Path. Res. Pract. 187, 348-352 (1991)
Bilateral Stromal Leydig Cell Tumour of the Ovary Case Report and Literature Review J. Bohm, M. Roder-Weber and H. Hofler Institute of Pathology, Technical University of Munich, School of Medicine, Munich, FRG
M. Kolben Institute of Gynecology and Obstetrics, Technical University of Munich, School of Medicine, Munich, FRG
SUMMARY
The stromal Leydig cell tumour of the ovary is a very rare benign neoplasm which usually occurs in postmenopausal women. Due to a significant production of androgens by the tumour, it is frequently associated with symptoms of virilization. To our knowledge only 7 cases have been reported in the literature, one of them with bilateral manifestation. We report an additional case affecting both ovaries in a 59-year-old nun with long-standing virilism, review the literature, and discuss the histomorphological features for differential diagnosis.
Introduction The stromal Leydig cell tumour of the ovary (SLCT) belongs to the thecoma-fibroma group of ovarian tumours 2,12. It is composed of a neoplastic theca cell proliferation with interspersed clusters of steroid-type cells. The presence of crystalloids of Reinke within the latter identifies them as Leydig cells 7 • Ovarian stromal cells most likely have the capacity to differentiate into Leydig cells 7, especially in association with stromal hyperplasia. Fox2 prefers the term "Leydig cell-containing thecoma" instead of "stromal Leydig cell tumour" to emphasize the essentially thecomatous nature. The intention of this report is to describe an additional case of this rare neoplasm, review the literature, and consider the histomorphological features for differential diagnosis. 0344-0338/9110187-0348 $3.5010
Case report In the present case a 59-year-old nun (nulligravida) was hospitalized to discover the reason for a hirsutism that had been developing for some 30 years (Fig. 1). On admission, the patient presented with signs of virilization, such as a beard which required shaving twice a day, masculine alopecia, a male distribution of pubic hair and a markedly enlarged clitoris. There was no deepening of her voice; no pelvic mass was palpable. Gynecological anamnesis revealed that the patient had suffered from menstrual disorders with oligomenorrhoe. In 1969 she had undergone a hysterectomy and uterine myomas had been found. Pre-operative laboratory tests showed increased blood levels of testosterone and decreased levels of sexual hormone binding globulin (SHBG), both consistent with considerable hyperandrogenemia. The blood levels of the © 1991 by Gustav Fischer Verlag, Stuttgart
Stromal Leydig Cell Tumour·
349
Fig. 1. Aspect of the patient. Note beard and masculine alopecia.
gonadotropins LH and FSH, and of estradiol were within normal limits (Table 1). Serum tumour markers CA 19-9 and CA 12-5 were not increased. The existence of a tumour of the adrenal glands was excluded clinically by computed tomography, sonography and dexamethasone inhibition test. A bilateral salpingo-oophorectomy was performed. When the patient left hospital two weeks after the operation, the blood level of testosterone had normalized (0.5 nmol/i). Morphological Findings On gross examination, the ovaries were enlarged compared to the normal size in postmenopausal women. The right ovary measured 5 em in greatest diameter, the left
Table 1. Blood plasma levels : Blood plasma levels of testosterone, sexual hormone binding globulin (SHBG), FSH, LH and estradiol showing the patient's preoperative levels (PAT), and normal levels usually found in postmenopausal women (NOR) Hormone
PAT
NOR
Units
Testosterone SHBG FSH LH Estradiol
6.1 23 47 10 < 37
< 2.4 30- 90 35-131 11- 61 37-100
nmoUl [lmolll UII UII pmolll
Fig. 2. Cut surface of the ovaries with solid areas of mostly diffusely arranged tumourous tissue in the cortex and medulla of both ovaries.
ovary 4 cm. Both ovaries were of firm consistence and had a slightly irregular cortical surface. On cut section, solid areas of diffusely arranged light-brown tissue could be seen in the ovarian parenchyma of the cortex and of the medulla (Fig. 2). The fallopian tubes measured 5 cm in length and were without pathological findings. Histologically, the neoplastic tissue consisted of a mostly diffuse, partly nodular stromal proliferation of theca cells with spindle-shaped or round nuclei embedded in varying amounts of collagen fibrils, with focal fibrosis and hyalinization. Reticulum stain showed a dense pericellular reticulum pattern. Numerous small clusters and nests of steroid-type cells were interspersed within this thecal proliferation. The steroid-type cells showed rather uniform central nuclei with a prominent nucleolus and abundant eosinophilic, sometimes pale and vacuolated cytoplasm. These cells contained rare but distinct crystalloids of Reinke (Fig. 3). Sudan-III-staining showed varying amounts of lipids in both kinds of tumour cells with some lipid-rich foci (Fig. 4). Neither the thecomatous nor the
350 .
J. Bbhm et al.
Fig. 3. Nests of steroid-type cells (broad arrows) in a thecomatous background (H & E, X 122). Inset: Steroid-type cell containing a crystalloid of Reinke (thin arrow; H & E, x 308).
Fig. 4. Foci of lipid-containing cells in the SLCT (Sudan III, x 122).
steroid-type cell components of the tumour showed mitotic activity or cellular atypia. Beyond the mostly ill-defined margins of the neoplastic stromal proliferation, the remaining ovarian parenchyma showed some small inclusion cysts. The ovarian hilus had foci of hyperplastic hilus cells but was not involved by the tumour.
tumours 7 • In two cases, however, endometrial proliferations indicating hyperestrogenism were found13. As recent immunohistochemical studies of ovarian steroidogenesis have shown, androgen-producing stromal tumours may show estrogenic effects as a result of enzymatic conversion outside the tumourous tissue 6 • Results of hormonal blood level measurements in SLCTs have not been reported previously in the literature. In the present case the testosterone blood levels showed a rapid decrease after extirpation of the ovaries. Macroscopically, SLCTs form solid lobulated masses developing in both the cortex and the medulla, reaching up to 12 cm in greatest diameter. Sectioning reveals firm multinodular yellow-tan or white tumourous tissue embedded in the surrounding ovarian parenchyma 3, 7, 13. Microscopically, SLCTs are characterized by clusters of Leydig cells containing crystalloids of Reinke within hyperplastic thecomatous tissue 3, 7, 13. The histologic appearance without any cellular atypia or mitotic activity, and the clinical course indicate that SLCTs are benign tumours. No case of SLCT reported in the literature has
Discussion SLCTs are thought to originate from stromal cells which are able to differentiate into Leydig cells, in a background of stromal hyperplasia 4, 7,13. At present 7 cases of this entity have been reported in literature3, 7, 13, one of them with bilateral manifestation 7• The case of SCLT reported here represents the second observation in which both ovaries were involved. Except for one case reported in a IS-year-old pregnant girl3, all the SLCTs described so far occurred in 52- to-68-year-old postmenopausal women. The majority of the patients showed symptoms of virilization, suggesting that SLCTs are androgen-producing
Stromal Leydig Cell Tumour· 351 Table 2. Differential diagnoses: Stromal Leydig cell tumour versus other ovarian stromal neoplasms. The parameters are: content of Leydig cells, content of a tumourous stromal component, predominant age distribution, hormonal activity and biological behaviour. "Leydig cell tumours" include Leydig cell tumour of non-hilar type as well as hilus cell tumour 1,4,5,11,12 Tumour
Leydig cells
Stromal component
Age distribution
Hormonal activity
Stromal Leydig cell tumour
+
+
postmenopausal
usually androgenic benign
Leydig cell tumours
+
postmenopausal
75% androgenic
benign
Sertoli-Leydig cell tumour
+
young women 75% < 30 y
33% androgenic 60% absent
18% malignant
postmenopausal 30% < 30 y
50% estrogenic 11 % androgenic
almost always benign
postmenopausal in 80%
60% estrogenic 12 % androgenic
benign
Luteinized thecoma
+
Stromal luteoma
shown metastases or recurrence after surgical treatment3, 7,13. Consequently, total hysterectomy and bilateral salpingo-oophorectomy is the treatment of choice in postmenopausal women. In younger women, fertility may be preserved in cases with unilateral ovarial involvement, by oophorectomy or excision of the tumour 3, 12. SLCTs have to be distinguished from a wide range of ovarian stromal tumours, especially from those consisting of nodular proliferations of Leydig cells but lacking an additional stromal component (Table 2). These include the extremely rare Leydig cell tumour of non-hilar type and the so-called hilus cell tumour. The latter originates from Leydig cells which can be found in the hilar region of the ovaries, typically surrounding non-myelinated nerve fibers 4 . The Sertoli-Leydig cell tumour differs from SLCT by containing Sertoli cells, mostly arranged in a tubular pattern. In addition, mainly young women are affected. Malignant variants of Sertoli-Leydig cell tumours are not uncommon ll . One case of SLCT containing minor sexcord elements was reported by Young lO • Although partially luteinized thecomas are less frequently associated with virilization and occur in younger age groups than SLCTs, there is a high degree of similarity between them. Both neoplasms have identical microscopic features except for the presence of crystalloids of Reinke in the steroid-type cells of SLCTs5, 8, 13. Indeed, only a minority of Leydig cell tumours show crystalloids of Reinke which, if present, may be few in number4,5, 7. Tumours in which no crystalloids are detectable - whether non-existent or simply overlooked - have to be classified as luteinized thecomas instead of SCLTs. Consequently, SLCTs may actually be far more common than reported in the literature3 ,7, 9, 13. Stromal luteomas, tumourous proliferations of steroidtype cells in the ovary, must also be considered in the differential diagnosis. These neoplasms belong to the group of steroid-cell tumours and are in most cases associated with hyperthecosis. Like SCLTs, they mainly affect postmenopausal women, but they are usually estrogenic, do not contain crystalloids, and do not possess a thecomatous component 1. A further problem is the distinction between hyperplasia and neoplasia. Sternberg7 reported on two women whose ovaries showed stromal hyperplasia including numerous
Biological behaviour
foci of non-neoplastic Leydig-cells. One of the patients, 86 years of age, had developed progressive masculinization during 32 years. The clinical course of this patient and of the patient reported here, as well as the histological appearance in both cases, i.e. lack of a demarcated ovarian tumour mass or clearly neoplastic Leydig cells, are identical. As in the cases an unequivocal distinction between hyperplastic and neoplastic lesions is impossible by histologic means, we conclude that these lesions, particularly those with long-standing clinical symptoms, should be called "stromal Leydig cell hyperplasia" rather than "stromal Leydig cell tumours". We therefore consider the former term to be the more appropriate one in the case reported here. References 1 Hayes MC, Scully RE (1987) Stromal luteoma of the ovary; a clinicopathological analysis of 25 cases. Int J Gynecol Pathol 6: 313-321 2 Fox H (1985) Sex-cord stromal tumours of the ovary. J Pathol145: 127-148 3 Paoletti M, Pridjian G, Okagaki T, Talerman A (1987) A stromal Leydig cell tumor of the ovary occurring in a pregnant 15-year-old girl. Ultrastructural findings. Cancer 60: 2806-2810 4 Roth LM, Sternberg WH (1973) Ovarian stromal tumors containing Leydig cells. II. Pure Leydig cell tumor, non-hilar type. Cancer 32: 952-960 5 Roth LM, Sternberg WH (1983) Partly luteinized theca cell tumour of the ovary. Cancer 51: 1697-1704 6 Sasano H, Sasano N (1989) What's new in the localization of sex steroids in the human ovary and its tumors? Path Res Pract 185: 942-948 7 Sternberg WH, Roth LM (1973) Ovarian stromal tumors containing Leydig cells. I. Stromal-Leydig cell tumor and nonneoplastic transformation of ovarian stroma to Leydig cells. Cancer 32: 940-951 8 Sternberg WH, Dhurandhar HN (1977) Functional ovarian tumors of stromal and sex cord origin. Hum Pathol 8: 565-582 9 Young RH, Scully RE (1982) Ovarian sex cord-stromal tumors: recent progress. Int J Gynecol Patholl: 101-123 10 Young RH, Scully RE (1983) Ovarian stromal tumors with minor sex cord elements: a report of seven cases. Int J Gynecol Pathol 2: 227-234
352 .
J. Bohm et al.
. B. Czernobilsky
11 Young RH, Scully RE (1985) Ovarian Sertoli-Leydig cell tumors: a clinicopathological analysis of 207 cases. Am J Surg Pathol 9: 543-569 12 Young RH, Scully RE (1987) Sex-cord stromal, steroid cell and other ovarian tumors with endocrine, paraendocrine and para neoplastic manifestations. In: Kurman RJ (Ed.) Blaustein's
Pathology of the Female Genital Tract, Third Edition. New York, Springer, 607-658 13 Zhang J , Young RH, Arseneau J, Scully RE (1982) Ovarian stromal tumors containing lutein or Leydig cells (luteinized thecomas and stromal Leydig cell tumors) - A clinicopathological analysis of fifty cases. Int J Gynecol Pathol 1: 270-285
Received February 19, 1990 . Accepted June 19, 1990
Key words: Ovary tumour - Leydig cells - Androgen producing tumor - Virilization H. Hofler M.D., Institute of Pathology, Technical University of Munich, School of Medicine, Ismaninger Str. 22, D-8000 Munich 80, FRG
Letters to the Case B. Czernobilsky Rehovot, Israel What is now being generally referred to as stromal Leydig cell tumor was originally described by Scully in 1953 4 as "an unusual ovarian tumor containing Leydig cells but associated with endometrial hyperplasia in a postmenopausal woman". In this publication Reinke crystals were identified in some of the cells, justifying their classification as Leydig cells. It is also common knowledge that the ovarian stroma is capable of undergoing focal transformation into lutein2 or Leydig-type cellss . In most instances these stromal changes occur in non-neoplastic, albeit hyperplastic stroma, designated as stromal hyperplasia and/or stromal hyperthecosis 1• Ovarian stromal tumors composed of these steroid hormone-secreting cells include stromal luteomas, Leydig cell tumors, tumors of adrenal cortical type and unclassified lipid cell tumors6. In contrast to these neoplasms in which almost the entire tumor is made up of steroid cells, other ovarian tumors such as thecomas or fibromas are predominantly fibromatous or thecomatous but contain collections of these steroid cells. Among the latter are the lesions which have been designated as "stromal Leydig cell tumors". Since the steroid cells are capable of hormonal production, endocrine manifestations in patients with steroid cells in non-neoplastic, as well as in neoplastic ovaries, are common. While in most instances Leydig cells are accompanied by symptoms of virilizations, there are also cases with evidence of hyperestrogenism 7 • The above described aspects have been well covered by the present "Teaching Case". I, like Fox3, prefer the term "Leydig cell-containing thecoma" since it emphasizes the thecomatous nature of the neoplasm. "Stromal Leydig cell tumor" may be confused with conditions of ovarian stromal hyperplasia containing Leydig cells. My main criticism of the submitted case report is about the actual nature of the ovarian lesions described. To me
both the macroscopic description and the microscopic illustrations are not diagnostic of neoplasms and I prefer the diagnosis of bilateral stromal hyperplasia with Leydig cells in this case. The authors actually discuss the differential diagnosis between these two entities and even reach the conclusion in the text that their case should be classified as "stromal Leydig cell hyperplasia". Nevertheless, the title of the teaching case is that of "bilateral stromal Leydig cell tumor". This lack of clarity emphasizes the problem of distinguishing hyperplastic from neoplastic lesions of this nature. Neoplasms should be restricted to well-demarcated macro- and microscopic lesions and even if these are present, the possibility that one is dealing with nodular stromal hyperplasia rather neoplasia cannot be entirely excluded. In conclusion - in the present case my diagnosis is that of bilateral ovarian stromal hyperplasia with Leydig cells. References 1 Clement PB (1987) Non-neoplastic lesions of the ovary. In: Kurman RJ (Ed.) Blaustein's Pathology of the Female Genital Tract, Third Edition, Springer, New York, 489-491 2 Dennefors BL, Janson PO, Knutson F, Hamberger I (1980) Steroid production and responsiveness to gonadotropin in isolated stromal tissue of human postmenopausal ovaries. Am J Obstet Gynecol136: 997-1002 3 Fox H (1985) Sex-cord stromal tumours of the ovary. J Pathol145: 127-148 4 Scully RE (1953) An unusual ovarian tumor containing Leydig cells but associated with endometrial hyperplasia in a postmenopausal woman. J Clin Endocr Metab 13: 1254-1263 5 Sternberg WH, Roth LM (1973) Ovarian stromal tumors containing Leydig cells. I. Stromal-Leydig cell tumor and nonneoplastic transformation of ovarian stroma to Leydig cells. Cancer 32: 940-951
Bilateral Stromal Leydig Cell Tumour of the Ovary Case Report and Literature Review J. Bohm, M. Roder-Weber and H. Hofler Institute of Pathology, Technical University of Munich, School of Medicine, Munich, FRG
M. Kolben Institute of Gynecology and Obstetrics, Technical University of Munich, School of Medicine, Munich, FRG
SUMMARY
The stromal Leydig cell tumour of the ovary is a very rare benign neoplasm which usually occurs in postmenopausal women. Due to a significant production of androgens by the tumour, it is frequently associated with symptoms of virilization. To our knowledge only 7 cases have been reported in the literature, one of them with bilateral manifestation. We report an additional case affecting both ovaries in a 59-year-old nun with long-standing virilism, review the literature, and discuss the histomorphological features for differential diagnosis.
Introduction The stromal Leydig cell tumour of the ovary (SLCT) belongs to the thecoma-fibroma group of ovarian tumours 2,12. It is composed of a neoplastic theca cell proliferation with interspersed clusters of steroid-type cells. The presence of crystalloids of Reinke within the latter identifies them as Leydig cells 7 • Ovarian stromal cells most likely have the capacity to differentiate into Leydig cells 7, especially in association with stromal hyperplasia. Fox2 prefers the term "Leydig cell-containing thecoma" instead of "stromal Leydig cell tumour" to emphasize the essentially thecomatous nature. The intention of this report is to describe an additional case of this rare neoplasm, review the literature, and consider the histomorphological features for differential diagnosis. 0344-0338/9110187-0348 $3.5010
Case report In the present case a 59-year-old nun (nulligravida) was hospitalized to discover the reason for a hirsutism that had been developing for some 30 years (Fig. 1). On admission, the patient presented with signs of virilization, such as a beard which required shaving twice a day, masculine alopecia, a male distribution of pubic hair and a markedly enlarged clitoris. There was no deepening of her voice; no pelvic mass was palpable. Gynecological anamnesis revealed that the patient had suffered from menstrual disorders with oligomenorrhoe. In 1969 she had undergone a hysterectomy and uterine myomas had been found. Pre-operative laboratory tests showed increased blood levels of testosterone and decreased levels of sexual hormone binding globulin (SHBG), both consistent with considerable hyperandrogenemia. The blood levels of the © 1991 by Gustav Fischer Verlag, Stuttgart
Stromal Leydig Cell Tumour·
349
Fig. 1. Aspect of the patient. Note beard and masculine alopecia.
gonadotropins LH and FSH, and of estradiol were within normal limits (Table 1). Serum tumour markers CA 19-9 and CA 12-5 were not increased. The existence of a tumour of the adrenal glands was excluded clinically by computed tomography, sonography and dexamethasone inhibition test. A bilateral salpingo-oophorectomy was performed. When the patient left hospital two weeks after the operation, the blood level of testosterone had normalized (0.5 nmol/i). Morphological Findings On gross examination, the ovaries were enlarged compared to the normal size in postmenopausal women. The right ovary measured 5 em in greatest diameter, the left
Table 1. Blood plasma levels : Blood plasma levels of testosterone, sexual hormone binding globulin (SHBG), FSH, LH and estradiol showing the patient's preoperative levels (PAT), and normal levels usually found in postmenopausal women (NOR) Hormone
PAT
NOR
Units
Testosterone SHBG FSH LH Estradiol
6.1 23 47 10 < 37
< 2.4 30- 90 35-131 11- 61 37-100
nmoUl [lmolll UII UII pmolll
Fig. 2. Cut surface of the ovaries with solid areas of mostly diffusely arranged tumourous tissue in the cortex and medulla of both ovaries.
ovary 4 cm. Both ovaries were of firm consistence and had a slightly irregular cortical surface. On cut section, solid areas of diffusely arranged light-brown tissue could be seen in the ovarian parenchyma of the cortex and of the medulla (Fig. 2). The fallopian tubes measured 5 cm in length and were without pathological findings. Histologically, the neoplastic tissue consisted of a mostly diffuse, partly nodular stromal proliferation of theca cells with spindle-shaped or round nuclei embedded in varying amounts of collagen fibrils, with focal fibrosis and hyalinization. Reticulum stain showed a dense pericellular reticulum pattern. Numerous small clusters and nests of steroid-type cells were interspersed within this thecal proliferation. The steroid-type cells showed rather uniform central nuclei with a prominent nucleolus and abundant eosinophilic, sometimes pale and vacuolated cytoplasm. These cells contained rare but distinct crystalloids of Reinke (Fig. 3). Sudan-III-staining showed varying amounts of lipids in both kinds of tumour cells with some lipid-rich foci (Fig. 4). Neither the thecomatous nor the
350 .
J. Bbhm et al.
Fig. 3. Nests of steroid-type cells (broad arrows) in a thecomatous background (H & E, X 122). Inset: Steroid-type cell containing a crystalloid of Reinke (thin arrow; H & E, x 308).
Fig. 4. Foci of lipid-containing cells in the SLCT (Sudan III, x 122).
steroid-type cell components of the tumour showed mitotic activity or cellular atypia. Beyond the mostly ill-defined margins of the neoplastic stromal proliferation, the remaining ovarian parenchyma showed some small inclusion cysts. The ovarian hilus had foci of hyperplastic hilus cells but was not involved by the tumour.
tumours 7 • In two cases, however, endometrial proliferations indicating hyperestrogenism were found13. As recent immunohistochemical studies of ovarian steroidogenesis have shown, androgen-producing stromal tumours may show estrogenic effects as a result of enzymatic conversion outside the tumourous tissue 6 • Results of hormonal blood level measurements in SLCTs have not been reported previously in the literature. In the present case the testosterone blood levels showed a rapid decrease after extirpation of the ovaries. Macroscopically, SLCTs form solid lobulated masses developing in both the cortex and the medulla, reaching up to 12 cm in greatest diameter. Sectioning reveals firm multinodular yellow-tan or white tumourous tissue embedded in the surrounding ovarian parenchyma 3, 7, 13. Microscopically, SLCTs are characterized by clusters of Leydig cells containing crystalloids of Reinke within hyperplastic thecomatous tissue 3, 7, 13. The histologic appearance without any cellular atypia or mitotic activity, and the clinical course indicate that SLCTs are benign tumours. No case of SLCT reported in the literature has
Discussion SLCTs are thought to originate from stromal cells which are able to differentiate into Leydig cells, in a background of stromal hyperplasia 4, 7,13. At present 7 cases of this entity have been reported in literature3, 7, 13, one of them with bilateral manifestation 7• The case of SCLT reported here represents the second observation in which both ovaries were involved. Except for one case reported in a IS-year-old pregnant girl3, all the SLCTs described so far occurred in 52- to-68-year-old postmenopausal women. The majority of the patients showed symptoms of virilization, suggesting that SLCTs are androgen-producing
Stromal Leydig Cell Tumour· 351 Table 2. Differential diagnoses: Stromal Leydig cell tumour versus other ovarian stromal neoplasms. The parameters are: content of Leydig cells, content of a tumourous stromal component, predominant age distribution, hormonal activity and biological behaviour. "Leydig cell tumours" include Leydig cell tumour of non-hilar type as well as hilus cell tumour 1,4,5,11,12 Tumour
Leydig cells
Stromal component
Age distribution
Hormonal activity
Stromal Leydig cell tumour
+
+
postmenopausal
usually androgenic benign
Leydig cell tumours
+
postmenopausal
75% androgenic
benign
Sertoli-Leydig cell tumour
+
young women 75% < 30 y
33% androgenic 60% absent
18% malignant
postmenopausal 30% < 30 y
50% estrogenic 11 % androgenic
almost always benign
postmenopausal in 80%
60% estrogenic 12 % androgenic
benign
Luteinized thecoma
+
Stromal luteoma
shown metastases or recurrence after surgical treatment3, 7,13. Consequently, total hysterectomy and bilateral salpingo-oophorectomy is the treatment of choice in postmenopausal women. In younger women, fertility may be preserved in cases with unilateral ovarial involvement, by oophorectomy or excision of the tumour 3, 12. SLCTs have to be distinguished from a wide range of ovarian stromal tumours, especially from those consisting of nodular proliferations of Leydig cells but lacking an additional stromal component (Table 2). These include the extremely rare Leydig cell tumour of non-hilar type and the so-called hilus cell tumour. The latter originates from Leydig cells which can be found in the hilar region of the ovaries, typically surrounding non-myelinated nerve fibers 4 . The Sertoli-Leydig cell tumour differs from SLCT by containing Sertoli cells, mostly arranged in a tubular pattern. In addition, mainly young women are affected. Malignant variants of Sertoli-Leydig cell tumours are not uncommon ll . One case of SLCT containing minor sexcord elements was reported by Young lO • Although partially luteinized thecomas are less frequently associated with virilization and occur in younger age groups than SLCTs, there is a high degree of similarity between them. Both neoplasms have identical microscopic features except for the presence of crystalloids of Reinke in the steroid-type cells of SLCTs5, 8, 13. Indeed, only a minority of Leydig cell tumours show crystalloids of Reinke which, if present, may be few in number4,5, 7. Tumours in which no crystalloids are detectable - whether non-existent or simply overlooked - have to be classified as luteinized thecomas instead of SCLTs. Consequently, SLCTs may actually be far more common than reported in the literature3 ,7, 9, 13. Stromal luteomas, tumourous proliferations of steroidtype cells in the ovary, must also be considered in the differential diagnosis. These neoplasms belong to the group of steroid-cell tumours and are in most cases associated with hyperthecosis. Like SCLTs, they mainly affect postmenopausal women, but they are usually estrogenic, do not contain crystalloids, and do not possess a thecomatous component 1. A further problem is the distinction between hyperplasia and neoplasia. Sternberg7 reported on two women whose ovaries showed stromal hyperplasia including numerous
Biological behaviour
foci of non-neoplastic Leydig-cells. One of the patients, 86 years of age, had developed progressive masculinization during 32 years. The clinical course of this patient and of the patient reported here, as well as the histological appearance in both cases, i.e. lack of a demarcated ovarian tumour mass or clearly neoplastic Leydig cells, are identical. As in the cases an unequivocal distinction between hyperplastic and neoplastic lesions is impossible by histologic means, we conclude that these lesions, particularly those with long-standing clinical symptoms, should be called "stromal Leydig cell hyperplasia" rather than "stromal Leydig cell tumours". We therefore consider the former term to be the more appropriate one in the case reported here. References 1 Hayes MC, Scully RE (1987) Stromal luteoma of the ovary; a clinicopathological analysis of 25 cases. Int J Gynecol Pathol 6: 313-321 2 Fox H (1985) Sex-cord stromal tumours of the ovary. J Pathol145: 127-148 3 Paoletti M, Pridjian G, Okagaki T, Talerman A (1987) A stromal Leydig cell tumor of the ovary occurring in a pregnant 15-year-old girl. Ultrastructural findings. Cancer 60: 2806-2810 4 Roth LM, Sternberg WH (1973) Ovarian stromal tumors containing Leydig cells. II. Pure Leydig cell tumor, non-hilar type. Cancer 32: 952-960 5 Roth LM, Sternberg WH (1983) Partly luteinized theca cell tumour of the ovary. Cancer 51: 1697-1704 6 Sasano H, Sasano N (1989) What's new in the localization of sex steroids in the human ovary and its tumors? Path Res Pract 185: 942-948 7 Sternberg WH, Roth LM (1973) Ovarian stromal tumors containing Leydig cells. I. Stromal-Leydig cell tumor and nonneoplastic transformation of ovarian stroma to Leydig cells. Cancer 32: 940-951 8 Sternberg WH, Dhurandhar HN (1977) Functional ovarian tumors of stromal and sex cord origin. Hum Pathol 8: 565-582 9 Young RH, Scully RE (1982) Ovarian sex cord-stromal tumors: recent progress. Int J Gynecol Patholl: 101-123 10 Young RH, Scully RE (1983) Ovarian stromal tumors with minor sex cord elements: a report of seven cases. Int J Gynecol Pathol 2: 227-234
352 .
J. Bohm et al.
. B. Czernobilsky
11 Young RH, Scully RE (1985) Ovarian Sertoli-Leydig cell tumors: a clinicopathological analysis of 207 cases. Am J Surg Pathol 9: 543-569 12 Young RH, Scully RE (1987) Sex-cord stromal, steroid cell and other ovarian tumors with endocrine, paraendocrine and para neoplastic manifestations. In: Kurman RJ (Ed.) Blaustein's
Pathology of the Female Genital Tract, Third Edition. New York, Springer, 607-658 13 Zhang J , Young RH, Arseneau J, Scully RE (1982) Ovarian stromal tumors containing lutein or Leydig cells (luteinized thecomas and stromal Leydig cell tumors) - A clinicopathological analysis of fifty cases. Int J Gynecol Pathol 1: 270-285
Received February 19, 1990 . Accepted June 19, 1990
Key words: Ovary tumour - Leydig cells - Androgen producing tumor - Virilization H. Hofler M.D., Institute of Pathology, Technical University of Munich, School of Medicine, Ismaninger Str. 22, D-8000 Munich 80, FRG
Letters to the Case B. Czernobilsky Rehovot, Israel What is now being generally referred to as stromal Leydig cell tumor was originally described by Scully in 1953 4 as "an unusual ovarian tumor containing Leydig cells but associated with endometrial hyperplasia in a postmenopausal woman". In this publication Reinke crystals were identified in some of the cells, justifying their classification as Leydig cells. It is also common knowledge that the ovarian stroma is capable of undergoing focal transformation into lutein2 or Leydig-type cellss . In most instances these stromal changes occur in non-neoplastic, albeit hyperplastic stroma, designated as stromal hyperplasia and/or stromal hyperthecosis 1• Ovarian stromal tumors composed of these steroid hormone-secreting cells include stromal luteomas, Leydig cell tumors, tumors of adrenal cortical type and unclassified lipid cell tumors6. In contrast to these neoplasms in which almost the entire tumor is made up of steroid cells, other ovarian tumors such as thecomas or fibromas are predominantly fibromatous or thecomatous but contain collections of these steroid cells. Among the latter are the lesions which have been designated as "stromal Leydig cell tumors". Since the steroid cells are capable of hormonal production, endocrine manifestations in patients with steroid cells in non-neoplastic, as well as in neoplastic ovaries, are common. While in most instances Leydig cells are accompanied by symptoms of virilizations, there are also cases with evidence of hyperestrogenism 7 • The above described aspects have been well covered by the present "Teaching Case". I, like Fox3, prefer the term "Leydig cell-containing thecoma" since it emphasizes the thecomatous nature of the neoplasm. "Stromal Leydig cell tumor" may be confused with conditions of ovarian stromal hyperplasia containing Leydig cells. My main criticism of the submitted case report is about the actual nature of the ovarian lesions described. To me
both the macroscopic description and the microscopic illustrations are not diagnostic of neoplasms and I prefer the diagnosis of bilateral stromal hyperplasia with Leydig cells in this case. The authors actually discuss the differential diagnosis between these two entities and even reach the conclusion in the text that their case should be classified as "stromal Leydig cell hyperplasia". Nevertheless, the title of the teaching case is that of "bilateral stromal Leydig cell tumor". This lack of clarity emphasizes the problem of distinguishing hyperplastic from neoplastic lesions of this nature. Neoplasms should be restricted to well-demarcated macro- and microscopic lesions and even if these are present, the possibility that one is dealing with nodular stromal hyperplasia rather neoplasia cannot be entirely excluded. In conclusion - in the present case my diagnosis is that of bilateral ovarian stromal hyperplasia with Leydig cells. References 1 Clement PB (1987) Non-neoplastic lesions of the ovary. In: Kurman RJ (Ed.) Blaustein's Pathology of the Female Genital Tract, Third Edition, Springer, New York, 489-491 2 Dennefors BL, Janson PO, Knutson F, Hamberger I (1980) Steroid production and responsiveness to gonadotropin in isolated stromal tissue of human postmenopausal ovaries. Am J Obstet Gynecol136: 997-1002 3 Fox H (1985) Sex-cord stromal tumours of the ovary. J Pathol145: 127-148 4 Scully RE (1953) An unusual ovarian tumor containing Leydig cells but associated with endometrial hyperplasia in a postmenopausal woman. J Clin Endocr Metab 13: 1254-1263 5 Sternberg WH, Roth LM (1973) Ovarian stromal tumors containing Leydig cells. I. Stromal-Leydig cell tumor and nonneoplastic transformation of ovarian stroma to Leydig cells. Cancer 32: 940-951
