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J Clin Pathol 1990;43:287-290 287 Histogenesis of ovarian malignant mixed mesodermal tumours J Clin Pathol: first published as 10.1136/jcp.43.4.287 on 1 April 1990. Downloaded from

T J Clarke

Abstract embedded tumour were cut at 4 im and The histogenesis of ovarian malignant stained with haematoxylin and eosin, periodic mixed mesodermal tumours, which acid Schiff (PAS) before and after diastase includes the concept of metaplastic car- treatment, Caldwell and Rannie's reticulin cinoma, is controversial. Four such stain, and phosphotungstic acid haematoxylin tumours were examined for evidence of (PTAH). Sequential sections were stained by metaplastic transition from carcinoma to the indirect immunoperoxidase technique using morphology and reticulin using monoclonal antibodies directed against stains. Consecutive sections were stained cytokeratin (PKK1 which reacts with low immunohistochemically using cyto- molecular weight cytokeratins of44, 46, 52 and keratin and vimentin to determine 54 kilodaltons), vimentin, a-l-antitrypsin and whether cells at the interface between myoglobin. Appropriate positive and negative carcinoma and sarcoma expressed both controls, with omission of specific antisera in cytokeratin and vimentin. There was no the latter, were performed. Haematoxylin and evidence ofmorphological, architectural, eosin stained sections were examined for or immunohistochemical transitions secondary fluorescence using a Leitz Dialux from carcinoma to sarcoma in the four 20ES microscope and mercury vapour light tumours studied. This suggests that source epifluorescence. ovarian malignant mixed mesodermal Four patients, aged 68, 71, 72 and 73 presen- tumours are not metaplastic carcinomas ted with abdominal distension and discomfort but are composed of histogenetically dif- and were found to have an ovarian malignant ferent elements. mixed mesodermal tumour of at least FIGO stage III.'" Three of the women were nulliparous and the parity of the fourth was not Ovarian malignant mixed mesodermal tumours known. Three died within one year of opera- are rare that arise typically in tion and one was alive and free from disease http://jcp.bmj.com/ nulliparous, postmenopausal women.1 nine years after surgery. None of the patients Recently they have been referred to as "mixed received radiotherapy or chemotherapy after Mullerian tumours of high grade malignancy" surgery. Necropsy was performed in one or as "". The prognosis is patient who died eight days after operation. bleak and most patients die within 12 months of This case has been reported previously.'" presentation.23 5 Theories concerning the his- togenesis of malignant mixed mesodermal on September 29, 2021 by guest. Protected copyright. tumours of the female genital tract have been Histopathology described as "a matter of art rather than of The tumours were all large at initial presenta- science".6 The same theoretical problems con- tion, ranging from 15 to 22 cm in maximum cerning histogenesis are encountered with diameter. Three were typical, solid, and cystic "carcinosarcomas" at other sites such as ovarian malignant mixed mesodermal tumours breast,' ,89 colon,'0 and urinary bladder." 12 composed of a haphazard mixture of adenocar- It has been suggested that ovarian malignant cinoma and undifferentiated sarcoma (fig 1), mixed mesodermal tumours are "metaplastic with heterologous elements of rhabdomyosar- carcinomas" in which the sarcomatous com- coma in one and chrondosarcoma in another. ponent (homologous and heterologous) arises The tumour in the fourth case was a unilocular directly from the carcinomatous component serous containing several (usually glandular in type). The concept of discrete intramural sarcomatous nodules up to metaplastic carcinomas differs from that of 2-5 cm in diameter and a 5 5 cm in diameter carcinosarcomas, which are regarded as fibroma. At necropsy a separate metastatic heterogeneous tumours of combination, com- spread of carcinoma and sarcoma was found; position, or collision in type.'3 This study was para-aortic lymph nodes contained metastatic Department of undertaken to investigate whether there were Histopathology, squamous carcinoma and the con- Derriford Hospital, morphological, cytoarchitectural, and tained deposits of sarcoma including rhab- Plymouth immunohistochemiccal transitions from car- domyosarcoma. There was no evidence of T J Clarke cinoma to sarcoma in ovarian malignant mixed endometriosis or teratomatous differentiation Correspondence to: mesodermal tumours. in any of the four tumours. Dr T J Clarke, Area Department of , Multiple sections of each tumour were Royal Devon and Exeter examined for evidence ofmorphological transi- Hospital, Exeter EX2 5DY Methods tion Accepted for publication between carcinoma and sarcoma and none 19 October 1989 Sections of formalin fixed, paraffin wax was found. Reticulin stains showed a crisp 288 Clarke J Clin Pathol: first published as 10.1136/jcp.43.4.287 on 1 April 1990. Downloaded from

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Figure I Ovarian malignant mixed mesodermal tumour Figure 2 Contrast in retzculin patterns between composed of adenocarcinoma and sarcoma. adenocarcinoma and sarcoma. (Rannie's reticulin.) (Haematoxylin and eosin.) demarcation in cytoarchitecture between the Coexpression of cytokeratin and vimentin periglandular pattern of adenocarcinoma and within the same cell, determined by staining the pericellular pattern of sarcoma which was serial sections alternately, was not found in any invariable in each tumour (fig 2). Immunohis- of the four tumours. tochemical techniques showed carcinomatous The rhabdomyoblasts in one primary elements positive for cytokeratin set in undif- tumour (fig 4) and in the hepatic metastases of ferentiated sarcoma positive for vimentin (fig another did not show cross-striations with 3). The intramural sarcomatous nodules in the PTAH but they did contain myoglobin. In two http://jcp.bmj.com/ serous cystadenocarcinoma were vimentin cases PAS positive, diastase resistant eosino- positive and entirely separate from the cyto- philic hyaline droplets ofvarying size (5-50 pm keratin positive, malignant epithelial lining. in diameter) were found mainly in the spindle on September 29, 2021 by guest. Protected copyright.

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% t¶ 0 .., Figure 3 Consecutive sections stained with anti-cytokeratin (3a) and anti-vimentin (3b). (Indirect immunoperoxidase.) Histogenesis of ovarian malignant mixed mesodermal tumours 289

Figure 4 epithelial cell lines.26 It is due to decreased cell Rhabdomyoblasts stained to cell contact27 and is, therefore, not proof of with anti-myoglobin (Indirect metaplasia. When examined by electron microscopy, two ovarian malignant mixed immunoperoxidase.) J Clin Pathol: first published as 10.1136/jcp.43.4.287 on 1 April 1990. Downloaded from mesodermal tumours showed no evidence of transitional cell forms or discontinuity in the basal lamina separating carcinoma from sar- coma."8 Electron microscopy was not used in this series but the difference in reticulin pat- terns between the two components supports the previously reported ultrastructural find- ings. The biphasic pattern of cytokeratin and vimentin expression has been described before29 but immunohistochemical transitions between the two elements were not inves- tigated. The light, electron microscopic, and immunohistochemical findings suggest that ovarian malignant mixed mesodermal tumours are not metaplastic carcinomas-that is, tumours in which the sarcomatous component derives from the carcinomatous. Meyer clas- sified carcinosarcomas into collision, combina- tion, and composition types."3 There is no evidence to suggest that ovarian malignant mixed mesodermal tumours are collision tumours formed following coalescence of two separate tumours; moreover, ovarian carcin- cell sarcomatous component. They stained omas are common and are rare."6 In a deep blue with PTAH but did not show combination tumour the is secondary fluorescence in sections stained with thought to arise from a precursor stem cell haematoxylin and eosin or contain ac-l- (Ahnzelle) which differentiates along two antitrypsin. divergent pathways. There is evidence from tissue culture experiments using cells from malignant mixed mesodermal tumours to sup- Discussion port"' and refute3' this; but, again, extrapola- Three tumours corresponded with the typical work tion from tissue culture is fraught with http://jcp.bmj.com/ descriptions of ovarian malignant mixed difficulties. In a composition tumour there is mesodermal tumours, being composed of a synchronous malignant change in adjacent disorganised mixture of carcinoma and sar- and stroma. This change was coma with a predominance of adenocarcinoma evident in the forme fruste ovarian malignant of serous type.2 In one case, however, the mixed mesodermal tumour in this series. The tumour was a "forme fruste" ovarian malig- other three tumours may have been either of nant mixed mesodermal tumour from which combination or composition in type. on September 29, 2021 by guest. Protected copyright. the separate metastatic spread ofcarcinoma and In conclusion, examination of the general sarcoma nevertheless fulfilled the necessary morphology, cytoarchitecture, and immuno- diagnostic criterion. The presence of rhab- histochemistry of four ovarian malignant domyosarcoma in metastases alone has been mixed mesodermal tumours produced no noted before.2 Ovarian endometriosis has evidence to suggest that such neoplasms are occasionally been described in association with metaplastic carcinomas, and it is suggested that ovarian malignant mixed mesodermal carcinosarcomas at other sites be reexamined in tumours,''`20 but none was found in this the manner described in this study. series. The eosinophilic hyaline droplets were tinctorially similar to those in previous This paper is based on work presented at the Association of reports2'2- but did not show secondary fluores- Clinical Pathologists' Junior Members Research Award in cence 23 or contain c-l-antitrypsin. 21-23 London on October 14, 1988. It has been suggested that ovarian malignant I thank Mrs Carol Stoddard for technical assistance. Mrs G Marshall for typing the manuscript, and Professor P P Anthony mixed mesodermal tumours are metaplastic for constructive criticism. carcinomas, and morphological transitions have been described. 12 The intraperitoneal and lymphatic spread of ovarian malignant mixed 1 Dehner LP, Norris HJ, Taylor HB. Carcinosarcomas and mesodermal tumours is consistent with this mixed mesodermal tumors of the ovary. Cancer mode of spread of a carcinoma,24 but the 1971;27:207-16. 2 Fenn ME, Abell MR. Carcinosarcoma of the ovary. Am J metastases are frequently sarcomatous.2 Obstet Gynecol 1971;1 10:1066-74. Masuda grew a carcinoma cell line derived 3 Dictor M. Malignant mixed mesodermal tumor ofthe ovary: a report of 22 cases. Obstet Gynceol 1985;65:720-4. from an ovarian malignant mixed mesodermal 4 Barwick KW, LiVolsi VA. Malignant mixed mesodermal tumour in low cell density tissue culture and tumors of the ovary: a clinico-pathologic assessment of 12 cases. Am J Surg Pathol 1980;4:37-42. found that there was a- loss of epithelial charac- 5 Hanjani P, Petersen RO, Lipton SE, Nolte -SA. Malignant teristics.25 This phenomenon has been des- mixed mesodermal tumors and carcinosarcoma of the ovary: report of eight cases and review of the literature. cribed, however, in tissue culture using other Obstet Gynecol Surv 1983;38:537-45. 290 Clarke

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