Small Cell Carcinoma of Ovary, Hypercalcemic Type Robert H.Young Professor of Pathology Director of Anatomic Pathology Massachusetts General Hospital Harvard Medical School Boston, Massachusetts, U.S.A.

Clinical History: A 19-year-old woman with abdominal swelling was found at laparotomy to have a 17 cm left ovarian mass with multiple foci of tumor involving the peritoneal surfaces. The ovarian tumor was predominantly solid and white with some cystic foci. Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer Diagnosis: Small Cell Carcinoma of Ovary, Hypercalcemic Type Discussion: This distinctive ovarian cancer is the most common form of undifferentiated ovarian carcinoma in women under 40 years of age. It was recognized by Dr. Scully in the early 1970's and first presented in detail by him in his first fascicle and in 1982 "officially" described [1]. It was the unusual occurrence in young women of a small cell undifferentiated carcinoma that was associated with paraneoplastic hypercalcemia that led it to being recognized as a distinct entity. Most undifferentiated carcinomas of the ovary are large cell tumors that occur in the usual older age group of patients with typical ovarian cancer. They are also almost never associated with hypercalcemia. The patients with the hypercalcemic tumor have ranged from 14 months to 43 (mean, 24} years of age [2, 3]. Most patients present with signs and symptoms related to an abdominal or pelvic mass, but rarely the clinical presentation is related to the hypercalcemia. Occasional familial cases have been encountered, the most dramatic example being its occurrence in three sisters. In the largest series in the literature the stage of the tumor was IA in 33%, 1B in 1%, 1C in 16%, stage II in 5%, stage III in 43%, and stage IV in 1%. This carcinoma has a dismal prognosis. The overall survival rate is approximately 16%; the corresponding figures are 33% for Stage 1A tumors and 7% for tumors >stage IA [2]. Favorable prognostic factors in the largest study included an age >30 years, a normal preoperative serum calcium, bilateral oophorectomy, tumors <10 cm, no large cell component, and the administration of adjuvant radiotherapy The tumors are almost always unilateral, usually large, solid, soft and white. This appearance is similar to that of dysgerminoma, which treacherously also can cause hypercalcemia [4] and lymphoma, and may contribute to the confusion with these neoplasms that occasionally arises as considered below. Necrosis and hemorrhage are conspicuous in many examples. Cystic degeneration is quite common and a rare neoplasm is predominantly cystic. On microscopic examination, the most common pattern is a more or less diffuse arrangement of small, closely packed cells with scant cytoplasm but evidence of their epithelial nature is provided by the focal presence of small nests, cords, and clusters of cells. An important feature that is seen in about 80% of the tumors is follicles that vary from small to large but are more often the latter. They are usually round to oval and with rare exceptions contain eosinophilic, rather than basophilic, fluid. A non-specific paucicellular fibrous stroma is usually present but rarely prominent. It is irregularly distributed and with possible rare exceptions does not resemble the delicate fibrous septa of a tumor in the differential (largely due to the similar age distribution), the dysgerminoma. Inflammatory cells may be seen in the small cell carcinoma, but do not have the same tendency to be sprinkled along the fibrous bands of stroma as is seen with the dysgerminoma. Occasionally the tumor cells are spindle shaped and a focal sarcomatoid morphology results but the differential with a spindle cell neoplasm has not been an issue in our experience to date. The tumor cells typically have scantly cytoplasm and small nuclei containing single nucleoli that are usually not striking and, despite the aggressive nature of this tumor, are relatively monotonous in appearance with the exception noted below. Rarely some cells have clear cytoplasm. Mitotic figures are numerous. Two main variant features may be seen which complicate the interpretation in many cases. The commonest of these is the presence in about half of the cases of a component of large cells with abundant eosinophilic cytoplasm, a pattern for convenience referred to as the "large cell variant." This pattern is quite distinctive in some cases because of the frequent presence of a prominent stroma which often is myxoid but may be pale and edematous. When the stroma of either of these types is prominent clusters of cells may "float" in it or there may be a vaguely reticular pattern. The large cells may have eccentric nuclei and dense globular cytoplasm. Nucleoli are usually more prominent in foci of the large cell variant and indeed are often conspicuous. The second variant finding is the intriguing finding in about 10% of these tumors of minor foci of mucinous epithelium that typically stands out sharply from the background sea of small cells. Occasionally, however, the mucinous epithelium is less conspicuous and more cytologically atypical, and may merge with the small cells. Rarely signet-ring type cells are even seen. Electron microscopical examination has failed to reveal any specific features to identify the cell type of the tumor. McMahon and Hart [5] found the most consistent and striking finding to be the presence of abundant dilated rough endoplasmic reticulum, forming large vesicles filled with homogeneous, granular (proteinaceous) material of variable density. They considered these ultrastructural features to be of diagnostic value in the differential diagnosis of this tumor. Ultrastructural examination in some cases has shown numerous whorls of microfilaments to account for the occasional globular cytoplasm. Immunohistochemical studies have also not helped identify the cell of origin but have simply confirmed an epithelial nature [6, 7, 8], the word epithelial being used in the broad sense without any implication that the tumors are of surface epithelial lineage. Evidence for a sex cord derivation is lacking, but it is not disproven either. This tumor is often confused with a granulosa cell tumor, sometimes the adult type but in other cases the juvenile type. With regard to the distinction from the adult form of granulosa cell tumor, which is not that rare in the young [9], it is crucial to be aware that although the cells of these tumors are essentially the same size these are important architectural and cytologic differences. Although nests and cords may be seen in the small cell carcinoma they do not have the more orderly growth of the much less malignant granulosa cell tumor. The cellular fibrothecomatous stroma of many granulosa cell tumors is not seen in the small cell carcinoma. From the cytologic viewpoint the cells of the small cell carcinoma do not have the characteristic pale grooved nuclei of the adult granulosa cell tumor and the mitotic rate in the small cell carcinoma far exceeds that encountered in adult granulosa cell tumors, albeit some of the latter can be briskly mitotic. Distinction from the juvenile form of granulosa cell tumor [10] is generally easy because the cells of the small cell carcinoma usually lack the abundant eosinophilic cytoplasm that is an almost invariable feature of the cells of the juvenile granulosa cell tumor. Even in cases of small cell carcinoma in which there are cells with abundant eosinophilic cytoplasm, distinction can usually be made because such cells are most often a focal finding and, in addition, they differ in appearance from the cells of the juvenile granulosa cell tumor, because of the dense, sometimes globular cytoplasm; the cells in a JGCT rarely have this appearance. When they do it is helpful that in cases of small cell carcinoma containing cells with abundant cytoplasm, there is generally a more disorderly architecture than seen in the juvenile granulosa cell tumor. Finally, with regard to distinction from both forms of granulosa cell tumor, it is often helpful that the small cell carcinoma has spread beyond the ovary at presentation, something which would be unusual for either variant of granulosa cell tumor. Because their peak frequency is at about the same time, they may be grossly indistinguishable, and both may cause hypercalcemia, the dysgerminoma and small cell carcinoma have sometimes been confused as noted earlier. It is rarely further confusing that dysgerminomas, like seminomas, may contain degenerative spaces which if rounded may suggest the follicles of the small cell carcinomas particularly if the dysgerminoma treacherously is one in which poor fixation or degenerative changes have resulted in small cells with apparently scan cytoplasm. A number of features should help distinguish these tumors even in these rare particularly tricky examples, it being worth noting that in the usual case confusion of the tumors should not be an issue. Although the small cell carcinoma may have a prominent fibrous stroma it differs in quality generally from the delicate fibrous septa of the dysgerminoma and although, like any tumor, there may be some non-specific inflammatory cell infiltrate, the classic lymphocytic infiltrate that tends to hug the septa, typical of dysgerminoma, is lacking in the small cell carcinoma. The clear cytoplasm of almost all cells in most well-fixed dysgerminomas is not a feature of the small cell carcinoma which rarely, and only focally in our experience, has cells with clear cytoplasm. The squared-off nuclei of dysgerminoma are not seen in the small cell carcinoma, although this feature, and others for that matter, are not as overt in cases of dysgerminoma that are poorly preserved. If necessary, the typical immunostaining profile of dysgerminoma for placental-like alkaline phosphatase and OCT 3/4 will be helpful [11]. The differential diagnosis of the small cell carcinoma is also with other small cell malignant tumors that may involve the ovaries. This issue has been considered in detail elsewhere [12, 13]. References Dickersin GR, Kline IW, Scully RE. Small cell carcinoma of the ovary with hypercalcemia. A report of 11 cases. Cancer 49:188-197, 1982. Young RH, Oliva E, Scully RE. Small cell carcinoma of the ovary, hypercalcemic type: A clinicopathologic analysis of 150 cases. Am J Surg Pathol 18:1102-1116, 1994. Florell SC, Bruggers CS, Matlak M, Young RH, Lowichik A. Ovarian small cell carcinoma of the hypercalcemic type in a 14-month-old: The youngest reported case. Med Pediatr Onc 32:304-307, 1999. Fleischhacker DS, Young RH. Dysgerminoma of the ovary associated with hypercalcemia. Gynecol Oncol 52:87-90, 1994. McMahon JT, Hart WR. Ultrastructural analysis of small cell carcinoma of the ovary. Am J Clin Pathol 90:523-529, 1988. Aguirre P, Thor AD, Scully RE. Ovarian small cell carcinoma - Histogenetic considerations based on immunohistochemical and other findings. Am J Clin Pathol 92:140-149, 1989. Riopel MA, Perlman PJ, Seidman JD, et al. Inhibin and epithelial membrane antigen immunohistochemistry assist in the diagnosis of sex cord-stromal tumors and provide clues to the histogenesis of hypercalcemic small cell carcinomas. Int J Gynecol Pathol 17:46-53, 1998. McCluggage WG, Oliva E, Connolly LE, McBride, HA, Young RH. An immunohistochemical analysis of ovarian small cell carcinoma of hypercalcemic type. Int J of Gynecol Pathol 23:330-336, 2004. Zaloudek C, Norris HJ. Granulosa tumors of the ovary in children. A clinical and pathologic study of 32 cases. Am J Surg Pathol 6:503-512, 1982. Young RH, Dickersin GR, Scully RE. Juvenile granulosa cell tumor. A clinicopathological analysis of 125 cases. Am J Surg Pathol 8:575-596, 1984. McCluggage, WG, Young RH. Immunohistochemistry as a diagnostic aid in the evaluation of ovarian tumors. Semin Diagn Pathol 22:3-32, 2005. Young RH, Scully RE. Malignant melanoma metastatic to the ovary: A clinicopathologic analysis of 20 cases. Am J Surg Pathol 15:849-860, 1991. Young RH, Scully RE. Alveolar rhabdomyosarcoma metastatic to the ovary. A report of two cases and discussion of the differential diagnosis of small cell malignant tumors of the ovary. Cancer 64:899-904, 1989. Additional References on Ovarian Tumors in the Young Abell MR, Johnson VJ, Holtz F. Ovarian neoplasms in childhood and adolescence. I. Tumors of germ cell origin. Am J Obstet Gynecol 92:1059-1081, 1965. Adelman S, Benson CD, hertzler JH. Surgical lesions of the ovary in infancy and childhood. Surg Gynecol Obstet 141:219, 1975. Bower, RJ, Adkins JC. Surgical ovarian lesions in children. Ann Surg 47:474, 1981. Breen JL, Maxson WS. Ovarian tumors in children and adolescents. Clin Obstet Gynecol 20:607-623, 1977. Breen JL, Neubecker RD. Ovarian malignancy in children, with special reference to the germ-cell tumors. Ann NY Acad Sci 142:658, 1967. Ehren IM, Mahour G, Isaacs J Jr. Benign and malignant ovarian tumors in children and adolescents. A review of 63 cases. Am J Surg 147:339, 1984. Groeber WR. Ovarian tumors during infancy and childhood. Am J Obst Gynecol 86:1027-1035, 1963. Jereb B, Golouh R, Havlicek S. Ovarian cancer in children and adolescents: A review of 15 cases. Med Pediatr Oncol 3:339, 1977. Junaid JA. Ovarian neoplasms in children and adolescents in Ibadan, Nigeria. Cancer 47:610-614, 1981. Granulosa theca cell tumors in premenarchal girls. A clinical and pathologic study of ten cases. Cancer 48:1846-1854, 1981. La Vecchia C, Morris HB, Draper GJ. Malignant ovarian tumours in childhood in Britain, 1962-78 Br J Cancer 48:363, 1983. Li FP, Fraumeni JR Jr, Dalager N. Ovarian cancers in the young. Epidemiologic observations. Cancer 32:969-972, 1973. Lindfors O. Primary ovarian neoplasms in infants and children. A study of 81 cases diagnosed in Finland and Sweden. Ann Chir Cynaecol Fin. 177:1, 1971. Lucraft HH. Ovarian tumours in children--A review of 40 cases. Clin Radiol 30:279, 1979. Mahour GH, Woolley MM, Landing BH. Ovarian teratomas in children. A thirty-three-year experience. Am J Surg 132:587-589, 1976. Moore JG, Schifrin BS, Erez S. Ovarian tumors in infancy, childhood and adolescence. Am J Obst Gynecol 99:913-922, 1967. Norris HJ, Jensen RD. Relative frequency of ovarian neoplasms in children and adolescents. Cancer. 30:713-719, 1972. Shawis RN, Gohary AEL, Cook RCM. Ovarian cysts and tumours in infancy and childhood. Ann Royal Coll Surg Engl 67:17, 1985. Szamborski JJ. Ovarian tumors in childhood and adolescence. Histological types and malignancy with reference to the age and menstrual activity of patients. Neoplasma. 25:493, 1978. Thompson JP, Dockerty MB, Symmonds RE, Hayles AB. Ovarian and paraovarian tumors in infants and children. Am J Obstet Gynecol 97:1059, 1967. Towne BH, Mahour GH, Woolley MM. Issacs H Jr. Ovarian cysts and tumors in infancy and childhood. J Pediatr Surg 10:311-320, 19