Primary malignant gonadal mesotheliomas and asbestos
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1 Histopathology 2000, 37, 150±159 Primary malignant gonadal mesotheliomas and asbestos R L Attanoos & A R Gibbs Department of Histopathology, University Hospital of Wales and Llandough Hospital, Cardiff, Wales, UK Date of submission 27 October 1999 Accepted for publication 20 December 1999 Attanoos R L & Gibbs A R (2000) Histopathology 37, 150±159 Primary malignant gonadal mesotheliomas and asbestos Aims: The clinicopathological, immunohistochemical and aetiological aspects, with respect to asbestos, of seven primary gonadal mesotheliomas (three intratesticular, four ovarian) are described and compared. These tumours are extremely rare, poorly described and the knowledge of their natural history is very limited. Methods and results: The cases were collated from the UK Health and Safety Executive Mesothelioma Register over a 24-year period (1968±91). Primary mesotheliomas of the tunica vaginalis and ovary comprised 0.09% (10 cases) and 0.03% (three cases) of mesothelioma deaths, respectively. No primary intratesticular (non-tunica vaginalis) malignant mesotheliomas have been described. In this study, we present seven (three intratesticular, four ovarian) primary malignant gonadal mesotheliomas. In both genders the tumours show a similar age distribution (with median onset in the sixth decade), a similar association with asbestos (in Keywords: asbestos, malignant mesothelioma, ovary, testis approximately 50% cases), a diverse histological spectrum (with predominantly tubulopapillary epithelial subtype tumours) and an immunophenotype that is comparable with malignant pleural and peritoneal mesothelioma. The clinical course appears variable (mean, 26 months; range, 9±50 months). All tumours in the study presented as localized masses and their prognosis appeared more favourable than that of diffuse pleural and peritoneal cases. Conclusions: An awareness of the existence of these rare forms of malignant mesothelioma is important to prevent misdiagnosis. Immunohistochemistry has an important role in confirmation of the diagnosis. The accurate diagnosis of primary gonadal mesothelioma has potentially important medicolegal compensation considerations as a significant proportion of these cases are associated with asbestos. Introduction Approximately 85% of malignant mesotheliomas arise within the pleural cavities, with a further 10±15% originating from the peritoneum. 1,2 In comparison, meotheliomas arising from both the pericardium and tunica vaginalis are rare, in total representing less than 1% of all cases. 3,4 Despite the common embryological association between peritoneal mesothelium and ovarian surface epithelium, `true' ovarian mesotheliomas are very rare. 5±7 In this study, a comparative clinicopathological analysis of seven cases of malignant mesothelioma arising as localized neoplasms from the ovarian (four cases) and testicular (three cases) parenchyma are Address for correspondence: Dr R L Attanoos, Department of Histopathology, Llandough Hospital, Penlan Road, Cardiff CF64 2XX, UK. described. The differential diagnoses and relationship with prior asbestos exposures are discussed. Materials and methods CASES STUDIED The demographic data was obtained from death certificates filed in the UK Health and Safety Executive Mesothelioma Register. Cases of malignant mesothelioma arising from the tunica vaginalis testis and parenchyma, ovary and peritoneum were reviewed over the study period 1968±91. One further case of malignant mesothelioma arising from the testicular parenchyma was found during routine surgical practice. Additional clinical data including occupational history and followup information was obtained from the medical records. q 2000 Blackwell Science Limited.
2 Primary malignant gonadal mesotheliomas and asbestos 151 Table 1. Clinicopathological aspects of gonadal mesothelioma Case Sex Age (years) Symptoms Size (mm) Asbestos exposure Treatment Survival (months) 1 M 71 Hydrocoele, right testis, mass, chylous ascites 15 Yes Orchidectomy Died (not known) 2 M 77 Left testis mass (5 mm) 5 No Orchidectomy Died (50) 3 M 33 Left testis mass (40 mm) 40 No Orchidectomy Alive (37) 4 F mm ovarian mass Right abdominal pain Peritoneal implants 5 F 61 Weight loss Left ovarian mass 70 mm 6 F 66 Ascites, 20 mm mass Left ovary 7 F 66 Right ovarian and adnexal mass 30 mm, ascites (localized disease) 70 No Chemotherapy Died (11) NK Yes Palliative care Died (not known) 10 No Conservative Alive and well (38) 30 Yes Palliative care Died (9) The criteria for selection of `ovarian' mesotheliomas were taken from a previous study and included the presence of unilateral or bilateral ovarian enlargement and/or parenchymal replacement in the absence of significant peritoneal disease. 7 As in the earlier study, the presence of a minor component of extra-ovarian disease did not exclude cases from the study. HISTOLOGICAL ASSESSMENT In all cases the histological diagnosis of malignant mesothelioma was confirmed by following established criteria. Mesotheliomas were subtyped as: epithelial, biphasic or sarcomatous and the prominent architectural patterns were documented as: tubulopapillary, adenomatoid, solid epithelioid, pleomorphic, deciduoid, fibroblastic, leiomyoid (with immunohistochemical confirmation with actin and desmin immunoreactivity), chondroid, osseous and/or desmoplastic. In addition, mucin stains (alcian blue ph 2.5, and periodic acid±schiff with and without diastase) and immunohistochemistry were performed as adjunct analyses. IMMUNOHISTOCHEMISTRY Immunohistochemistry was performed by use of the ABC method with antibodies to: AE1/AE3 (prediluted: Dako, Copenhagen, Denmark); CEA (polyclonal 1:1000 Dako, and monoclonal 1:50; Dako), Leu-M1 (1:10; Becton Dickinson, Sunnyvale, CA), Ber-EP4 (1:10; Dako), thrombomodulin (1:75; Dako); CD44H (1:80; Novocastra, Newcastle, UK); calretinin (1:8000; Swant, Switzerland) and cytokeratin 5/6 (1:80; Dako). For cases with possible leiomyoid differentiation antibodies to alpha smooth muscle actin (1:256; Sigma, Poole, Dorset, UK) and desmin (1:10; Dako) were employed. ELECTRON MICROSCOPY In cases where the diagnosis was equivocal and tissue available, transmission electron microscopy was performed on a Phillips 11 electron microscope. Results Of the 883 cases of peritoneal mesothelioma registered in the United Kingdom over the study period 1968±92, 10 cases of `mesothelioma of the tunica vaginalis' or `scrotal mesothelioma' were identified and three cases of `ovarian mesothelioma' were found from data on the death certificate. Biopsy tissue and/or post-mortem material was available in two of the 10 tunica vaginalis
3 152 R L Attanoos & A R Gibbs Figure 1. Low-power appearance of an intratesticular malignant mesothelioma ( 8). mesotheliomas, and a further biopsy case was found during routine surgical practice. Two of the three cases of `ovarian mesotheliomas' were retrieved and two additional cases were identified on review of autopsy reports and tissue material. Although death was originally assigned to peritoneal mesothelioma, in both cases, post mortem did not reveal significant extra-ovarian disease and therefore they were included in the study. CLINICAL FEATURES The main clinical features are presented in Table 1. The age range for men was 33±77 years (mean, 62 years) and for women was 47±66 years (mean, 60 years). The most common symptoms in both sexes related to a mass lesion with associated serosal effusion (hydrocoele or ascites). In one female patient, weight loss was the most significant clinical feature. Occupational details were available in six cases. A history of prior asbestos exposure was evident in one Figure 3. Tubulopapillary epithelial subtype mesothelioma (case 1). male (case 1: dockyard crane driver of over 20 years duration) and one female (case 5: cleaner in asbestos factory for 7 years over the period 1945±1951). A possible domestic asbestos exposure was noted in another female (case 7: housewife, husband was a builders' labourer). No known asbestos exposure was evident for case 2 (publican licensee) or 3 (student) with testicular mesothelioma, or for case 4 (housewife, husband clerical officer) with ovarian mesothelioma. No details were available for case 6. All male subjects underwent an orchidectomy and received no adjuvant therapy. In case 2, 28 months after orchidectomy and a disease-free interval, the patient developed chest pain and dyspnoea and following biopsy a pleural mesothelioma was diagnosed. In this case the subject subsequently died of bronchopneumonia secondary to the pleural mesothelioma. All female patients were treated conservatively after the biopsy diagnosis of malignant mesothelioma was made. Follow-up was available in five cases. For two patients, survival was in excess of 3 years. In those patients who died the mean survival time was 23 months (ranged 9±50 months) PATHOLOGICAL FINDINGS Figure 2. Low-power appearance of case 6 demonstrating periadnexal disease and minimal paranchymal involvement ( 8). Grossly the testicular tumours formed primary parenchymal nonencapsulated lesions which were pale
4 Primary malignant gonadal mesotheliomas and asbestos 153 Table 2. Pathology of gonadal mesotheliomas Case Subtype Architecture Mucin Asbestos bodies (lung) 1 Biphasic Tubulopapillary; myxoid Fibroblastic stroma Psammoma bodies Alcian blue 1 Yes, occasional 2 Epithelial Tubulopapillary; solid Alcian blue 1 3 Epithelial Solid epithelioid Alcian blue 1 4 Biphasic Pleomorphic myxochondroid Alcian blue ± Not seen Lung tissue not reviewed Not seen 5 Epithelial Tubulopapillary Adenomatoid Alcian blue ± Yes, easily seen in clusters 6 Epithelial Solid epithelioid Alcian blue ± 7 Epithelial Tubulopapillary Alcian blue ± Lung tissue not reviewed No asbestos bodies seen Pleural plaque present grey in colour and firm in consistency (Figure 1). In cases 1 and 2, the tumour formed intratesticular masses (ranging 5±15 mm) and demonstrated invasion of the tunica vaginalis as a minor component via the hilum. In case 3, the tumour was purely intraparenchymal and measured 40 mm in diameter. The tunica albuginea was not involved by tumour in any of the cases. The ovarian tumours were poorly defined and of similar colour and consistency to the testicular counterparts. The tumours ranged from 10 to 70 mm in size and usually replaced the ovary. In case 6 (Figure 2), the ovary was encased by tumour but showed no unequivocal parenchymal involvement. There was no evidence of necrosis or haemorrhage. Figure 4. Loose aggregates of polygonal epithelioid cells with adundant eosinophilic cytoplasm set in a myxoid stroma (case 6). Figure 5. Adenomatoid pattern with `lace-like' appearance of vacuolated cells (case 5).
5 154 R L Attanoos & A R Gibbs Figure 6. Case 1 demonstrates a focal sarcomatous stroma with haphazard arrangement of pleomorphic and mitotically active spindle cells. The morphological features of primary gonadal mesotheliomas are shown in Table 2. By light microscopy, two of the three (67%) testicular mesotheliomas and three of four (75%) ovarian cases showed the typical histological appearances of epithelial type mesothelioma as seen in the diffuse forms of the neoplasm. In two cases, a distinct sarcomatous component was present in addition to the malignant epithelial component and these cases were morphologically similar to biphasic subtype mesothelioma. The most common architectural pattern seen in four of seven (two testicular, two ovarian) cases was tubulopapillary comprising hyaline vascular cores lined by oval or hobnail shaped cells exhibiting mild cytonuclear pleomorphism (Figure 3). Mitotic activity was inconspicuous in all four cases (, 1 per 10 hpf). In one case (case 1) numerous psammoma bodies were identified. In a further three (two testicular, one ovarian) cases, the tumour was partly or extensively composed of sheets of polygonal epithelioid cells with vesicular nuclei, prominent nucleoli and abundant eosinophilic cytoplasm set in a myxoid stroma (Figure 4). In these areas mitotic figures were more frequently seen. In two (one testicular, one ovarian) cases, the tumour had a prominent `adenomatoid' pattern with a lace-like appearance of vacuolated cells admixed with myxoid areas rich in alcianophilic material (Figure 5). In the biphasic tumours the epithelial component was of admixed tubulopapillary and adenomatoid patterns. The sarcomatous component comprised long haphazardly arranged cellular fascicles of pleomorphic spindle cells(figure 6) mitotic figures including atypical forms were more frequently seen (. 5 per 10 hpf). The immunohistochemical results are given in Table 3. All cases were diffusely positive for the pancytokeratin marker AE1/AE3. Conversely, there was no immunoreactivity with the `carcinoma' markers, Table 3. Immunohistochemical details of the gonadal mesotheliomas Case AE/13 PCEA MCEA Leu Ml Ber EP4 THR CD44H Calretinin CK 5/6 1 3D IF 3F 3D 2D 3D 2 3D F 3D 2D 3 3D ND 2D 3D 4 3D F 2F 0 3D ID 5 3D F 0 0 3D 3D 6 3D D 3D 2D 0 7 3D D 0 0 3D 3D ND, not done; D; diffuse staining; F, focal staining; PCEA; polyclonal CEA; MCEA, monoclonal CEA; THR, thrombomodulin; CK 5/6, cytokeratin 5/6.
6 Primary malignant gonadal mesotheliomas and asbestos 155 polyclonal or monoclonal carcinoembryonic antigen or Leu MI. The adenocarcinoma marker Ber EP4 showed focal membranous expression in one of three (33%) testicular and in three of four (75%) ovarian mesotheliomas. The `mesothelial' markers calretinin and cytokeratin 5/6 were positive in all three (100%) testicular cases and in three of four (75%) ovarian mesotheliomas. Thrombomodulin showed focal membranous expression in one of three (33%) testicular and two of four (50%) ovarian tumours. CD44H showed strong membranous expression in both testicular mesotheliomas studied and in one of four (25%) ovarian tumours. No leiomyoid differentiation was present based on actin and desmin immunoreactivity. Lung tissue was available for histological assessment in five of the seven cases. In case 1, the male dockyard worker had evidence of grade 2 (peribronchiolar and alveolar duct fibrosis) interstitial fibrosis in association with occasional asbestos bodies. In case 5, the asbestos factory cleaner had evidence of grade 4 fibrosis (honeycomb lung) and numerous asbestos bodies. In case 7 (possible domestic asbestos exposure) the lung exhibited no interstitial fibrosis or asbestos bodies, although pleural plaques were detailed in postmortem data. In cases 2 and 4, no history of asbestos exposure was stated and in both cases the lung parenchyma was normal with no asbestos bodies seen. In cases 3 and 6, the patients were alive precluding the formal assessment of the lung tissue. Discussion Primary malignant mesotheliomas arising from the ovary and testis are very uncommon. Of the malignant mesothelioma deaths registered in the UK, mesothelioma register over the 24 years' study period (1968±91), primary mesotheliomas of the tunica vaginalis and ovary comprised 0.09% and 0.03% mesothelioma deaths, respectively. In the literature there are three primary ovarian cases with a further seven cases representing periadnexal (probable localized ovarian peritoneal mesotheliomas). 6±8 Similarly the largest published study of tunica vaginalis mesotheliomas comprises 11 cases and the authors identified approximately 75 further cases from the literature. 4 However, this is not an accurate representation of the prevalence of these tumours for a number of reasons. First, cases identified at surgical resection are not counted unless the patient has died and `mesothelioma' was recorded on the death certificate. Secondly, on account of the aetiological association with asbestos and potential for medicolegal litigation, most mesothelioma studies are prone to selection bias. In this way, subjects working with, or exposed to asbestos via a nonoccupational means are more likely to have a tumour diagnosed as mesothelioma, than individuals developing neoplasms in a non-asbestos exposed cohort. To support this, the authors note that in five of eight (63%) registered testicular mesotheliomas, and in two of three (67%) registered ovarian mesotheliomas there was a history of asbestos exposure. This association with asbestos is stronger than in other series collated from surgical resections. Thirdly, on account of the morphological diversity of malignant mesothelioma there is potential for misdiagnosis. The World Health Organization classification of ovarian and testicular tumours each recognize `mesothelioma' as a diagnostic category although an awareness of the occurrence of the tumour at these sites is not widely known. Two of 10 (20%) testicular mesotheliomas and two of three (67%) ovarian mesotheliomas present in the mesothelioma register were available for diagnostic confirmation by use of adjunct techniques. In contrast to pleural and peritoneal mesothelioma, where some 85±90% cases are associated with prior amphibole asbestos exposure, the association between asbestos and gonadal mesotheliomas has not been well made. In the largest series of mesotheliomas of the tunica vaginalis testis, 4 only one of 11 (9%) cases had a history of asbestos exposure and many single case reports document no asbestos history. 9 In one review of 64 cases of tunica vaginalis mesothelioma, asbestos exposure was detailed in 11 of 27 (41%) and a long latent period (similar to pleural and peritoneal cases) of up to 40 years was noted. 10 However, with respect to ovarian mesothelioma, no asbestos exposure was identified in a total of 26 localized peritoneal mesotheliomas in women. 7,8 In this study with cases identified from the mesothelioma register, approximately one-half of the all gonadal mesotheliomas (33% testicular and 67% ovarian) had alleged prior asbestos exposure of occupational origin. The difference in the proportion of asbestos-related gonadal mesotheliomas in this series from others, can be partially explained by selection bias. Clearly, a life-long asbestos history is difficult to ascertain from case series collated from surgical referral specimens. In contrast, most of our cases were occupationally exposed to asbestos and therefore `recall' of exposure is high. It is possible that in a significant proportion of the reported cases where no asbestos history is documented, exposure had occurred in the past but because of the long latency from initial exposure to asbestos and the development of the tumour and subsequent death of the patient, exposure has been forgotten or not enquired into. Nevertheless, the link with asbestos exposure appears
7 156 R L Attanoos & A R Gibbs to be less strong than with pleural and peritoneal mesothelioma. The mechanisms by which inhaled asbestos fibres reach the peritoneal mesothelium and produce their tumorigenic effects are poorly understood. Asbestos fibres have been noted in the peritoneum and are considered to have originated from either inhaled fibres passing through the lung, pleura and diaphragm, or via migration across the gastrointestinal tract wall from swallowed expectorated mucus. 11 In addition, asbestos fibres within the bladder may potentially traverse the bladder wall. In the female, the peritoneum is `open' at the ostia of the fallopian tubes providing an additional means of access of asbestos to the pelvic peritoneum and ovarian surface. An association between asbestos and gastrointestinal, pancreatic and ovarian carcinoma has also been made in some series 12 but the case is far from confirmed. To date, no consistent link has been demonstrated between asbestos and intra-abdominal malignancy other than peritoneal mesothelioma. The results of this study strongly suggest an additional association between asbestos exposure and localized primary ovarian and testicular mesothelioma. Further multicentre studies with formal mineral analysis are considered essential to address issues pertaining to dose-response effect and tumour latency. In this study of primary malignant gonadal mesotheliomas, a number of clinicopathological features are shared between the cases in the different genders. The localized gonadal malignant mesotheliomas have a similar age distribution with peak onset on the sixth decade and presentation with masses or effusions. In both testicular and ovarian types of gonadal mesothelioma the epithelial subtype of mesothelioma is predominant (67% men, 75% women) and sarcomatoid variants are not identified. This compares closely with the findings of one large series of malignant peritoneal mesotheliomas in which the epithelial subtype accounted for 75%, biphasic 22% and sarcomatous variant 2.4% cases, respectively. 2 Similarly in the series of 19 genital and peritoneal mesotheliomas in women, 85% were epithelial and 15% were biphasic subtype tumours. 8 The spectrum of architectural patterns are similarly diverse in primary gonadal mesotheliomas with tubulopapillary (58%) and solid epithelioid (28%) patterns being most common. The socalled deciduoid peritoneal mesothelioma 13 described exclusively in peritoneal mesotheliomas in women was not seen but in the authors' experience it does not represent either a gender or site specific morphological appearance in malignant mesothelioma. The differential diagnoses in malignant gonadal mesothelioma are similar in both genders, and include mesothelial hyperplasia, adenomatoid tumour, well differentiated papillary mesothelioma, malignant germ cell neoplasia (embryonal carcinoma, yolk sac tumour), neoplasms of MuÈ llerian-type and rete (testis/ovarii) origin, desmoplastic small round cell tumour and metastatic tumours. Diagnostic distinction of primary gonadal mesothelioma from diffuse peritoneal mesothelioma may not be possible in small biopsies, as the spectrum of histological and immunophenotypic profiles are identical and confirmation requires radiological or surgical information pertaining to the tumour site and distribution. Diffuse peritoneal mesothelioma may invade the tunica vaginalis and present as a testicular mass although this is very rare. Similarly, ovarian parenchymal involvement in diffuse peritoneal mesothelioma in uncommon. From the 25 years analysis of the Health and Safety Executive Mesothelioma Register, 59 peritoneal mesotheliomas in women were identified (unpublished results). Ovarian involvement was seen in only four (7%) cases and was confined to the serosa and superficial cortex. In contrast, in one other study of 13 diffuse peritoneal mesotheliomas in women, ovarian involvement was seen in 10 patients. These authors reported a further five localized mesotheliomas although none was identified as a primary ovarian tumour. 8 The immunohistochemical features of gonadal mesotheliomas appear similar in both genders and compare closely to that found in diffuse peritoneal mesothelioma. 14,15 The tumours are consistently immunoreactive for pan-cytokeratin and negative with the carcinoma markers, carcinoembryonic antigen and Leu M1. The adenocarcinoma marker Ber EP4 shows some immunoreactivity in 58% gonadal mesotheliomas precluding its use as a first line antibody in the distinction of adenocarcinoma from mesothelioma. The mesothelial markers cytokeratin 5/6 and calretinin were found to be most uniformally expressed in epithelial subtypes of mesothelioma although the stromal component in both biphasic gonadal mesotheliomas was negative with both markers. Thrombomodulin expression was seen in approximately 42% mesotheliomas in this series. Comparative immunohistochemical studies of ovarian and testicular (tunica vaginalis) mesotheliomas are limited but support the notion that the immunophenotype in these anatomical locations are similar to those in the pleura and peritoneum. Particularly in small biopsy specimens, florid reactive mesothelial hyperplasia may mimic malignant mesothelioma. Benign mesothelial proliferation is a common response to serosal injury and may be seen in
8 Primary malignant gonadal mesotheliomas and asbestos 157 hernia sacs 16 in the adnexae of women with chronic salpingitis, endometriosis and in response to adjacent ovarian neoplasia. 17 A diagnosis of reactive mesothelial hyperplasia is favoured if macroscopically there is no tumour mass and light microscopy reveals small sheets of mesothelial cells which lack marked cytonuclear atypia, necrosis, papillary formation and deep stromal invasion. Superficial extension of mesothelial cells arranged in parallel and linear layers may be seen in benign mesothelial proliferations. Inflammation per se is unreliable as an indicator of benignancy. The role of immunohistochemistry in the distinction of benign and malignant mesothelial proliferation is limited although epithelial membrane antigen, 18 p53, 19 platelet-derived growth factor-beta chain 20 and p have been reported to be of use. A lack of staining with the stated markers is considered to favour a benign process, although their reliability requires further scrutiny before use in routine surgical practice. In the ovarian and testicular adnexa, benign mesothelial tumours such as adenomatoid tumour and well-differentiated papillary mesothelioma have been reported. 6, 22±23 In this series, morphological features simulating both these lesions were seen in both sexes, although the diagnosis of malignant mesothelioma was favoured by the presence of tumour necrosis, marked cytological atypia, focal biphasic growth pattern and infiltrative growth pattern. Large tumour size and a diffuse serosal growth pattern are useful diagnostic features although for primary intragonadal mesotheliomas this important diagnostic feature has less utility. In the ovary, the main neoplastic differential diagnosis of primary gonadal tubulopapillary epithelial subtype mesothelioma is with primary serous papillary carcinoma and is important because of the different aetiological considerations, clinical course and treatment. 24,25 Despite occasional claims there is no clear association between ovarian carcinoma and asbestos. Macroscopically, the two tumours may be indistinguishable, although in this study and in one other study on ovarian mesothelioma the tumours did not exceed 150 mm and showed no cystic appearance as is common in serous carcinomas. By light microscopy, serous papillary carcinomas have broader papillae, may demonstrate cellular stratification and budding and are lined by columnar cells exhibiting more marked nuclear atypia than are commonly seen in tubulopapillary mesotheliomas. Psammoma bodies are more frequent in serous ovarian neoplasms although they can be seen in about 5% of peritoneal mesotheliomas and they were identified in one case (14%) of seven gonadal mesotheliomas. Clear cell carcinoma of the ovary and peritoneum 26 may also mimic malignant mesothelioma with tubulopapillary areas, hyaline cores and hobnail cells. Nuclear atypia is usually more marked in clear cell carcinoma and neutral mucin may be present which would make a diagnosis of mesothelioma very unlikely. Rarely, morphologically similar MuÈ llerian-type neoplasms have been described in the paratesticular region. 27 In both ovary and testis certain forms of germ cell neoplasia may produce diagnostic difficulty with primary gonadal mesothelioma. Yolk sac tumours demonstrate a prominent fine reticulated `lacy' pattern and tubulopapillary areas are also seen. These morphological patterns may mimic tubulopapillary or adenomatoid pattern epithelial subtype mesothelioma. Yolk sac tumour is favoured by its occurence in a younger age group. The typical Schiller±Duval bodies are not seen in malignant mesothelioma. Immunohistochemical expression of alpha fetoprotein would further support the diagnosis of yolk sac tumour. Malignant teratoma (and malignant mixed MuÈ llerian tumours) are considered as favoured differential diagnoses in the differential diagnosis of biphasic cases of gonadal mesothelioma. In each case careful attention to the morphological and immunophenotypic appearances of the epithelial component in each tumour should allow for adequate distinction from malignant mesothelioma. In none of the primary testicular mesotheliomas was there evidence of intratubular germ cell neoplasia. Tumours of rete (ovarii or testis) origin are extremely uncommon although morphologically produce tubulopapillary structures and may mimic epithelial mesothelioma. 28 Limited immunohistochemical studies suggest that the tumour are cytokeratin and epithelial membrane antigen positive and 25% expressed CEA. However, ultrastructural studies allowed for distinction from malignant mesothelioma on account of the shorter microvillous structure and lack of dense perinuclear tonofilaments seen in neoplasms of rete origin. Metastatic tumour may invade the ovarian and testicular parenchyma. In most ovarian cases diffuse gastric adenocarcinoma (Krukenberg tumour), colonic, breast or pulmonary carcinoma are the primary tumour sites and are clinically apparant prior to the diagnosis of an ovarian tumour. 29 In the testis, prostatic and pulmonary carcinoma metastases are most frequently documented and form intraparenchymal lesions. 30,31 In contrast, most cases of malignant mesothelioma at this site form a diffuse serosal growth within the tunica vaginalis. Further distinction should
9 158 R L Attanoos & A R Gibbs be straight forward by use of mucin stains and appropriate immunohistochemical studies. Malignant gonadal mesotheliomas appear to follow a variable clinical course with mean survival from diagnosis of 26 months and survival times over 3 years recorded in three (42%) of the seven cases. In some of our cases the tumour behaviour was found to be similar to that seen in diffuse pedtoneal mesothelioma. Survival for longer than 5 years is exceptional in bone fide cases of diffuse peritoneal mesothelioma although rare cases have been reported. 31,32 Extent of disease at presentation is important prognostically with localized tumours conferring a more favourable prognosis. In one series only localized mesothelial tumours with a uniform benign morphological appearance were found to predictably have a benign clinical behaviour, and diffuse or multifocal tumours were invariably associated with more malignant cytonuclear features and a progressive clinical course. 8 In the two gonadal mesotheliomas associated with prolonged survival, no histopathological features were identified which may be considered to be associated with an indolent course. Furthermore neither case represented an adenomatoid tumour, multicystic mesothelioma or well-differentiated papillary mesothelioma. The presence of ascites and abdominal mass formation or recurrent hydrocele are often associated with malignant forms of mesothelioma but are not specific clinical findings. In summary, we present seven primary malignant gonadal mesotheliomas. These tumours represent a poorly described tumour category in both sites. An awareness of their existence is important to prevent misdiagnosis. 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