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An unusual multifocal leiomyosarcoma of the stomach: A light and electron microscopic study
MEDICAL INTELLIGENCE ~nosis o f s y n o v i a l s a r c o m a , s i n c e s y n o "comas d e s c r i b e d in t h e n e c k a n d : h a v e b e e n o b s e r v e d in y o u n g p e o p l e Y treatment of this subject, the physicians to a d m i n i s t e r r a d i a t i o n t h e r a p y ; a ive d o s e o f 7 6 0 0 r a d s was g i v e n . O n e e r n o r e c u r r e n c e was o b s e r v e d , alan u l c e r t h a t f o l l o w e d s u r g i c a l e x c i s i o n t t h r o u g h o u t t h e site o f o r i g i n o f t h e
18. Tillotson. J. F., ,~,IcDonald, J. R., and Janes, J..xt.: Synovial sarcomata. J. Bone Joint Surg., 53A;459473, 1951.
AN UNUSUAL MULTIFOCAL LEIOMYOSARCOMA OF THE STOMACH: A LIGHT AND ELECTRON MICROSCOPIC STUDY
edgment JOEL A. RUTH, M . D . , *
a r e i n d e b t e d to Dr. R a f f a e l e L a t t e s o f a U n i v e r s i t y , f o r c o n f i r m i n g tire d i a g ,4 k i n d l y r e v i e w i n g t h i s m a n u s c r i p t .
HARRY CARTER, M . D . , t AND DOUGLAS COSTABILE, M . D . *
_~rences trdi, J. G., and Smith, O. D.: Salivary gland tu-s and their mucins. J. l'ath. Bact., 77:131-140, L.: Synovial sarcomas in serous bursae and m sheaths. Am. j. Cancer, 34:501-539, 1938. n, N. L., Soule, E. lI., and Kelly, P. J.: Synuvial mat an anal)'sis of 134 tumors. Cancer, 18:6131965. :, D. W., and Stout, A. 1'.: Synovial sarcoma in "en. Cancer, 12:1123-1133, 1959. :y, M. B., l'arkhill, E. M., Dablin, D. C., Woolner, • Soule, E. 11., and Harrison, E. G., Jr.: Tumors : oral cavity and pharynx. Atlas of Tumor PatholSect. IV. Fasc. 10b. Washington, I).C., Armed s Institute of Pathology, 1968, V., and Russomanno, E.: Su di on caso di alosarcoma a Iocalizzazione retroperitoneale. Ital. Anat. instol. Pat., 43:260-270, 1969. ,i, G., Kaye, G. I., Lattes, R., and Majno, G.: ial sarcoma. Electron microscopic stud)• of a I case. Cancer, 28:1031-1039, 1971. ~en, C. D., and Stout, A. P.: Synovial sarcoma. Surg., 120:826-842, 19-t4. I, E. G., Jr., Black, B. M., and Devine, K. D.: ial sarcoma primary in the neck• Arch. l'ath., 7-141, 1961. • L.: Tumors and Tumorous Conditions of the and Joints. London, tlenry Kimpton, 1958. m, P.: Synovial sarcoma of the pharynx. Report tse. Am. J. Clin. l'ath., 24:957-961, 1954. "n, L. G., and Angervall, L.: ttistochemical terizatiou of mucosubstances in bone ~tnd soft tumors• Cancer, 36:985-994, 1975. J., and Ariel. I. M.: Tumors of the Soft Somatic s and Bone. Treatment of Cancer and Allied -'s. New York, Harper and Row, 1964, Vol. VII. • D. A., Tennant, R., and Rosahn, P. D.: Synorcomas in joints, bursae and tendon sheaths. A and pathological stud)' of 16 cases• Surg. Obstet., 72:951-981, 1941. E., and DuEling, J.: Differential staining of acid tminogl)cans (mucopol)saccharides) b)' alcian salt solutions. Histocbemie, 5:221-233. 1965. P., and Lattes, R.: Tumors of the Soft Tissues. )f Tumor i'athology. Second series, Fasc. 1. tgton, D.C., Armed Forces Institute of Pathol~67. K. H., and Goldman, H. M.: Oral Pathology. St. Louis. The C. V. Mosby Company, 1960.
Abstract A multifocal leiomyosarcoma of the stomach originating from the muscularis mucosae w#h lymph node and distant metastases is described in a 66 year oM man. The electron microscopic features of a representative tumor mass and a metastasis colzfirmed the
smooth muscle histogenesis. The light microscopic appearance coasistently suggested malignant fibrous histocytoma. The pathological features of gastric leiomyosarcomas are reviewed with special emphasis on the problem of practical diagnosis. This case also imlicates that not all sarcomas with storiform features are necessarily histioo'tic in orion. l'rimary sarcomas of the stotnach represent less t h a n 10 p e r c e n t o f all m a l i g n a n t g a s t r i c tumors, and although malignant lymphomas compose the bulk of these mesenchymal tum o r s , g a s t r i c l e i o m y o s a r c o m a s m a k e u p 10 to 4 0 p e r c e n t o f t h i s g r o u p , t-5 S k a n d a l a k i s e t al. 6 f o u n d in a c o l l e c t i v e r e v i e w o f t h e l i t e r a t u r e n p to 1958 t h a t 35 p e r c e n t o f 1017 g a s t r i c smooth muscle tumors were malignant. Benign a n d m a l i g n a n t g a s t r i c s m o o t h m u s c l e t u m o r s in animals are rare. 7 We describe a muhifocal gastric leiomyosarcoma, which on light microscopy resembled a malignant fibrous histiocytoma. The ultras t r u c t u r a l f e a t u r e s o f s m o o t h m u s c l e cells in
*Clinical htstructor ill Pathology, Columbia University College o f Ph)'sicians and Surgeons, New York, New York. A t t e n d i n g Pathologist, Overlook Hospital, Summit, New Jersey. - i A n e n d i n g Pathologist, St. Barnabas Medical Center, l.ivingston, New Jersey. :[:Attending Surgeon, Overlook ttospital, Summit, New Jersey.
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H U M A N P A T H O L O G Y - - V O L U M E 9, N U M B E R 3 both the p r i m a r y t u m o r and a metastasis confirmed the true nature o f the neoplastic process. CLINICAL HISTORY A 66 )'ear old white man was admitted to Overlook Hospital on October 25, 1975, for evaluation o f a six month Itistory of vague abdominal discomfort associated with a two to three ntondl ltistory o f decreasing appetite, rapid satiety, and a 10 to 15 p o t m d weight loss. Pltysical examination was unremarkable. Pertinent laboratory data included tlte following: hemoglobin, 11.0 gin. p e r 1O0 ml.; bematocrit, 32 p e r cent; erytltrocyte cotntt, 3.8 million (ttypochromic, microcytic); leukocyte count, 8800 (with a normal differential count); and guaiac positive stools. A n u p p e r gastrointestinal series demonstrated multiple gastric polypoid lesions, and a bariunt e n e m a was unremarkable. Gastroscopy confirmed the presence o f mtdtiple ulcerated polypoid tumors and a routine biopsy was reported as "sarcoma, ? type." Exploratory laparotomy, gastrotomy, and biopsy o f one polypoid lesion for frozen section diagnosis were p e r f o r m e d followed by a 95 per cent gastrectomy and gastrojejnnostomy. No metastases were noted at operation. T h r e e weeks following surgery, conabinatiou c h e m o t h e r a p y consisting of adriamycin (100 nag.), vincristine (2 nag.), and cytoxan (50 rag.) was begun. During the next five months ttte patient tolerated the c h e m o t h e r a p y with the exception o f peripheral nerve toxicity due to vincristine. At six and eight months postoperatively,
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respectively, a 2 cm. subcutaneous back nteta. stasis and a 5 cm. intramnscular left flank metastasis were excised. Mettmtrexate was added to the chemotherap)" regimen. T h e patient was readmitted to the hospital ira August 1976 for intractable back pain. The work-up, including chest x-ra)" examination, an u p p e r gastrointestinal series, a barium enema, and bone x-ray examination, failed to reveal metastatic disease. Despite excision o f a recur. rence in the T I 2 paravertebral soft tissue and a nerve block, he continued to have pain and subsequently received a dose o f 2660 rads to this area. He became progressively cachectic and received only supportive care during the last month o f his life, expiring on September 26, 1976. Permission for autopsy was not obtained. PATHOLOGIC FINDINGS T h e 95 p e r cent gastrectomy specimen showed 25 polypoid and sessile endogastric ulcerated tumors in tile fnndus and body situated predominantly on tile anterior and posterior walls (Fig. 1). T h e proximal line o f resection was invoh-ed. T h e largest tulnor measured 7.5 by 5.0 by 5.0 cm. and had a base o f attachment 2.0 cm. wide. T h e rest o f the lesions varied front 0.5 to 2.0 cm. in diameter, and most were separated fl-om each other by normal intervening mucosa. On sectioning, all the tttmors were f o u n d to be located superficially and were composed o f gray pliable tissue with mucosal ulceration. Histologic examination o f all the tumors revealed similar findings. All the lesions were mucosal in location, with some focally infiltrating
Figure 1. Gastrectom)' specimen demonstrating tile multiple endogastric polypoid tumors.
MEDICAL INTELLIGENCE
are 2. Microphotograph of typical, superficially located gastric tumor. (Hematoxylin and eosin stain.
e superficial and middle submucosal reFig. 2). None o f these tumors involved scularis propria. lected tissue blocks were stained with t's tricltrome, Gomori's reticulin, phostgstic acid-hematoxylin, Mayer's mucie, and oil red O stains in addition to helin and eosin.
All tile tumors were contposed o f spindle shaped ceils with convoluted nnclei exbibiting bhmt to pointed ends a r r a n g e d in a storiform pattern (Fig. 3). Individual cells were invested b)" reticulin fibers and minimal collagen was found. Fuchsinoplfilic fibrils were occasionally noted in tile cytoplasm o f individual cells. T h e adjacent intact mucosa was infiltrated
are 3. A storiform pattern, prominent in this field of a gastric lesion, was evident in all the tumors d. (Hematoxylin and eosin stain, x76.)
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Figure 4. The infiltrating component in the adjacent gastric mucosa exhibits a more epithelioid or histiocytic cell population. (Hematox)lin and eosin stain, x 176.)
by t u m o r cells, which w e r e r o u n d to oval a n d c o n t a i n e d p r o m i n e n t nuclei a u d nucleoli (Fig. 4). N o neoplastic glands w e r e identified n o r did any t u m o r cells d e m o n s t r a t e intracellular mucin. A l t h o u g h a few m u h i u u c l e a t e d t u m o r cells
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w e r e seen, no x a n t h o m a t o u s o r T o u t o n giant cells w e r e seen. Staining for neutral lipid was negative. An a v e r a g e o f o n e mitosis per two high p o w e r fields was o b s e r v e d , s o m e areas cont a i n i n g u p to seven mitoses p e r high power field.
Figure 5. Lesser curvature lymph node with sarcomatous metastasis. (tlematoxylin and eosin stain. X30.)
MEDICAL INTELLIGENCE ocal t u m o r thrombi were found in subsal veins and l)'mphatics, and three o f six curvature lymph nodes exhibited metasFig. 5). he subsequent soft tissue metastases ;imilar histologically to the primary gastric "S.
tron dense material. Pinocytotic vesicles were rarely found, most probably because o f the unavoidable delay in fixation. Poorly developed cellular junctions were infrequently found, and a discontinuous basal laminae was occasionally noted. T h e rest o f the intracytoplasmic organelles (i.e., mitochondria and Golgi) were mconspict|ous.
TRON MICROSCOPIC FINDINGS issue from the gastrostom)' biopsy and mk metastasis were cart into 1 ram. cubes, n 3 per cent phosphate buffered glutaral.e for 24 hours, washed in phosphate buf)stfixed in phosplmte buffered 1 per cent m tetroxide, d e h y d r a t e d in g r a d e d alcoabsolute, and e m b e d d e d in Epon 812 ?ropylene oxide and Epon. ne micron thick sections stained with tolublue were used to select the areas to be ned with the electron microscope. Areas storiform pattern and giant cells were ned. T h e spindle ceils as well as the giant retained na, merous cytoplasmic filaments, 80 /~. wide adjacent to the cytoplasmic rane, usually a r r a n g e d parallel to the xis o f the cell. In addition dense plaques airly n u m e r o u s and were predominantl)" I adjacent to tire cytoplasmic m e m b r a n e 5, 7). A few cells had a dilated rot|gh eramic reticulum containing slightl)" elec-
DISCUSSION O u r initial impression was that the stomach lesions represented a multifocal malignant fibrous histiocytoma arising from the lamina propria, since the storiform pattern is considered virtually pathognomonic o f these tumors, s Tissue was sent ira consultation to Dr. Raffaele Lattes, Presbyterian Hospital, New York, who wrote that "this is histologically consistent with a fibrous histiocytoma, a n d . . , it is malignant." T h e light microscopic observation of fuchsinoplfilic fibrils in t u m o r cells in the absence o f intracytoplasmic lipid was m o r e in favor o f a leiomyosarcoma. Although not utilized in tire evaluation o f the present case material, immunofluorescence staining by h u m a n smooth muscle antibodies might have h e l p e d ? However, a recent r e p o r t d e m o n s t r a t e d no immunofluorescence reactMty in a series o f leiomyosarcom a s . I0
T h e uhrastructural features of the gastric
are 6. Electron microphotograph of gastric tumor demonstrating intracytoplasnlic filaments and aque (arrow). (x4130.)
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Figure 7. Spindle shaped cell with convoluted nucleus, prominent nucleolus, and dense plaques. Inset shows typical dcqse plaques. (x4200. Inset, x8400.)
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lesion and metastasis consisted of bundles o f filaments (60 to 80/~ in width) associated with fusiform dense plaques; occasional cells with prominent, focally dilated, rough surfaced endoplasmic reticulin; convoluted nuclei; infrequent cell junctions; and rare pinocytotic vesicles. T h e s e ultrastructttral features lmve been observed in one gastric leiomyosarcoma I1 and in leiomyosarcomas at o t h e r sites) 2-x5 No o t h e r types o f cells (i.e., fibroblasts or histiocytes) were observed as have been reported in malignant fibrous histiocytomas.6'tn Another histogenetic consideration was the myofibroblast, a hybrid with ultrastructural features o f both fibroblasts and smooth muscle cells, which within the last five )'ears has been found in a variety o f instances o f tissue proliferation and t u m o r s ) 7-2~ Such studies have demonstrated both fibroblasts and myofibroblasts, which p r o d u c e extracellular collagen. T h e s e uhrastructural findings were absent in the present case. T h e subject o f gastric leiomyosarcomas has been reviewed ill several reference articles,L~" 6 , z 2 - 2 n but some pathologic features o f interest presented by o u r case r e p o r t deserve further comment. Gastric leiomyosarcomas a r e roughly equally distributed t h r o u g h o u t all regions o f the stomach, and approxinmtely one-third are entirel)' superficial,n Multifocal lesions are uncommon, but have been found in 10 per cent
o f the cases in one large series 6 and infiequently in other studies, z7 Similarly, 6.8 p e r cent of the patients with gastric leiomyoblastomas have had multiple foci o f gastric involvement. 2s The present case r e p o r t appears to have exhibited the most n n m e r o n s foci o f sarcomatous change. In contrast, only 2 p e r cent o f leiomyomas have been r e p o r t e d to be mohiple, e AIthotlgh gastric leiomyosarcomas are generally large, 16 per cent o f leiomyosarcomas were fotmd to be less than 5 cm. in size and 33 per cent were r e p o r t e d in the 5 to 9 cm. range3 Similar findings have been noted in other articles.4.2s In tile absence of gross invasion of adjacent organs or metastases, histologic criteria of malignancy are equivocal, since only 95 p e r cent o f diagnosed leiomyosarcomas actually metastasize3 Microscopic features o f malignant change have included t u m o r cell pleomorphism, blood vessel invasion, and increased mitotic activity. Golden and Stout 29 stated that if there were two o r more mitoses per high power f e l d , one conld be certain that the t u m o r was a leiomysarconm. Gilberson et a13 f o u n d metastases in 16 of 25 gastric leiomyosarcomas with one or more mitoses p e r high power field; two tumors with one mitosis per three to five high power fields metastasized. More recently Ranchod and Kempson 26 fonnd that gastric leiomyosarcomas could confidently be diagnosed if
MEDICAL INTELLIGENCE here were five or tnore initoses per 10 itigh Power fields or if t u m o r necrosis was present in gastric smooth muscle tumor with less titan !ve mitoses per 10 high power fields• Infreuently metastases have been reported in gastic smooth mttscle tumors that show no t u m o r ecrosis, pleomorphism, or appreciable n u m ers of mitoses36 T o account in part for the iscrepancy between the total nunaber of diagosed leioinyosarcomas and those tlmt metasasize, a recent article on mitosis counting in terine stnooth muscle tumors suggested that his is a subjective u n d e r t a k i n g and can vary ddely among individttal patltologists.3° Altlmugh tim liver is the most frequent site f metastasis, regional lymph node metastases roin gastric leiomyosarcomas have been noted ccasionally,6.2~,3t as was found in the present ase, suggesting that extensive surgery be per~rmed whenever possible. T h e treatment of gastric leiomyosarcomas primarily surgical, and it is generally agreed aat radiation and the present chemotimrapeuc regimens are ineffective. T h e five )ear over11survival rate is reported to be between 40 and 0 per cent with better survival figures for paents in whotn the tnmors are resectable3 '2s'
10. 1 I.
12.
13. 14. 15.
16. 17. 18.
• 26, 32, 33
19.
[cknowledgment T h e authors wish to tltank Mrs. Ida Natltan or the photography and Mrs. Eleanore Steel or her secretarial assistance.
20• 21. 22.
References • B u r g e s s , J. N., Dockerty, M. B., and ReMine, W. It.: Sarcomatons lesions of the stomach. Ann. Surg., 173:758, 1971. !. Gilberson, R. G., Dockerty, M. B., and Gray, il. K.: Leiomyosarcoma of the stomach. Clinicopathologic study of 40 cases. Surg. Gynecol. Obstet., 98:186, 1954. L Nelson, R. S.: Malignaut tumors of tile stomach other titan carcinoma. In Bockus, tl. L. (Editor): Gastroenterology. Ed. 3. Philadelphia, W. B. Sauuders Compauy, 1974, Vol. 1. I. Salmela, tl.: Smooth muscle tumors of the stomach. A clinical study of 112 cases. Acta Clair. Scand., 134:383, 1968. i. Salmela, It.: I.} mphosarcoma of tim stomach• A clinical stud)" of 39 cases. Acta Chir. Stand., 134:567, 1968. i. Skandalakis, J. E., Gray, S. W., and Shepard, D.: Smooth muscle tumors of the stomach. Surg. Gyuccol. Obstet., 110:209, 1960. 7. Mouhon, J. E.: T u m o r s of muscle, cartilage and bone. In T u m o r s in Domestic Animals. Berkeley, University of California Press, 1961. ]. Fu, Y.-S., Gabbiani, G., Kaye, G. I., and l,attes, R.: Malignant soft tissue tmnors of probable histioc)tic origin (malignant fibrous histiocytomas): general considerations and electron microscopic and tissue cuhure studies. Cancer, 35:176, 1975. ). Hirschel, B.J., Gabbiani, G., Ryan, G. 15., and Majno, G.:
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Fibroblasts of granulation tissue: immunofluorescent staining with antismooth muscle serum. Proc. Soc. Exp. Biol. Med., 138:.166, 1971. l'ertschuk, L. P.: lmmunoflnorescence of soft tissue tumors with anti-smooth-muscle and anti-skeletal-muscle antibodies. Am. J. Clin. Path., 63:332, 1975. Kay, S., and Still, W. J. S.: A comparative electron microscopic study of a leiomyosarcoma and bizarre leiomyoma (leiomyoblastoma) of the stomach. Am. J. Clin. Path., 52:403, 1969. Morales, A. R., Fine, G., Pardo, V., and Horn, R. C.,Jr.: Tile uhrastructure of smooth muscle tumors with a consideration of the possible relationship of glomangiomas, hemangiopericytomas, and cardiac nuxomas. In Summers, S. C. (Editor): Pathology Annual. New York. Apllleton-Centnry-Crofts, 1975. Bocker, W., and Strecker, tt.: Electron microscopy of uterine leiomyosarcomas. Virch. Arch. Path. Anat. [list., 367:59, 1975. Tobou, H., Murphy, A. 1., and Salazer, [I.: Primary leiomyosarcoma of the vagina. Light and electron microscopic observations. Cancer, 32:450, 1973. Fereuczy, A., Richart, R. M., and Okagaki, T.: A comparative uhrastructural stud)" of leiomyosarcoma, cellular leiom) oma and leiomyoma of the uterus. Cancer, 28: 1004, 1971. Merkow, l.. ILl Frich,J. C., Slifkin, M., Kyreages, C. G., and Pardo, M.: Uhrastructure o f a fibroxanthosarcoma (malignant fibroxanthoma). Cancer, 28:372, 1971. Gabbiani, G., and Majno, G.: Dupu)tren's coutracture: fibroblast contraction? An ohrastructural stud)'. Amer. J. Path., 66:131, 1972. Ryan, G. B., Cliff, w . J . , Gabbiani, G., Irle, C., Montandon, D., Statkov, P. R., and Majno, G.: Myofibroblasts in human granulation tissue. H u m a n Path., 5:55, 1974. Croker, D.J., and Murad, T. M.: Uhrastructureof fibrosarcoma in a male breast. Cancer, 23:891, 1969. Feiuer, !I., and Kaye, G. I.: Uhrastructural evidence of myofibroblasts in circumscribed fibromatosis. Arch. l'athol. Lab. Med., 100:265, 1976. Chorg, A. M., anti Kahn, L. 1',.: Myofibroblasts and related cells in malignant fibrous and fibrohistiocytic tumors. H u m a n Path., 8:205, 1977. Grigg, E. R. N.: Esopbagogastroiutestinal leiomyo(sarco)mas. Am. J. Med.. 31:591, 1961. Ming, S.-C.: T u m o r s of muscular tissue. In T u m o r s of the Esophagus and Stomach. Fasc. 7. Washington, D.C., Armed Forces Institute of l'athology, 1973. Wurlitzer, F. P., Mares, A•J., Isaacs, ll.,Jr., Landing. B. H., and Woolley, M. M.: Smooth muscle tumors of the stomach in childhood and adolescence. J. l'ed. Surg., 8:421, 1973. Welch,J. P.: Smooth muscle tumors of the stomach. Am. J. Surg., 130:279, 1975. Ranchod, M., and Kempson, R. L.: Smooth muscle tumors of the gastrointestinal tract and retroperitoneum. Cancer, 39:255, 1977. Bazaz-Malik, G., and Gnpta, D. N.: Sarcoma of the stomach. Am. J. Gastroeut., 48:512, 1967. Abramson, D. J.: Leiomyoblastomas of the stomach• Surg. Gynecol. Obstet., 138:118, 1973. Golden, T., and Stout, A. P.: Smooth muscle tumors of tile gastrointestinal tract and retroperitoneal tissues. Surg. Gynecol. Obstet., 73:784, 1941. Silverberg, S. G.: Reproducibility of the mitosis count in tile histologic diagnosis of smooth muscle tumors of the uterus. H u m a n Path., 7:451, 1976. Thorbjarnarson, B., l'earce, J. M., and Beal, J. M.: Sarcoma of the stomach. Am. J. Surg., 97:36, 1959. Garvie, W. It. H.: Leiomyosarcoma of the stomach. Br. J. Surg., 52:32, 1965. Berg, J., and McNeer, G.: Leiomyosarcoma of the stomach. A clinical and pathological stud}'. Cancer, 13: 25, 1960.
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18. Tillotson. J. F., ,~,IcDonald, J. R., and Janes, J..xt.: Synovial sarcomata. J. Bone Joint Surg., 53A;459473, 1951.
AN UNUSUAL MULTIFOCAL LEIOMYOSARCOMA OF THE STOMACH: A LIGHT AND ELECTRON MICROSCOPIC STUDY
edgment JOEL A. RUTH, M . D . , *
a r e i n d e b t e d to Dr. R a f f a e l e L a t t e s o f a U n i v e r s i t y , f o r c o n f i r m i n g tire d i a g ,4 k i n d l y r e v i e w i n g t h i s m a n u s c r i p t .
HARRY CARTER, M . D . , t AND DOUGLAS COSTABILE, M . D . *
_~rences trdi, J. G., and Smith, O. D.: Salivary gland tu-s and their mucins. J. l'ath. Bact., 77:131-140, L.: Synovial sarcomas in serous bursae and m sheaths. Am. j. Cancer, 34:501-539, 1938. n, N. L., Soule, E. lI., and Kelly, P. J.: Synuvial mat an anal)'sis of 134 tumors. Cancer, 18:6131965. :, D. W., and Stout, A. 1'.: Synovial sarcoma in "en. Cancer, 12:1123-1133, 1959. :y, M. B., l'arkhill, E. M., Dablin, D. C., Woolner, • Soule, E. 11., and Harrison, E. G., Jr.: Tumors : oral cavity and pharynx. Atlas of Tumor PatholSect. IV. Fasc. 10b. Washington, I).C., Armed s Institute of Pathology, 1968, V., and Russomanno, E.: Su di on caso di alosarcoma a Iocalizzazione retroperitoneale. Ital. Anat. instol. Pat., 43:260-270, 1969. ,i, G., Kaye, G. I., Lattes, R., and Majno, G.: ial sarcoma. Electron microscopic stud)• of a I case. Cancer, 28:1031-1039, 1971. ~en, C. D., and Stout, A. P.: Synovial sarcoma. Surg., 120:826-842, 19-t4. I, E. G., Jr., Black, B. M., and Devine, K. D.: ial sarcoma primary in the neck• Arch. l'ath., 7-141, 1961. • L.: Tumors and Tumorous Conditions of the and Joints. London, tlenry Kimpton, 1958. m, P.: Synovial sarcoma of the pharynx. Report tse. Am. J. Clin. l'ath., 24:957-961, 1954. "n, L. G., and Angervall, L.: ttistochemical terizatiou of mucosubstances in bone ~tnd soft tumors• Cancer, 36:985-994, 1975. J., and Ariel. I. M.: Tumors of the Soft Somatic s and Bone. Treatment of Cancer and Allied -'s. New York, Harper and Row, 1964, Vol. VII. • D. A., Tennant, R., and Rosahn, P. D.: Synorcomas in joints, bursae and tendon sheaths. A and pathological stud)' of 16 cases• Surg. Obstet., 72:951-981, 1941. E., and DuEling, J.: Differential staining of acid tminogl)cans (mucopol)saccharides) b)' alcian salt solutions. Histocbemie, 5:221-233. 1965. P., and Lattes, R.: Tumors of the Soft Tissues. )f Tumor i'athology. Second series, Fasc. 1. tgton, D.C., Armed Forces Institute of Pathol~67. K. H., and Goldman, H. M.: Oral Pathology. St. Louis. The C. V. Mosby Company, 1960.
Abstract A multifocal leiomyosarcoma of the stomach originating from the muscularis mucosae w#h lymph node and distant metastases is described in a 66 year oM man. The electron microscopic features of a representative tumor mass and a metastasis colzfirmed the
smooth muscle histogenesis. The light microscopic appearance coasistently suggested malignant fibrous histocytoma. The pathological features of gastric leiomyosarcomas are reviewed with special emphasis on the problem of practical diagnosis. This case also imlicates that not all sarcomas with storiform features are necessarily histioo'tic in orion. l'rimary sarcomas of the stotnach represent less t h a n 10 p e r c e n t o f all m a l i g n a n t g a s t r i c tumors, and although malignant lymphomas compose the bulk of these mesenchymal tum o r s , g a s t r i c l e i o m y o s a r c o m a s m a k e u p 10 to 4 0 p e r c e n t o f t h i s g r o u p , t-5 S k a n d a l a k i s e t al. 6 f o u n d in a c o l l e c t i v e r e v i e w o f t h e l i t e r a t u r e n p to 1958 t h a t 35 p e r c e n t o f 1017 g a s t r i c smooth muscle tumors were malignant. Benign a n d m a l i g n a n t g a s t r i c s m o o t h m u s c l e t u m o r s in animals are rare. 7 We describe a muhifocal gastric leiomyosarcoma, which on light microscopy resembled a malignant fibrous histiocytoma. The ultras t r u c t u r a l f e a t u r e s o f s m o o t h m u s c l e cells in
*Clinical htstructor ill Pathology, Columbia University College o f Ph)'sicians and Surgeons, New York, New York. A t t e n d i n g Pathologist, Overlook Hospital, Summit, New Jersey. - i A n e n d i n g Pathologist, St. Barnabas Medical Center, l.ivingston, New Jersey. :[:Attending Surgeon, Overlook ttospital, Summit, New Jersey.
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H U M A N P A T H O L O G Y - - V O L U M E 9, N U M B E R 3 both the p r i m a r y t u m o r and a metastasis confirmed the true nature o f the neoplastic process. CLINICAL HISTORY A 66 )'ear old white man was admitted to Overlook Hospital on October 25, 1975, for evaluation o f a six month Itistory of vague abdominal discomfort associated with a two to three ntondl ltistory o f decreasing appetite, rapid satiety, and a 10 to 15 p o t m d weight loss. Pltysical examination was unremarkable. Pertinent laboratory data included tlte following: hemoglobin, 11.0 gin. p e r 1O0 ml.; bematocrit, 32 p e r cent; erytltrocyte cotntt, 3.8 million (ttypochromic, microcytic); leukocyte count, 8800 (with a normal differential count); and guaiac positive stools. A n u p p e r gastrointestinal series demonstrated multiple gastric polypoid lesions, and a bariunt e n e m a was unremarkable. Gastroscopy confirmed the presence o f mtdtiple ulcerated polypoid tumors and a routine biopsy was reported as "sarcoma, ? type." Exploratory laparotomy, gastrotomy, and biopsy o f one polypoid lesion for frozen section diagnosis were p e r f o r m e d followed by a 95 per cent gastrectomy and gastrojejnnostomy. No metastases were noted at operation. T h r e e weeks following surgery, conabinatiou c h e m o t h e r a p y consisting of adriamycin (100 nag.), vincristine (2 nag.), and cytoxan (50 rag.) was begun. During the next five months ttte patient tolerated the c h e m o t h e r a p y with the exception o f peripheral nerve toxicity due to vincristine. At six and eight months postoperatively,
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respectively, a 2 cm. subcutaneous back nteta. stasis and a 5 cm. intramnscular left flank metastasis were excised. Mettmtrexate was added to the chemotherap)" regimen. T h e patient was readmitted to the hospital ira August 1976 for intractable back pain. The work-up, including chest x-ra)" examination, an u p p e r gastrointestinal series, a barium enema, and bone x-ray examination, failed to reveal metastatic disease. Despite excision o f a recur. rence in the T I 2 paravertebral soft tissue and a nerve block, he continued to have pain and subsequently received a dose o f 2660 rads to this area. He became progressively cachectic and received only supportive care during the last month o f his life, expiring on September 26, 1976. Permission for autopsy was not obtained. PATHOLOGIC FINDINGS T h e 95 p e r cent gastrectomy specimen showed 25 polypoid and sessile endogastric ulcerated tumors in tile fnndus and body situated predominantly on tile anterior and posterior walls (Fig. 1). T h e proximal line o f resection was invoh-ed. T h e largest tulnor measured 7.5 by 5.0 by 5.0 cm. and had a base o f attachment 2.0 cm. wide. T h e rest o f the lesions varied front 0.5 to 2.0 cm. in diameter, and most were separated fl-om each other by normal intervening mucosa. On sectioning, all the tttmors were f o u n d to be located superficially and were composed o f gray pliable tissue with mucosal ulceration. Histologic examination o f all the tumors revealed similar findings. All the lesions were mucosal in location, with some focally infiltrating
Figure 1. Gastrectom)' specimen demonstrating tile multiple endogastric polypoid tumors.
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are 2. Microphotograph of typical, superficially located gastric tumor. (Hematoxylin and eosin stain.
e superficial and middle submucosal reFig. 2). None o f these tumors involved scularis propria. lected tissue blocks were stained with t's tricltrome, Gomori's reticulin, phostgstic acid-hematoxylin, Mayer's mucie, and oil red O stains in addition to helin and eosin.
All tile tumors were contposed o f spindle shaped ceils with convoluted nnclei exbibiting bhmt to pointed ends a r r a n g e d in a storiform pattern (Fig. 3). Individual cells were invested b)" reticulin fibers and minimal collagen was found. Fuchsinoplfilic fibrils were occasionally noted in tile cytoplasm o f individual cells. T h e adjacent intact mucosa was infiltrated
are 3. A storiform pattern, prominent in this field of a gastric lesion, was evident in all the tumors d. (Hematoxylin and eosin stain, x76.)
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Figure 4. The infiltrating component in the adjacent gastric mucosa exhibits a more epithelioid or histiocytic cell population. (Hematox)lin and eosin stain, x 176.)
by t u m o r cells, which w e r e r o u n d to oval a n d c o n t a i n e d p r o m i n e n t nuclei a u d nucleoli (Fig. 4). N o neoplastic glands w e r e identified n o r did any t u m o r cells d e m o n s t r a t e intracellular mucin. A l t h o u g h a few m u h i u u c l e a t e d t u m o r cells
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w e r e seen, no x a n t h o m a t o u s o r T o u t o n giant cells w e r e seen. Staining for neutral lipid was negative. An a v e r a g e o f o n e mitosis per two high p o w e r fields was o b s e r v e d , s o m e areas cont a i n i n g u p to seven mitoses p e r high power field.
Figure 5. Lesser curvature lymph node with sarcomatous metastasis. (tlematoxylin and eosin stain. X30.)
MEDICAL INTELLIGENCE ocal t u m o r thrombi were found in subsal veins and l)'mphatics, and three o f six curvature lymph nodes exhibited metasFig. 5). he subsequent soft tissue metastases ;imilar histologically to the primary gastric "S.
tron dense material. Pinocytotic vesicles were rarely found, most probably because o f the unavoidable delay in fixation. Poorly developed cellular junctions were infrequently found, and a discontinuous basal laminae was occasionally noted. T h e rest o f the intracytoplasmic organelles (i.e., mitochondria and Golgi) were mconspict|ous.
TRON MICROSCOPIC FINDINGS issue from the gastrostom)' biopsy and mk metastasis were cart into 1 ram. cubes, n 3 per cent phosphate buffered glutaral.e for 24 hours, washed in phosphate buf)stfixed in phosplmte buffered 1 per cent m tetroxide, d e h y d r a t e d in g r a d e d alcoabsolute, and e m b e d d e d in Epon 812 ?ropylene oxide and Epon. ne micron thick sections stained with tolublue were used to select the areas to be ned with the electron microscope. Areas storiform pattern and giant cells were ned. T h e spindle ceils as well as the giant retained na, merous cytoplasmic filaments, 80 /~. wide adjacent to the cytoplasmic rane, usually a r r a n g e d parallel to the xis o f the cell. In addition dense plaques airly n u m e r o u s and were predominantl)" I adjacent to tire cytoplasmic m e m b r a n e 5, 7). A few cells had a dilated rot|gh eramic reticulum containing slightl)" elec-
DISCUSSION O u r initial impression was that the stomach lesions represented a multifocal malignant fibrous histiocytoma arising from the lamina propria, since the storiform pattern is considered virtually pathognomonic o f these tumors, s Tissue was sent ira consultation to Dr. Raffaele Lattes, Presbyterian Hospital, New York, who wrote that "this is histologically consistent with a fibrous histiocytoma, a n d . . , it is malignant." T h e light microscopic observation of fuchsinoplfilic fibrils in t u m o r cells in the absence o f intracytoplasmic lipid was m o r e in favor o f a leiomyosarcoma. Although not utilized in tire evaluation o f the present case material, immunofluorescence staining by h u m a n smooth muscle antibodies might have h e l p e d ? However, a recent r e p o r t d e m o n s t r a t e d no immunofluorescence reactMty in a series o f leiomyosarcom a s . I0
T h e uhrastructural features of the gastric
are 6. Electron microphotograph of gastric tumor demonstrating intracytoplasnlic filaments and aque (arrow). (x4130.)
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Figure 7. Spindle shaped cell with convoluted nucleus, prominent nucleolus, and dense plaques. Inset shows typical dcqse plaques. (x4200. Inset, x8400.)
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lesion and metastasis consisted of bundles o f filaments (60 to 80/~ in width) associated with fusiform dense plaques; occasional cells with prominent, focally dilated, rough surfaced endoplasmic reticulin; convoluted nuclei; infrequent cell junctions; and rare pinocytotic vesicles. T h e s e ultrastructttral features lmve been observed in one gastric leiomyosarcoma I1 and in leiomyosarcomas at o t h e r sites) 2-x5 No o t h e r types o f cells (i.e., fibroblasts or histiocytes) were observed as have been reported in malignant fibrous histiocytomas.6'tn Another histogenetic consideration was the myofibroblast, a hybrid with ultrastructural features o f both fibroblasts and smooth muscle cells, which within the last five )'ears has been found in a variety o f instances o f tissue proliferation and t u m o r s ) 7-2~ Such studies have demonstrated both fibroblasts and myofibroblasts, which p r o d u c e extracellular collagen. T h e s e uhrastructural findings were absent in the present case. T h e subject o f gastric leiomyosarcomas has been reviewed ill several reference articles,L~" 6 , z 2 - 2 n but some pathologic features o f interest presented by o u r case r e p o r t deserve further comment. Gastric leiomyosarcomas a r e roughly equally distributed t h r o u g h o u t all regions o f the stomach, and approxinmtely one-third are entirel)' superficial,n Multifocal lesions are uncommon, but have been found in 10 per cent
o f the cases in one large series 6 and infiequently in other studies, z7 Similarly, 6.8 p e r cent of the patients with gastric leiomyoblastomas have had multiple foci o f gastric involvement. 2s The present case r e p o r t appears to have exhibited the most n n m e r o n s foci o f sarcomatous change. In contrast, only 2 p e r cent o f leiomyomas have been r e p o r t e d to be mohiple, e AIthotlgh gastric leiomyosarcomas are generally large, 16 per cent o f leiomyosarcomas were fotmd to be less than 5 cm. in size and 33 per cent were r e p o r t e d in the 5 to 9 cm. range3 Similar findings have been noted in other articles.4.2s In tile absence of gross invasion of adjacent organs or metastases, histologic criteria of malignancy are equivocal, since only 95 p e r cent o f diagnosed leiomyosarcomas actually metastasize3 Microscopic features o f malignant change have included t u m o r cell pleomorphism, blood vessel invasion, and increased mitotic activity. Golden and Stout 29 stated that if there were two o r more mitoses per high power f e l d , one conld be certain that the t u m o r was a leiomysarconm. Gilberson et a13 f o u n d metastases in 16 of 25 gastric leiomyosarcomas with one or more mitoses p e r high power field; two tumors with one mitosis per three to five high power fields metastasized. More recently Ranchod and Kempson 26 fonnd that gastric leiomyosarcomas could confidently be diagnosed if
MEDICAL INTELLIGENCE here were five or tnore initoses per 10 itigh Power fields or if t u m o r necrosis was present in gastric smooth muscle tumor with less titan !ve mitoses per 10 high power fields• Infreuently metastases have been reported in gastic smooth mttscle tumors that show no t u m o r ecrosis, pleomorphism, or appreciable n u m ers of mitoses36 T o account in part for the iscrepancy between the total nunaber of diagosed leioinyosarcomas and those tlmt metasasize, a recent article on mitosis counting in terine stnooth muscle tumors suggested that his is a subjective u n d e r t a k i n g and can vary ddely among individttal patltologists.3° Altlmugh tim liver is the most frequent site f metastasis, regional lymph node metastases roin gastric leiomyosarcomas have been noted ccasionally,6.2~,3t as was found in the present ase, suggesting that extensive surgery be per~rmed whenever possible. T h e treatment of gastric leiomyosarcomas primarily surgical, and it is generally agreed aat radiation and the present chemotimrapeuc regimens are ineffective. T h e five )ear over11survival rate is reported to be between 40 and 0 per cent with better survival figures for paents in whotn the tnmors are resectable3 '2s'
10. 1 I.
12.
13. 14. 15.
16. 17. 18.
• 26, 32, 33
19.
[cknowledgment T h e authors wish to tltank Mrs. Ida Natltan or the photography and Mrs. Eleanore Steel or her secretarial assistance.
20• 21. 22.
References • B u r g e s s , J. N., Dockerty, M. B., and ReMine, W. It.: Sarcomatons lesions of the stomach. Ann. Surg., 173:758, 1971. !. Gilberson, R. G., Dockerty, M. B., and Gray, il. K.: Leiomyosarcoma of the stomach. Clinicopathologic study of 40 cases. Surg. Gynecol. Obstet., 98:186, 1954. L Nelson, R. S.: Malignaut tumors of tile stomach other titan carcinoma. In Bockus, tl. L. (Editor): Gastroenterology. Ed. 3. Philadelphia, W. B. Sauuders Compauy, 1974, Vol. 1. I. Salmela, tl.: Smooth muscle tumors of the stomach. A clinical study of 112 cases. Acta Clair. Scand., 134:383, 1968. i. Salmela, It.: I.} mphosarcoma of tim stomach• A clinical stud)" of 39 cases. Acta Chir. Stand., 134:567, 1968. i. Skandalakis, J. E., Gray, S. W., and Shepard, D.: Smooth muscle tumors of the stomach. Surg. Gyuccol. Obstet., 110:209, 1960. 7. Mouhon, J. E.: T u m o r s of muscle, cartilage and bone. In T u m o r s in Domestic Animals. Berkeley, University of California Press, 1961. ]. Fu, Y.-S., Gabbiani, G., Kaye, G. I., and l,attes, R.: Malignant soft tissue tmnors of probable histioc)tic origin (malignant fibrous histiocytomas): general considerations and electron microscopic and tissue cuhure studies. Cancer, 35:176, 1975. ). Hirschel, B.J., Gabbiani, G., Ryan, G. 15., and Majno, G.:
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Fibroblasts of granulation tissue: immunofluorescent staining with antismooth muscle serum. Proc. Soc. Exp. Biol. Med., 138:.166, 1971. l'ertschuk, L. P.: lmmunoflnorescence of soft tissue tumors with anti-smooth-muscle and anti-skeletal-muscle antibodies. Am. J. Clin. Path., 63:332, 1975. Kay, S., and Still, W. J. S.: A comparative electron microscopic study of a leiomyosarcoma and bizarre leiomyoma (leiomyoblastoma) of the stomach. Am. J. Clin. Path., 52:403, 1969. Morales, A. R., Fine, G., Pardo, V., and Horn, R. C.,Jr.: Tile uhrastructure of smooth muscle tumors with a consideration of the possible relationship of glomangiomas, hemangiopericytomas, and cardiac nuxomas. In Summers, S. C. (Editor): Pathology Annual. New York. Apllleton-Centnry-Crofts, 1975. Bocker, W., and Strecker, tt.: Electron microscopy of uterine leiomyosarcomas. Virch. Arch. Path. Anat. [list., 367:59, 1975. Tobou, H., Murphy, A. 1., and Salazer, [I.: Primary leiomyosarcoma of the vagina. Light and electron microscopic observations. Cancer, 32:450, 1973. Fereuczy, A., Richart, R. M., and Okagaki, T.: A comparative uhrastructural stud)" of leiomyosarcoma, cellular leiom) oma and leiomyoma of the uterus. Cancer, 28: 1004, 1971. Merkow, l.. ILl Frich,J. C., Slifkin, M., Kyreages, C. G., and Pardo, M.: Uhrastructure o f a fibroxanthosarcoma (malignant fibroxanthoma). Cancer, 28:372, 1971. Gabbiani, G., and Majno, G.: Dupu)tren's coutracture: fibroblast contraction? An ohrastructural stud)'. Amer. J. Path., 66:131, 1972. Ryan, G. B., Cliff, w . J . , Gabbiani, G., Irle, C., Montandon, D., Statkov, P. R., and Majno, G.: Myofibroblasts in human granulation tissue. H u m a n Path., 5:55, 1974. Croker, D.J., and Murad, T. M.: Uhrastructureof fibrosarcoma in a male breast. Cancer, 23:891, 1969. Feiuer, !I., and Kaye, G. I.: Uhrastructural evidence of myofibroblasts in circumscribed fibromatosis. Arch. l'athol. Lab. Med., 100:265, 1976. Chorg, A. M., anti Kahn, L. 1',.: Myofibroblasts and related cells in malignant fibrous and fibrohistiocytic tumors. H u m a n Path., 8:205, 1977. Grigg, E. R. N.: Esopbagogastroiutestinal leiomyo(sarco)mas. Am. J. Med.. 31:591, 1961. Ming, S.-C.: T u m o r s of muscular tissue. In T u m o r s of the Esophagus and Stomach. Fasc. 7. Washington, D.C., Armed Forces Institute of l'athology, 1973. Wurlitzer, F. P., Mares, A•J., Isaacs, ll.,Jr., Landing. B. H., and Woolley, M. M.: Smooth muscle tumors of the stomach in childhood and adolescence. J. l'ed. Surg., 8:421, 1973. Welch,J. P.: Smooth muscle tumors of the stomach. Am. J. Surg., 130:279, 1975. Ranchod, M., and Kempson, R. L.: Smooth muscle tumors of the gastrointestinal tract and retroperitoneum. Cancer, 39:255, 1977. Bazaz-Malik, G., and Gnpta, D. N.: Sarcoma of the stomach. Am. J. Gastroeut., 48:512, 1967. Abramson, D. J.: Leiomyoblastomas of the stomach• Surg. Gynecol. Obstet., 138:118, 1973. Golden, T., and Stout, A. P.: Smooth muscle tumors of tile gastrointestinal tract and retroperitoneal tissues. Surg. Gynecol. Obstet., 73:784, 1941. Silverberg, S. G.: Reproducibility of the mitosis count in tile histologic diagnosis of smooth muscle tumors of the uterus. H u m a n Path., 7:451, 1976. Thorbjarnarson, B., l'earce, J. M., and Beal, J. M.: Sarcoma of the stomach. Am. J. Surg., 97:36, 1959. Garvie, W. It. H.: Leiomyosarcoma of the stomach. Br. J. Surg., 52:32, 1965. Berg, J., and McNeer, G.: Leiomyosarcoma of the stomach. A clinical and pathological stud}'. Cancer, 13: 25, 1960.
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