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Mucinous adenocarcinoma as heterologous element in intermediately differentiated Sertoli–Leydig cell tumor of the ovary
ARTICLE IN PRESS Pathology – Research and Practice 206 (2010) 489–492
Contents lists available at ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.de/prp
Teaching cases
Mucinous adenocarcinoma as heterologous element in intermediately differentiated Sertoli–Leydig cell tumor of the ovary Renu Virk, Di Lu Biotech three, One innovation drive, Department of Pathology, UMass Memorial Medical Center, Worcester, MA 01605, USA
a r t i c l e in fo
abstract
Article history: Received 24 December 2008 Received in revised form 9 July 2009 Accepted 17 July 2009
Sertoli–Leydig cell tumor (SLCT) is a rare tumor involving the ovary. Approximately 20% of SLCT are associated with heterologous elements that are either of endodermal or mesodermal origin. The gastrointestinal-type epithelium is the most commonly described endodermal heterologous element. SLCT with benign and borderline mucinous neoplasm has been reported in the literature. However, SLCT with mucinous adenocarcinoma as heterologous element has been rarely documented. Herein, we describe a rare case of intermediately differentiated Sertoli–Leydig cell tumor with mucinous adenocarcinoma as the heterologous element in a 21-year-old woman. She presented with throbbing lower abdominal pain and was found to have a large, complex left ovarian mass on imaging studies. She underwent left salpingo-oophorectomy, appendectomy and lymph node staging. Gross examination of the surgical specimen showed a large, encapsulated, solid-cystic mass completely replacing the ovary. Microscopically, the tumor was composed of intermediately differentiated Sertoli–Leydig cell tumor and well-differentiated mucinous adenocarcinoma. Interestingly, the bulk of the tumor (more than 90%) was composed of mucinous adenocarcinoma, whereas the SLCT component comprised less than 10% of the total tumor. The mucinous adenocarcinoma expressed positivity for CK20, CEA, CDX2 and CK7, and the SLCT component was positive for inhibin expression. The histopathological features and results of immunostaining were consistent with the diagnosis of the intermediately differentiated SLCT with mucinous adenocarcinoma as the heterologous element. This case was a diagnostic challenge as more than 90% of the tumor was composed of mucinous adenocarcinoma and SLCT constituted only the minor part of the tumor. This feature was in contrast to the previously described two cases, where mucinous adenocarcinoma as heterologous element was present as microscopic foci. This case highlights the importance of identifying the SLCT component in a case of an apparently pure mucinous adenocarcinoma in a young patient. & 2009 Published by Elsevier GmbH.
Keywords: Adenocarcinoma Heterologous element Sertoli–Leydig cell tumor
Introduction The Sertoli–Leydig cell tumor (SLCT) is a rare tumor, accounting for less than 0.5% of all ovarian tumors. Young and Scully [12] published the largest case series in 1985, where they described the clinico-pathological features and biological behavior of 207 cases of SLCT. These tumors typically occur in young women in their second and third decade (mean age of 25 years) [12]. The patients may present clinically with an abdominal mass or endocrine symptoms. Most common endocrine manifestation includes virilizing symptoms such as hirsutism. Very rarely, these tumors can be feminizing, inducing isosexual precocity in prepubertal females, or menstrual abnormalities in women of reproductive age group. Histologically, SLCT contains variable proportions of Sertoli and Leydig cell components. The characteristic microscopic feature of
Corresponding author. Tel.: +1 508 793 6146; fax: +508 793 6110.
E-mail address: [email protected] (D. Lu). 0344-0338/$ - see front matter & 2009 Published by Elsevier GmbH. doi:10.1016/j.prp.2009.07.012
SLCT is the presence of Sertoli cell tubules distributed in the gonadal stroma. Approximately 20% of SLCT show heterologous elements that can be either endodermal or mesenchymal derivatives [9]. The endodermal derivatives are usually seen in association with intermediately differentiated SLCT and mesenchymal derivatives are seen more commonly with poorly differentiated SLCT. This report describes a rare case of intermediately differentiated SLCT with predominant heterologous element composed of mucinous adenocarcinoma. Mucinous adenocarcinoma as predominant heterologous element in SLCT has never been described. This case may contribute to the literature and help in understanding the biological behavior of mucinous adenocarcinoma as heterologous element in SLCT.
Clinical presentation A 21-year-old female presented to the emergency room with throbbing pain in her lower abdomen. She had a history of early satiety and significant weight loss for the past one month. Her
ARTICLE IN PRESS 490
R. Virk, D. Lu / Pathology – Research and Practice 206 (2010) 489–492
past medical history was remarkable for one abnormal Pap smear and chlamydial infection. Her family history was significant for ovarian cancer in her mother (at the young age of 30 years). Physical examination was remarkable for left lower quadrant tenderness on deep palpation and left adnexal fullness on bimanual examination. Further work-up with transvaginal ultrasonography and computed tomography (CT) scan demonstrated the left ovary to be contiguous with a large complex mass with septations throughout the mass. The patient underwent elective left salpingo-oophorectomy. The frozen section performed on the ovarian mass was reported as a well-differentiated mucinous adenocarcinoma. She was subjected to omentectomy, appendectomy, peritoneal biopsies and staging lymph node dissection.
Pathological findings Gross findings The left salpingo-oophorectomy specimen revealed an encapsulated, multinodular mass completely replacing the ovary and measuring 12.5 11.0 6.0 cm3 in maximum dimensions. The capsule was smooth and intact without any areas of breach. The cut surface of the mass was solid with cystic areas. The solid areas were tanyellow in color and had granular appearance. The cystic spaces contained mucinous material. Small areas of necrosis were also identified within the mass. Residual normal ovarian tissue was not identified. The left fallopian tube and appendix were unremarkable. Light microscopic findings Microscopic examination of the ovarian mass revealed a tumor predominantly composed of back-to-back arranged glands with
complex architecture (Fig. 1A). The glands were lined by stratified columnar epithelium with interspersed goblet cells (Fig. 1B). The cells lining the glands showed moderate cytological atypia, a high nuclear to cytoplasmic ratio, hyperchromatic nuclei and numerous mitotic figures (Fig. 1C). Many glands showed necrotic material within the lumen. In addition, the tumor showed typical areas of intermediately differentiated Sertoli–Leydig cell tumor at the periphery of the tumor and between the malignant mucinous glands. The Sertoli cells were predominantly present as cellular lobules (Fig. 2A) and formed tubules in a very focal area. The Leydig cells were seen as tiny clusters at the margin of Sertoli cell lobules (Fig. 2B). In several sections, small foci of the Sertoli–Leydig cell tumor component were intermixed with the mucinous adenocarcinoma (Fig. 2D). The fallopian tube did not show any involvement by the tumor. The appendix was completely examined microscopically and was unremarkable.
Immunohistochemical findings The tumor was immunostained with a panel of immunohistochemical markers comprising cytokeratin AE1/AE3, CK-20, CK-7, carcinoembryonic antigen (CEA), CDX2 and inhibin. The mucinous adenocarcinoma component expressed strong cytoplasmic positivity for cytokeratin AE1/AE3, CK-20 (Fig. 1D), CEA and nuclear positivity for CDX2. CK-7 was focally positive. Inhibin highlighted the SLCT component at the periphery of the tumor and in the areas between the mucinous glands (Fig. 2C). Based on the morphological features and the results of immunostaining, a diagnosis of intermediately differentiated Sertoli–Leydig cell tumor with mucinous adenocarcinoma as heterologous element was rendered. There was no evidence of local invasion or regional metastasis. Finally, the tumor was staged as T1N0M0, stage I.
Fig. 1. (A) Mucinous adenocarcinoma with back-to-back arranged glands, lined by stratified intestinal-type epithelium (hematoxylin-eosin, original magnification 100). (B) Mucinous glands lined by stratified malignant epithelium with interspersed goblet cells. The lining cells show hyperchromatic nuclei, high N/C ratio (hematoxylin–eosin, original magnification 400). (C) Numerous mitotic figures are seen in one of the glands (hematoxylin–eosin, original magnification 400). (D) The epithelial cells show diffuse cytoplasmic positivity for CK-20 by immunohistochemistry (original magnification 200).
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Fig. 2. (A) Round to oval Sertoli cells are present in diffuse sheets and forming tubules (hematoxylin–eosin, original magnification 200). (B) Tiny clusters of Leydig cells are seen interspersed among the Sertoli cells (hematoxylin–eosin, original magnification 400). (C) Sertoli cells show diffuse strong cytoplasmic positivity for inhibin by immunohistochemistry (original magnification 400). (D) Inhibin staining of Sertoli–Leydig cell tumor (SLCT) surrounding the mucinous glands (original magnification 200).
Discussion This article describes a rare case of intermediately differentiated SLCT with extensive mucinous adenocarcinoma as the heterologous element. In the literature review, we found only two cases of SLCT containing mucinous adenocarcinoma as the heterologous element [11]. The present case differs appreciably from those previously described cases by the presence of extensive heterologous elements of mucinous adenocarcinoma, almost masking the SLCT. In contrast, the previously described two cases of SLCT contained only microscopic foci of mucinous adenocarcinoma. SLCT is a solid or solid-cystic tumor and usually affects unilateral ovary. Very rarely, SLCT has been described to be a predominant cystic tumor [12]. The tumor may range in size from microscopic to 35 cm (average size—12.5 cm). In the present case, the tumor was solid-cystic and measured 12.5 cm in maximum dimensions. Histologically, SLCT is characterized by the presence of Sertoli cell tubules in the gonadal stroma. The Leydig cell component is present as sheets, variable-sized clusters or single cells in the intervening stroma between the Sertoli cell tubules or at the margin of Sertoli cell nodules. In the past, only Sertoli cells were considered to be the malignant component and Leydig cells were thought to be reactive [7]. However, Emerson et al. [1] recently demonstrated Leydig cells to be neoplastic. SLCT is subclassified into well-differentiated, intermediately differentiated and poorly differentiated tumor based on the degree of tubular differentiation of Sertoli cells and the amount of primitive gonadal stroma [9]. In well-differentiated SLCT, the Sertoli cells form hollow to solid tubules with Leydig cell clusters present between the tubules. SLCT with intermediate differentiation contains cords or poorly developed tubules or cellular lobules of Sertoli cells with primitive gonadal stroma. Poorly differentiated SLCT is sarcomatoid in appearance and demonstrates diffuse
growth of poorly differentiated Sertoli cells with high mitotic activity. In the present case, the Sertoli cells were present as small lobules of round to oval cells with focal tubule formation with Leydig cells at the margin of these lobules, consistent with the diagnosis of intermediately differentiated SLCT. The histopathological diagnosis of the SLCT is quite challenging. Many factors contribute to the diagnostic difficulty. The first reason is that the tumor is very uncommon. Secondly, the tumor shows uncommon and overlapping morphological features shared by other ovarian tumors such as endometrioid tumors [4]. The diagnostic difficulty is further complicated by the presence of heterologous elements, which are seen in approximately 20% of SLCT. The heterologous elements can be present in a variable proportion, ranging from microscopic foci to predominant tumor masking the typical SLCT as in the present case. In our case, the heterologous element constituted more than 90% of the total tumor. Young et al. [11] described 36 cases of SLCT with endodermal elements. In their series, the most common endodermal elements were glands and cysts lined by gastrointestinal-type epithelium. In the majority of cases (29/36), the epithelium was cytologically benign. Five out of 36 cases contained gastrointestinal epithelium with features of borderline malignancy and two cases had microscopic foci of mucinous adenocarcinoma. In addition, they found microscopic foci of insular carcinoid in 8 out of 36 cases. Later on, Prat et al. [8] described a series of 12 SLCT cases with mesenchymal heterologous elements including benign cartilage, skeletal muscle and neuroblastoma. A few cases of SLCT with rhabdomyosarcoma as heterologous element have also been documented in the literature [2]. In the present case, the tumor was diagnosed as mucinous adenocarcinoma on frozen section. However, the microscopic examination of permanent sections revealed an additional component of intermediately differentiated SLCT, which
ARTICLE IN PRESS 492
R. Virk, D. Lu / Pathology – Research and Practice 206 (2010) 489–492
constituted less than 10% of the total tumor. The Sertoli cells were present as small clusters of immature-looking round to oval cells at the periphery of the tumor and between the mucinous glands. The Sertoli cell nature of these cells was further confirmed on immunostaining. These cells showed strong, diffuse, cytoplasmic reaction to inhibin. The mucinous adenocarcinoma expressed CK20, CEA, CDX2 and focal CK7. On the basis of the morphological features and immunostaining, the tumor was diagnosed as intermediately differentiated SLCT with mucinous adenocarcinoma as the heterologous element. Mucinous adenocarcinoma occurs mostly in women in their fourth to seventh decade. This patient was a 21-year-old young woman, an unlikely candidate for the occurrence of pure mucinous adenocarcinoma. Considering the young age of the patient, the possibility of teratoma with mucinous neoplasm was considered. Extensive sampling of the tumor was done, and it did not reveal any teratoma component. The other possibility in the present case could have been the collision tumor, in which the mucinous adenocarcinoma collides with SLCT, resulting in a grossly single mass of two discrete entities. However, the SLCT foci were closely admixed with mucinous adenocarcinoma on microscopic examination and immunostaining, arguing against the diagnosis of collision tumor. Mucinous neoplasm has been rarely described in combination with granulosa cell tumor, carcinoid tumor and cystic teratoma. Mucinous neoplasm has been reported as a composite tumor with granulosa cell tumor [5]. In addition, there has been one documented case report of mucinous tumor and granulosa cell tumor in mature cystic teratoma [6]. Very rarely, mucinous tumor may coexist with minor sex-cord stromal elements [10]. The prognosis of the SLCT depends on the stage, degree of differentiation of the tumor and the presence of malignant mesenchymal heterologous elements. The histopathological features associated with poor outcome include an intermediate to poor degree of differentiation and the presence of a malignant mesenchymal component such as rhabdomyosarcoma. Eleven percent of intermediately differentiated SLCT behave in a malignant fashion, whereas primary ovarian well-differentiated mucinous adenocarcinoma, stage I, without tumor rupture has an excellent prognosis with a 5-year survival of 98% [3,12]. However, the prognostic implication of mucinous adenocarcinoma on the overall prognosis of otherwise stage I intermediately differentiated SLCT as in this case is not known. Only two cases of well-differentiated mucinous adenocarcinoma as heterologous element in SLCT have been described in the literature [11]. Both cases contained only microscopic foci of welldifferentiated mucinous adenocarcinoma rather than a predominant component as in this case and were followed up for a short period. It is unknown whether the prognosis of SLCT with
extensive mucinous adenocarcinoma is different compared to typical primary ovarian mucinous adenocarcinoma. The small number of cases described in the literature makes it difficult to draw any conclusion regarding the accurate prognosis. This patient, in the meantime, is doing well on one-year follow-up. To summarize, we describe a rare case of intermediately differentiated SLCT with mucinous adenocarcinoma as heterologous element in a young woman. The unique feature of this case was the presence of an extensive heterologous component of mucinous adenocarcinoma with only small areas of intermediately differentiated SLCT. This case expands the morphological spectrum of heterologous endodermal elements in SLCT and may contribute to the limited existing literature as the biological behavior and clinical course of such tumors is not well known. A longer follow-up and a higher number of cases will help in better predicting the prognosis of such cases.
References [1] R.E. Emerson, M. Wang, L.M. Roth, et al., Molecular genetic evidence supporting the neoplastic nature of the Leydig cell component of ovarian Sertoli–Leydig cell tumors, Int. J. Gynecol. Pathol. 26 (4) (2007) 368–374. [2] A. Grove, V. Vestergaard, Ovarian Sertoli–Leydig cell tumor of intermediate grade with heterologous elements of rhabdomyosarcoma. A case report and a review of the literature, Ann. Diagn. Pathol. 10 (5) (2006) 288–293. [3] K.R. Lee, R.E. Scully, Mucinous tumors of the ovary: a clinicopathologic study of 196 borderline tumors (of intestinal type) and carcinomas, including an evaluation of 11 cases with ‘pseudomyxoma peritonei’, Am. J. Surg. Pathol. 24 (11) (2000) 1447–1464. [4] W.G. McCluggage, R.H. Young, Ovarian Sertoli–Leydig cell tumors with pseudoendometrioid tubules (pseudoendometrioid Sertoli–Leydig cell tumors), Am. J. Surg. Pathol. 31 (4) (2007) 592–597. [5] M. McKenna, B. Kenny, G. Dorman, W.G. McCluggage, Combined adult granulosa cell tumor and mucinous cystadenoma of the ovary: granulosa cell tumor with heterologous mucinous elements, Int. J. Gynecol. Pathol. 3 (2005) 224–227. [6] F.Y. Moid, R.V. Jones, Granulosa cell tumor and mucinous cystadenoma arising in a mature cystic teratoma of the ovary: a unique case report and review of literature, Ann. Diagn. Pathol. 8 (2) (2004) 96–101. [7] E.E. Mooney, Y.G. Man, G.L. Bratthauer, F.A. Tavassoli, Evidence that Leydig cells in Sertoli–Leydig cell tumors have a reactive rather than a neoplastic profile, Cancer 86 (11) (1999) 2312–2319. [8] J. Prat, R.H. Young, R.E. Scully, Ovarian Sertoli–Leydig cell tumors with heterologous elements. II. Cartilage and skeletal muscle: a clinicopathologic analysis of twelve cases, Cancer 50 (11) (1982) 2465–2475. [9] F.A. Tavassoli, P. Devilee (Eds.), World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Breast and Female Genital Organs, IARC Press, Lyon, 2003. [10] S.W. Yang, M.Y. Cho, S.H. Jung, K.G. Lee, D.S. Cha, K.R. Kim, Mucinous cystadenoma coexisting with stromal tumor with minor sex-cord elements of the ovary: a case report, J. Korean Med. Sci. 16 (2) (2001) 237–240. [11] R.H. Young, J. Prat, R.E. Scully, Ovarian Sertoli–Leydig cell tumors with heterologous elements. I. Gastrointestinal epithelium and carcinoid: a clinicopathologic analysis of thirty-six cases, Cancer 50 (11) (1982) 2448–2456. [12] R.H. Young, R.E. Scully, Ovarian Sertoli–Leydig cell tumors. A clinicopathological analysis of 207 cases, Am. J. Surg. Pathol. 9 (8) (1985) 543–569.
Contents lists available at ScienceDirect
Pathology – Research and Practice journal homepage: www.elsevier.de/prp
Teaching cases
Mucinous adenocarcinoma as heterologous element in intermediately differentiated Sertoli–Leydig cell tumor of the ovary Renu Virk, Di Lu Biotech three, One innovation drive, Department of Pathology, UMass Memorial Medical Center, Worcester, MA 01605, USA
a r t i c l e in fo
abstract
Article history: Received 24 December 2008 Received in revised form 9 July 2009 Accepted 17 July 2009
Sertoli–Leydig cell tumor (SLCT) is a rare tumor involving the ovary. Approximately 20% of SLCT are associated with heterologous elements that are either of endodermal or mesodermal origin. The gastrointestinal-type epithelium is the most commonly described endodermal heterologous element. SLCT with benign and borderline mucinous neoplasm has been reported in the literature. However, SLCT with mucinous adenocarcinoma as heterologous element has been rarely documented. Herein, we describe a rare case of intermediately differentiated Sertoli–Leydig cell tumor with mucinous adenocarcinoma as the heterologous element in a 21-year-old woman. She presented with throbbing lower abdominal pain and was found to have a large, complex left ovarian mass on imaging studies. She underwent left salpingo-oophorectomy, appendectomy and lymph node staging. Gross examination of the surgical specimen showed a large, encapsulated, solid-cystic mass completely replacing the ovary. Microscopically, the tumor was composed of intermediately differentiated Sertoli–Leydig cell tumor and well-differentiated mucinous adenocarcinoma. Interestingly, the bulk of the tumor (more than 90%) was composed of mucinous adenocarcinoma, whereas the SLCT component comprised less than 10% of the total tumor. The mucinous adenocarcinoma expressed positivity for CK20, CEA, CDX2 and CK7, and the SLCT component was positive for inhibin expression. The histopathological features and results of immunostaining were consistent with the diagnosis of the intermediately differentiated SLCT with mucinous adenocarcinoma as the heterologous element. This case was a diagnostic challenge as more than 90% of the tumor was composed of mucinous adenocarcinoma and SLCT constituted only the minor part of the tumor. This feature was in contrast to the previously described two cases, where mucinous adenocarcinoma as heterologous element was present as microscopic foci. This case highlights the importance of identifying the SLCT component in a case of an apparently pure mucinous adenocarcinoma in a young patient. & 2009 Published by Elsevier GmbH.
Keywords: Adenocarcinoma Heterologous element Sertoli–Leydig cell tumor
Introduction The Sertoli–Leydig cell tumor (SLCT) is a rare tumor, accounting for less than 0.5% of all ovarian tumors. Young and Scully [12] published the largest case series in 1985, where they described the clinico-pathological features and biological behavior of 207 cases of SLCT. These tumors typically occur in young women in their second and third decade (mean age of 25 years) [12]. The patients may present clinically with an abdominal mass or endocrine symptoms. Most common endocrine manifestation includes virilizing symptoms such as hirsutism. Very rarely, these tumors can be feminizing, inducing isosexual precocity in prepubertal females, or menstrual abnormalities in women of reproductive age group. Histologically, SLCT contains variable proportions of Sertoli and Leydig cell components. The characteristic microscopic feature of
Corresponding author. Tel.: +1 508 793 6146; fax: +508 793 6110.
E-mail address: [email protected] (D. Lu). 0344-0338/$ - see front matter & 2009 Published by Elsevier GmbH. doi:10.1016/j.prp.2009.07.012
SLCT is the presence of Sertoli cell tubules distributed in the gonadal stroma. Approximately 20% of SLCT show heterologous elements that can be either endodermal or mesenchymal derivatives [9]. The endodermal derivatives are usually seen in association with intermediately differentiated SLCT and mesenchymal derivatives are seen more commonly with poorly differentiated SLCT. This report describes a rare case of intermediately differentiated SLCT with predominant heterologous element composed of mucinous adenocarcinoma. Mucinous adenocarcinoma as predominant heterologous element in SLCT has never been described. This case may contribute to the literature and help in understanding the biological behavior of mucinous adenocarcinoma as heterologous element in SLCT.
Clinical presentation A 21-year-old female presented to the emergency room with throbbing pain in her lower abdomen. She had a history of early satiety and significant weight loss for the past one month. Her
ARTICLE IN PRESS 490
R. Virk, D. Lu / Pathology – Research and Practice 206 (2010) 489–492
past medical history was remarkable for one abnormal Pap smear and chlamydial infection. Her family history was significant for ovarian cancer in her mother (at the young age of 30 years). Physical examination was remarkable for left lower quadrant tenderness on deep palpation and left adnexal fullness on bimanual examination. Further work-up with transvaginal ultrasonography and computed tomography (CT) scan demonstrated the left ovary to be contiguous with a large complex mass with septations throughout the mass. The patient underwent elective left salpingo-oophorectomy. The frozen section performed on the ovarian mass was reported as a well-differentiated mucinous adenocarcinoma. She was subjected to omentectomy, appendectomy, peritoneal biopsies and staging lymph node dissection.
Pathological findings Gross findings The left salpingo-oophorectomy specimen revealed an encapsulated, multinodular mass completely replacing the ovary and measuring 12.5 11.0 6.0 cm3 in maximum dimensions. The capsule was smooth and intact without any areas of breach. The cut surface of the mass was solid with cystic areas. The solid areas were tanyellow in color and had granular appearance. The cystic spaces contained mucinous material. Small areas of necrosis were also identified within the mass. Residual normal ovarian tissue was not identified. The left fallopian tube and appendix were unremarkable. Light microscopic findings Microscopic examination of the ovarian mass revealed a tumor predominantly composed of back-to-back arranged glands with
complex architecture (Fig. 1A). The glands were lined by stratified columnar epithelium with interspersed goblet cells (Fig. 1B). The cells lining the glands showed moderate cytological atypia, a high nuclear to cytoplasmic ratio, hyperchromatic nuclei and numerous mitotic figures (Fig. 1C). Many glands showed necrotic material within the lumen. In addition, the tumor showed typical areas of intermediately differentiated Sertoli–Leydig cell tumor at the periphery of the tumor and between the malignant mucinous glands. The Sertoli cells were predominantly present as cellular lobules (Fig. 2A) and formed tubules in a very focal area. The Leydig cells were seen as tiny clusters at the margin of Sertoli cell lobules (Fig. 2B). In several sections, small foci of the Sertoli–Leydig cell tumor component were intermixed with the mucinous adenocarcinoma (Fig. 2D). The fallopian tube did not show any involvement by the tumor. The appendix was completely examined microscopically and was unremarkable.
Immunohistochemical findings The tumor was immunostained with a panel of immunohistochemical markers comprising cytokeratin AE1/AE3, CK-20, CK-7, carcinoembryonic antigen (CEA), CDX2 and inhibin. The mucinous adenocarcinoma component expressed strong cytoplasmic positivity for cytokeratin AE1/AE3, CK-20 (Fig. 1D), CEA and nuclear positivity for CDX2. CK-7 was focally positive. Inhibin highlighted the SLCT component at the periphery of the tumor and in the areas between the mucinous glands (Fig. 2C). Based on the morphological features and the results of immunostaining, a diagnosis of intermediately differentiated Sertoli–Leydig cell tumor with mucinous adenocarcinoma as heterologous element was rendered. There was no evidence of local invasion or regional metastasis. Finally, the tumor was staged as T1N0M0, stage I.
Fig. 1. (A) Mucinous adenocarcinoma with back-to-back arranged glands, lined by stratified intestinal-type epithelium (hematoxylin-eosin, original magnification 100). (B) Mucinous glands lined by stratified malignant epithelium with interspersed goblet cells. The lining cells show hyperchromatic nuclei, high N/C ratio (hematoxylin–eosin, original magnification 400). (C) Numerous mitotic figures are seen in one of the glands (hematoxylin–eosin, original magnification 400). (D) The epithelial cells show diffuse cytoplasmic positivity for CK-20 by immunohistochemistry (original magnification 200).
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491
Fig. 2. (A) Round to oval Sertoli cells are present in diffuse sheets and forming tubules (hematoxylin–eosin, original magnification 200). (B) Tiny clusters of Leydig cells are seen interspersed among the Sertoli cells (hematoxylin–eosin, original magnification 400). (C) Sertoli cells show diffuse strong cytoplasmic positivity for inhibin by immunohistochemistry (original magnification 400). (D) Inhibin staining of Sertoli–Leydig cell tumor (SLCT) surrounding the mucinous glands (original magnification 200).
Discussion This article describes a rare case of intermediately differentiated SLCT with extensive mucinous adenocarcinoma as the heterologous element. In the literature review, we found only two cases of SLCT containing mucinous adenocarcinoma as the heterologous element [11]. The present case differs appreciably from those previously described cases by the presence of extensive heterologous elements of mucinous adenocarcinoma, almost masking the SLCT. In contrast, the previously described two cases of SLCT contained only microscopic foci of mucinous adenocarcinoma. SLCT is a solid or solid-cystic tumor and usually affects unilateral ovary. Very rarely, SLCT has been described to be a predominant cystic tumor [12]. The tumor may range in size from microscopic to 35 cm (average size—12.5 cm). In the present case, the tumor was solid-cystic and measured 12.5 cm in maximum dimensions. Histologically, SLCT is characterized by the presence of Sertoli cell tubules in the gonadal stroma. The Leydig cell component is present as sheets, variable-sized clusters or single cells in the intervening stroma between the Sertoli cell tubules or at the margin of Sertoli cell nodules. In the past, only Sertoli cells were considered to be the malignant component and Leydig cells were thought to be reactive [7]. However, Emerson et al. [1] recently demonstrated Leydig cells to be neoplastic. SLCT is subclassified into well-differentiated, intermediately differentiated and poorly differentiated tumor based on the degree of tubular differentiation of Sertoli cells and the amount of primitive gonadal stroma [9]. In well-differentiated SLCT, the Sertoli cells form hollow to solid tubules with Leydig cell clusters present between the tubules. SLCT with intermediate differentiation contains cords or poorly developed tubules or cellular lobules of Sertoli cells with primitive gonadal stroma. Poorly differentiated SLCT is sarcomatoid in appearance and demonstrates diffuse
growth of poorly differentiated Sertoli cells with high mitotic activity. In the present case, the Sertoli cells were present as small lobules of round to oval cells with focal tubule formation with Leydig cells at the margin of these lobules, consistent with the diagnosis of intermediately differentiated SLCT. The histopathological diagnosis of the SLCT is quite challenging. Many factors contribute to the diagnostic difficulty. The first reason is that the tumor is very uncommon. Secondly, the tumor shows uncommon and overlapping morphological features shared by other ovarian tumors such as endometrioid tumors [4]. The diagnostic difficulty is further complicated by the presence of heterologous elements, which are seen in approximately 20% of SLCT. The heterologous elements can be present in a variable proportion, ranging from microscopic foci to predominant tumor masking the typical SLCT as in the present case. In our case, the heterologous element constituted more than 90% of the total tumor. Young et al. [11] described 36 cases of SLCT with endodermal elements. In their series, the most common endodermal elements were glands and cysts lined by gastrointestinal-type epithelium. In the majority of cases (29/36), the epithelium was cytologically benign. Five out of 36 cases contained gastrointestinal epithelium with features of borderline malignancy and two cases had microscopic foci of mucinous adenocarcinoma. In addition, they found microscopic foci of insular carcinoid in 8 out of 36 cases. Later on, Prat et al. [8] described a series of 12 SLCT cases with mesenchymal heterologous elements including benign cartilage, skeletal muscle and neuroblastoma. A few cases of SLCT with rhabdomyosarcoma as heterologous element have also been documented in the literature [2]. In the present case, the tumor was diagnosed as mucinous adenocarcinoma on frozen section. However, the microscopic examination of permanent sections revealed an additional component of intermediately differentiated SLCT, which
ARTICLE IN PRESS 492
R. Virk, D. Lu / Pathology – Research and Practice 206 (2010) 489–492
constituted less than 10% of the total tumor. The Sertoli cells were present as small clusters of immature-looking round to oval cells at the periphery of the tumor and between the mucinous glands. The Sertoli cell nature of these cells was further confirmed on immunostaining. These cells showed strong, diffuse, cytoplasmic reaction to inhibin. The mucinous adenocarcinoma expressed CK20, CEA, CDX2 and focal CK7. On the basis of the morphological features and immunostaining, the tumor was diagnosed as intermediately differentiated SLCT with mucinous adenocarcinoma as the heterologous element. Mucinous adenocarcinoma occurs mostly in women in their fourth to seventh decade. This patient was a 21-year-old young woman, an unlikely candidate for the occurrence of pure mucinous adenocarcinoma. Considering the young age of the patient, the possibility of teratoma with mucinous neoplasm was considered. Extensive sampling of the tumor was done, and it did not reveal any teratoma component. The other possibility in the present case could have been the collision tumor, in which the mucinous adenocarcinoma collides with SLCT, resulting in a grossly single mass of two discrete entities. However, the SLCT foci were closely admixed with mucinous adenocarcinoma on microscopic examination and immunostaining, arguing against the diagnosis of collision tumor. Mucinous neoplasm has been rarely described in combination with granulosa cell tumor, carcinoid tumor and cystic teratoma. Mucinous neoplasm has been reported as a composite tumor with granulosa cell tumor [5]. In addition, there has been one documented case report of mucinous tumor and granulosa cell tumor in mature cystic teratoma [6]. Very rarely, mucinous tumor may coexist with minor sex-cord stromal elements [10]. The prognosis of the SLCT depends on the stage, degree of differentiation of the tumor and the presence of malignant mesenchymal heterologous elements. The histopathological features associated with poor outcome include an intermediate to poor degree of differentiation and the presence of a malignant mesenchymal component such as rhabdomyosarcoma. Eleven percent of intermediately differentiated SLCT behave in a malignant fashion, whereas primary ovarian well-differentiated mucinous adenocarcinoma, stage I, without tumor rupture has an excellent prognosis with a 5-year survival of 98% [3,12]. However, the prognostic implication of mucinous adenocarcinoma on the overall prognosis of otherwise stage I intermediately differentiated SLCT as in this case is not known. Only two cases of well-differentiated mucinous adenocarcinoma as heterologous element in SLCT have been described in the literature [11]. Both cases contained only microscopic foci of welldifferentiated mucinous adenocarcinoma rather than a predominant component as in this case and were followed up for a short period. It is unknown whether the prognosis of SLCT with
extensive mucinous adenocarcinoma is different compared to typical primary ovarian mucinous adenocarcinoma. The small number of cases described in the literature makes it difficult to draw any conclusion regarding the accurate prognosis. This patient, in the meantime, is doing well on one-year follow-up. To summarize, we describe a rare case of intermediately differentiated SLCT with mucinous adenocarcinoma as heterologous element in a young woman. The unique feature of this case was the presence of an extensive heterologous component of mucinous adenocarcinoma with only small areas of intermediately differentiated SLCT. This case expands the morphological spectrum of heterologous endodermal elements in SLCT and may contribute to the limited existing literature as the biological behavior and clinical course of such tumors is not well known. A longer follow-up and a higher number of cases will help in better predicting the prognosis of such cases.
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