Relevance of Molecular Pathology for the Diagnosis of Sex Cord-Stromal Tumors of the Ovary: A Narrative Review

Abstract

Ovarian sex cord-stromal tumors (SCSTs) account for 8% of all primary ovarian neo-plasms. Accurate diagnosis is crucial since each subtype has a specific prognostic and treatment. Apart from fibrosarcomas, stromal tumors are benign while sex cord tumors may recur, sometimes with a significant time to relapse. Although the diagnosis based on morphology is straightforward, in some cases the distinction between stromal tumors and sex cord tumors may be tricky. Indeed, the immunophenotype is usually nonspecific between stromal tumors and sex cord tumors. Therefore, molecular pathology plays an important role in the diagnosis of such entities, with pathognomonic or recurrent alterations, such as FOXL2 variants in adult granulosa cell tumors. In addition, these neoplasms may be associated with genetic syndromes, such as Peutz-Jeghers syndrome for sex cord tumors with annular tubules, and DICER1 syndrome for Sertoli-Leydig cell tumors (SLCTs), for which the pathologist may be in the front line of syndromic suspicion. Molecular pathology of SCST is also relevant for patient prognosis and management. For instance, the DICER1 variant is associated with moderately to poorly differentiated SLCTS and a poorer prognosis. The present review summarizes the histomolecular criteria useful for the diagnosis of SCST, using recent molecular data from the literature.

Keywords: DICER1; FOXL2; Sertoli–Leydig cell tumor; diagnostic algorithm; granulosa cell tumor; molecular diagnosis.

Figure 1

Histopathological illustrations of ovarian sex cord–stromal tumors classified into 5 groups according to predominant cell morphology. Group 1: predominance of fibromatous/thecomatous cells and/or stromal cells of unusual morphology (A–C [Hematoxylin-eosin-saffron (HES) ×400] and (D) [reticuline stain ×400]). Group 2: predominance of Leydig/steroid (E–G [HES, ×400]) or luteinized cells (H [HES, ×400]). Group 3: predominance of follicular cells (I [HES, ×400], J [HES, ×500], K [HES, ×400] and L [HES, ×350]). Group 4: predominance of Sertoli cells (M–P [HES, ×400]). Group 5: predominance of poorly differentiated sex cord cells (Q–S [HES, ×400] and T [reticulin stain, ×400]).

Figure 2

Main microscopic features of ovarian fibromas and thecomas (Group 1). (A) (hematoxylin-eosin-saffron [HES], ×40) and (B) (HES, ×400), classic fibroma composed of spindle-shaped cells, with scant cytoplasm, elongated or ovoid nuclei without atypia. (C) (HES, ×200), necrosis and hemorrhage remodeling. (D) (reticulin stain, ×400), dense monocellular reticulin fiber network. (E) (HES, ×400), cellular and mitotically active fibroma (yellow arrow: mitosis). (F) (HES, ×200) and (G) (reticulin stain, ×200), fibroma with minor sex cord element, highlighted by reticulin stain with nests/cords of sex cord elements. (H) (HES, ×40) and (I) (HES, ×400), thecoma composed of uniform, plump and round, or spindle-shaped cells with pale cytoplasm and indistinct cell membranes.

Figure 3

Diagnostic algorithm for Group 1 tumors with predominance of fibromatous/thecomatous cells. * A thecoma component is sometimes associated and usually expresses inhibin and calretinin more intensely than the fibroma component. AGCT: adult granulosa cell tumor; mut: mutation/variant; NOS: not otherwise specified; SLCT: Sertoli–Leydig cell tumor; WT: Wild type.

Figure 4

Main microscopic and immunohistochemical features of sclerosing stromal tumor (Group 1). (A) (hematoxylin-eosin-saffron [HES], ×20), pseudolobular pattern composed of cellular nodules separated by poorly cellular areas and thin-walled vessels with a hemangiopericytoma-like appearance. (B) (HES, ×40), solid/cellular areas may be misleading in a subset of cases. (C) (HES, ×200), the tumor is composed of a mix of epithelioid and spindle-shaped cells, alternating with hypocellular areas of fibrosis and sclerosis ((D), HES, ×80). (E) (HES, ×400), epithelioid cells (luteinized cells) may be predominant, with clear to eosinophilic vacuolated cytoplasm, and may show prominent luteinization. (F) (TFE3 immunohistochemistry, ×200), epithelioid cells (luteinized cells) show expression of TFE3.

Figure 5

Main microscopic and immunohistochemical features of signet ring cell tumors and microcystic stromal tumors (MCSTs, Group 1). (A) (hematoxylin-eosin-saffron [HES], ×40), signet ring cell tumor shows an admixture of fibromatous and signet ring cell areas, sometimes with edematous changes ((B), HES, ×80). (C) (HES, ×400), signet ring cells have a small, homogenous nuclei, eccentrically located, no to mild atypia, and an empty vacuole, sometimes with hyalin globules, which are degenerating erythrocytes phagocytized by the tumor cells ((D), HES, ×400). (E) (HES, ×160) and (F) (HES, ×400), in contrast, MCSTs exhibit a mix of microcystic, and solid areas composed of epithelioid tumor cells, and fibromatous areas. Cells may show an empty vacuole, resembling signet ring cell tumor ((G), HES, ×400); however, in most cases, tumor cells diffusely and intensely express β-catenin ((H), ×200) and CyclinD1 ((I), ×200).

Figure 6

Diagnostic algorithm to differentiate unusual morphological tumor of Group 1: signet ring cell tumor and Microcystic Stromal Tumor (MCST) with signet ring cell changes, according to recently published data [73]. In the case of predominant microcystic and/or follicle-like spaces, combined with intense and diffuse inhibin and calretinin expression, other sex cord tumors and FATWO must be ruled out. * In the case of signet ring cell tumor with diffuse β-catenin and CyclinD1 expression, a search for ACP of CTNNB1 variant may be necessary before concluding signet ring cell stromal tumor [73]. AGCT: Adult granulosa-cell tumor; EMA: Epithelial membrane antigen; FATWO: Female adnexial tumor of Wolfian origin; IHC: Immunohistochemistry; JGCT: Juvenile granulosa-cell tumor; SLCT: Sertoli Leydig-cell tumor.

Figure 7

Main microscopic features of Group 2 tumors: Steroid and luteinized cells. (A) (hematoxylin-eosin-saffron [HES], ×5), hilar location of a Leydig cell tumor. (B) (HES, ×100), Leydig cell tumor: diffuse cell growth. (C) (HES, ×400), clustering of nuclei, separated by eosinophilic nuclear-free areas. (D) (HES, ×400), Leydig cells with abundant eosinophilic cytoplasms and round nuclei with a central nucleolus. (E) (HES, ×200), eosinophilic fibrinoid material within vessel walls. (F) (HES, ×80), steroid cell tumor not otherwise specified (NOS) with diffuse and lobulated architecture. (G) (HES, ×400), tumor cells of a steroid cell tumor NOS, displaying abundant eosinophilic and granular cytoplasm, lipochrome pigment, round nuclei with a central nucleolus. (H) (HES, ×200), luteinized adult granulosa cell tumor, with diffuse architecture. (I) (HES, ×200), luteinized cells of a luteinized adult granulosa cell tumor, displaying abundant grey cytoplasm, as seen in some thecomas, with round nuclei that have lost typical granulosa cell nucleolus features.

Figure 8

Diagnostic algorithm for Group 2 tumors with a predominance of steroid/luteinized cells. * Rule out the luteinized thecoma associated with sclerosing peritonitis, which is almost always bilateral, with ascites, and bowel obstruction because of the sclerosing peritonitis, and for which the reticulin stain also surrounds the cluster of luteinized cells. ** In the absence of the FOXL2 variant, this diagnosis must be performed only if true sex cord or nest cells are visible on the reticulin stain, and after ruling out other neoplasms with luteinized cells, such as sclerosing stromal tumors and luteinized thecoma associated with sclerosing peritonitis. *** In the case of pregnancy or immediate post-partum. AGCT: Adult granulosa-cell tumor; JGCT: Juvenile granulosa-cell tumor; NOS: Not other specified.

Figure 9

Main microscopic features of Group 3 tumors: predominance of follicular cells. (A) (hematoxylin-eosin-saffron [HES], ×45) and (B) (HES, ×60), diffuse and insular architectures of adult granulosa cell tumor. (C) (HES, ×200), microfollicular with Call–Exner bodies of adult granulosa cell tumor. (D) (HES, ×40), cord/trabecular pattern of adult granulosa cell tumor. (E) (HES, ×80) and (F) (HES, ×30), macrofollicular pattern of adult granulosa cell tumor. (G) (HES, ×100), moire-silk pattern of adult granulosa cell tumor. (H) (HES, ×80), sarcomatoid pattern of adult granulosa cell tumor. (I) (HES, ×400), typical nuclear grooves of adult granulosa cell tumor. (J) (HES, ×30), juvenile granulosa cell tumor displays a diffuse, lobulated, and follicle-like architecture. (K) (HES, ×200) and (L) (HES, ×200), tumor cells have abundant eosinophilic cytoplasm, and round vesicular to hyperchromatic nucleus that typically lack the nuclear grooves observed in the adult granulosa cell tumor, with numerous mitoses (red arrows).

Figure 10

Main microscopic features of Pure Sertoli cell tumors and Sex cord tumors with annular tubules (SCTAT) and differential diagnoses (Group 4). (A) (hematoxylin-eosin-saffron [HES], ×80), Sertoli cell tumors are typically composed of hollow or solid tubules resembling prepubertal testicular tubules. (B) (HES, ×400), Sertoli cells have moderate amount of clear vacuolated lipid-rich to brightly eosinophilic cytoplasm, with small round nuclei with a central nucleolus without atypia, and a low mitotic count. (C) (HES, ×100) and (D) (HES, ×400), ovarian carcinoids may display insular, tubular, trabecular, and acinar architectures, with monomorphic cells composed of a centrally-located, round to oval nuclei, salt-and-pepper chromatin, and pink cytoplasm, resembling sex cord–stromal tumors. (E) (HES, ×100) and (F) (HES, ×400), some endometrioid carcinomas may show sex cord–stromal features characterized by nested and corded arrangements, and cells resembling sex cord tumor cells (e.g., Sertoli cells, adult granulosa cells). (G) (HES, ×100), SCTAT are composed of well-circumscribed round or complex nests of Sertoli cells, tubule-forming, that encircle hyaline basement membrane-like material with a round or oval shape. (H) (HES, ×400) and (I) (HES, ×400), tumor cells have abundant clear, lipid-rich, vacuolated to pale eosinophilic cytoplasms, with small round to oval nuclei, with single small nucleoli, but without atypia, and with a low mitotic count. (J) (HES, ×100), in SCTAT, areas of Sertoli tubules may be observed. (K) (HES, ×40) and (L) (HES, ×200), in SCTAT associated with Peutz–Jeghers syndrome, simple nests of Sertoli cells with are usually distributed within the ovarian fibromatous stroma, surrounding hyaline basement membrane-like material. (M) (HES, ×80) and (N) (HES, ×400), adult granulosa cell tumor with SCTAT-like features (abundant hyalinized basement membrane-like material within Call–Exner bodies). (O) (HES, ×400), gonadoblastoma are composed of sex cord component surrounding hyaline basement membrane-like material, mixed with a germ cell component.

Figure 11

Main microscopic features of Sertoli–Leydig cell tumors (SLCT; Group 4). (A) (hematoxylin-eosin-saffron [HES], ×200) and (B) (HES, ×120), well-differentiated SLCT. (C) (HES, ×100), moderately differentiated SLCT. (D) (HES, ×40) and (E) (HES, x200), poorly differentiated SLCT. (F) (HES, ×100), retiform component in a poorly differentiated SLCT. (G) (HES, ×100), heterologous element: benign intestinal type epithelium. (H) (HES, ×80), heterologous element: rhabdomyosarcoma. (I) (HES, ×400), heterologous element: carcinoid tumor.

Figure 12

Simplified diagnostic algorithm between sex cord tumors based on the main molecular alterations. * Recent data tend to separate well-differentiated SLCT as a distinct entity from other SLCT [6]. ** In the case of poorly differentiated sex cord tumor with FOXL2 and DICER1 WT status. *** Although other moderately/poorly differentiated neoplasms could belong to this category of FOXL2/DICER1 WT sex cord tumors (such as adult granulosa cell tumor FOXL2 WT, moderately/poorly differentiated SCLT DICER1 WT), some features are usually present (well-differentiated areas and “coffee bean” nuclei for adult granulosa tumor, Leydig cells and Sertoli tubes for SLCT), allowing the classification as adult granulosa cell tumor or moderately/poorly differentiated SLCT, respectively. Otherwise, the neoplasm must be classified as sex cord–stromal tumor NOS. NOS: Not otherwise specified; SCTAT: Sex cord tumor with annular tubules; SLCT: Sertoli–Leydig cell tumor; WT: Wild type.