Case 4 -

Sertoli Cell Tumor of the Ovary Louis P Dehner St. Louis Children's Hospital, Washington University Medical Center St. Louis, MO

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Clinical History The patient is a 5-year-old female who was seen in the emergency department with a 4-5 day history of moderate to severe, cramping intermittent pain in the periumbilical region. There was regularity to the pain especially over the prior two days. She had had several bouts of vomiting over the last 24 hours. Physical examination revealed an afebrile child who did not appear to be in acute distress, was well nourished and was normally developed without any signs of endocrine dysfunction. Thoracic and abdominal scars were noted. The physical examination was otherwise unremarkable including a negative abdominal examination. A hemogram was performed with a hemoglobin of 12.1 g/dl and a white cell count of 16,500 with 85% segmented neutrophils. CT examination revealed a multicystic mass in the left kidney measuring 4.0 x 2.5 cm and a rounded soft tissue mass in the left pelvis immediately adjacent and anterior to the rectum which measured 3.4 x 3.2 cm. This mass was questioned as possibly arising in the left ovary. The pre-operative diagnosis was torsion of the left ovary. At the time of surgery, there was torsion of the left ovary with an intensely hemorrhagic appearance to the ovary as well as the presence of a 3-4 cm mass which was contiguous to the ovary. The section is from the resected left ovary which was described as weighing 48 gm and a lobulated, hemorrhagic mass measuring 8 x 4 x 2 cm. Case 4 - Figure 1 Hemorrhagic external surface and hemorrhagic contents of the cystic left ovary also demonstrates bulging nodules as seen through the capsular surface. Case 4 - Figure 2 Extensive areas of the left ovary have undergone hemorrhagic necrosis which is the typical pathology of torsion. In some cases, it may be difficult to appreciate any underlying additional pathology, but not in this specimen. Case 4 - Figure 3 Though the nodules of tumor also displayed the presence of interstitial hemorrhage, there is sufficient preservation to appreciate both architectural and individual microscopic features. The multinodular character is appreciated in this low magnification view. There is variation in the histologic composition of this tumor from one area to another. Case 4 - Figure 4 This microscopic field shows the presence of uniformly small tubules adjacent to the loosely textured spindle cell mesenchyme. Case 4 - Figure 5 Other foci are composed of well formed tubules and poorly formed cord-like structures. Case 4 - Figure 6 This microscopic field shows the presence of poorly formed cords of basophilic cells which blend into a fibroma-like stroma. Case 4 - Figure 7 Cystic areas show the presence of papillary profiles whose papillae are lined by a similar population of basophilic cells seen elsewhere in the tubules. Case 4 - Figure 8 Immunohistochemistry confirms the diagnosis of a sex-cord stromal tumor with a panel of stains including cytokeration. Case 4 - Figure 9 Vimentin expression by the tumor cells is less intense than the cytokeratin in Figure 8. Case 4 - Figure 10 Calretinin staining is focally positive in tumor cells. The immunophenotype of sex-cord stromal tumors has some overlap with surface epithelial tumors of the ovary and mesothelioma except for the expression of inhibin. These three tumor types have considerable overlap since they share a common embryogenesis. Case 4 - Figure 11 Inhibin positivity is a useful marker in the differentiation of a sex-cord stromal tumor from a surface epithelial neoplasm of the ovary. Case 4 - Figure 12 The tumor demonstrates strong and diffuse nuclear reactivity for WT-1. Pathologic Findings The left ovary has a bosselated appearance from the capsular aspects. It measures 8 X 4 X 2 cm and weighs 48 gm. An attached fallopian tube is identified. A smooth, glistening, brownish-tan to hemorrhagic capsular surface is noted, but it is also appreciated that a substantial portion of the ovary is cystic and hemorrhagic from the external aspects. Bisection reveals the presence of three mural nodules measuring from 2.2 to 3.5 cm in greatest dimension; these nodules have a brownish-red to tan appearance. Overall, there is a hemorrhagic quality to the entire mass consistent with the clinical impression of torsion. Microscopically, the nodules are composed of a relatively uniform, densely packed small tubules, cords, solid nests and cysts in a variably conspicuous edematous and hemorrhagic immature appearing stroma. The individual tumor cells are uniformly basophilic due to the dense nuclear chromatin and an inconspicuous rim of cytoplasm. Mitotic figures are sparing in number. Leydig cells are not identified within the interstitum or cellular profiles. Some foci have a mixed pattern of tubular structures associated with a spindle cell stroma having a resemblance to a cellular fibroma. Cystic areas are limited in extent, but some of these foci are associated with papillary profiles. A loosely cellular mesenchyme without obvious tumor has variably edematous appearance resembling massive edema of the ovary. Extensive areas are hemorrhagic where the tumor had undergone hemorrhagic necrosis. The tumor appears to be confined to the ovary and there is no evidence of capsular invasion or surface implants. Immunohistochemically, the tubular structures, cords and nests display uniform staining for cytokeratin and less intense reactivity for vimentin. These same structures are positive for inhibin, calretinin and the nuclei for WT-1. It is almost one year following the most recent surgery and the patient is doing well without evidence of recurrent or metastatic disease. The cystic lesions in the lung remain stable and the cysts in the left kidney are likely residual cystic nephroma. Discussion When this 5-year-old girl presented with acute abdominal pain and was discovered to have a mass in the left lower quadrant-pelvis, the perioperative impression favored a torsion of the left ovary. Though ovarian torsion in children is a relatively uncommon clinical event, it is estimated to be responsible for an acute surgical abdomen in 3% of females in the first two decades of life. A review of the experience of ovarian pathology resulting in an oophorectomy or cystectomy among 521 females between the ages of 0 and 20 years from the St. Louis Children's Hospital (SLCH), revealed that torsion with infarction of the ovary accounted for 11% of cases, exceeded only by mature teratomas (24% of cases) and non-neoplastic cysts (23%). Approximately 5% of the mature teratomas presented with torsion, but most of the torsion-infarctions did not have obvious underlying pathology which can be difficult to appreciate if there is extensive hemorrhagic infarction. Among the 59 cases of torsion-infarction (SLCH), 46% presented at or before one year of age, 20% between 2 and 11 years and 34% between 12 and 20 years. Underlying pathology in a torsed ovary may be seen in less than 50% of cases whereas it is appreciably higher in young adult to middle-aged women. Another perspective on our case is the topic of ovarian neoplasms in childhood and adolescence. Over the years, several series of ovarian tumors in this age group have appeared in the literature with similar experiences which not surprisingly contrasts with that seen in adult women beyond the age of 20 years where surface epithelial-mullerian tumors in the three pathologic categories of benign, borderline and malignant are the most common. If one restricts the discussion to the 20-40 year age group, the mature teratoma accounts for 65% to 70% of all primary ovarian neoplasms. Drawing upon the SLCH experience, neoplasms were diagnosed pathologically in 64% of all resected ovaries. In keeping with experience of others, germ cell neoplasms represented 51% of cases, surface epithelial-mullerian tumors in 28% and sex-cord stromal tumors in 14%. The tumors and the age groups at diagnosis are summarized in Table 1. Approximately 75% of all ovarian tumors are diagnosed between the ages of 12 and 20 years and 2% in infants one year old or less. Our patient is one of the 12 who were diagnosed with a sex-cord stromal tumor in the 2-11 age group. Mature and immature teratomas constituted almost 50% of ovarian tumors in the latter age group. Sex-cord stromal tumors (SCST) in children and adolescents represent the smallest category of primary ovarian neoplasms. In our series, the number of SCSTs is disproportionately larger when compared to other series since several of these cases were seen in consultation. The case under discussion is a patient who has been seen at the SLCH on several prior occasions to be discussed later. A more representative figure for SCSTs in children is 5% or so of primary ovarian neoplasms. The pathologic types of SCSTs from our series are summarized in Table 2 with almost 50% of cases diagnosed as granulosa cell tumors with the juvenile type as the single most common type of SCST. The single largest clinicopathologic series of 72 SCSTs in children is from the Kiel Pediatric Tumor Registry which reported the juvenile granulosa cell tumor as constituting 65% of cases followed by the Sertoli Leydig cell tumor (19% of cases). There were no examples of pure Sertoli cell tumors in the latter study. Since pure Sertoli cell tumors are so uncommon and especially so in children, there is some uncertainty about their clinical behavior except for the fact that this neoplasm has the potential for malignant behavior like several of the other SCSTs. In terms of the morphology, these tumors are recognized by the formation of tubulo-glandular and cystic structures which can mimic or suggest the possibility of a neuroendocrine, endometrioid, germinomatous or alveolar soft part neoplasm. A poorly differentiated or unclassified type of SCST may be considered in those cases with a more stromal appearance and poorly formed tubules. Oliva and associates have reported on the clinicopathologic features of 54 cases of ovarian Sertoli cell tumors which is seemingly the largest series of such cases. The youngest patient in this study was a 2-year-old and 7 (13%) of 54 patients were "prepubertal" at the time of diagnosis and six presented with isosexual pseudoprecocity. Most tumors had a solid, tan to yellow lobulated appearance on cut surface, but nine cases were cystic and solid like our case. Tubules with a resemblance to immature seminiferous tubules are arranged in lobular formations and represents the most common microscopic feature. If there is stromal separating the lobules, Leydig cells, if present, are found within a loose myxomatous mesenchyme to establish the tumor as a Sertoli Leydig cell tumor. The immunohistochemical phenotype of the Sertoli cell tumor is similar in most respects to the other SCSTs. These tumors are positive for vimentin, cytokeratin, CD99, calretinin and inhibin in 50% or more of cases. WT-1 is also a useful marker as it was in our case. If one is considering a neuroendocrine neoplasm, it should be noted that neuron specific enolase is expressed in about one-half of Sertoli cell tumors, but chromogranin is uniformly negative. Juvenile granulosa cell tumor, Sertoli-Leydig cell tumor and Sertoli cell tumor are neoplasms whose prognosis are determined to a great extent by the pathologic stage as documented by Schneider and associates in a pediatric population. Since the overwhelming majority of SCSTs in children are confined to the ovary and completely resectable, the overall survival is 90% or greater in most cases. However, extension beyond ovary into the pelvis is accompanied by a reduction of survival to 70% or less. To this point in our discussion, this case would seem to have offered us several pedagogical points on ovarian masses in childhood and the types of neoplasms presenting in the ovary of children. However, there is one more lesson which this case serves up. In the pediatric pathology slide seminar in 2004, Hill discussed the case of a five-month-old female who presented with fever and respiratory symptoms to suggest the diagnosis of influenza. Imaging studies at that time revealed a cyst in the left lower lobe which was thought to represent congenital cystic adenomatoid malformation. A lobectomy was performed. On pathologic examination, the filmy, multicystic structure was a cystic pleuropulmonary blastoma or type I PPB. Subsequent imaging studies revealed a cystic nephroma in the left kidney and additional cystic lesions in the right lung which were excised and proved to be type I PPBs. There was also a positive family history of childhood malignancies in the mother and a maternal cousin. This patient is the same little girl and is now the fourth child that we have seen with a previously diagnosed PPB who has developed an ovarian SCST, three Sertoli cell tumors and one Sertoli Leydig cell tumor. Family members of other children with PPBs have been reported with SCSTs, one of these the mother of a child with a PPB and SCST. Given the relative rarity of ovarian SCSTs in children, it is thought that this association with PPB is more than simply chance. Our patient is undoubtedly the proband in another family with the familial PPB predisposition syndrome (OMIM 601200). It is estimated that approximately 40% of children with PPB have a family history to suggest the presence of the syndrome. A summary of the various diseases associated with PPB has been recently compiled by Priest and associates. This child qualified shortly after her initial presentation with the development of multifocal PPBs and cystic nephroma. The latter is the most common extrapulmonary pathology found in these children. One final note relates to some of this specific syndromic settings of ovarian SCSTs which are well documented including the sex-cord stromal tumor with annular tubules in Peutz-Jeghers syndrome, fibromas in the basal cell nevus syndrome, juvenile granulosa cell tumor in Ollier disease and Maffuci syndrome and Sertoli cell tumor in Peutz-Jeghers syndrome and we propose in the familial PPB tumor predisposition syndrome. TABLE 1. OVARIAN NEOPLASMS AND AGE GROUP PRESENTATION* TUMOR TYPE 1 YR OR LESS 2-11 YRS 12-20 YRS Mature teratoma (124) 1 21 102 Benign serous tumor (49) - 7 42 Sex-cord stromal tumor (46) 4 12 30 Immature teratoma (29) - 12 17 Benign mucinous tumor (28) - 1 27 Miscellaneous tumors (19) 2 8 9 Borderline surface tumors (15) - - 15 Dysgerminoma (7) - 3 4 Malignant surface tumors (3) - 1 2 Tumorlike conditions (3) - - 3 Endodermal sinus tumors (2) - 1 1 Total 7(2%) 66(20%) 252(75%) From the Lauren V. Ackerman Laboratory of Surgical Pathology, Barnes-Jewish and St. Louis Children's Hospital, Washington University Medical Center, St. Louis, MO. TABLE 2. OVARIAN SEX-CORD STROMAL TUMORS (1989-2008)* TUMOR TYPE N % Granulosa cell tumor 22 47 Juvenile 15 (33)   Adult 7 (15)   Sertoli-Leydig cell tumor 9 20 Thecoma - fibroma 7 15 Sertoli cell tumor 5 11 Sclerosing stromal tumor 2 4 Unclassified type 1 3 Total 46 100 From the Lauren V. Ackerman Laboratory of Surgical Pathology, Barnes-Jewish and St. Louis Children's Hospital, Washington University Medical Center, St. Louis, MO. References: Aktas S, Yigits S, Diniz G, Pehlivan FS, Ortac R. Comparison of underlying lesions in pediatric and adult ovarian torsion. Saudi Med J 2006;27:1183-1186. Anders JF, Powell EC. Urgency of evaluation and outcome of acute ovarian torsion in pediatric patients. Arch Pediatr Adolesc Med 2005;159:532-535. Aziz D, Davis V, Allen L, Langer JC. Ovarian torsion in children: Is oophorectomy necessary? 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