An Immunohistochemical Analysis of Ovarian Small Cell Carcinoma of Hypercalcemic Type

Abstract

Ovarian small cell carcinoma of hypercalcemic type (OSCCHT) is a rare neoplasm with an aggressive behavior, broad differential diagnosis, and unknown histogenesis. To add to knowledge concerning the possible aid of immunohistochemistry in resolving problems in differential diagnosis and to further explore whether that modality points to any specific histogenesis, we undertook an immunohistochemical study of this neoplasm. Fifteen OSCCHTs (including four of the ''large cell" variant) were stained with a range of antibodies, some of which have not been investigated previously in this neoplasm. Cases were stained with AE1/3, EMA, BerEP4, CK5/6, calretinin, WT1, chromogranin, CD56, synaptophysin, CD99, NB84, desmin, S100, CD10, alpha inhibin, TTFI, and p53. Staining was classified as 0 (negative), 1+ (<5% cells positive), 2+ (5% to 25% cells positive), 3+ (26% to 50% cells positive), or 4+ (>50% cells positive). All cases were positive with p53 (two 1+, five 3+, eight 4+), 14 of 15 cases were positive with WT1 (one 1+, thirteen 4+), 14 of 15 with CD10 (three 1+, four 2+, two 3+, five 4+), 13 of 15 with EMA (three 1+, three 2+, two 3+, five 4+), 11 of 15 with calretinin (nine 1+, one 3+, one 4+), 9 of 15 with AE1/3 (eight 1+, one 2+), 4 of 15 with CD56 (one 1+, two 2+, one 4+), 3 of 15 with BerEP4 (two 2+, one 4+), 2 of 15 with synaptophysin (two 1+), and 1 of 15 with S100 (4+). All cases were negative with CK5/6, chromogranin, CD99, NB84, desmin, alpha inhibin, and TTF1. The only noticeable difference in the immunophenotype between typical OSCCHT and the large cell variant was that there was 4 +EMA positivity in three of four cases of large cell variant compared with two of 11 cases of typical OSCCHT. OSCCHT is characteristically positive with AE1/3, EMA, CD10, calretinin, WT1, and p53. Combined EMA and WT1 positivity, the latter usually intense and diffuse, may be of diagnostic value, inasmuch as only a few of the neoplasms in the differential diagnosis are positive with both antibodies. Negative staining with CD99, desmin, NB84, alpha-inhibin, and TTF1 may aid in the cases in which primitive neuroectodermal tumor, rhabdomyosarcoma, intraabdominal desmoplastic small round cell tumor, neuroblastoma, a sex cord-stromal tumor, and metastatic pulmonary small cell carcinoma are in the differential. Calretinin positivity precludes its use in the differential with granulosa cell tumors. The results of this investigation do not settle the issue of histogenesis, which remains enigmatic. The typical age distribution, follicle formation, and calretinin positivity are consistent with a sex cord origin. On the other hand, WT1 and EMA positivity and negative staining with alpha-inhibin would be unusual in a sex cord-stromal neoplasm and can be used as an argument for a surface epithelial origin. Germ cell and neuroendocrine origins seem highly unlikely.

The Utility of Immunohistochemistry in the Differential Diagnosis of Gynecologic Disorders

“…212 Commonly, SCCHT is positive for p53, WT1, CD10, EMA, CK(AE1/AE3), and calretinin, and negative for CK5/6, inhibin, S100, CD99, TTF-1, and chromogranin. 213,214 Inhibin-positive and EMA-negative staining of a densely cellular tumor with scant cytoplasm distinguishes granulosa cell tumor from SCCHT. WT1 and calretinin cannot be used as differentiating markers owing to their positivity in both tumors.…”

Dose-dense and dose-intense chemotherapy for small cell ovarian cancer: 2 cases and review of literature

“…Since the report by Dickersin et al in 1982 [7], numerous case reports and case series have been published on this rare condition [1,8,9]. Apart from the two widely recognised types, namely hypercalcaemic type (SCCOHT) and pulmonary type (SCCOPT), there are other similar conditions within the spectrum of disease including large-cell variant of Small Cell Neuroendocrine Carcinoma and Primary Carcinoid of the ovary [10].…”

“…The ovarian small cell tumours of pulmonary type (SCCOPT) are more likely to occur in slightly older women of peri-menopausal or post-menopausal age with peak incidence at 50-60 years [1,11,12,25]. Differential diagnosis includes other tumours with a small round cell pattern, such as granulosa cell and undifferentiated sex cord tumours, lymphomas, primary neuroectodermal tumours and dysgerminomas [10]. In younger women, germ-cell tumours are ruled out by testing the relevant tumour markers (AFP, beta-HCG, LDH, CEA and NSE).…”

“…After a staging scan, early cases are managed with staging procedures including laparotomy as for epithelial ovarian cancers; and occasionally an unexpected diagnosis of SCCO is made at histology. However, in cases of extensive disease in a younger woman with an atypical pattern of metastasis, small cell carcinoma should be considered [1,3,[6][7][8][9][10][11][14][15][16]. More recently, PET-CT imaging may have a role in highly selected patients to take advantage of the aggressive metabolic pattern [28,29].…”

“…The histological pattern of SCCOHT is poorly differentiated small cells with densely hyperchromatic nuclei and scanty cytoplasm. Confusion with juvenile granulosa cell tumours can occur [10]. Attempts to stain for PTH (parathyroid hormone) are usually unsuccessful but PTHRP has been shown in some cases [1,13].…”