FALL SEMINAR· PAGE 27

REFERENCES

1. Enzin~er FM: Clear-cell sarcoma of tendons and aponeroses: An analysts of 21 cases. Cancer 18:1163, 1965.

2. Mukai M, Torikata C, Iri H, Mikata A, et al: H istogenesis of clear cell sarcoma of tendons and aponeuroses. An electron-microscopic, biochemical, enzyme histochemical" and .immunohistochemical study. Am J Patho1114:264,1984.

3. Ohno T, Park P, Utsunomiya Y, Hirahata H, and Inoue K: Ultrastructural study of a clear cell sarcoma suggesting schwannian differentiation. Ultrastruct Pathol1(}39, 1986.

CASE JS - DUODENUM - SPINDLE CELL <PLEOMORPHIC) CARCINOMA

The pathologist who submitted this case in consultation to me identified the tumor as: "a pleomorphic, focally spindle celled neoplasm which, when given the site and patient's age, was most consistent with a sarcoma and probably a leiomyosarcoma". I went along with that diagnosis. To my surprise, both components of the neoplasm strongly expressed keratins in a large proportion of the cells. Coexpresston of vimentin, but with Jesser intensity of immunoreactivity, was also noticed. Neither muscle-specific actin, desmin, nor production of collagen type IV could be detected. S100 protein stains were, likewise, negative.

In view of these results, I interpreted the tumor as a pleomorphic carcinoma with spindle cell areas. Such tumors are more common in the pancreas than in the duodenum, but the exact site of origin of the present neoplasm is by no means certain. Unfortunately the patient expired of post­operative complications and autopsy permission was not obtained.

In recent months there have been several reports indicatingJ'resence of keratin expression by leiomyomas and leiomyosarcomas2.3 Coul this be one such case"'? With Dr. Norio Azumi, in our laboratory, we have studied the immunoreactivity of 19 leiomyosarcomas of various sites, 14 specimens of normal myometrium and 8 uterine leiomyomas with a panel of antikeratin monoclonal antibodies as well as monoclonal antibodies to the muscle markers desmin and muscle-specific actin.1 Two of the samples f rom normal myometrium and one of the leiomyomas showed focal immunoreactivity with several antikeratjn antibodies. One cutaneous and one retroperitoneal leiomyosarcoma also stained for keratin with more than one monoclonal antibody. All leiomyosarcomas, leiomyomas and' the normal myometrium stained for muscle-specific actin and the majority stained for desmin as well. The expression of keratins by smooth muscle cells is unlikely to be due to cross reactivity due to fixation artifact for the following reasons: first, it is improbable that other intermediate filaments or cytoplasmic proteins would share epitopes with keratin which can be detected by several anti-keratin monoclonal antibodies, because these antibodies detect different keratin epitopes; secondly, immunoreactivit{ to keratin was observed both in formalin- and alcohol-fixed tissue o the same specimen, in which the mechanisms of fixation are different. However, whether this phenomenon

MSCP 1987 FALL SEMINAR -PAGE 2&

truly represents aberrant keratin expression by smooth muscle cells must ultimately be proven by immunobiochemical investigation. Nevertheless, leiomyosarcomas must be added to the group of sarcomas which may show · immunoreactivity with anti-keratin antibodtes.

The question is, how to interpret results in a case like the present one in the light of the fact that keratin may be occasionally found in leiomyosarcoma? First, it is important to emphasize that only a few cells stained in the cases of leiomyosarcoma with apparent keratin expression in our series. Second, coexpression of muscle spectfic antigen rules out an epithelial tumor. We have stained hundreds of non-muscle derived neoplasms and, with the exception of those containing myoepithelial cells, no muscle­specific actin was found. Thus, the importance of using a panel of antibodies for accurate immunodiagnosis is re-emphasized by these obsevations.

REFERENCES

1. Azumi NA, Sheibani K, and Battifora H: Keratin-like immunoreactivity in leiomyosarcomas, uterine leiomyomas, and normal myometrium by multiple antikeratin antibodies. Submitted to the 77th Annual Meeting, U.S. and Canadian Academy of Pathology.

2. Brown DC, Theaker JM, Banks PM, Gatter KC, and Mason DY: Cytokeratin expression in smooth muscle and smooth muscle tumors. Histopathol11:477, 1987. -

3. Norton AJ, Thomas JA, and Isaacson PG: Cytokeratin-specific monoclonal antibodies are reactive with tumours of smooth muscle derivation. An immunocytochemical and biochemical study using ' antibodies to intermediate filament cytoskeletal proteins. Histopathol 11:487, 1977.

CASE 16 - MEDIASTINUM - EXTRAOSSEOUS CHORDOMA

There was no evidence of bone involvement in x-rays and cat-scans of the tharacic spine. The pathologists who originally studied this material were assured of that by the chnicians, and re-examinatjon of these tests confirmed the soft tissue nature of the neoplasm. The gross examination of the resected esophagus showed a 9x8x6 em bosselated mass appearing to arise in the esophageal wall. The mucosa, save for a small area of ulceration, was intact. Microscofically, in practically every section, the tumor was c0mposed of lobules o amphophylic myxoid stroma containing clumps of cells with eosinophilic cytoplasm and small, round to oval nuclei and scant mitoses. In places the stroma had a decidedly chondroid appearance. Additional biopsy material revealed metastatic tumor deposits in the pericardium, confirmmg the malignant nature of the tumor. Tlie case was stgned out as a rare example of extraskeletal myxoid chondrosarcoma. However, electron microscopic study revealed that the neoplastic cells had a few features suggesting epitheliai (or endothelial differentiation), in particular the presence of desmosome-like junctions, a feature not reportedly seen in chondrosarcoma.5

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MSCP 1987 FALL SEMINAR- PAOE 29

The immunophenotype as obtained in our laboratory was inconsistent with a tumor of cartilaginous origin as practically every neoplastic cell stained strongly for keratins and with several monoclonal antibodies. We have examined more than 20 chondrosarcomas of various degrees of differentiation with the same antibodies, including 4 cases of myxoid chondrosarcoma and 2 of myxoid chondrosarcomas of extraskeletal origin, so called chordoid sarcoma (unpublished data). None of these showed keratin immunostainin~, nor, to the best of my knowled~e, has anyone described keratin expressiOn by tumors of cartila~inous ongin. The literature on the immunohistochemistry of chordoma is m complete agreement in this regard;1.S·6 keratins are expressed, even sarcomatous and dedifferentiated types.3•4 Thus, chordoma, which is notorious for having chondroid areas, is always keratin positive. This is not surprising given its origin from the epithelial notochord. Cartilaginous tumors, as well as chordoma, are SlOO protein positive, and so was the present case. Another l'ossibility to be considered would be a malignant mixed tumor originatmg in minor salivary gland tissue, which could exhibit a similar immunophenotype. Against this possibility, however, is the total absence of ductal or tubular structures and the generally inconsistent architectural and cytologic appearance. On the contrary, acceptable examples of physalipherous cells are not difficult to see in virtually every section.

A more difficult proposition is to explain what a chordoma is doing in the esophageal wall. One would first have to consider a metastatic chordoma. This is, however, out of the question because metastasis is a late event in chordoma and the diagnosis 1s clinically obvious by then. Furthermore, as already stated, there was no radiological evidence of disease in the spine. A nebulous entity with the title "parachordoma" creeps up in the literature once in a while. Parachordoma was originally describecf by Laskowski as a tumor occuring in soft tissues near tendons as well as within bone. 2 Ten cases were described in 1977 by Dabska, 2 un fortunately without shedding light on their histogenesis. Nevertheless, based in current immunohistochemical studies, it appears that most tumors reported as "chordoid" tumor, "chordoid" sarcoma and "parachordoma" (also called chordoma periphericum) are merely examples of high grade myxoid chondrosarcoma8 Thus the present case may be a "rara avis" indeed, the first case of myxoid chondrosarcoma expressing keratins or, as I prefer to interpret it, a true example of extraspinal chordoma. Ectopic notochordal tissue {ecchordosis physahphora) may explain the unusual site of this tumor. Ectopic notochordal tissue was first described by Luschka in 1856.3

It is an incidental finding at autopsy, found most commonly in the area of the clivus and the sacrococcygeal regiOn, but has also been found in the nasopharyngeal submucosa.3 If my diagnosis is the correct one, I would have to postulate origin in heterotopic notochordal remnant in the soft tissues near the esophagus or, once again, invoke the convenient and mysterious "multi­potential cell".

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REfERENCES

Abenoza P, and Sibley RK: Chordoma: An immunohistochemical study. Human Patho1 17:174, 1986.

Dabska M: Parachordoma: A new clinicopathologic entity. Cancer 40:1586, 1977.

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MSCP 1987 FALL SEMlNAR - PAOE 30

3. . Ho KL: Ecchordosis physaliphora and chordoma: A comparative ultrastructural study. Clin Neuropathol4:77, 1985.

4. Meis JM, Raymond AK, Evans HL, Charles RE, and Giraldo AA: "Dedifferentiated" chordoma. A clinicopathologic and immunohistochemical study of three cases. Am J Surg Patholl1:516, 1987.

5. Miettinen M, Karaharju E, and Jarvinen H: Chordoma with a massive spindle-cell sarcomatous transformation. A light and electron­microscopic and immunohistochemical study. Am J Surg Patholl1:5631 1987.

6. Miettinen M, Lehto V-P, Dahl D, and Virtanen I: Differential dia~nosis of chordoma, chondroid and ependymal tumors as aided by anti-intermediate filament antibodies. Am J Patholll2: 160, 1983.

7. Rutherfoord GS, and Davies AG: Chordomas-ultrastructure and immunohistochemistry: A report based on the examination of six c~ses. Histopatholll:775, 1987.

8. Weiss SW: Ultrastructure of the so-called "chordoid sarcoma". Evidence supporting cartilaginous differentiation. Cancer 37:300, 1976.

CASE 17- DIAPHRAGM - EMBRYONAL RHABDOMYOSARCOMA

This is not a particularly difficult case to diagnose by simple examination of an H&E preparation, even without considering the clinical history. Having a "good eye" to recognize rhabdomyoblasts is all it takes. In this case clearly distinguishable rhabdomyoblasts abound. Criteria for the recognition of rhabdomyoblasts are well known and will not be discussed here. It is, however, important to reiterate that if one expects to limit his diagnosis of rhabdomyosarcoma to tumors featuring cross-striations, one is rarely going to make such a diagnosis. The trick is to learn to recognize early rhabdomyoblasts. The location, as we are told that this tumor is apparently arising from the diaphragm, is not a frequent one. A disproportionate number of rhabdomyosarcomas take origin in the head and neck and genitalia and relatively few of these tumors featuring muscle differentiation actually develop from muscle (one more example of discrepancy between histo~enesis and differentiation). Another unusual feature in this particular case ts the presence of a pronounced degree of phagocytic activity, especially of red blood cells by the neoplastic cells. This might have led us to consider a malignant histiocytic neoplasm if it was not for the presence of typical rhabdomyoblasts.

Going back to the question of histologic diagnosis, there are many cases of rhabdomyosarcoma that cannot confidently be diagnosed by routine histologic flpp~oaches. In the past electron-mtcroscopy was invaluable in these cases because 1t could demonstrate ultrastructural features of muscle differentiation that were not discernible by light microscopy.5 Nowadays, better results can be obtained with immunohistochemistry. One of the earliest markers for this purpose was myoglobin. Brooks reported nearly 90%

;

MSCP 1987 FALL SEMINAR · PAGE 31

positivity for myoglobin in rhabdomyosarcoma.2 My own experience is much less encouraging. In general, rhabdomyosarcomas containing relatively well differentiated myoblasts, as in the present case, have readily demonstrable myoglobin-contaming cells; however, these correspond to rhabdomyoblasts which are readily identifiable by conventional microscopy. Unfortunately, many rhabdomyosarcomas do not contain such well-differentiated rhabdomy­oblasts. Furthermore, it has been shown that myoglobin can be demonstrated within nonmuscular cells present in malignant tumors infiltrating skeletal muscle probably as a result of phagocytosis of myoglobin released by damaged myocytes. 4 As shown by this case, these cells can be quite pha~ocytic. Another problem can be caused by the presence of natural antlkeratin antibodies in the rabbits used to raise the antimyoglobin antiserum. Cross reaction with keratin-containing neoplasms may lead to error if the interpre­tation is solely based on results of the myoglobin antibodies. Antibodies to the intermediate filament desmin have been found useful in some cases by Miettinen, et al.6 and also by Altmannsberger, et al.1 Unfortunately many of the commercially available antibodies to desmin require special fixation or protease pre-treatment of the tissue sections and their results are not always reliable. DeJong, et al. have reported that an antiserum to antifast myosin is superior to regular anti-myoglobin antisera.3 However, their study was performed with a "homemade" anti-myosin antiserum, which is not not available for evaluation.

Recently, a monoclonal antibody to muscle-specific actio (HHF35) was recommended as a sensitive and fairly specific-marker for muscle differentiation? We have evaluated this antibody against a large panel of normal tissues and neoplasms of varying histogenesis and found it to be much more sensitive than antibodies to myoglobin and desmin, even when fixation was adequate, and a lot better when it was not because the epitope recognized by this antibody is quite resistant to mishandling of the tissue. Even rhabdomyosarcomas containing predominantly poorly differentiated rhabdomyoblasts gave positive results with HHF35. In the present case, practically all the neoplastic cells stained very well with thts antibody, despite the fact that we found evidence that our sample had probably been overfixed (as judged by its failure to stain with anti-vimentin antibody). It should be emphasized that antibody HHF35 is not specific for skeletal muscle and it will stam smooth muscle, myoepithelium and, weakly, myofibroblasts. However, in the context of the differential diagnosis posed by rhabdomyosarcoma this lesser degree of specificity over myoglobin ordinarily poses no problem. Incidentally, we have tried several monoclonal antibodies of high sensitivity to myoglobin and found them to be not much better than antisera to diagnose rhabdomyosarcoma. Apparently it is not a matter of sensitivity but of lack of expression of myoglobin by poorly differentiated rhabdomyoblasts.

Finally, how should we subclassify this rhabdomyosarcoma? Since it is occurring in a child, and it does not have features of alveolar rhabdomyosarcoma, I decided to call it an embryonal rhabdo. However, it is not unusual for mixed types to occur. Furthermore, in the case of rhabdomyosarcoma, histologic classifications are less valuable predictors of outcome than the location of the tumor and the clinical stage.

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MSCP 1987 FALL SEMINAR- PAGE 32

REFERENCES

Altmannsberger M et al: Diagnosis of human childhood rhab­domyosarcoma by antibodies to desmin, the structural protein of muscle specific intermediate filaments. Virchows Arch (Cell Pathol) 39-203,.1982.

Brooks JJ: Immunohistochemistry of soft tissue tumors. Myoglobin as a tumor marker for rhabdomyosarcoma. Cancer 5:1757, 1982.

de Jong ASH, et al: Myosin and myoglobin as tumor markers in the diagnosis of rhabdomyosarcoma. A comparative study. Am J Surg Pathol8:521, 1984.

Eusebi V, Bondi A and Rosai J: Immunohistochemical localization of myoglobin in nonmuscular cells. Am J Surg Pathol, 8:51, 1984.

Kahn HJ, et al: Immunohistochemical and electron microscopic assessment of childhood rhabdomyosarcoma. Increased frequency of diagnosis over routine histologic methods. Cancer 51:1897, 1983.

Miettinen M, et al: Alveolar rhabdomyosarcoma. Demonstration of the muscle type of intermediate filament protein, desmin, as a diagnostic aid. Am J Pathol108:246, 1982. _

Tsukada T, Tippens D, Mar H, Gordon D, Ross R, and Gown AM: HHF35, a muscle-actin-specific monoclonal antibody: I. Immunocytochemical and biochemical characterization. Am J Pathol 127:51, 1987.

CASE 18- UTERUS· LEIOMYOSARCOMA WITH OSTEOCLAST-LIKE GIANT CELLS

This is a most unusual neoplasm. The predominant pattern is suggestive of a spindle-cell sarcoma with occasional bizarre giant cells. However, uniformly distributed throughout the neoplasm are multinucleated giant cells with features identical to those of osteoclasts and give the tumor a resemblance to giant cell tumor of bone. Although osteoclast-like ~iant cells may be occasionally seen in a variety of mesenchymal and even ep1thelial neoplasms? they are usually only limited to small areas of the tumors, and frequently in association with foci of tumor necrosis or old hemorrhage. The differential diagnosis in this case includes malignant fibrous histiocytoma, and mixed mullerian tumor, as well as leimyosarcoma. In favor of MFH is the fact that some of the multinucleated giant cells have distinctly neoplastic appearance. However, atypical multinucleated giant cells are not uncommon in high grade leiomyosarcoma, especially uterine ones. Against an epithelial neoplasm is the lack of recognizable epithelial structures and the relatively uniform histologic pattern.

The results of the immunohistochemistry provided convincing evidence of muscle differentiation of the neoplastic cells. The majority of the spindle cells, pleomorphic multinucleated cells, but not the osteoclast-like giant cells

MSCP 1987 FALL SEMINAR - PAOE 33

stained with monoclonal antibody HHF35. Since th.e staining was quite . uniform, and no cells resembling rhabdomyoblasts were found (as a triple M tumor may contain), these results strongly favor smooth muscle differentiation. Another argument against mixed mullerian tumor was the negative immunostaining for keratins. Malignant fibrous histiocytoma usually has few osteoclast-like giant cells, with the exception of the so-called malignant giant cell tumor of the soft parts.2 Against these two diagnoses is the fact that muscle-specific actin is negative. · A few myofibroblast-like cells may, however, stain. These are usually sparse and weakly stained.

In searching the English literature I was able to find only one case of of a leiomyosarcoma of the uterus with osteoclast-like giant cells in the last 20 years, a paper by Darl;>y, et al.1 Their case was very similar to the present one, and the smooth muscle differentiation of the neoplastic cells was convincingly supported by ultrastructural studies.

REFERENCES

1. Darby AJ, Papadaki L, and Beilby JOW: An unusual leiomyosarcoma of the uterus containing osteoclast-like giant cells. Cancer 36:495, 1975.

2. Guccion JG, and Enzinger FM: Malignant giant cell tumor of soft parts-An analysis of 32 cases. Cancer 29:1518, 1972.

3. Oyasu R, Battifora H, and Buckingham -w: Metaplastic squamous cell carcinoma of bronchus simulating giant cell tumor of bone. Cancer 39-.1119, 1977.

CASE 19- FALX CEREBRI- MENINGIOMA

This is a most unusual neoplasm. The location immediately brings to mind meningioma. However, neither the pattern nor the cytolog10al features are familiar to any example of meningioma that I have seen. There is, to be sure, a component of spindle cells but these are loosely arranged along vessels. More promment are round and cuboidal cells in small clusters, surrounded by an edematous or myxomatous matrix. Conspicuous for their absence are whorls and psammomatous areas, the usual accompaniments of meningioma, at least in the material available to us. The cells have relatively bland nuclei and mitoses are absent; this is okay for meningioma. The differential diagnosis includes chordoma, metastatic carcinoma, metastatic melanoma, extra sellar pituitary adenoma, some rare form of glioma and, of course, meningioma.

Intracranial neoplasms are "terra incognitd' to me, so, in this case I have to rely a Jot on the results of immunohistochemistry to guide me towards the most reasonable dia~nosis. The results of the intermediate filament phenotyping immediately help in ruling out some of the possibilities. A reliable absence of keratins within the neoplastic cells helped me rule out metastatic carcinoma, chordoma and pituitary adenoma. Absence of immunoreactivity with mon0clonal antibodies to GFAP virtually rules out glioma because a benign glioma would be expected to express tlus IF. On the other hand, strong immunoreactivity for vimentin was observed in this case.

MSCP 1987 FALL SEMINAR· PAGE 34

This is typical of meningioma, but is also seen in melanoma. The latter is ruled out by the negative results of the SlOO protein stain and the lack of mitoses. We are thus left, by exclusion, with an immunopbenotype favoring · meningioma. There is ample evidence that the primary (and sole) intermediate filament in the vast majority of meningiomas is vimentin. This is remarkable because of the abundance of well developed desmosomes-a structure generally associated with keratin and epithehallineage-in these tumors. Indeed attachement of vimentin filaments to desmosomes in meningioma and normal arachnoidal tissue has been convincingly demonstrated by researchers of the Heidelberg group.2 Expression of keratin by meningioma is exceptional and, to date, has only been reliably described in the so-called secretory meningioma.1

The current meningioma, however, does not fit the pattern of any of the recognized types of meningioma as described by Rubinstein.3 I shall therefore limit myself to calljng it meningioma, without any further qualifications.

Incidentally, I take advantage of the opportunity to decry the use of the term angioblastic meningioma to designate a lesion which is neither histogenetically related to true meningioma nor has a com :parable clinical behavior. I am referring to hemangiopericytomas originatmg in the meninges. There is little reason to continue to use the misnomer angioblastic meningioma and, in my experience, such terll!.inology may lead to misintrepretations and inadequate therapy.

REFERENCES

1. Halliday WC, Ye~er H, Duwe GF, and Phillips J: In termediate filaments in menmgioma. J Neuropathol Exper Neurol 44:617, 1985.

2. Kartenbeck J, Schwechheimcr K, Moll R, and Franke WW: Attachment of vimentin filaments to desmosomal plaques in human meningioma! cells and arachnoidal tissue. J Cell BJOI 98:1072, 1984.

3. Rubinstein L: Tumors of the central nervous system. AFIP fascicles, second series, #6.

CASE 20 - PERITONEUM - EPITHELIOID HEMANGIOENDQTHELIOMA

This is a typical example of a recently described neoplasm, the so-called epithelioid heman~ioendothelioma,7 a vascular tumor of intermediate degree of mali_?nancy wh1ch belongs within the spectrum of the "histiocytoid heman­gioma". What is unique is that this P.articular example seems to be arising in the peritoneum or, at least, 'secondanly involving it. This is indeed an extraordinary occurrence and led to the initial interpretation of mesothelioma. I have seen an example of this neoplasm arising within a lymph node, which was misdiagnosed as metastatic carcinoma. A similar case, with long follow-up, has been recently described.6 Short strands and solid clusters and sheets of neoplastic cells predominate in this neoplasm. Formation of abortive vascular spaces, rarely displaying open lumina, are the first clue to its histogenesis. Occasional sharply demarcated cytoplasmic

MSCP 1987 FALL SEMINAR- PAGE 35

vacuoles, resembling the intracytoplasmic lumina of some epithelial neo­plasms are common in this tumor. Mitotic activity is sparse but intravascular growth, within perivascular lymphatics, can be seen frequently and was no­ticeable in many areas of this tumor.

Metastatic carcinoma and mesothelioma can be readily excluded in view of the results of the immunohistochemistry. The neoplastic cells were extraordinarily rich in vimentin and displayed no keratin content. These tumors are notoriously vimentin-rich, which correlates with the intense cytoplasmic eosinophilia responsible for the "rhabdoid" appearance of the tumor cells. This is in keeping with observations with the electron microscope which consistently reveals the cells to be packed with diffusely distributed (not forming tonofilaments) intermediate filaments. The absence of keratin in the present case effectively eliminates carcinoma and mesothelioma. Melanoma is excluded because neither S100 protein nor the antigen recognized by HMB45 were expressed by the tumor cells. Immunostains for collagen type IV were useful in outlining the capillary structures, but onlY. in very focal areas. It would be nice to confirm the diagnosis with antibodies to factor VIII. Unfortunately, the tumor cells did not show evidence of this substance. I think this is because of improper fixation and poor sensitivity of the antisera used, as even the normal capillaries stained rather weakly or not at all. Be that as it may, it is not unusual for vascular tumors, even benign ones, to fail to stain with these reagents. However, it is important to emphasize that most examples of epithelioid hemangioendothelioma with gooct fixation that I have studied, did stain for factor VIII. Wick and Manivel have recently published their experience with factor VIII related antigen and Ulex europaeus antigen (UEA) lectin histochemistry. Five of their 8 cases of epithelioid hemangioendothelioma stained for factor VIII and 7 stained for UEA.8

However, UEA was also expressed by epithelioid sarcoma, a tumor which may be easily mistaken for epitheliOid hemangioendothelioma. These observations underscore the lack of specificity of UEA. Of course, this differential diagnosis can be readily solved wtth antibodies to keratins (ES=positive; HE=negative). In the present case, final proof of the diagnosis was provided by my trustworthy (and not for sale) electron microscope. Ultrastructural study revealed characteristic features of endothelial cells and clearly outlined the formation of vascular buds.

This tumor may also occur in parenchymal organs. In the lung it was formerly regarded as an intravascular bronchioloal veolar tumor (IVBA T),1 in the liver as sclerosing cholangiocarcinoma,2·4 and in the bone as a form of hemangioendothelioma.3 Recently Yousem and Hochholzer have described unusual manifestations of epithehoid hemangioendothelioma, including a case involving the pleura and resembling a malignant mesothelioma.9

REFERENCES

1 Dail DH, Liebow AA, Gmelich JT, et al: Intravascular, bronchiolar and alveolar tumor of the lung (IVBA T). An analysis of twenty cases of a peculiar sclerosing endothelial tumor. Cancer 51:451, 1983.

2. Dean PJ, Haggitt RC, and O'Hara lCJ: Malignant epithelioid hemangioendotheli0ma of the liver in young women. Rei a tionship to oral contraceptive use. Am J Surg Pathol 9:695, 1985.

MSCP 1987 FALL SEMINAR- PAGB36

3. Dorfman HD, Tsuneyoshi M, and Bauer T: Epithelioid heman­gioendothelioma or bone. Lab Invest 45:17A, 1986 .

. 4. l ishak KG, Sesterhenn IA, Goodman ZD, et al: Epithelioid _ hemangioendothelioma of the liver: a clinicopathologic and follow up study of 32 cases, Hum Pathol15:839, 1982.

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Rosai J, Gold J, and Landy R: The histiocytoid hemangiomas. A unifying concept embracing several previously described entities of skin, soft tissue, large vessels, bone and heart. Hum Pathol10:707, 1979.

Silva EG, Phillips J, Langer B, and Ordonez NG~ Spindle and histiocytoid (eptthelioid) hemangioendothelioma. Primary in lymph node. Am J Clin Pathof 85:731,1986.

Weiss SW, and Enzinger FM: Epithelioid hemangioendothelioma. A vascular tumor often mistaken for a carcinoma Cancer 50:970, 1982.

Wick MR, and Manivel JC: Epithelioid sarcoma and epithelioid hemangioendothelioma: An immunocytochemical and lectin­histochemical comparison. Virchows Arch 410:309, 1987.

Yousem SA, and Hochholzer L: Unusual thoracic manifestations of epithelioid hemangioendothelioma. A!ch Pathol Lab Med 111;459, 1987.