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Juvenile granulosa cell tumor arising in ovarian adenosarcoma: an unusual form of sarcomatous overgrowth
Human Pathology (2015) 46, 614–619
www.elsevier.com/locate/humpath
Case study
Juvenile granulosa cell tumor arising in ovarian adenosarcoma: an unusual form of sarcomatous overgrowth Claire Carleton MD, Oisín P. Houghton FRCPath, W. Glenn McCluggage FRCPath ⁎ Dept of Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland BT126BA Received 16 October 2014; revised 15 December 2014; accepted 19 December 2014
Keywords: Ovary; Adenosarcoma; Juvenile granulosa cell tumor; Sex cord; Immunohistochemistry
Summary We report 2 ovarian neoplasms in women aged 58 and 69 years composed of an admixture of adenosarcoma and a predominant stromal component morphologically and immunohistochemically in keeping with juvenile granulosa cell tumor. As far as we are aware, this association has not been reported previously. We speculate that, in both cases, the juvenile granulosa cell tumor component arose from the adenosarcoma as an unusual form of sarcomatous overgrowth of sex cord elements. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Mullerian adenosarcomas are uncommon mixed epithelial and mesenchymal neoplasms containing a benign epithelial element and a malignant, usually low-grade, stromal component [1,2]. They most commonly arise in the uterus, especially the corpus [3,4], but rarely occur as primary neoplasms in extrauterine sites, especially the ovary [5]. Occasionally, the stromal component of both uterine and extrauterine adenosarcomas contains so-called sex cord–like elements [1,5,6]. Although referred to as sex cord–like, these may exhibit a true sex cord immunophenotype with positive staining with inhibin, calretinin, and other sex cord markers [5,6]. We report 2 unusual ovarian neoplasms composed of
⁎ Corresponding author. W. Glenn McCluggage, Department of Pathology, Royal Group of Hospitals Trust, Grosvenor Road, Belfast BT12 6BA, United Kingdom. E-mail address: [email protected] (W. G. McCluggage).
http://dx.doi.org/10.1016/j.humpath.2014.12.010 0046-8177/© 2015 Elsevier Inc. All rights reserved.
an admixture of adenosarcoma and a predominant stromal component morphologically and immunohistochemically in keeping with juvenile granulosa cell tumor (JGCT). As far as we are aware, this combination of neoplasms has not been previously reported, and we speculate that the JGCT arose from the adenosarcoma, probably from sex cord elements, this representing an unusual form of sarcomatous overgrowth. In reporting these cases, we review the phenomenon of sex cord elements occurring within ovarian neoplasms, which are not intrinsically of sex cord lineage.
2. Case reports Case 1 was an in-house case from the Department of Pathology, Belfast Health and Social Care Trust, Belfast, and case 2 was from the referral practice of one of the authors (W.G.M.). The hematoxylin and eosin–stained slides (40 in case 1 and 10 in case 2) and immunohistochemistry slides were reviewed.
Ovarian juvenile granulosa cell tumour and adenosarcoma
2.1. Case 1 2.1.1. Clinical details A 69-year-old woman presented with a 6-month history of abdominal discomfort, decreased appetite and, nausea and was found to have a pelvic mass. Ultrasound and computed tomographic scans showed a large pelvic mass probably arising from the left ovary with a small amount of ascites. No extraovarian spread was seen. The serum CA125 was elevated at 551 U/mL (normal, b35 U/mL). She had undergone a hysterectomy for uterine fibroids 34 years previously. At laparotomy, there were ascites and a large solid left ovarian mass that was stuck to the sigmoid mesentery. Tumor was also present in the Pouch of Douglas. The right ovary, upper abdomen, and omentum appeared normal. She underwent bilateral salpingo-oophorectomy and omentectomy. Pelvic peritoneal tissue from the Pouch of Douglas containing tumor nodules was also removed. After the pathology result and discussion at the multidisciplinary gynecologic oncology meeting, it was decided to follow the patient up, and no adjuvant therapy was administered. The case is recent, and there is no follow-up.
615 approximately 95% of the neoplasm was composed of the JGCT component. There was a relatively sharp transition between the 2 components with minimal intermingling. Fig. 1 shows representative images of the neoplasm. Immunohistochemistry of the JGCT component showed diffuse positivity for calretinin (nuclear and cytoplasmic), CD56 (membranous), steroidogenic factor 1 (nuclear), and CD99 (membranous) (Fig. 2). There was focal cytoplasmic positivity with inhibin and focal nuclear staining with progesterone receptor. Melan A, estrogen receptor (ER), epithelial membrane antigen, and AE1/3 were negative. The immunophenotype was in keeping with an ovarian sex cord tumor. The epithelial element of the adenosarcoma component was diffusely ER positive, and the stromal element was negative. Histology of the right ovary showed a focus of endometriosis. The right fallopian tube and the omentum exhibited no histologic abnormality. Cytologic examination of the ascitic fluid showed no malignant cells. Because there was involvement of the pelvic peritoneal tissue, the tumor was staged as FIGO IIB.
2.2. Case 2 2.1.2. Pathologic findings The left ovary measured 20.5 cm in maximum dimension and weighed 1200 g. The capsule was disrupted in several places. On sectioning, the ovary was composed entirely of a predominantly solid tumor with occasional small cystic areas. The solid areas had a slightly nodular, rubbery, pale yellow cut surface with occasional areas of hemorrhage. The left fallopian tube was not identified grossly. The peritoneal tissue from the Pouch of Douglas contained grossly visible tumor nodules. The right ovary (1.5 cm in maximum dimension), right fallopian tube (5 cm in length), and omentum (30 cm in maximum dimension) were grossly unremarkable. Fifteen milliliters of ascitic fluid was also submitted. Histology of the left ovary showed a low-power lobulated architecture with multiple cellular nodules separated by edematous stromal tissue. The nodules were composed predominantly of a diffuse population of cells with moderate to abundant, pale or eosinophilic cytoplasm. Many folliclelike spaces containing basophilic fluid were present within the otherwise diffuse arrangements. The cells were epithelioid with atypical nuclei, and there was marked mitotic activity (N20 per 10 high-power fields). There were areas of necrosis. These areas were morphologically in keeping with JGCT. The peritoneal tissue from the Pouch of Douglas contained similar tumor. In 2 of the 40 slides, there was a different morphological appearance in the form of a polypoid “club-like” (phyllodeslike) architecture with benign ciliated epithelium lining stromal cores. The cells within the stromal cores contained spindle-shaped nuclei with mild to moderate nuclear atypia, and there was condensation around the epithelium forming a cambium layer within which mitotic figures were present, in excess of 20 per 10 high-power fields. The features in this component were in keeping with adenosarcoma. Overall,
2.2.1. Clinical details A 58-year-old woman was found at a routine health check to have an elevated serum CA125 of 72 U/mL. Ultrasound and computed tomographic scans showed a large right-sided pelvic mass probably arising from the right ovary. There was no extraovarian spread and no ascites. She had undergone a hysterectomy for benign reasons 23 years previously. She underwent a bilateral salpingo-oophorectomy, appendectomy, and omentectomy. After the pathology result and discussion at the multidisciplinary gynecologic oncology meeting, it was decided to follow the patient up, and no adjuvant therapy was administered. The patient has been followed up for 20 months with no evidence of tumor recurrence or metastasis. 2.2.2. Pathologic findings The right ovary consisted of a cystic mass with a smooth capsule measuring 18 cm in maximum dimension. Sectioning revealed a partly cystic and partly solid appearance. The right fallopian tube was not identified. The left ovary (2.5 cm in maximum dimension), left fallopian tube (5 cm in length), omentum (13 cm in maximum dimension), and appendix (10 cm in length) were grossly unremarkable. Histology of the right ovary showed a minor component with a polypoid club-like (phyllodes-like) architecture with benign ciliated and endometrioid-type epithelium lining stromal cores. The stromal component was morphologically bland with spindle-shaped nuclei, but there was increased cellularity surrounding the epithelial elements forming a cambium layer. Mitotic figures were identified within the cambium layer (several within a single high-power field in areas). This component was in keeping with adenosarcoma. In addition, there was a predominant component similar to the JGCT described in case 1 with diffuse areas, follicle-like
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Fig. 1 A, Low-power view of adenosarcoma component in case 1 with phyllodes-like architecture and increased cellularity around the epithelial elements. B, There is a degree of nuclear atypia, and mitotic figures are present within the cambium layer surrounding the epithelium. C, Medium-power view of juvenile granulosa cell tumor component with follicle-like spaces containing basophilic fluid. D, On high power, the cells are epithelioid and atypical.
spaces containing basophilic fluid, and a few corded arrangements. The tumor cells had moderate to abundant eosinophilic cytoplasm, and mitoses were easily identified (approximately 10 per 10 high-power fields). Overall, approximately 80% of the neoplasm comprised the JGCT component. There was a relatively sharp transition between the 2 components with minimal intermingling. Fig. 3 shows representative images of the neoplasm. The JGCT component was diffusely positive with inhibin (cytoplasmic), steroidogenic factor 1 (nuclear), CD56 (membranous), CD99 (membranous), and calretinin (nuclear and cytoplasmic). There was focal weak nuclear staining with ER, whereas CD10, epithelial membrane antigen, and AE1/3 were negative. The left ovary and fallopian tube, omentum, and appendix were histologically normal. The tumor represented a FIGO stage IA neoplasm.
3. Discussion Adenosarcoma and JGCT are 2 relatively uncommon ovarian neoplasms. We report 2 cases where these neoplasms
coexisted within the same ovary, a combination that, as far as we are aware, has not been previously described. In both cases, the adenosarcoma represented a minor component of the neoplasm, the predominant element having the morphology and immunophenotype of a JGCT. Mullerian adenosarcomas most commonly occur within the uterus but also arise at various extrauterine sites, especially the ovary [1-5]. In most cases, the stromal component is composed entirely of homologous mesenchymal elements, usually resembling endometrial stromal sarcoma or representing a nonspecific fibromatous stroma, but heterologous elements, such as rhabdomyoblasts and cartilage, can also occur [1,5]. Sarcomatous overgrowth, defined as the presence of areas of pure sarcoma involving more than 25% of the tumor, can occur within these neoplasms and is an adverse prognostic indicator [7]. The areas of sarcomatous overgrowth most commonly represent undifferentiated high-grade sarcoma with greater atypia and higher mitotic activity than in the low-grade sarcomatous element of the areas of typical adenosarcoma; this can be regarded as dedifferentiation of the low-grade stromal component [1]. Occasionally, a high-grade sarcoma is identified as a recurrent or metastatic neoplasm in what was initially a typical adenosarcoma with low-grade sarcomatous
Ovarian juvenile granulosa cell tumour and adenosarcoma
617
Fig. 2 Juvenile granulosa cell tumor component in case 1 showing focal cytoplasmic staining with inhibin (A), diffuse nuclear and cytoplasmic staining with calretinin (B), diffuse membranous staining with CD56 (C), and diffuse nuclear staining with steroidogenic factor 1 (D).
elements. In both our cases, we made a diagnosis of adenosarcoma rather than adenofibroma given the degree of mitotic activity within the mesenchymal component. Sex cord–like elements can occur within the stromal component of adenosarcoma, including in areas of sarcomatous overgrowth [1,5,6]. They may exhibit a true sex cord immunophenotype with positive staining with sex cord markers [1,6]. Sex cord–like areas have been found to occur within a higher proportion of ovarian adenosarcomas (15%) compared with their uterine counterparts (7%) [5]. Usually, the sex cord–like elements involve only small microscopic foci, but 2 uterine adenosarcomas have been reported where the sex cord–like component comprised more than 75% of the neoplasm in keeping with overgrowth of uterine tumor resembling ovarian sex cord tumor [8]. In addition, in the largest reported series of ovarian adenosarcomas, the authors mentioned 1 case with a focal component within the stroma morphologically similar to adult granulosa cell tumor (AGCT) with diffuse and “watered-silk” patterns [5]. They also mentioned, but did not illustrate, a case where the sex cord–like elements were arranged in cords and nests as well as follicle-like spaces of varying sizes. Altogether, 6 (15%) of their 40 cases contained sex cord–like elements that accounted for between 25% and 75% of the mesenchymal component. The authors mentioned the possibility of misdiagnosis as a pure sex cord–stromal tumor when the
sex cord–like areas were prominent. We speculate that, in the 2 cases we report, the adenosarcoma represents the parent neoplasm in which there has been overgrowth of sex cord– like elements resulting in a neoplasm morphologically and immunohistochemically in keeping with a JGCT; as such, this can be regarded as an unusual form of sarcomatous overgrowth. The term JGCT was introduced because many of these neoplasms occur in young females. However, they may also occur in patients who are no longer juvenile. In the largest published study, 44% occurred in patients 10 years or younger, 34% between ages 11 and 20 years, 18% between ages 21 and 30 years, and 3% older than 30 years [9]. In the 2 cases we report, the patients were aged 58 and 69 years, which suggests a different histogenesis from that of conventional JGCT. Although we considered the possibility that our cases represent collision tumors of 2 uncommon neoplasms, especially because there was little intermingling of the 2 components, that JGCTs are very uncommon in patients older than 50 years makes this unlikely. It would also seem unlikely that 2 ovarian neoplasms that are both uncommon in themselves would occur in combination in 2 individuals. Because this represents an unusual combination of neoplasms, the prognosis is essentially unknown. Ovarian adenosarcomas have a worse prognosis than their uterine
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Fig. 3 A, Low-power view of adenosarcoma component in case 2 with increased cellularity around the epithelial elements resulting in a cambium layer. B, Mitotic figures are present within the areas of increased cellularity surrounding the epithelial elements. C and D, Juvenile granulosa cell tumor component with follicle-like spaces and epithelioid tumor cells with abundant eosinophilic cytoplasm.
counterparts, probably because of the greater ease of peritoneal spread [5]. In the largest reported series, only 6 (23%) of 26 women who had greater than 5 years postoperative follow-up were free of tumor [5]. Age younger than 53 years, tumor rupture, high grade, and the presence of high-grade sarcomatous overgrowth were associated with recurrence or extraovarian spread [5]. In the largest reported series of ovarian JGCT, follow-up was available in 95 of 125 patients (average, 5 years), and 92% of these were alive and free of disease [9]. Only tumor stage correlated with survival. In both our cases, no adjuvant therapy was administered after surgical removal. One case is recent (the stage IIB neoplasm), and in the other case (stage IA), there has been no tumor recurrence with a follow-up of 20 months. In 1 of our cases, there was endometriosis in the contralateral ovary raising the possibility that the neoplasm arose from endometriosis. It has been speculated that ovarian adenosarcomas may arise in endometriosis [10]. However, in the largest reported series, there was histologic evidence of endometriosis in only 4 (10%) of 40 cases [9]. Although this could be explained by overgrowth of underlying endometriosis, the low incidence of endometriosis tends to suggest that many or most ovarian adenosarcomas do not arise in this condition.
As well as occurring in adenosarcomas, sex cord differentiation may also be seen in ovarian epithelial and pure stromal neoplasms. An example of the latter is fibroma or thecoma with minor sex cord elements where within an otherwise typical fibroma or thecoma there are small microscopic sex cord elements (b10%) resembling Sertoli or granulosa cells [11]. A case of an ovarian serous cystadenofibroma exhibiting extensive sex cord differentiation within the stroma, in the form of solid and hollow tubules resembling Sertoli cell elements, has been reported [12]. There are also several reports of ovarian epithelial neoplasms (benign, borderline, or malignant), especially but not exclusively of mucinous type, associated with a stromal component morphologically in keeping with AGCT [13,14]. Different theories have been put forward to explain this combination, and some examples are likely to represent a collision of 2 separate individual tumors where there are 2 distinct components without intermingling. Others are likely to represent composite tumors occurring because of induction of 1 component by the other “parent” neoplasm [14]. One study reported a series of neoplasms consisting of small microscopic foci resembling AGCT (AGCT-like) within the stromal component of an epithelial neoplasm [14]. The AGCT-like components lacked FOXL2 mutations
Ovarian juvenile granulosa cell tumour and adenosarcoma [14]. FOXL2 mutations occur in most (N95%) AGCTs, and this is a sensitive and specific molecular marker of this tumor type [14,15]. That FOXL2 mutations do not occur within these AGCT-like areas within the stroma of epithelial neoplasms suggests that they are not true AGCTs but instead may represent non-neoplastic stromal proliferations morphologically indistinguishable from small AGCTs [14]. It is probable that, analogous to these AGCT-like areas, both our cases represent a proliferation within an adenosarcoma that is morphologically and immunohistochemically indistinguishable from JGCT but with a different histogenesis and molecular basis compared with conventional forms of this neoplasm. In summary, we report 2 cases of ovarian adenosarcoma associated with a predominant stromal component morphologically and immunohistochemically in keeping with JGCT; as far as we are aware, this association has not been reported previously. We speculate that, in both cases, the JGCT component arose from the adenosarcoma as an unusual form of sarcomatous overgrowth of sex cord elements.
References [1] McCluggage WG. Mullerian adenosarcoma of the female genital tract. Adv Anat Pathol 2010;17:122-9. [2] Kurman RJ, Carcangiu ML, Herrington CS, Young RH, editors. WHO Classification of Tumours of Female Reproductive Organs. Lyon: International Agency for Research on Cancer; 2014. [3] Clement PB, Scully RE. Mullerian adenosarcoma of the uterus: a clinicopathologic analysis of ten cases of a distinctive type of mullerian mixed tumor. Cancer 1974;34:1138-49.
619 [4] Clement PB, Scully RE. Mullerian adenosarcoma of the uterus: a clinicopathologic analysis of 100 cases with a review of the literature. HUM PATHOL 1990;21:363-81. [5] Eichhorn JH, Young RH, Clement PB, Scully RE. Mesodermal (Mullerian) adenosarcoma of the ovary: a clinicopathologic analysis of 40 cases and a review of the literature. Am J Surg Pathol 2002;26:1243-58. [6] Clement PB, Scully RE. Mullerian adenosarcomas of the uterus with sex cord-like elements. A clinicopathologic analysis of eight cases. Am J Clin Pathol 1989;91:664-72. [7] Clement PB. Adenosarcomas of the uterus with sarcomatous overgrowth. A clinicopathologic analysis of 10 cases. Am J Surg Pathol 1989;13:28-38. [8] Stolnicu S, Balachandran K, Aleykutty MA, et al. Uterine adenosarcomas overgrown by sex-cord-like tumour: report of two cases. J Clin Pathol 2009;62:942-4. [9] Young RH, Dickersin GR, Scully RE. Juvenile granulosa cell tumor of the ovary. A clinicopathological analysis of 125 cases. Am J Surg Pathol 1984;8:575-96. [10] Czernobilsky B, Gillespie JJ, Roth LM. Adenosarcoma of the ovary: a light and electron microscopic study with review of the literature. Diagn Gynecol Obstet 1982;4:25-36. [11] Young HR, Scully RE. Ovarian stromal tumors with minor sex cord elements: a report of seven cases. Int J Gynecol Pathol 1983;2:227-34. [12] Dillon K, Boyde A, Murphy JK, McCluggage WG. Ovarian serous cystadenofibroma with stromal sex cord elements: report of a unique case. Int J Gynecol Pathol 2006;25:336-9. [13] McKenna M, Kenny B, Dorman G, McCluggage WG. Combined adult granulosa cell tumor and mucinous cystadenoma of the ovary: granulosa cell tumor with heterologous mucinous elements. Int J Gynecol Pathol 2005;24:224-7. [14] Singh N, Gilks CB, Huntsman DG, et al. Adult granulosa cell tumourlike areas occurring in ovarian epithelial neoplasms: report of a case series with investigation of FOXL2 mutation status. Histopathology 2014;64:626-32. [15] Shah SP, Kobel M, Senz J, et al. Mutation of FOXL2 in granulosa-cell tumors of the ovary. N Engl J Med 2009;360:2719-29.
www.elsevier.com/locate/humpath
Case study
Juvenile granulosa cell tumor arising in ovarian adenosarcoma: an unusual form of sarcomatous overgrowth Claire Carleton MD, Oisín P. Houghton FRCPath, W. Glenn McCluggage FRCPath ⁎ Dept of Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland BT126BA Received 16 October 2014; revised 15 December 2014; accepted 19 December 2014
Keywords: Ovary; Adenosarcoma; Juvenile granulosa cell tumor; Sex cord; Immunohistochemistry
Summary We report 2 ovarian neoplasms in women aged 58 and 69 years composed of an admixture of adenosarcoma and a predominant stromal component morphologically and immunohistochemically in keeping with juvenile granulosa cell tumor. As far as we are aware, this association has not been reported previously. We speculate that, in both cases, the juvenile granulosa cell tumor component arose from the adenosarcoma as an unusual form of sarcomatous overgrowth of sex cord elements. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Mullerian adenosarcomas are uncommon mixed epithelial and mesenchymal neoplasms containing a benign epithelial element and a malignant, usually low-grade, stromal component [1,2]. They most commonly arise in the uterus, especially the corpus [3,4], but rarely occur as primary neoplasms in extrauterine sites, especially the ovary [5]. Occasionally, the stromal component of both uterine and extrauterine adenosarcomas contains so-called sex cord–like elements [1,5,6]. Although referred to as sex cord–like, these may exhibit a true sex cord immunophenotype with positive staining with inhibin, calretinin, and other sex cord markers [5,6]. We report 2 unusual ovarian neoplasms composed of
⁎ Corresponding author. W. Glenn McCluggage, Department of Pathology, Royal Group of Hospitals Trust, Grosvenor Road, Belfast BT12 6BA, United Kingdom. E-mail address: [email protected] (W. G. McCluggage).
http://dx.doi.org/10.1016/j.humpath.2014.12.010 0046-8177/© 2015 Elsevier Inc. All rights reserved.
an admixture of adenosarcoma and a predominant stromal component morphologically and immunohistochemically in keeping with juvenile granulosa cell tumor (JGCT). As far as we are aware, this combination of neoplasms has not been previously reported, and we speculate that the JGCT arose from the adenosarcoma, probably from sex cord elements, this representing an unusual form of sarcomatous overgrowth. In reporting these cases, we review the phenomenon of sex cord elements occurring within ovarian neoplasms, which are not intrinsically of sex cord lineage.
2. Case reports Case 1 was an in-house case from the Department of Pathology, Belfast Health and Social Care Trust, Belfast, and case 2 was from the referral practice of one of the authors (W.G.M.). The hematoxylin and eosin–stained slides (40 in case 1 and 10 in case 2) and immunohistochemistry slides were reviewed.
Ovarian juvenile granulosa cell tumour and adenosarcoma
2.1. Case 1 2.1.1. Clinical details A 69-year-old woman presented with a 6-month history of abdominal discomfort, decreased appetite and, nausea and was found to have a pelvic mass. Ultrasound and computed tomographic scans showed a large pelvic mass probably arising from the left ovary with a small amount of ascites. No extraovarian spread was seen. The serum CA125 was elevated at 551 U/mL (normal, b35 U/mL). She had undergone a hysterectomy for uterine fibroids 34 years previously. At laparotomy, there were ascites and a large solid left ovarian mass that was stuck to the sigmoid mesentery. Tumor was also present in the Pouch of Douglas. The right ovary, upper abdomen, and omentum appeared normal. She underwent bilateral salpingo-oophorectomy and omentectomy. Pelvic peritoneal tissue from the Pouch of Douglas containing tumor nodules was also removed. After the pathology result and discussion at the multidisciplinary gynecologic oncology meeting, it was decided to follow the patient up, and no adjuvant therapy was administered. The case is recent, and there is no follow-up.
615 approximately 95% of the neoplasm was composed of the JGCT component. There was a relatively sharp transition between the 2 components with minimal intermingling. Fig. 1 shows representative images of the neoplasm. Immunohistochemistry of the JGCT component showed diffuse positivity for calretinin (nuclear and cytoplasmic), CD56 (membranous), steroidogenic factor 1 (nuclear), and CD99 (membranous) (Fig. 2). There was focal cytoplasmic positivity with inhibin and focal nuclear staining with progesterone receptor. Melan A, estrogen receptor (ER), epithelial membrane antigen, and AE1/3 were negative. The immunophenotype was in keeping with an ovarian sex cord tumor. The epithelial element of the adenosarcoma component was diffusely ER positive, and the stromal element was negative. Histology of the right ovary showed a focus of endometriosis. The right fallopian tube and the omentum exhibited no histologic abnormality. Cytologic examination of the ascitic fluid showed no malignant cells. Because there was involvement of the pelvic peritoneal tissue, the tumor was staged as FIGO IIB.
2.2. Case 2 2.1.2. Pathologic findings The left ovary measured 20.5 cm in maximum dimension and weighed 1200 g. The capsule was disrupted in several places. On sectioning, the ovary was composed entirely of a predominantly solid tumor with occasional small cystic areas. The solid areas had a slightly nodular, rubbery, pale yellow cut surface with occasional areas of hemorrhage. The left fallopian tube was not identified grossly. The peritoneal tissue from the Pouch of Douglas contained grossly visible tumor nodules. The right ovary (1.5 cm in maximum dimension), right fallopian tube (5 cm in length), and omentum (30 cm in maximum dimension) were grossly unremarkable. Fifteen milliliters of ascitic fluid was also submitted. Histology of the left ovary showed a low-power lobulated architecture with multiple cellular nodules separated by edematous stromal tissue. The nodules were composed predominantly of a diffuse population of cells with moderate to abundant, pale or eosinophilic cytoplasm. Many folliclelike spaces containing basophilic fluid were present within the otherwise diffuse arrangements. The cells were epithelioid with atypical nuclei, and there was marked mitotic activity (N20 per 10 high-power fields). There were areas of necrosis. These areas were morphologically in keeping with JGCT. The peritoneal tissue from the Pouch of Douglas contained similar tumor. In 2 of the 40 slides, there was a different morphological appearance in the form of a polypoid “club-like” (phyllodeslike) architecture with benign ciliated epithelium lining stromal cores. The cells within the stromal cores contained spindle-shaped nuclei with mild to moderate nuclear atypia, and there was condensation around the epithelium forming a cambium layer within which mitotic figures were present, in excess of 20 per 10 high-power fields. The features in this component were in keeping with adenosarcoma. Overall,
2.2.1. Clinical details A 58-year-old woman was found at a routine health check to have an elevated serum CA125 of 72 U/mL. Ultrasound and computed tomographic scans showed a large right-sided pelvic mass probably arising from the right ovary. There was no extraovarian spread and no ascites. She had undergone a hysterectomy for benign reasons 23 years previously. She underwent a bilateral salpingo-oophorectomy, appendectomy, and omentectomy. After the pathology result and discussion at the multidisciplinary gynecologic oncology meeting, it was decided to follow the patient up, and no adjuvant therapy was administered. The patient has been followed up for 20 months with no evidence of tumor recurrence or metastasis. 2.2.2. Pathologic findings The right ovary consisted of a cystic mass with a smooth capsule measuring 18 cm in maximum dimension. Sectioning revealed a partly cystic and partly solid appearance. The right fallopian tube was not identified. The left ovary (2.5 cm in maximum dimension), left fallopian tube (5 cm in length), omentum (13 cm in maximum dimension), and appendix (10 cm in length) were grossly unremarkable. Histology of the right ovary showed a minor component with a polypoid club-like (phyllodes-like) architecture with benign ciliated and endometrioid-type epithelium lining stromal cores. The stromal component was morphologically bland with spindle-shaped nuclei, but there was increased cellularity surrounding the epithelial elements forming a cambium layer. Mitotic figures were identified within the cambium layer (several within a single high-power field in areas). This component was in keeping with adenosarcoma. In addition, there was a predominant component similar to the JGCT described in case 1 with diffuse areas, follicle-like
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Fig. 1 A, Low-power view of adenosarcoma component in case 1 with phyllodes-like architecture and increased cellularity around the epithelial elements. B, There is a degree of nuclear atypia, and mitotic figures are present within the cambium layer surrounding the epithelium. C, Medium-power view of juvenile granulosa cell tumor component with follicle-like spaces containing basophilic fluid. D, On high power, the cells are epithelioid and atypical.
spaces containing basophilic fluid, and a few corded arrangements. The tumor cells had moderate to abundant eosinophilic cytoplasm, and mitoses were easily identified (approximately 10 per 10 high-power fields). Overall, approximately 80% of the neoplasm comprised the JGCT component. There was a relatively sharp transition between the 2 components with minimal intermingling. Fig. 3 shows representative images of the neoplasm. The JGCT component was diffusely positive with inhibin (cytoplasmic), steroidogenic factor 1 (nuclear), CD56 (membranous), CD99 (membranous), and calretinin (nuclear and cytoplasmic). There was focal weak nuclear staining with ER, whereas CD10, epithelial membrane antigen, and AE1/3 were negative. The left ovary and fallopian tube, omentum, and appendix were histologically normal. The tumor represented a FIGO stage IA neoplasm.
3. Discussion Adenosarcoma and JGCT are 2 relatively uncommon ovarian neoplasms. We report 2 cases where these neoplasms
coexisted within the same ovary, a combination that, as far as we are aware, has not been previously described. In both cases, the adenosarcoma represented a minor component of the neoplasm, the predominant element having the morphology and immunophenotype of a JGCT. Mullerian adenosarcomas most commonly occur within the uterus but also arise at various extrauterine sites, especially the ovary [1-5]. In most cases, the stromal component is composed entirely of homologous mesenchymal elements, usually resembling endometrial stromal sarcoma or representing a nonspecific fibromatous stroma, but heterologous elements, such as rhabdomyoblasts and cartilage, can also occur [1,5]. Sarcomatous overgrowth, defined as the presence of areas of pure sarcoma involving more than 25% of the tumor, can occur within these neoplasms and is an adverse prognostic indicator [7]. The areas of sarcomatous overgrowth most commonly represent undifferentiated high-grade sarcoma with greater atypia and higher mitotic activity than in the low-grade sarcomatous element of the areas of typical adenosarcoma; this can be regarded as dedifferentiation of the low-grade stromal component [1]. Occasionally, a high-grade sarcoma is identified as a recurrent or metastatic neoplasm in what was initially a typical adenosarcoma with low-grade sarcomatous
Ovarian juvenile granulosa cell tumour and adenosarcoma
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Fig. 2 Juvenile granulosa cell tumor component in case 1 showing focal cytoplasmic staining with inhibin (A), diffuse nuclear and cytoplasmic staining with calretinin (B), diffuse membranous staining with CD56 (C), and diffuse nuclear staining with steroidogenic factor 1 (D).
elements. In both our cases, we made a diagnosis of adenosarcoma rather than adenofibroma given the degree of mitotic activity within the mesenchymal component. Sex cord–like elements can occur within the stromal component of adenosarcoma, including in areas of sarcomatous overgrowth [1,5,6]. They may exhibit a true sex cord immunophenotype with positive staining with sex cord markers [1,6]. Sex cord–like areas have been found to occur within a higher proportion of ovarian adenosarcomas (15%) compared with their uterine counterparts (7%) [5]. Usually, the sex cord–like elements involve only small microscopic foci, but 2 uterine adenosarcomas have been reported where the sex cord–like component comprised more than 75% of the neoplasm in keeping with overgrowth of uterine tumor resembling ovarian sex cord tumor [8]. In addition, in the largest reported series of ovarian adenosarcomas, the authors mentioned 1 case with a focal component within the stroma morphologically similar to adult granulosa cell tumor (AGCT) with diffuse and “watered-silk” patterns [5]. They also mentioned, but did not illustrate, a case where the sex cord–like elements were arranged in cords and nests as well as follicle-like spaces of varying sizes. Altogether, 6 (15%) of their 40 cases contained sex cord–like elements that accounted for between 25% and 75% of the mesenchymal component. The authors mentioned the possibility of misdiagnosis as a pure sex cord–stromal tumor when the
sex cord–like areas were prominent. We speculate that, in the 2 cases we report, the adenosarcoma represents the parent neoplasm in which there has been overgrowth of sex cord– like elements resulting in a neoplasm morphologically and immunohistochemically in keeping with a JGCT; as such, this can be regarded as an unusual form of sarcomatous overgrowth. The term JGCT was introduced because many of these neoplasms occur in young females. However, they may also occur in patients who are no longer juvenile. In the largest published study, 44% occurred in patients 10 years or younger, 34% between ages 11 and 20 years, 18% between ages 21 and 30 years, and 3% older than 30 years [9]. In the 2 cases we report, the patients were aged 58 and 69 years, which suggests a different histogenesis from that of conventional JGCT. Although we considered the possibility that our cases represent collision tumors of 2 uncommon neoplasms, especially because there was little intermingling of the 2 components, that JGCTs are very uncommon in patients older than 50 years makes this unlikely. It would also seem unlikely that 2 ovarian neoplasms that are both uncommon in themselves would occur in combination in 2 individuals. Because this represents an unusual combination of neoplasms, the prognosis is essentially unknown. Ovarian adenosarcomas have a worse prognosis than their uterine
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Fig. 3 A, Low-power view of adenosarcoma component in case 2 with increased cellularity around the epithelial elements resulting in a cambium layer. B, Mitotic figures are present within the areas of increased cellularity surrounding the epithelial elements. C and D, Juvenile granulosa cell tumor component with follicle-like spaces and epithelioid tumor cells with abundant eosinophilic cytoplasm.
counterparts, probably because of the greater ease of peritoneal spread [5]. In the largest reported series, only 6 (23%) of 26 women who had greater than 5 years postoperative follow-up were free of tumor [5]. Age younger than 53 years, tumor rupture, high grade, and the presence of high-grade sarcomatous overgrowth were associated with recurrence or extraovarian spread [5]. In the largest reported series of ovarian JGCT, follow-up was available in 95 of 125 patients (average, 5 years), and 92% of these were alive and free of disease [9]. Only tumor stage correlated with survival. In both our cases, no adjuvant therapy was administered after surgical removal. One case is recent (the stage IIB neoplasm), and in the other case (stage IA), there has been no tumor recurrence with a follow-up of 20 months. In 1 of our cases, there was endometriosis in the contralateral ovary raising the possibility that the neoplasm arose from endometriosis. It has been speculated that ovarian adenosarcomas may arise in endometriosis [10]. However, in the largest reported series, there was histologic evidence of endometriosis in only 4 (10%) of 40 cases [9]. Although this could be explained by overgrowth of underlying endometriosis, the low incidence of endometriosis tends to suggest that many or most ovarian adenosarcomas do not arise in this condition.
As well as occurring in adenosarcomas, sex cord differentiation may also be seen in ovarian epithelial and pure stromal neoplasms. An example of the latter is fibroma or thecoma with minor sex cord elements where within an otherwise typical fibroma or thecoma there are small microscopic sex cord elements (b10%) resembling Sertoli or granulosa cells [11]. A case of an ovarian serous cystadenofibroma exhibiting extensive sex cord differentiation within the stroma, in the form of solid and hollow tubules resembling Sertoli cell elements, has been reported [12]. There are also several reports of ovarian epithelial neoplasms (benign, borderline, or malignant), especially but not exclusively of mucinous type, associated with a stromal component morphologically in keeping with AGCT [13,14]. Different theories have been put forward to explain this combination, and some examples are likely to represent a collision of 2 separate individual tumors where there are 2 distinct components without intermingling. Others are likely to represent composite tumors occurring because of induction of 1 component by the other “parent” neoplasm [14]. One study reported a series of neoplasms consisting of small microscopic foci resembling AGCT (AGCT-like) within the stromal component of an epithelial neoplasm [14]. The AGCT-like components lacked FOXL2 mutations
Ovarian juvenile granulosa cell tumour and adenosarcoma [14]. FOXL2 mutations occur in most (N95%) AGCTs, and this is a sensitive and specific molecular marker of this tumor type [14,15]. That FOXL2 mutations do not occur within these AGCT-like areas within the stroma of epithelial neoplasms suggests that they are not true AGCTs but instead may represent non-neoplastic stromal proliferations morphologically indistinguishable from small AGCTs [14]. It is probable that, analogous to these AGCT-like areas, both our cases represent a proliferation within an adenosarcoma that is morphologically and immunohistochemically indistinguishable from JGCT but with a different histogenesis and molecular basis compared with conventional forms of this neoplasm. In summary, we report 2 cases of ovarian adenosarcoma associated with a predominant stromal component morphologically and immunohistochemically in keeping with JGCT; as far as we are aware, this association has not been reported previously. We speculate that, in both cases, the JGCT component arose from the adenosarcoma as an unusual form of sarcomatous overgrowth of sex cord elements.
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