Tumoren des Gonadenstromas

According to the World Health Organization (WHO) classification from 2004, sex cord gonadal stromal tumors are divided into Leydig cell tumors, Sertoli cell tumors, granulosa cell tumors, tumors of the thecoma-fibroma group, incompletely differentiated sex cord gonadal stromal tumors, mixed forms of sex cord gonadal stromal tumors and tumors containing both germ cell and sex cord gonadal stromal elements. These tumors can appear sporadically or in combination with hereditary syndromes. To diagnose these rare tumors the combination of characteristic morphological aspects and various immunohistochemical markers is useful. Latest investigations demonstrate the potential role of mutation analyses in the diagnosis of this heterogeneous group of tumors.     

Recent developments in gastroesophageal mesenchymal tumours

The pathologist’s approach to gastroesophageal mesenchymal tumours has changed dramatically during the last 25 years. In particular, gastrointestinal stromal tumour (GIST) has evolved from a wastebasket mesenchymal tumour category to a precisely defined entity with an increasingly detailed genetic subclassification. This subclassification has brought gastrointestinal mesenchymal neoplasia into the realm of precision medicine, with specific treatments optimised for particular genetic subtypes. Molecular genetic data have also greatly improved our understanding of oesophageal mesenchymal tumours, including the discovery that so‐called ‘giant fibrovascular polyps’ in fact represent a clinically distinctive presentation of well‐differentiated liposarcoma. Here, we will focus on gastroesophageal mesenchymal tumours for which there have been recent developments in classification, molecular genetics or tumour biology: granular cell tumour, ‘giant fibrovascular polyp’/well‐differentiated liposarcoma, plexiform fibromyxoma, gastroblastoma and, of course, GIST.     

Endokrine Tumoren des Hodens

The most characteristic endocrine tumours of the testis are germ cell tumours and sex cord/gonadal stromal tumours. They include the primary carcinoid, the relation of which to teratomas is still unclear. In general, gonadal stromal tumours are rare, however, endocrine activity occurs in at least 10%-20%. Among gonadal stromal tumours, only Leydig cell tumours and Sertoli cell tumours are of practical importance. Endocrine disorders are mostly related to Leydig cell tumours (gynaecomastia, pubertas praecox). Although less frequent than the other gonadal stromal tumours, they can, in principle, occur. The large cell calcifying Sertoli cell tumour occurs in association with other complex disorders (i.e. Peutz-Jeghers syndrome). Valuable markers are: inhibin, calretinin, cytokeratin, melan-A, CD-99, Ki-67, androgen receptor and p53. As the conventional morphology and immunohistological markers frequently overlap, unclear cases should be referred to specialised centres.     

Diagnostic value of inhibin immunoreactivity in ovarian gonadal stromal tumours and their histological mimics

Aims : Inhibin is a heterodimeric protein hormone which appears to be a sensitive serological and immunohistochemical marker of ovarian granulosa cell tumours. The purposes of this study were to examine inhibin immunoreactivity in a wide range of gonadal stromal neoplasms and to assess its value in the differential diagnosis of problematic ovarian tumours. Methods and results : Inhibin immunostaining was identified in eight cases of stromal hyperthecosis, 24 adult-type granulosa cell tumours, two juvenile granulosa cell tumours, nine Sertoli cell or Sertoli–Leydig cell tumours, one gynandroblastoma, three gonadoblastomas, two cases of sex cord tumour with annular tubules, two steroid cell tumours and two sclerosing stromal tumours. Inhibin was also present in 4/6 fibrothecomas and 2/3 unclassified gonadal stromal tumours. There was no staining of neoplastic cells in any of the problematic ovarian tumours, in many of which a diagnosis of gonadal stromal tumour had been initially considered. However, inhibin was detected in reactive stromal cells in many cases. Conclusions : Inhibin is a sensitive immunohistochemical marker of a wide range of gonadal stromal tumours and is of value in the differential diagnosis of ovarian neoplasia.     

Recent developments in uterine mesenchymal neoplasms

Smooth muscle and endometrial stromal tumours represent the two most common uterine mesenchymal neoplasms that may present diagnostic dilemmas for the practising surgical pathologist. Recent changes in morphological and staging criteria, as well as the discovery of new immunohistochemical markers, have improved the diagnosis and classification of these tumours. We highlight the difficulty in distinguishing tumour cell necrosis from infarct‐type necrosis and the limited utility of p16 immunohistochemical expression in the diagnosis of leiomyosarcoma. We also discuss the controversial use of mitotic activity and necrosis as prognostic factors in endometrial stromal sarcomas. Emerging genetic information has also greatly expanded our understanding of ‘sarcomagenesis’ in both tumour types and may provide insight into potential therapeutic targets for the treatment of leiomyosarcoma and endometrial stromal sarcomas, harboring MED12 (mediator complex subunit 12) mutations and recurrent gene rearrangements, respectively. In this review, we discuss the core updates in the diagnosis and classification of uterine leiomyosarcomas and endometrial stromal sarcomas, highlighting new and important molecular genetic findings that may drive pathogenesis.     

Origin and evolution of somatic cell testicular tumours in transgenic mice

Transgenic mice bearing a construct in which the expression of the SV40 oncogene is directed by the AMH promoter (AT mice) develop testicular tumours in adult life. We aimed to study early steps of tumour development and characterize tumours at different ages by histological, morphometric, and immunohistochemical techniques. One‐ to 3‐month‐old AT mice depicted multifocal Leydig cell hyperplasia. The testicular volume occupied by interstitial tissue was significantly higher in 3‐month‐old AT mice in comparison with littermate controls. Between 5 1/2 and 7 months, microscopic interstitial tumours developed that progressively evolved to form large confluent areas of high mitotic index in 7‐ to 14‐month‐old AT mice. Tumour cells had the characteristics and histoarchitecture of Leydig cells, or formed solid cord‐like structures reminiscent of those seen in Sertoli cell tumours. Hyperplastic areas and tumours diffusely expressed 3β‐hydroxysteroid dehydrogenase (3β‐HSD) in Leydig cell areas. AMH expression was negative in Leydig cell conglomerates and tumours and variable in cord‐like tumours. The SV40 T antigen and markers of cell proliferation (PCNA) were intensely positive in hyperplastic cells and tumours. Control mice of similar ages showed neither hyperplasia nor tumours, and SV40 T expression was always negative. In conclusion, transgenic mice develop large testicular tumours that are preceded by interstitial hyperplasia and microtumours. The histological and immunohistochemical phenotype of tumours (Leydig and Sertoli cell differentiation, positive 3β‐HSD, and variable AMH) suggests a mixed differentiation of somatic cells of the specialized gonadal stroma. The finding that an oncogene directed by a promoter specifically active in fetal Sertoli cells has given rise to testicular tumours of mixed differentiation is compatible with a common origin of Leydig and Sertoli cells from the specific stroma of the gonadal ridge, as supported by double labelling experiments in fetal mice showing co‐localization of the transgene with Sertoli and Leydig cell markers. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Value of A103 (melan-A) immunostaining in the differential diagnosis of ovarian sex cord stromal tumours

AIMS: To assess A103 (melan-A) immunoreactivity in a range of ovarian sex cord stromal tumours and to evaluate it for the differential diagnosis of other neoplasms. METHODS: Paraffin embedded tissue sections from 45 sex cord stromal tumours and 44 potential histological mimics were examined immunohistochemically using the antibody A103. The sex cord stromal group included 21 adult granulosa cell tumours (AGCT), two juvenile granulosa cell tumours (JGCT), eight tumours showing Sertoli cell or Sertoli-Leydig cell differentiation, two unclassified tumours, two gonadoblastomas, one sex cord tumour with annular tubules, two steroid cell tumours, five thecomas/fibrothecomas, and two sclerosing stromal tumours. The histological mimics include 14 primary ovarian carcinomas, 13 metastatic carcinomas, four carcinoid tumours, four lymphomas, three endometrioid stromal sarcomas, two ovarian tumours of probable Wolffian origin, and one case each of small cell carcinoma, desmoplastic small round cell tumour, melanoma, and primitive neuroectodermal tumour. RESULTS: A103 immunoreactivity was identified in 25 sex cord stromal tumours including 10 AGCT, two JGCT, six Sertoli/Sertoli-Leydig cell tumours, two steroid cell tumours, three thecomas/fibrothecomas, and two sclerosing stromal tumours. Of the potential histological mimics, staining was present only in the two ovarian tumours of probable Wolffian origin and the melanoma. Immunoreactive stromal cells were noted in a minority of cases. Normal hilus cells and rete ovarii epithelium also expressed A103. CONCLUSIONS: A103 is a moderately sensitive and specific marker of sex cord stromal differentiation within the range of tumours examined in this study and as such is a valuable adjunct to other immunocytochemical markers in the assessment of diagnostically problematic ovarian tumours. The staining of normal and neoplastic Wolffian elements merits further investigation.     

Gynandroblastoma. Report of an unusual ovarian tumour and literature review

Gynandroblastoma is a rare variant of ovarian sex cord stromal tumours that demonstrates morphological evidence of both male and female differentiation. We report a new case of gynandroblastoma in a 22-year-old nulliparous female with a history of menstrual disturbance. Physical examination disclosed a painless pelvic mass measuring 20 cm across with normal secondary sex characteristics, and no signs of virilisation. Histological examination of the surgically resected primary tumour revealed a predominant adult granulosa cell component admixed with a minor Sertoli cell component that did not exceed 20% of the tumour. Immunohistochemical analysis showed positive immunostaining of Sertoli cell areas with inhibin. The final diagnosis was gynandroblastoma. The post-operative course was uneventful and there was no evidence of recurrence during the 9-month follow-up period.     

Papillary and neuroendocrine breast lesions: the WHO stance

In this review, we highlight adaptations in the WHO 2012 classification of papillary and neuroendocrine breast lesions as compared with the previous 2003 version. Consensus criteria for distinguishing atypical ductal hyperplasia from ductal carcinoma in situ within an intraductal papilloma are proposed. The absence of myoepithelial cells around the wall of an encapsulated papillary carcinoma, although raising consideration of an indolent tumour with minimal invasion, is currently regarded as in‐situ disease for staging purposes. The majority of solid papillary carcinomas are classified as in‐situ tumours, but lesions with irregular tumour islands within desmoplastic stroma may be considered to be invasive. The diagnosis of solid papillary carcinoma without further qualification as either in‐situ or invasive disease is discouraged. When invasive papillary carcinoma is seen in the breast, metastatic papillary carcinoma from other organ sites needs to be excluded. WHO 2012 classifies neuroendocrine breast tumours as well‐differentiated neuroendocrine tumour, small‐cell carcinoma, and invasive breast carcinoma with neuroendocrine differentiation. There is currently no clinical impact of identifying neuroendocrine differentiation in conventional invasive breast carcinomas, apart from acknowledging its frequent occurrence in subtypes such as the hypercellular variant of mucinous carcinoma and solid papillary carcinoma.     

Practical roles for molecular diagnostic testing in ovarian adult granulosa cell tumour,Sertoli–Leydig cell tumour,microcystic stromal tumour and their mimics

Within the last decade, molecular advances have provided insights into the genetics of several ovarian sex cord–stromal tumours that have otherwise been enigmatic. Chief among these advances are the identification of FOXL2, DICER1 and CTNNB1 mutations in adult granulosa cell tumours, Sertoli–Leydig cell tumours (SLCTs), and microcystic stromal tumours (MCSTs), respectively. As access to molecular diagnostic laboratories continues to become more widely available, the potential roles for tumour mutation testing in the pathological diagnosis of these tumours merit discussion. Furthermore, links to inherited cancer susceptibility syndromes may exist for some women with SLCT (DICER1 syndrome) and MCST [familial adenomatous polyposis (FAP)]. This review will address practical issues in deciding when and how to apply mutation testing in the diagnosis of these three sex cord–stromal tumours. The pathologist's role in recommending referral for formal risk assessment for DICER1 syndrome and FAP will also be discussed.     

Clear cell renal cell carcinoma with wild‐type von Hippel‐Lindau gene: a non‐existent or new tumour entity?

The current World Health Organisation (WHO) classification of renal tumours is based on characteristic histological features or specific molecular alterations. von Hippel‐Lindau (VHL) alteration is the hallmark of clear cell renal cell carcinoma (RCC). After identification of the MiT translocation family of tumours, clear cell papillary renal cancer and others, the group of ccRCC with wild‐type VHL is small. TCEB1 mutation combined with chromosome 8q loss is an emerging tumour entity with wild‐type VHL. Inactivation of TCEB1 increases HIF stabilisation via the same mechanism as VHL inactivation. Importantly, recent molecular analyses suggest the existence of another ‘VHL wild‐type’ evolutionary subtype of clear cell RCC in addition to TCEB1 mutated RCC and clear cell papillary renal cancer. These tumours are characterised by an aggressive behaviour, high tumour cell proliferation rate, elevated chromosomal instability and frequent presence of sarcomatoid differentiation. Future clinicopathological studies will have to provide data to determine whether TCEB1 tumours and clear cell RCC with wild‐type VHL are separate tumour entities or represent variants of a clear cell RCC tumour family.     

Malignant sex cord–stromal tumour in a patient with the androgen insensitivity syndrome

A malignant sex cord–stromal tumour that occurred in a 56-year-old patient with the androgen insensitivity syndrome is reported. Although hamartomas composed of sex cord cells are common in the testes of patients with this syndrome, unequivocal neoplasms of sex cord type are rare. The tumour described herein most closely resembled, but lacked the overall morphology of, a juvenile granulosa cell tumour, and Charcot-Böttcher filaments, indicative of Sertoli cell differentiation, were seen on electron microscopy. The features of the androgen insensitivity syndrome and the various tumours that have been reported in patients with this syndrome are briefly reviewed.     

Germ cell neoplasia in situ (GCNIS): evolution of the current nomenclature for testicular pre‐invasive germ cell malignancy

The pre‐invasive lesion associated with post‐pubertal malignant germ cell tumours of the testis was first recognized in the early 1970s and confirmed by a number of observational and follow‐up studies. Until this year, this scientific story has been confused by resistance to the entity and disagreement on its name. Initially termed ‘carcinoma in situ’ (CIS), it has also been known as ‘intratubular germ cell neoplasia, unclassified’ (IGCNU) and ‘testicular intraepithelial neoplasia’ (TIN). In this paper, we review the history of discovery and controversy concerning these names and introduce the reasoning for uniting behind a new name, endorsed unanimously at the World Health Organization (WHO) consensus classification 2016: germ cell neoplasia in situ (GCNIS).     

The C134W (402 C>G) FOXL2 mutation is absent in ovarian gynandroblastoma: insights into the genesis of an unusual tumour

Oparka R, Cassidy A, Reilly S, Stenhouse A, McCluggage W G & Herrington C S
(2012) Histopathology  60, 838–842
The C134W (402 C>G) FOXL2 mutation is absent in ovarian gynandroblastoma: insights into the genesis of an unusual tumour Aims: Ovarian gynandroblastomas are rare tumours that, by definition, comprise a combination of components resembling both female, typically granulosa cell tumour (GCT), and male, typically Sertoli or Sertoli/Leydig cell tumour (ST/SLT), sex cord/stromal differentiation. The histogenesis of these tumours is unknown and, in view of the very strong association between the C134W (402 C>G) FOXL2 mutation and adult‐type GCT, we analysed a series of gynandroblastomas for this mutation. Methods and results: Both components of each lesion were isolated by laser capture microdissection and the C134W (402 C>G) FOXL2 mutation was analysed by polymerase chain reaction sequencing. No mutation was identified in either the GCT or ST/SLT component of six cases, three of which contained adult‐type GCT. Conclusions: This suggests that, despite their similar morphological appearances, the GCT‐like component of gynandroblastoma has a different molecular basis from conventional adult‐type GCT. This finding underscores a more general principle that morphological similarity does not necessarily indicate molecular identity.     

Molecular-cytogenetic characterisation of sex cord-stromal tumours: CGH analysis in sertoli cell tumours of the testis

Sertoli cell tumours (SCT) are rare and poorly explored neoplasias, and the genetic features of these uncommon tumours are largely unknown. Data about chromosomal aberrations in human SCT of the testis are very rare. We present in this paper the first molecular-cytogenetic study of SCT of the testis. DNA was isolated from paraffin-embedded tumour material from 11 patients with unilateral SCT. We used comparative genomic hybridisation to investigate changes in DNA copy number. The detected DNA imbalances showed variation from case to case, indicating a high genetic heterogeneity. Chromosomal aberrations were detected in 9 of the 11 tumours evaluated, with 13 losses versus 14 gains. The most frequent aberrations detected were gain of chromosome X (5 of 11 cases) followed by losses of entire or part of chromosomes 2 and 19 in three cases. This study suggests a high variability in histomorphological and genetic patterns. Only gain of the entire chromosome X seems to be a frequent aberration in these tumours. Further studies of these tumour types are necessary to clarify the significance of chromosomal alterations in carcinogenesis of SCT.     

Sclerosing stromal tumours of the ovary

Sclerosing stromal tumours of the ovary have recently been described as a histologically and clinically distinct subgroup within the thecoma-fibroma spectrum of benign ovarian sex cord stromal tumours. Reported cases occurred predominantly in young women and only occasional tumours showed evidence of hormonal activity. The present series of five cases expands the spectra of both histological patterns and clinical presentations and suggests that the entity of sclerosing stromal tumours may not be as clearly circumscribed as has been previously reported.     

Testicular sex cord stromal tumour with granulosa cell differentiation: detection of steroid hormone receptors as a possible basis for tumour development and therapeutic management.

A testicular sex cord stromal tumour with granulosa cell differentiation, typical of granulosa cell tumours of the adult type, was investigated immunohistologically on snap frozen and paraffin wax embedded material. The predominance of vimentin and the additional expression of cytokeratin subtypes 8 and 18, as well as the negative staining for epithelial membrane antigen, accorded with results previously reported, for ovarian granulosa cell tumours; the lack of expression of desmoplakin, however, was a distinctive feature. Together with negative staining for leucocyte common antigen, the antigen pattern facilitates the differential diagnosis between granulosa cell tumour and undifferentiated carcinoma or gonadal lymphoma, although its suitability for differentiating within the group of gonadal stromal tumours seems to be limited. The small growth fraction, shown by the monoclonal antibody Ki-67, is typical of the clinical behaviour of granulosa cell tumours. The expression of oestrogen and progesterone receptors, also recently found in testicular Leydig cell tumours, may provoke new approaches to the management of testicular granulosa cell tumours, as well as a new hypothesis on the development of these tumours.     

The 2022 World Health Organization classification of germ cell tumors and updates of American Joint Committee for Cancer tumor staging classification

Testicular tumors are most common in young men between 15 and 45 years of age. Germ cell tumors make up the biggest proportion of malignant tumors of the testis. Due to the diverse morphologic spectrum and overlapping morphologies, it is a very challenging area in the anatomic pathology field, which needs significant expertise and experience to render a precise diagnosis. The World Health Organization (WHO) has recently presented a new tumor classification with significant modifications in nomenclature as well as some refinement of criteria. The changes encompass germ cell tumors, sex cord stromal tumors, and tumors arising from testicular appendages. The "primitive neuroectodermal tumor (PNET)" terminology is replaced with "embryonic-type neuroectodermal tumor (ENET). The carcinoid terminology is replaced with neuroendocrine tumors (NET). In sex cord stromal tumors, two new entities were included, "Signet ring stromal tumor" and "Myoid gonadal stromal tumor" in the new classification. Sertoliform cystadenoma is now considered a sertoli cell tumor (NOS). "Well-differentiated papillary mesothelioma" is now termed as "well-differentiated papillary mesothelial tumor." Tumor Node Metastasis (TNM) Classification published by the American Joint Committee for Cancer (AJCC) is recommended for testicular tumors listed as germ cell tumors. In its 8th edition, the AJCC has provided regular updates in printed form as AJCC tumor classification. Currently, the AJCC has changed its process of publishing the TNM classification and is moving away from editions, and the new updates will be released as versions. Several organ systems have already updated the content, while the remaining will be updated per their scheduled timeline.     

Distribution of alpha glutathione S-transferase in ovarian neoplasms: an immunohistochemical study

AIMS: Alpha glutathione S-transferase (alpha-GST) has been shown to be an immunohistochemical marker for delta(4-5) isomerase, an enzyme active in steroidogenesis. The purpose of this study was to document the distribution of alpha-GST in ovarian neoplasms in order to evaluate its usefulness as a diagnostic tool. METHODS AND RESULTS: A total of 92 tumours (25 sex cord/stromal, 53 epithelial and 14 germ cell) were subjected to immunohistochemistry using a commercially available polyclonal antibody to alpha-GST. The avidin-biotin complex was used as a detection system. Positive staining was found in luteinized stromal cells of all tumour types (58/92). This included the Leydig cells of Sertoli-Leydig cell tumours (7/7) and was particularly prominent in the stromal cells of both benign and malignant mucinous tumours (24/25). Granulosa and Sertoli cells showed weak or no intracytoplasmic staining, which is expected because they do not normally produce androstenedione. They did show some intranuclear staining. Malignant mucinous (12/25) and occasional other epithelial tumours showed focal intracytoplasmic positive staining. Yolk sac tumours showed focal positivity (7/8). CONCLUSIONS: Intracytoplasmic staining of stromal cells is considered to indicate steroidogenesis and intranuclear staining the intracytoplasmic transport function of alpha-GST. The intracytoplasmic staining of mucinous carcinomas might represent an up-regulation of some detoxification function. The findings suggest that antibody to alpha-GST has some value in the investigation of ovarian pathology and could readily be included in any panel of antibodies used to investigate ovarian neoplasms of uncertain histogenesis.