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Bilateral malignant brenner tumor: Report of a case with ultrastructural study
MEDICAL Ahhough the composition of the antigen-antibody c o m p l e x e s in o u r p a t i e n t h a s n o t b e e n i d e n t i f i e d , t h e p r e s e n c e o f identical u l t r a s t r u c t u r e s in t h e c r y o p r e c i p i t a t e a n d in t h e g l o m e r u l a r d e p o s i t s f i l r n i s h e s m o r p h o l o g i c evidence for the proposition that cryoglobulins may be d e p o s i t e d in t h e g l o m e r u l i in s y s t e m i c l u p u s e r y t h e m a t o s u s a n d , c o n v e r s e l y , t h a t t h e f i n g e r p r i n t s t r u c t u r e s in l u p u s n e p h r i t i s m a y s e r v e as m a r k e r s o f c o e x i s t e n t c r y o g l o b u l i n emit.
Acknowledgments T h e a u t h o r s a r e i n d e b t e d to Dr. N o o r b i b i L. Day f o r p e r f o r m i n g assays o f C lq, C2, C4, f a c t o r B, a n d c i r c u l a t i n g immnne complexes.
References 1. Druet, P., Letonturier, P., Contet, A., and Mandet, C.: Cryoglobulinemit in human renal disease: a stud)9of 76 cases. Clin. Exp. lmmuno1., 15:483, 1973. 2. Stastn)', P., and Ziff, .Xl. P.: Cold-insoluble complexes and complement levels in systemic lupus erythematosus. N. Engl. J. Med., 280:1376, 1969.
3. Brouet, J.-C., Clauvel, J.-R., Danon, F., Klein, M., and Seligmann, M.: Biologic and clinical significance of cr) oglobulins: a report of 86 cases. Am.J. Med.,57:775, 1974. 4. Mehzer, M., Franklin, E. C., Elias, K., McCluskey, R. T., and Cooper, N.: Cryoglobulinemia--a clinical and laboratory study. I!. Cryoglobulins with rheumatoid factor activity. Am.J. Med., 40:837, 1966. 5. MoreI-Maroger, L., and Mery, J.-P.: Renal lesions in mixed lgC-IgM essential cryoglobulinemia. In Villarreal, H. (Editor): Proceedings of the Fifth International Congress of Nephrology, Mexico, 1972. Vol. 1. Morphology and Pathology. Basel, S. Karger, 1974, pp. 173-178. 6. Verroust, P., Mery, J.-P., Morel-Maroger, L., Clauvel, J.-P., and Richet, G.: Glomerular lesions in monoclonal gammopatlfies and mixed essential cryoglobulinemias IgG-IgM. Adv. Nephrol., 1 : 161, 1971. 7. tlanauer, L., and Christian, C. L.: Studies of cryoproteins in systemic lupus er)thematosus. J. Clln. lnvest., 46:400, 1967. 8. Agnello, V., Koffler, D., and Knnke], it. G.: Immune complex systems in the nephritis of systemic lupus erythematosus. Kidney Int., 5:90, 1973.
9. Grishman, E., Porush, J. C., Rosen, S. M., and Churg, J.: Lupus nephritis with organized deposits in the kidneys. Lab. Invest., 16:717, 1967. 10. Cohen, A. S., Reynokls, W. E., Franklin, E. C., Kulka, P. J., Ropes, M. W., Shuhfian, L. E., and Wallace, S. E.: Preliminary criteria for the classification of systemic lupus erythematosus. Bull. Rheum. Dis., , 21:613, 1971. 11. Mehzer, M., and Franklin, E. C-: Cryoglobulinemia - - a study oftwentynine patients. !. IgG anti lgM cryoglobulins and factors affecting eryopreeipitability. Am. J. Med., 40:826, 1966. 12. Theofilopoulos, A. N., Wilson, C..B., and Dix6n, F. J.: The Raft cell radioimmune assay for detecting immune complexes in human sera. J. Clin. Invest., 57:169, 1976. 13. Day, N. K., Geigcr, H., McLean, R., Resnick,J., Michael, A., and Good, R. A.: The association of respirator)" infection, rectlrrent hematuria, attd. focal glomerulonephritis with activation of the complement systent in the cold. J. Clin. Invest., 52:1698] 1973. 14. Ehrenreich, T., and Espiuosa, T.: Chromotrope silver methenamine stain of glomernlar lesions. Am. J. Clin. Pathol., 56:448, 1971. 15. McKenzie, M. R., Gohlberg, L. S., Barnett, E. V., and Fudenberg, It. H.: Serological heterogeneity of the IgM components of mixed (monoehmal IgM-polyelonal lgG) cr)oglobulins. Clin. Exp.hnmunol., 3:931, 1968. 16. Cordonnier, D., Martin, 11., Groslambert, P., Micouin, C., Chenais, F., and Stoebner, P.: Mixed IgG-lgM cryoglobulinemia with glomerulonephritis: chemical, fluorescent and uhrastrnetnral study of kidney and in vitro cryopri:eipitate. Arn. J..Med., 59:867, 1975. 17. Feiner, t1.. and Gallo, G.: UItrastructure in glomerulonephritis associated 9~vith cr)og]obulinemia: a report of six cases and review of the literature. Am. J. t'athol., 88:146, 1 9 7 7 . Deparnnent of Pathology "Ihe Bronx-Lebanon ttospital Center 9 1276 Fuhon Avenue Bronx, New York 10456 (Dr. Kim)
INTELLIGENCE
BILATERAL MALIGNANT BRENNER TUMOR: REPORT OF A CASE WITH ULTRASTRUCTURAL STUDY 3,1OLLY TAN HAYDEN, M.D.*
Abstract
An unusual case of bilateral malignant Brenner tumor u4th liver and omental metastases is reported. The tumor was histologically a transitional cell carcinoma comparable to a grade 111 bladder carcinoma. A benign component was not identified, but there were a fezv nests of malignant epithelial cel~ distributed in a dense stroma, a pattern identical to that seen in a benign Brenner tumor, lVhetber this represents malignant change in a previously benign focus or a well differentiated part of a de novo carcinoma is unclear. Nevertheless it is suggested that the current histologic criteria for malignant Brenner tumor be modified to exclude the requirement of an intimately associated benign Brenner tumor. Ultrastructurally the malignant Brenner tumor has many features of the benign Brenner tumor. Some features, notably the basal lamina, mieropinocytotic vesicles, and intrack'topIasmic microfibrils, are herein described for the first time in a malignant Brenner tttmor.
B r e n n e r t u m o r s o f t h e o v a r y a r e n o w g e n e r a l l y classified as b e n i g n , p r o l i f e r a t i v e , a n d m a l i g n a n t . A h h o u g h t h e b e n i g n B r e n n e r t u m o r h a s easily i d e n t i f i a b l e a n d well d e f i n e d histologic f e a t u r e s , a c c e p t a b l e c r i t e r i a f o r t h e p r o liferative a n d m a l i g n a n t f o r m s a r e less well e s t a b l i s h e d anti t h e i r s e p a r a t i o n is o f t e n subjective. Bilaterality a n d m a l i g n a n c y a r e a r a r e c o m b i n a t i o n in Brenner tumors. Only four examples have been reported in t h e l i t e r a t u r e t h u s far3" to U h r a s t r u c t u r a l f i n d i n g s in b e n i g n B r e n n e r t u m o r s h a v e b e e n d e s c r i b e d b y a n u m b e r o f a t t t h o r s , t" 9. tz, t3, 1G I n c o n t r a s t , t h e r e is b u t o n e r e p o r t o f two p a t i e n t s with m a l i g n a n f B r e n n e r t u m o r s in w h o m e l e c t r o n m i c r o s c o p i c studies w e r e d o n e . n I n this article t h e clinical a n d m o r p h o l o g i c f i n d i n g s in a p a t i e n t with b i l a t e r a l m a l i g n a n t B r e n n e r t u m o r s a r e p r e s e n t e d , i n c l u d i n g f o r t h e first t i m e e l e c t r o n m i c r o s c o p i c findings. Because of some of these findings, a modification o f t h e histologic c r i t e r i a f o r m a l i g n a n t B r e n n e r t u m o r is suggested. CASE REPORT A 68 y e a r old b l a c k w o m a n was a d m i t t e d to t h e D e t r o i t G e n e r a l H o s p i t a l o n O c t o b e r 3, 1977, b e m u s e o f a 50 lb. w e i g h t loss a n d i n c r e a s e d a b d o m i n a l g i r t h o v e r t h e p r e c e d ing month. She did not have vaginal bleeding. Physical e x a m i n a t i o n r e v e a l e d massive ascites a n d a firm fixed m a s s e x t e n d i n g f r o m t h e left u p p e r q u a d r a n t to t h e m i d l i n e . O n pelvic e x a m i n a t i o n a left a d n e x a l mass was palpable. P a r a c e n t e s i s was p e r f o r m e d a n d t h e ascitic fluid was positive f o r m a l i g n a n t cells. O t h e r investigative studies w e r e n o r m a l , i n c l u d i n g c h e s t x-ray e x a m i n a t i o n , b r a i n scan,
Accepted for publication March 19, 1979. *Clinical Associate Professor, Department of Pathology, Wayne State University College of Medicine, Detroit. Pathoh)gist attd Chief of Henaatopathology, William Beaunlont ltospital, Troy, Michigan.
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intravenous pyelogram, a n d blood u r e a nitrogen and serum ereatinine determinations. At exploratory laparatomy bilateral ovarian tnmors were seen with innumerable metastatic nodules in the peritoneum and liver. A biopsy specimen from a mass in the o m e n t u m measuring 8 by 5 by 4 cm. was snbmitted for frozen section examination. It was interpreted as an anaplastic carcinoma suggestive o f squamous cells. A total hysterectomy a n d bilateral salpingooophorectomy was p e r f o r m e d . T h e two ovaries had been separated from the uterus. Each was approximately 6.5 cm. in maximal d i a m e t e r and was replaced by a partly cystic tumor; a tortuous fallopian tube stretched out over each. T h e masses were mutlilocnlated, containing a cloudy a m b e r fluid. About half o f each t u m o r was solid, gray-tan, fleshy, anti soft, with palpillary projections extending into the cyst lumens. T h e r e were no surface excrescences. T h e t u m o r o f the left ovary had invaded the left cornu and posterior myometrium o f the 70 gm. uterus. T h e e n d o m e t r i u m was thin, smooth, and tan. T h e r e were two small benign leiomyomas in the fundus. T h e cervix was smooth a n d glistening. MATERIAL AND METHODS T h e surgical specimen was fixed in phosphate buffered, I0 p e r cent formaldehyde. T h e sections were stained with hematoxylin attd eosin, periodic acid-Schiff, Mayer's mucicarmine, and alcian blue stains. Oil red O stain was used on a wet tissue section from the tumor. A papillary area including underlying solid t u m o r in one ovary was obtained for transmission electron microscopy following fixation in the buffered f o r m a l d e h y d e for several days. T h e tissue was transferred to 1 p e r cent glutaraldehyde and then postfixed in 1 p e r cent osmium tetroxide and e m b e d d e d in Epon. Ultrathin sections were stained with uranyl acetate and lead citrate.
LIGHT MICROSCOPIC FINDINGS T h e t u m o r in the ovaries was a transitional cell carcinonta, comparable to a g r a d e I l l b l a d d e r carcinoma. Moderately to poorly differentiated transitional cells lined the cyst wails and the papillary fronds (Fig. 1). T h e solid areas were composed o f closely packed sheets of similar transitional cells with little intervening stroma. In some areas the cells had oval nuclei and a scant)" cytoplasnt, and in others the ceils were larger a n d squamoid with lobated or convoluted, often gigantic, nuclei and an a b u n d a n t clear cytoplasm, which was PAS positive. Keratin pearls and intercellular bridges were not found. T h e r e were n u m e r o u s mitoses in all areas. Mayer's mucicarmine and oil red O stained specimens were negative. T h e epithelial ceils o f the t u m o r stained negatively with alcian blue, but edematous areas in the stroma o f papillary fronds and a m o r p h o u s material in the cysts in some areas gave a positive reaction. A benign c o m p o n e n t was not identified, but in one o f the many sections there were a few nests of stratified epithelium in a dense stroma, a pattern identical to that o f a benign B r e n n e r ttunor (Fig. 1). T h e s e epithelial cells were pleomorphic with hyperchromatic nuclei a n d atypical ntitoses. Nuclear folds were haphazardly rather than longitudinally oriented. T h e tissue o f the omental biopsy specimen was identical to portions o f the ovarian tttmor. T h e endontetriunt a n d cervix were free o f malignant change. ELECTRON M I C R O S C O P I C F I N D I N G S Tile epithelial cells varied in size and were separated from the stroma by a basal lamina (Fig. 2). T h e plasma membranes were generally closely a p p o s e d and had interdigitating processes anti a variable n u m b e r o f desmosomes. T h e r e were n u m e r o u s microvilli along the hmfinal surface
Figure I. A, Papillary fronds lined by moderatel)' differentiated transitional cells. B, Nests of stratified epithelium in a dense stroma, a pattern identical to that of the benign Brenner tumor, but the cells are malignant. (Hematoxylin and eosin stain. • 150.)
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Figure 2. Electron micrograph of tumor cells showing closely apposed plasma membranes with desmosome (D) and a widened intercellular space with many microvilli and pinocytotic vesicles (PV). In the cytoplasm are numerous glycogen particles and free ribosomes, few profiles ofendoplasmic reticulunl (ER), and microfilaments (MF).Inset, Elsewhere at the junction between tumor epithelium and stroma is a continuous basal lamina. (• Inset, • of tile cells and at widened intercellular spaces. Mtdtiple micropinocytotic vesicles were seen in some cells (Fig. 2). Despite hlitial formalin fixation, organelles could be readily identified in most cells. T h e r e were scant n u m b e r s of mitochondria and profiles of rough e n d o p l a s m i c reticulum, and occasional Golgi complexes. Free ribosomes a n d glycogen granules were found, particularly a b u n d a n t in larger ceils. T h e r e were secondary lysosomes, inchtding autol~hagic vacuoles, phagolysosomes, and occasional lipid droplets. Microfilaments were demonstrable, some near l)lasma m e m b r a n e s , but they did not form definite tonofilament-desnaosonae complexes (Fig. 2). T h e r e were no oval or filsiform intracytoplasmic vesicles. T h e nuclei were oval, often lobated, or convoluted. In a few cells a deep narrow groove was evident in tile nucleus or nuclear lobes. Nucleoli were prominent. Tile stromal cells resembled fibroblasts, lacked lipid globules, and were s u r r o u n d e d by a b u n d a n t collagen. DISCUSSION Bilateral B r e n n e r tulnors of tile ovary are tmcommon. Tile frequencies of 3.7 and 8.0 per cem are prol)ably too high, since not all unilateral B r e n n e r tumors are reported3 Of the 25 cases of malignant B r e n n e r t u m o r that Idelsoil ~ collected from the literature ill 1963, three were bilateral. Miles and Norris ~~tlescribed seven cases each of
proliferative and malignant B r e n n e r tumors, and only one, a malignant tumor, was bilateral. In yon Nnmers' first reported cases of malignant B r e n n e r tumor, one case was l~resumed by him to be bilateral? 7 However, tiffs i)resump tion was u n p r o v e n because histologic sections were available only fi'om the left ovary. T h e present case therefore represents the rare combination of bilaterality and proven malignancy. Histologically benign t u m o r is a well defined entity. Acceptable criteria for proliferative and malignant types lmve not been firmly established, and their separation is often difficult. A case of proliferative B r e n n e r t u m o r that later metastasized to the liver demonstrates this difficulty? ~ T h e present case was both clinically and cytologically malignant. Malignant B r e n n e r t u m o r was subclassified by earlier authors into epidermoid or squamous carcinonm, adenocarcinoma, and a nfixed t)'pe ~,~5,~8 idelson~ added to tile first two cystadenocarcinoma and sarcoma. Recent authors have considered.malignant B r e n n e r t u m o r to be basically a transitional cell carcinoma, which may be anaplastic or show sqtmmous differentiation or mucinous glandular differentiation.4, s. t0 Many of tile previous squamous carcinomas would now be reclassified as transitional cell carcinomas. Whether tile presence of l~eratinization or intercellular bridges should be required for designating a t u m o r as squamous is unclear.
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T h e t u m o r in o u r p a t i e n t was a t r a n s i t i o n a l cell carcin o m a , c o m p a r a b l e to a g r a d e I I I b l a d d e r c a r c i n o m a . Alt h o u g h s o m e nests o f stratified e p i t h e l i u m r e s e m b l e d s q u a m o u s cells, n o k e r a t i n p e a r l s o r i n t e r c e l h f l a r b r i d g e s w e r e identified, and the intracytoplasrnic microfibrils,'cbaracteristic o f cells o r i g i n a t i n g f r o m c e l o m i c e p i t h e l i u m , d i d n o t form the tonofilament-desmosome complexes ofsquamous epithelitmt. Most p r o l i f e r a t i v e a n d m a l i g n a n t B r e n n e r t u m o r s h a v e a n associated b e n i g n c o m p o n e n t . I n o u r p a t i e n t t h e r e w e r e nests o f e p i t h e l i u m in a d e n s e s t r o m a , a p a t t e r n i d e n t i c a l to t h a t s e e n in a b e n i g n B r e n n e r t u m o r , b u t t h e cells w e r e m a l i g n a n t . W h e t h e r this f i n d i n g r e p r e s e n t s m a l i g n a n t c h a n g e in a p r e v i o u s l y b e n i g n a r e a o r a d e n o v o m a l i g n a n t tumor could not be determined. A criterion for malignant B r e n n e r t u m o r is t h e i d e n t i f i c a t i o n o f i n t i m a t e l y a s s o c i a t e d b e n i g n B r e n n e r t u m o r with epithelial t r a n s i t i o n b e t w e e n t h e m . 5 H a l l g r i m s s o n a n d S c u l l y t f o u n d this r e q u i r e m e n t too r e s t r i c t i v e b e c a u s e t h r e e o f t h e i r 15 cases l a c k e d d e m o n strable benign elements. We would agree, and further suggest that the reqttirement be excluded from the histologic c r i t e r i a f o r m a l i g n a n t B r e m t e r t u m o r . A number of authors have sfttdiedthe uhrastructure of benign Brenner tumors and coitcluded that Brenner tumors originate frbm celomic or ovarian surface epithel i u m directly o r b y m e t a p l a s i a , t ' 9 ' m t 3 , t 6 S o m e h a v e d e s c r i b e d t h e man}" similarities a n t o n g B r e n n e r e p i t h e l i a l cells, t h e W a l t h a r d cell nest, a n t i u r o t h e l i a l cells)" ~3 By e l e c t r o n m i c r o s c o p i c s t u d y o u r m a l i g n a n t B r e n n e r t u m o r s h a r e s man)" f e a t u r e s o f t h e b e n i g n t u m o r . T h e s e i n c l u d e t h e p r e s e n c e o f a basal l a m i n a , d e s m o s o m e s , i n t e r d i g | r a t i n g p l a s m a m e m b r a n e s , microvilli, p i n o c y t o t i c vesicles, p h a g o l y s o s o m e s anti i n t r a c y t o p l a s m i c m i c r o f i l a m e n t s , t h e a b u n d a n c e o f g l y c o g e n a n d f r e e r i b o s o m e s , a n d tlte paucity of endoplasmic reticulum and mitochondria. Some f e a t u r e s , n o t a b l y t h e basal l a m i n a , p i n o c y t o t i c vesicles, a n d intracytoplasmic microfilaments, are being reported for the first t i m e in a m a l i g n a n t B r e n h e r t u m o r . Deep nuclear grooves, a constant feature of the benign t u m o r , w e r e p r e s e n t o n l y in a few cells in o u r t t t m o r . P r a t t - T h o m a s et al. tt f o u n d t h e n t i c l e a r g r o o v e s to b e v e r y s h a l l o w in t h e i r case o f m a l i g n a n t B r e n n e r t u m o r . T h e s e d e v i a t i o n s f r o m t h e b e n i g n t u m o r , t o g e t h e r with o u r findi n g o f l a r g e c o n v o l u t e d nuclei, reflect t h e a n a p l a s t i c n a t u r e o f t h e t u m o r a n d n o t a c h a n g e in cell type. T h e a b s e n c e o f oval o r f u s i f o r m intracytol~lasntic vesicles o f t h e t y p e s e e n in superficial n r o t h e l i a l cells a n d in b e n i g n B r e n n e r t u m o r s was p r o b a b l y d u e to cell d e d i f f e r e n t i a t i o n also)" 3. ~a. ~6
Acknowledgment T h e a u t h o r wishes to t h a n k Dr. J a c o b L. C h a s o n f o r his encouragements and helpful suggestions during the prepar a t i o n o f this m a n u s c r i p t . "
5. Hull, M. G. R., and Campbell, G. R.: The malignant Brenner tumor. Obstet. Gynecol., 42:527, 1973. 6. Idelson, M. G.: Malignancy in Brenner tumors of the ovary, with comments on histogenesis and possible estrogen production. Obstet. Gynecol. Survey, 18:246, 1963. 7. Lamping, J. D., and Blythe, J. G.: Bilateral Brenner tumors: a case report and review of the literature. Human Pathol., 8:583, 1977. 8. Mackinlay, C. J.: Brenner tumors of the ovary. A report of 9 cases including one with malignant degeneration. J. Obstet. Gynaecol. Brit. Emp., 63:58, 1956, 9. Merkow, L. P., Salazar, H., and Pardo, M.: ttuman ovarian neoplasms, light and electron microscopic correlation. I. The Brenner tumor. Obstet. Gynecol., 40:667, 1972. 10. Miles, P. A., and Norris, It. J.: Proliferative and malignant Brenner tumors of the ovary. Cancer, 30:174, 1972. 11. l'ratt-Thomas, H. R., Kreutner, A., Underwood, P. B., and Dowdeswell, R. l-t.: Proliferative and malignant Brenner tumors of ovary. Report of two cases, one with Melg's syndrome, review of literature and ultrastructural comparisons. Gynecol. Oncol., 4:176, 1976. 12. Roth, L. M.: Fine structure of the Brenner tumor. Cancer. 27:1482, 1971. 13. Roth, L. M.: The Brenner tumor and the Wahhard cell nest. An electron microscopic stud)'. Lab. Invest., 31:15, 1974. 14. Roth, L. M., and Sternberg, W. H.: Proliferating Brenner tumors. Cancer, 27:687, 1971. 15. Shay, M. D., and Janovski, N. A.: Malignant Brenner tumor associated with endometrial adenocarcinonta. Obstet. Gynecol., 22:246, 1966. 16. Silverberg, S. G., and Willson, M. A.: Uhrastructure of the Brenner tumor. Am. J. Obstet. Gynecol., 112:91, 1972. 17. yon Numers, C.: A contribution to the case knowledge and history of the Brenner tumor. Do malignant forms of the Brenner tumor also occur? Acta Obstet. Gynecol. Scand., 25(Suppl. 2):114, 1945. Department of Pathology Wayne State University College of Medicine 540 E. Canfield Avenue Detroit, Michigan 48201
PRIMARY P U L M O N A R Y RHABDOMYOSARCOMA: A CASE REPORT A N D REVIEW OF THE LITERATURE SAING "HEE LEE, M.D.,* SETTI S. RENGACtiARY, M.D.,'~ AND JAYA PARAMES}I, M.D.
Abstract Although several primary pulmonary neoplasms containing striated muscle fibers have in the past been described as rhabdomyoma or rhabdomyosarcoma, it was not until 1939 that McDonald and Heather described the first acceptable case of this neoplasm. Since then 13 such cases have been reported in the world literature.
Accepted for publication March 19, 1979. References
I. Cummins, P. A., Fox, it., and Langley, F. A.: An uhrastructural study of the natu re and origin of the Brenner tumor of the ovary. J. Pathol., 110:167, 1973. 2. Foda, M., and Shafeek, M. A.: Malignant Brenner tumor. Obstet. Gynecol., 13:226, 1959. 3. Fulker, M. J., Cooper, E. tl., and Tanaka, T.: Proliferation and uhrastructure of papillary transitional cell carcinoma of the human bladder. Cancer, 27:71, 1971. 4. tlallgrimsson, J., attd Scully, R. E.: Borderline and malignant Brenner tunmrs of the ovary. Acta Pathol. Microbkfl. Stand., Sect. A80(Suppl.), 233:56, 1972.
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*Assistant Professor of Pathology, College of Health Sdences a n d Hospital, University of Kansas Medical Center. Senior Staff Pathologist, Veterans Administration Medical Center, Kansas City, Missouri. tAssociate Professor of Surgery, College of Heahh Sciences and ttospital, University of Kansas Medical Center. Chief, Neurosnrgery Section, Veterans Administration Medical Center, Kansas City, Missouri. :~Resident n Pathology, College of Heahh Sciences and Hospital, University of Kansas Medical Center, Kansas City, Missouri.
Acknowledgments T h e a u t h o r s a r e i n d e b t e d to Dr. N o o r b i b i L. Day f o r p e r f o r m i n g assays o f C lq, C2, C4, f a c t o r B, a n d c i r c u l a t i n g immnne complexes.
References 1. Druet, P., Letonturier, P., Contet, A., and Mandet, C.: Cryoglobulinemit in human renal disease: a stud)9of 76 cases. Clin. Exp. lmmuno1., 15:483, 1973. 2. Stastn)', P., and Ziff, .Xl. P.: Cold-insoluble complexes and complement levels in systemic lupus erythematosus. N. Engl. J. Med., 280:1376, 1969.
3. Brouet, J.-C., Clauvel, J.-R., Danon, F., Klein, M., and Seligmann, M.: Biologic and clinical significance of cr) oglobulins: a report of 86 cases. Am.J. Med.,57:775, 1974. 4. Mehzer, M., Franklin, E. C., Elias, K., McCluskey, R. T., and Cooper, N.: Cryoglobulinemia--a clinical and laboratory study. I!. Cryoglobulins with rheumatoid factor activity. Am.J. Med., 40:837, 1966. 5. MoreI-Maroger, L., and Mery, J.-P.: Renal lesions in mixed lgC-IgM essential cryoglobulinemia. In Villarreal, H. (Editor): Proceedings of the Fifth International Congress of Nephrology, Mexico, 1972. Vol. 1. Morphology and Pathology. Basel, S. Karger, 1974, pp. 173-178. 6. Verroust, P., Mery, J.-P., Morel-Maroger, L., Clauvel, J.-P., and Richet, G.: Glomerular lesions in monoclonal gammopatlfies and mixed essential cryoglobulinemias IgG-IgM. Adv. Nephrol., 1 : 161, 1971. 7. tlanauer, L., and Christian, C. L.: Studies of cryoproteins in systemic lupus er)thematosus. J. Clln. lnvest., 46:400, 1967. 8. Agnello, V., Koffler, D., and Knnke], it. G.: Immune complex systems in the nephritis of systemic lupus erythematosus. Kidney Int., 5:90, 1973.
9. Grishman, E., Porush, J. C., Rosen, S. M., and Churg, J.: Lupus nephritis with organized deposits in the kidneys. Lab. Invest., 16:717, 1967. 10. Cohen, A. S., Reynokls, W. E., Franklin, E. C., Kulka, P. J., Ropes, M. W., Shuhfian, L. E., and Wallace, S. E.: Preliminary criteria for the classification of systemic lupus erythematosus. Bull. Rheum. Dis., , 21:613, 1971. 11. Mehzer, M., and Franklin, E. C-: Cryoglobulinemia - - a study oftwentynine patients. !. IgG anti lgM cryoglobulins and factors affecting eryopreeipitability. Am. J. Med., 40:826, 1966. 12. Theofilopoulos, A. N., Wilson, C..B., and Dix6n, F. J.: The Raft cell radioimmune assay for detecting immune complexes in human sera. J. Clin. Invest., 57:169, 1976. 13. Day, N. K., Geigcr, H., McLean, R., Resnick,J., Michael, A., and Good, R. A.: The association of respirator)" infection, rectlrrent hematuria, attd. focal glomerulonephritis with activation of the complement systent in the cold. J. Clin. Invest., 52:1698] 1973. 14. Ehrenreich, T., and Espiuosa, T.: Chromotrope silver methenamine stain of glomernlar lesions. Am. J. Clin. Pathol., 56:448, 1971. 15. McKenzie, M. R., Gohlberg, L. S., Barnett, E. V., and Fudenberg, It. H.: Serological heterogeneity of the IgM components of mixed (monoehmal IgM-polyelonal lgG) cr)oglobulins. Clin. Exp.hnmunol., 3:931, 1968. 16. Cordonnier, D., Martin, 11., Groslambert, P., Micouin, C., Chenais, F., and Stoebner, P.: Mixed IgG-lgM cryoglobulinemia with glomerulonephritis: chemical, fluorescent and uhrastrnetnral study of kidney and in vitro cryopri:eipitate. Arn. J..Med., 59:867, 1975. 17. Feiner, t1.. and Gallo, G.: UItrastructure in glomerulonephritis associated 9~vith cr)og]obulinemia: a report of six cases and review of the literature. Am. J. t'athol., 88:146, 1 9 7 7 . Deparnnent of Pathology "Ihe Bronx-Lebanon ttospital Center 9 1276 Fuhon Avenue Bronx, New York 10456 (Dr. Kim)
INTELLIGENCE
BILATERAL MALIGNANT BRENNER TUMOR: REPORT OF A CASE WITH ULTRASTRUCTURAL STUDY 3,1OLLY TAN HAYDEN, M.D.*
Abstract
An unusual case of bilateral malignant Brenner tumor u4th liver and omental metastases is reported. The tumor was histologically a transitional cell carcinoma comparable to a grade 111 bladder carcinoma. A benign component was not identified, but there were a fezv nests of malignant epithelial cel~ distributed in a dense stroma, a pattern identical to that seen in a benign Brenner tumor, lVhetber this represents malignant change in a previously benign focus or a well differentiated part of a de novo carcinoma is unclear. Nevertheless it is suggested that the current histologic criteria for malignant Brenner tumor be modified to exclude the requirement of an intimately associated benign Brenner tumor. Ultrastructurally the malignant Brenner tumor has many features of the benign Brenner tumor. Some features, notably the basal lamina, mieropinocytotic vesicles, and intrack'topIasmic microfibrils, are herein described for the first time in a malignant Brenner tttmor.
B r e n n e r t u m o r s o f t h e o v a r y a r e n o w g e n e r a l l y classified as b e n i g n , p r o l i f e r a t i v e , a n d m a l i g n a n t . A h h o u g h t h e b e n i g n B r e n n e r t u m o r h a s easily i d e n t i f i a b l e a n d well d e f i n e d histologic f e a t u r e s , a c c e p t a b l e c r i t e r i a f o r t h e p r o liferative a n d m a l i g n a n t f o r m s a r e less well e s t a b l i s h e d anti t h e i r s e p a r a t i o n is o f t e n subjective. Bilaterality a n d m a l i g n a n c y a r e a r a r e c o m b i n a t i o n in Brenner tumors. Only four examples have been reported in t h e l i t e r a t u r e t h u s far3" to U h r a s t r u c t u r a l f i n d i n g s in b e n i g n B r e n n e r t u m o r s h a v e b e e n d e s c r i b e d b y a n u m b e r o f a t t t h o r s , t" 9. tz, t3, 1G I n c o n t r a s t , t h e r e is b u t o n e r e p o r t o f two p a t i e n t s with m a l i g n a n f B r e n n e r t u m o r s in w h o m e l e c t r o n m i c r o s c o p i c studies w e r e d o n e . n I n this article t h e clinical a n d m o r p h o l o g i c f i n d i n g s in a p a t i e n t with b i l a t e r a l m a l i g n a n t B r e n n e r t u m o r s a r e p r e s e n t e d , i n c l u d i n g f o r t h e first t i m e e l e c t r o n m i c r o s c o p i c findings. Because of some of these findings, a modification o f t h e histologic c r i t e r i a f o r m a l i g n a n t B r e n n e r t u m o r is suggested. CASE REPORT A 68 y e a r old b l a c k w o m a n was a d m i t t e d to t h e D e t r o i t G e n e r a l H o s p i t a l o n O c t o b e r 3, 1977, b e m u s e o f a 50 lb. w e i g h t loss a n d i n c r e a s e d a b d o m i n a l g i r t h o v e r t h e p r e c e d ing month. She did not have vaginal bleeding. Physical e x a m i n a t i o n r e v e a l e d massive ascites a n d a firm fixed m a s s e x t e n d i n g f r o m t h e left u p p e r q u a d r a n t to t h e m i d l i n e . O n pelvic e x a m i n a t i o n a left a d n e x a l mass was palpable. P a r a c e n t e s i s was p e r f o r m e d a n d t h e ascitic fluid was positive f o r m a l i g n a n t cells. O t h e r investigative studies w e r e n o r m a l , i n c l u d i n g c h e s t x-ray e x a m i n a t i o n , b r a i n scan,
Accepted for publication March 19, 1979. *Clinical Associate Professor, Department of Pathology, Wayne State University College of Medicine, Detroit. Pathoh)gist attd Chief of Henaatopathology, William Beaunlont ltospital, Troy, Michigan.
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intravenous pyelogram, a n d blood u r e a nitrogen and serum ereatinine determinations. At exploratory laparatomy bilateral ovarian tnmors were seen with innumerable metastatic nodules in the peritoneum and liver. A biopsy specimen from a mass in the o m e n t u m measuring 8 by 5 by 4 cm. was snbmitted for frozen section examination. It was interpreted as an anaplastic carcinoma suggestive o f squamous cells. A total hysterectomy a n d bilateral salpingooophorectomy was p e r f o r m e d . T h e two ovaries had been separated from the uterus. Each was approximately 6.5 cm. in maximal d i a m e t e r and was replaced by a partly cystic tumor; a tortuous fallopian tube stretched out over each. T h e masses were mutlilocnlated, containing a cloudy a m b e r fluid. About half o f each t u m o r was solid, gray-tan, fleshy, anti soft, with palpillary projections extending into the cyst lumens. T h e r e were no surface excrescences. T h e t u m o r o f the left ovary had invaded the left cornu and posterior myometrium o f the 70 gm. uterus. T h e e n d o m e t r i u m was thin, smooth, and tan. T h e r e were two small benign leiomyomas in the fundus. T h e cervix was smooth a n d glistening. MATERIAL AND METHODS T h e surgical specimen was fixed in phosphate buffered, I0 p e r cent formaldehyde. T h e sections were stained with hematoxylin attd eosin, periodic acid-Schiff, Mayer's mucicarmine, and alcian blue stains. Oil red O stain was used on a wet tissue section from the tumor. A papillary area including underlying solid t u m o r in one ovary was obtained for transmission electron microscopy following fixation in the buffered f o r m a l d e h y d e for several days. T h e tissue was transferred to 1 p e r cent glutaraldehyde and then postfixed in 1 p e r cent osmium tetroxide and e m b e d d e d in Epon. Ultrathin sections were stained with uranyl acetate and lead citrate.
LIGHT MICROSCOPIC FINDINGS T h e t u m o r in the ovaries was a transitional cell carcinonta, comparable to a g r a d e I l l b l a d d e r carcinoma. Moderately to poorly differentiated transitional cells lined the cyst wails and the papillary fronds (Fig. 1). T h e solid areas were composed o f closely packed sheets of similar transitional cells with little intervening stroma. In some areas the cells had oval nuclei and a scant)" cytoplasnt, and in others the ceils were larger a n d squamoid with lobated or convoluted, often gigantic, nuclei and an a b u n d a n t clear cytoplasm, which was PAS positive. Keratin pearls and intercellular bridges were not found. T h e r e were n u m e r o u s mitoses in all areas. Mayer's mucicarmine and oil red O stained specimens were negative. T h e epithelial ceils o f the t u m o r stained negatively with alcian blue, but edematous areas in the stroma o f papillary fronds and a m o r p h o u s material in the cysts in some areas gave a positive reaction. A benign c o m p o n e n t was not identified, but in one o f the many sections there were a few nests of stratified epithelium in a dense stroma, a pattern identical to that o f a benign B r e n n e r ttunor (Fig. 1). T h e s e epithelial cells were pleomorphic with hyperchromatic nuclei a n d atypical ntitoses. Nuclear folds were haphazardly rather than longitudinally oriented. T h e tissue o f the omental biopsy specimen was identical to portions o f the ovarian tttmor. T h e endontetriunt a n d cervix were free o f malignant change. ELECTRON M I C R O S C O P I C F I N D I N G S Tile epithelial cells varied in size and were separated from the stroma by a basal lamina (Fig. 2). T h e plasma membranes were generally closely a p p o s e d and had interdigitating processes anti a variable n u m b e r o f desmosomes. T h e r e were n u m e r o u s microvilli along the hmfinal surface
Figure I. A, Papillary fronds lined by moderatel)' differentiated transitional cells. B, Nests of stratified epithelium in a dense stroma, a pattern identical to that of the benign Brenner tumor, but the cells are malignant. (Hematoxylin and eosin stain. • 150.)
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MEDICAL I N T E L L I G E N C E
Figure 2. Electron micrograph of tumor cells showing closely apposed plasma membranes with desmosome (D) and a widened intercellular space with many microvilli and pinocytotic vesicles (PV). In the cytoplasm are numerous glycogen particles and free ribosomes, few profiles ofendoplasmic reticulunl (ER), and microfilaments (MF).Inset, Elsewhere at the junction between tumor epithelium and stroma is a continuous basal lamina. (• Inset, • of tile cells and at widened intercellular spaces. Mtdtiple micropinocytotic vesicles were seen in some cells (Fig. 2). Despite hlitial formalin fixation, organelles could be readily identified in most cells. T h e r e were scant n u m b e r s of mitochondria and profiles of rough e n d o p l a s m i c reticulum, and occasional Golgi complexes. Free ribosomes a n d glycogen granules were found, particularly a b u n d a n t in larger ceils. T h e r e were secondary lysosomes, inchtding autol~hagic vacuoles, phagolysosomes, and occasional lipid droplets. Microfilaments were demonstrable, some near l)lasma m e m b r a n e s , but they did not form definite tonofilament-desnaosonae complexes (Fig. 2). T h e r e were no oval or filsiform intracytoplasmic vesicles. T h e nuclei were oval, often lobated, or convoluted. In a few cells a deep narrow groove was evident in tile nucleus or nuclear lobes. Nucleoli were prominent. Tile stromal cells resembled fibroblasts, lacked lipid globules, and were s u r r o u n d e d by a b u n d a n t collagen. DISCUSSION Bilateral B r e n n e r tulnors of tile ovary are tmcommon. Tile frequencies of 3.7 and 8.0 per cem are prol)ably too high, since not all unilateral B r e n n e r tumors are reported3 Of the 25 cases of malignant B r e n n e r t u m o r that Idelsoil ~ collected from the literature ill 1963, three were bilateral. Miles and Norris ~~tlescribed seven cases each of
proliferative and malignant B r e n n e r tumors, and only one, a malignant tumor, was bilateral. In yon Nnmers' first reported cases of malignant B r e n n e r tumor, one case was l~resumed by him to be bilateral? 7 However, tiffs i)resump tion was u n p r o v e n because histologic sections were available only fi'om the left ovary. T h e present case therefore represents the rare combination of bilaterality and proven malignancy. Histologically benign t u m o r is a well defined entity. Acceptable criteria for proliferative and malignant types lmve not been firmly established, and their separation is often difficult. A case of proliferative B r e n n e r t u m o r that later metastasized to the liver demonstrates this difficulty? ~ T h e present case was both clinically and cytologically malignant. Malignant B r e n n e r t u m o r was subclassified by earlier authors into epidermoid or squamous carcinonm, adenocarcinoma, and a nfixed t)'pe ~,~5,~8 idelson~ added to tile first two cystadenocarcinoma and sarcoma. Recent authors have considered.malignant B r e n n e r t u m o r to be basically a transitional cell carcinoma, which may be anaplastic or show sqtmmous differentiation or mucinous glandular differentiation.4, s. t0 Many of tile previous squamous carcinomas would now be reclassified as transitional cell carcinomas. Whether tile presence of l~eratinization or intercellular bridges should be required for designating a t u m o r as squamous is unclear.
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T h e t u m o r in o u r p a t i e n t was a t r a n s i t i o n a l cell carcin o m a , c o m p a r a b l e to a g r a d e I I I b l a d d e r c a r c i n o m a . Alt h o u g h s o m e nests o f stratified e p i t h e l i u m r e s e m b l e d s q u a m o u s cells, n o k e r a t i n p e a r l s o r i n t e r c e l h f l a r b r i d g e s w e r e identified, and the intracytoplasrnic microfibrils,'cbaracteristic o f cells o r i g i n a t i n g f r o m c e l o m i c e p i t h e l i u m , d i d n o t form the tonofilament-desmosome complexes ofsquamous epithelitmt. Most p r o l i f e r a t i v e a n d m a l i g n a n t B r e n n e r t u m o r s h a v e a n associated b e n i g n c o m p o n e n t . I n o u r p a t i e n t t h e r e w e r e nests o f e p i t h e l i u m in a d e n s e s t r o m a , a p a t t e r n i d e n t i c a l to t h a t s e e n in a b e n i g n B r e n n e r t u m o r , b u t t h e cells w e r e m a l i g n a n t . W h e t h e r this f i n d i n g r e p r e s e n t s m a l i g n a n t c h a n g e in a p r e v i o u s l y b e n i g n a r e a o r a d e n o v o m a l i g n a n t tumor could not be determined. A criterion for malignant B r e n n e r t u m o r is t h e i d e n t i f i c a t i o n o f i n t i m a t e l y a s s o c i a t e d b e n i g n B r e n n e r t u m o r with epithelial t r a n s i t i o n b e t w e e n t h e m . 5 H a l l g r i m s s o n a n d S c u l l y t f o u n d this r e q u i r e m e n t too r e s t r i c t i v e b e c a u s e t h r e e o f t h e i r 15 cases l a c k e d d e m o n strable benign elements. We would agree, and further suggest that the reqttirement be excluded from the histologic c r i t e r i a f o r m a l i g n a n t B r e m t e r t u m o r . A number of authors have sfttdiedthe uhrastructure of benign Brenner tumors and coitcluded that Brenner tumors originate frbm celomic or ovarian surface epithel i u m directly o r b y m e t a p l a s i a , t ' 9 ' m t 3 , t 6 S o m e h a v e d e s c r i b e d t h e man}" similarities a n t o n g B r e n n e r e p i t h e l i a l cells, t h e W a l t h a r d cell nest, a n t i u r o t h e l i a l cells)" ~3 By e l e c t r o n m i c r o s c o p i c s t u d y o u r m a l i g n a n t B r e n n e r t u m o r s h a r e s man)" f e a t u r e s o f t h e b e n i g n t u m o r . T h e s e i n c l u d e t h e p r e s e n c e o f a basal l a m i n a , d e s m o s o m e s , i n t e r d i g | r a t i n g p l a s m a m e m b r a n e s , microvilli, p i n o c y t o t i c vesicles, p h a g o l y s o s o m e s anti i n t r a c y t o p l a s m i c m i c r o f i l a m e n t s , t h e a b u n d a n c e o f g l y c o g e n a n d f r e e r i b o s o m e s , a n d tlte paucity of endoplasmic reticulum and mitochondria. Some f e a t u r e s , n o t a b l y t h e basal l a m i n a , p i n o c y t o t i c vesicles, a n d intracytoplasmic microfilaments, are being reported for the first t i m e in a m a l i g n a n t B r e n h e r t u m o r . Deep nuclear grooves, a constant feature of the benign t u m o r , w e r e p r e s e n t o n l y in a few cells in o u r t t t m o r . P r a t t - T h o m a s et al. tt f o u n d t h e n t i c l e a r g r o o v e s to b e v e r y s h a l l o w in t h e i r case o f m a l i g n a n t B r e n n e r t u m o r . T h e s e d e v i a t i o n s f r o m t h e b e n i g n t u m o r , t o g e t h e r with o u r findi n g o f l a r g e c o n v o l u t e d nuclei, reflect t h e a n a p l a s t i c n a t u r e o f t h e t u m o r a n d n o t a c h a n g e in cell type. T h e a b s e n c e o f oval o r f u s i f o r m intracytol~lasntic vesicles o f t h e t y p e s e e n in superficial n r o t h e l i a l cells a n d in b e n i g n B r e n n e r t u m o r s was p r o b a b l y d u e to cell d e d i f f e r e n t i a t i o n also)" 3. ~a. ~6
Acknowledgment T h e a u t h o r wishes to t h a n k Dr. J a c o b L. C h a s o n f o r his encouragements and helpful suggestions during the prepar a t i o n o f this m a n u s c r i p t . "
5. Hull, M. G. R., and Campbell, G. R.: The malignant Brenner tumor. Obstet. Gynecol., 42:527, 1973. 6. Idelson, M. G.: Malignancy in Brenner tumors of the ovary, with comments on histogenesis and possible estrogen production. Obstet. Gynecol. Survey, 18:246, 1963. 7. Lamping, J. D., and Blythe, J. G.: Bilateral Brenner tumors: a case report and review of the literature. Human Pathol., 8:583, 1977. 8. Mackinlay, C. J.: Brenner tumors of the ovary. A report of 9 cases including one with malignant degeneration. J. Obstet. Gynaecol. Brit. Emp., 63:58, 1956, 9. Merkow, L. P., Salazar, H., and Pardo, M.: ttuman ovarian neoplasms, light and electron microscopic correlation. I. The Brenner tumor. Obstet. Gynecol., 40:667, 1972. 10. Miles, P. A., and Norris, It. J.: Proliferative and malignant Brenner tumors of the ovary. Cancer, 30:174, 1972. 11. l'ratt-Thomas, H. R., Kreutner, A., Underwood, P. B., and Dowdeswell, R. l-t.: Proliferative and malignant Brenner tumors of ovary. Report of two cases, one with Melg's syndrome, review of literature and ultrastructural comparisons. Gynecol. Oncol., 4:176, 1976. 12. Roth, L. M.: Fine structure of the Brenner tumor. Cancer. 27:1482, 1971. 13. Roth, L. M.: The Brenner tumor and the Wahhard cell nest. An electron microscopic stud)'. Lab. Invest., 31:15, 1974. 14. Roth, L. M., and Sternberg, W. H.: Proliferating Brenner tumors. Cancer, 27:687, 1971. 15. Shay, M. D., and Janovski, N. A.: Malignant Brenner tumor associated with endometrial adenocarcinonta. Obstet. Gynecol., 22:246, 1966. 16. Silverberg, S. G., and Willson, M. A.: Uhrastructure of the Brenner tumor. Am. J. Obstet. Gynecol., 112:91, 1972. 17. yon Numers, C.: A contribution to the case knowledge and history of the Brenner tumor. Do malignant forms of the Brenner tumor also occur? Acta Obstet. Gynecol. Scand., 25(Suppl. 2):114, 1945. Department of Pathology Wayne State University College of Medicine 540 E. Canfield Avenue Detroit, Michigan 48201
PRIMARY P U L M O N A R Y RHABDOMYOSARCOMA: A CASE REPORT A N D REVIEW OF THE LITERATURE SAING "HEE LEE, M.D.,* SETTI S. RENGACtiARY, M.D.,'~ AND JAYA PARAMES}I, M.D.
Abstract Although several primary pulmonary neoplasms containing striated muscle fibers have in the past been described as rhabdomyoma or rhabdomyosarcoma, it was not until 1939 that McDonald and Heather described the first acceptable case of this neoplasm. Since then 13 such cases have been reported in the world literature.
Accepted for publication March 19, 1979. References
I. Cummins, P. A., Fox, it., and Langley, F. A.: An uhrastructural study of the natu re and origin of the Brenner tumor of the ovary. J. Pathol., 110:167, 1973. 2. Foda, M., and Shafeek, M. A.: Malignant Brenner tumor. Obstet. Gynecol., 13:226, 1959. 3. Fulker, M. J., Cooper, E. tl., and Tanaka, T.: Proliferation and uhrastructure of papillary transitional cell carcinoma of the human bladder. Cancer, 27:71, 1971. 4. tlallgrimsson, J., attd Scully, R. E.: Borderline and malignant Brenner tunmrs of the ovary. Acta Pathol. Microbkfl. Stand., Sect. A80(Suppl.), 233:56, 1972.
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*Assistant Professor of Pathology, College of Health Sdences a n d Hospital, University of Kansas Medical Center. Senior Staff Pathologist, Veterans Administration Medical Center, Kansas City, Missouri. tAssociate Professor of Surgery, College of Heahh Sciences and ttospital, University of Kansas Medical Center. Chief, Neurosnrgery Section, Veterans Administration Medical Center, Kansas City, Missouri. :~Resident n Pathology, College of Heahh Sciences and Hospital, University of Kansas Medical Center, Kansas City, Missouri.