Case 5 -

Retiform Sertoli-Leydig Cell Tumor Robert H.Young Professor of Pathology Director of Anatomic Pathology Massachusetts General Hospital Harvard Medical School Boston, Massachusetts, U.S.A.

Clinical History: A 20-year-old woman was found to have a 15 cm left ovarian mass. The tumor had a smooth external surface, and on sectioning was largely cystic, containing abundant, clear, watery fluid. A minor component of nodular tan neoplastic tissue was also present. The tumor was confined to the ovary. Case 5 - Figure 1 Click to view with ImageScope Click to view with a Web-Based Viewer Diagnosis: Retiform Sertoli-Leydig Cell Tumor Discussion: This neoplasm is of particular interest because of its tendency to occur in the young and its intriguing morphology [1, 2, 3]. They account for about 10% of Sertoli-Leydig cell tumors (SLCTs), they are less often androgenic than other variants, being so only about 20% of the time, and represent the commonest subtype in the first decade [4]. As androgenic manifestations tend to make the diagnosis of SLCT come to mind in a young person their absence and unusual morphology may lead to the diagnosis being overlooked. Retiform tumors are often soft and spongy, cystic with edematous intraluminal polypoid excrescences, or combinations thereof. They are so named because they are characterized microscopically by growth patterns that simulate those of the rete testis. Accordingly the basic pattern is an irregular network of elongated, sometimes slit-like tubules and cysts which often contain papillae. The papillae may be short and rounded or blunt, often containing hyalinized cores, or larger with fibrous or edematous cores. Cysts may be markedly dilated with eosinophilic secretion imparting a struma-like appearance in some cases. The tubules are usually lined by a single layer of cuboidal epithelial cells with round to oval nuclei although stratification is conspicuous in some cases. The cytoplasm is typically scanty and mitotic activity variable, but sometimes marked. Similar cells typically line the papillae and cysts, but large cysts may be lined by flattened cells. The stromal component varies from moderately cellular fibrous tissue (which is occasionally focally hyalinized) to markedly edematous (accounting for the soft, spongy consistency) to very cellular, immature mesenchymal tissue which may show heterologous differentiation as in seen in about 20% of all SLCTs [4]. Retiform SLCTs are misinterpreted most often as yolk sac tumor, a serous neoplasm or as a malignant mixed mesodermal tumor. Because of the young age of the patient and frequent papillae yolk sac tumor is often considered. The papillae in the retiform tumors do not have the central blood vessel of the classic papilla in a yolk sac tumor (the famed Schiller-Duval body), but rather are cellular (an uncommon features of the papillae in a yolk sac tumor) or are hyalinized, the latter to my knowledge never being a feature of the papillae of a yolk sac tumor. Like many ovarian tumors the retiform SLCT may contain hyaline bodies. Resemblance to a serous borderline tumor may be imparted by the presence of cellular papillary clusters in the cyst lumens. The clefts, papillae and a complex branching pattern associated with cellular stratification and atypicality may suggest a serous adenocarcinoma. The admixture of retiform tubules with immature mesenchymal tissue which may show heterologous differentiation can suggest the diagnosis of a malignant mixed mesodermal tumor. The presence in most cases of typical foci of SLCT, although sometimes very small in amount, and other clinical and pathologic features of the tumors should enable the diagnosis of a retiform SLCT to be established even in these cases and is also crucial in the various other differential considerations. One of the rarest of these considerations is when the retiform pattern is somewhat reminiscent of the neoplastic vascular channels of an angiosarcoma. If routine microscopy were not to be definitive immunohistochemistry could be called upon. A similar comment pertains to the differential with a Wilms' tumor. Any pattern of SLCT may co-exist with the retiform pattern but most typically the retiform foci merge with long, thick ribbons of immature cells consistent with Sertoli cells. When a tumor is entirely retiform, knowledge of the existence of this distinctive subtype of SLCT is essential to avoiding a serious diagnostic error. Rather than repeat what now should be well known other features of SLCTs and issues in their differential diagnosis I have elected to use this case to make some remarks about ovarian tumors in the young arbitrarily, but reasonably, defined as females up to 30 years of age. This general discussion will lead into case 6, itself one of the important tumors of the young. Although there are obviously exceptions, it is only when a woman is over 30 that she starts to progressively be at appreciable risk for most of the common ovarian neoplasms, both benign and malignant, in the surface epithelial-stromal category that represent such an issue in the middle and later years of life. Accordingly various tumors that are broadly speaking uncommon in the first three decades are commoner then than later and of course management decisions, dependent on current pathologic diagnosis, are particularly crucial in the young woman. There are marked differences in the frequency of ovarian neoplasms in the first three decades compared with later years and, to a lesser degree, within each of the first three decades. In these decades there is a much higher percentage of germ cell and sex cord-stromal tumors because of the lesser frequency of surface epithelial neoplasms and great rarity of metastatic tumors. This is borne out by the over 50 years experience at the Children's Hospital in Boston (even allowing for that consideration being only of the first two decades); 70% of the tumors were germ cell and 13% sex cord-stromal [5]. One-third of the germ cell tumors were in the primitive category, a much greater percentage than seen beyond 30 years. The surface epithelial tumors accounted for 16% of the neoplasms. Tumor-like lesions accounted for almost one-third of ovarian masses. This exceeds the figure for later years because of the relative high frequency of follicle cysts in the first two decades, which has two time periods, the neonatal and perimenarchal, when these lesions are common [6]. General Remarks Concerning the First Decade This decade has a unique aspect related to tumor-like lesions, namely, the contribution to the numbers of ovarian masses provided by the occurrence, just noted, of follicle cysts in the neonatal period as a response to maternal stimulation. Sixteen of the 76 tumor-like lesions in the Children's Hospital series were in this category [5]. These cysts are larger than follicle cysts seen later (except for those related to pregnancy), averaging 8.3 cm. in the Children's Hospital series. Their size makes them prone to torsion with significant symptomatology as a result. Follicle cysts are rare after the first six months and other tumor-like lesions are rare at any time in this decade. A corpus luteum cyst has also rarely occurred, in neonates [7]. Dermoid cysts are rare in the first two years of life but become progressively more common thereafter. Primitive germ cell tumors are seen but are much commoner in the next two decades. As an example, in the Children's Hospital Series, only one of 8 patients with dysgerminoma was in the first decade. Surface epithelial tumors of any type are exceptionally rare. Granulosa cell tumors, particularly of the juvenile type are seen occasionally, although it should be remembered that adult granulosa cell tumors are also seen in the young. SLCTs are seen occasionally and the retiform subtype accounts for a greater percentage than in any other decade except the second. Two, to date, unique, ovarian sex cord tumors associated with Peutz-Jeghers syndrome, each responsible for sexual precocity, occurred in the first decade [8]. The small cell carcinoma of hypercalcemic type is rare before 10 years. Within the family of sarcomas, as one might expect, the rhabdomyosarcomas of embryonal and alveolar type, particularly the former, which have a skew to young individuals in general, are seen occasionally in the first three decades. Of the thirteen ovarian rhabdomyosarcomas reported by Nielsen et al [9], one was in a 7-year old, one in a 10-year old, and one in a 14-year old. Three of the remaining patients were in their 20's. Two of the tumors were alveolar, the remainder, embryonal. One infantile hemangioendothelioma has been reported in a neonate [10] but vascular sarcomas become commoner in the third decade. One tumor with a predilection for children, the neuroblastoma, accounts for the majority of the rare cases of ovarian metastasis in children, and may be seen in the first decade [11]. General Remarks Concerning the Second Decade The second decade is noteworthy for the acceleration of the frequency of all the primitive germ cell tumors as shown by the average age of occurrence of all of them being circa 18 - 19 years. One rare but important monodermal teratoma, the primitive neuroectodermal tumor, is seen much more often in the second than in the first decade. The commoner monodermal tumors, struma ovarii and carcinoid, are uncommon in the first three decades. Surface epithelial tumors remain uncommon although measurably more frequent than in the first decade. Virtually the only cell types seen are serous and mucinous. In the Children's Hospital series serous slightly outnumbered mucinous. In our consultation material mucinous tumors are much more numerous. This is accounted for presumably by the fact that the serous tumors are almost always benign whether in the mucinous group, tumors in the borderline or low-grade carcinoma categories are encountered with some frequency and are more likely to provoke a consultative opinion. All surface epithelial carcinomas in teenagers are a great rarity. The small cell carcinoma of hypercalcemic type begins to be seen with an accelerated pace once children enter the second decade and this tumor is only somewhat less common in the second, compared to the third decade. Metastatic carcinomas which are virtually unheard of in the first decade are seen occasionally in the teenage years with well documented examples of Krukenberg tumor and even metastatic colonic carcinoma (we have seen one of the latter in a 12-year-old) being documented. Lymphoma and leukemia involving the ovary is occasionally seen in the second decade and even before having no great predilection for any of the first three decades. Ovarian involvement by the intra-abdominal desmoplastic small round cell tumor with divergent differentiation is commonest in the teenage years, the three original cases of this type reported by us being in the mid teens and subsequent experience has borne out a peak in this decade [12]. General Remarks Concerning the Third Decade One significant aspect of the third decade, particularly when compared to the prior two, is the appreciably greater frequency of surface epithelial tumors, particularly as the decade moves along. For example, serous borderline tumors, which are exceptionally rare before 20 are seen with some frequency in the third decade although the pace of occurrence accelerates even more after the age of 30. Of all tumors with any malignant potential in the surface epithelial category, serous borderline tumors and mucinous borderline tumors account for the majority encountered in the third decade. Mucinous carcinomas are occasionally seen, but less frequently than borderline tumors and serous carcinomas remain exceptionally rare. Indeed, the extent to which they are dwarfed by serous borderline tumors is worthy of comment and in this age group one should always favor a borderline tumor rather than serous carcinoma unless evidence for the latter is incontrovertible. Germ cell tumors of all types are seen with slightly greater frequency than in the second decade. The exception to that comment is secondary malignant change in teratomas, and monodermal teratomas, which remain rare until patients pass beyond 30 years. However, three of 19 cases of squamous cell carcinoma arising in dermoids reported by Pins et al [13] were in patients of 21, 25, and 30 years of age. One other patient in his series with a squamous cell carcinoma and associated endometriosis was a 29-year-old and another patient without an association with either a dermoid cyst or endometriosis was a 27-year-old. The third decade sees a peak in the frequency of SLCTs. Granulosa cell tumors of both adult and juvenile types continue to be seen with some frequency in this decade. Steroid cell tumors are also seen and even before; about 7% of these tumors occur in prepubertal girls [14]. Pure stromal tumors, except the sclerosing stromal tumor remain rare; the latter has an average age of 27 years and is commoner in the third decade than any other. The rare primary angiosarcoma of the ovary appears to be commonest in the third decade [15]. Ovarian Masses Discovered During Pregnancy As the era from menarche through the end of the third decade accounts for a significant component of the reproductive era in females, it is obvious that during this time, a number of ovarian neoplasms will be discovered in patients who are pregnant. Furthermore, pregnancy itself is responsible occasionally for the development of some specific tumor-like lesions. In this brief summary I will comment upon four issues, namely 1. Tumor-like lesions associated with pregnancy; 2. Alterations in sex cord stromal tumors due to pregnancy which may hinder their microscopic recognition; 3. Non-specific changes in ovarian neoplasms associated with pregnancy; and 4. Ovarian tumors with functioning stroma related to pregnancy. When a patient is known to be pregnant that a mass lesion of the ovary, either cystic or solid, might be non-neoplastic should always be considered assuming appropriate gross and microscopic findings. Otherwise completely benign lesions if misdiagnosed may result in overly aggressive treatment with unfortunate consequences upon future fertility and increased morbidity. Two lesions may mimic cystic neoplasms, hyperreactio lutealis (multiple luteinized follicle cysts) and the large solitary luteinized follicle cyst of pregnancy and the puerperium. It is helpful that the first lesion is bilateral in contrast to many cystic neoplasms that might be in the differential diagnosis and certainly when a frozen section is done on a cystic lesion of the ovaries from a pregnant patient, careful search for the distinctive features of follicle cysts and other changes of the intervening tissue that are seen in hyperreactio lutealis, such as edema, should be sought. When a massive unilocular smooth walled cyst is encountered in pregnancy, the large solitary follicle cyst should be considered. In contrast to most cystic granulosa cell tumors it has a lining of cells with copious eosinophilic cytoplasm and rather characteristically, focal bizarre nuclei. The solid tumor-like lesion of pregnancy is the pregnancy luteoma and it is a time honored adage that the diagnosis of steroid cell tumor should not be made in pregnancy unless a pregnancy luteoma has been ruled out. It is helpful in many cases that the pregnancy lutetoma is bilateral and multi-nodular, the nodules typically being beefy red in contrast to the yellow appearance of many steroid cell tumors, although should be acknowledged that some steroid cell tumors may be beefy and red. A well-known trap is the brisk mitotic activity of many pregnancy luteomas. The pregnancy luteoma has follicle like spaces much more often than a steroid cell tumor. The fourth tumor-like lesion is the incidentally discovered microscopic process known as granulosa cell tumorlets. They are unlikely to cause clinical mischief inasmuch even if they are considered erroneously neoplasms it would be tiny microscopic ones of no clinical consequence. As the early reproductive era sees a peak in incidence of SLCTs and the majority of juvenile granulosa cell tumors and a sizable number of adult granulosa cell tumors occur in this age range, it is obvious that occasional patients with one of these neoplasms will encountered while she is pregnant. A pitfall is that these neoplasms may show considerable intercellular edema, or be extensively luteinized, both features which may obscure their characteristic morphologic features and render them, on average, more difficult to diagnose than similar neoplasms encountered outside of the setting of pregnancy [16]. Perhaps the most specific trap is that the edema may produce a pattern which simulates, at least to some degree, the reticular pattern of yolk sac tumor and we have certainly seen cases of sex cord stromal tumors erroneously considered to be yolk sac tumors during pregnancy, for this reason. Although thorough sampling is important at any time, it is particularly so when evaluating a perplexing mass lesion from a pregnant patient because sometimes only minor areas will show diagnostic features of one or another form of sex cord stromal tumor, making it evident that that is the diagnosis. Any ovarian neoplasm from a pregnant patient is more likely to undergo hemorrhagic infaraction and rupture than outside the setting of pregnancy. This may result in a clinically dramatic presentation and also, because of the infarction, serves to make diagnostic foci often limited and is a further contribution to diagnostic difficulty. Finally, yet another mischievous feature of ovarian tumors in pregnancy is their much greater tendency to exhibit stromal luteinization, which is often striking, and may be associated with dramatic androgenic manifestations. This may result in a clinician being convinced the patient has the most well-known androgenic neoplasm of young females, the Sertoli-Leydig cell tumor, rather than in reality potentially a variety of other neoplasms such as a tubular Krukenberg tumor (see Case 8). At the end of the references specifically cited in case 6 (the second distinctive lesion of the young I am discussing) I have listed a selection of references covering ovarian lesions in the young which the reader may find helpful to have available. References Young RH, Scully RE. Ovarian Sertoli-Leydig cell tumors with a retiform pattern: A problem in histopathologic diagnosis. A report of 25 cases. Am J Surg Pathol 7:755-771, 1983. Roth LM, Slayton RE, Brady LW, Blessing JA, Johnson G. Retiform differentiation in ovarian Sertoli-Leydig cell tumors. A clinicopathologic study of six cases from a gynecologic oncology group study. Cancer 55:1093-1098, 1985. Talerman A. Ovarian Sertoli-Leydig cell tumor (androblastoma) with retiform pattern. A clinicopathologic study. Cancer 60:3056-3064, 1989. Young RH, Scully RE. Ovarian Sertoli-Leydig cell tumors. A clinicopathological anaylsis of 207 cases. Am J Surg Pathol 9:543-569, 1985. Lack EE, Goldstein DP. Primary ovarian tumors in childhood and adolescence. Current Problems in Obstetrics and Gynecology 7:4-90, 1984. Lack EE, Young RH, Scully RE. Pathology of ovarian neoplasms in childhood and adolescence. Pathol Annu 27(pt.2): 281-356, 1992. Miles PA, Penney LL. Corpus luteum formation in the fetus. Obstet Gynecol 61:525-529, 1983. Young RH, Dickersin GR, Scully RE. A distinctive ovarian sex cord-stromal tumor causing sexual precocity in the Peutz-Jeghers syndrome. Am J Surg Pathol 7:233-243, 1983. Nielsen GP, Oliva E, Young RH, Rosenberg AE, Prat, J, Scully RE. Primary ovarian rhabdomyosarcoma: A report of 13 cases. Int J Gynecol Pathol 17:113-119, 1998. Prus D, Rosenberg AE, Blumenfeld A, Udassin R, Ne'eman Z, Young RH, Ariel I. Infantile hemangioendothelioma of the ovary: a monodermal teratoma or a neoplasm of ovarian somatic cells? Am J Surg Pathol 21:1231-1235, 1997. Young RH, Kozakewich HPW, Scully RE. Metastatic ovarian tumors in children: A report of 14 cases and review of the literature. Int J Gynecol Pathol 12:8-19, 1993. Young RH, Eichhorn JH, Dickersin GR, Scully RE. Ovarian involvement by the intra-abdominal desmoplastic small round cell tumor with divergent differentiation. A report of three cases. Hum Pathol 23:454-464, 1992. Pins, MR, Young RH, Daly WJ, Scully RE. Primary squamous cell carcinoma of the ovary. Report of 37 cases. Am J Surg Pathol 20:823-833, 1996. Hayes MC, Scully RE. Ovarian steroid cell tumor, not otherwise specified. A clinicopathologic analysis of 63 cases. Am J Surg Pathol 11:835-845, 1987. Nielsen GP, Young RH, Prat J, Scully, RE. Primary Angiosarcoma of the Ovary. A report of seven cases and review of the literature. Int J Gynecol Pathol 16:378-382, 1997. Young RH, Dudley AG, Scully RE. Granulosa cell, Sertoli-Leydig cell and unclassified sex cord-stromal tumors associated with pregnancy: a clinicopathological analysis of thirty-six cases. Gynecol Oncol 18:181-205, 1984.