J Clin Pathol 1990;43:287-290

Histogenesis of ovarian malignant mixedmesodermal tumours

T J Clarke

AbstractThe histogenesis of ovarian malignantmixed mesodermal tumours, whichincludes the concept of metaplastic car-cinoma, is controversial. Four suchtumours were examined for evidence ofmetaplastic transition from carcinoma tosarcoma using morphology and reticulinstains. Consecutive sections were stainedimmunohistochemically using cyto-keratin and vimentin to determinewhether cells at the interface betweencarcinoma and sarcoma expressed bothcytokeratin and vimentin. There was noevidence ofmorphological, architectural,or immunohistochemical transitionsfrom carcinoma to sarcoma in the fourtumours studied. This suggests thatovarian malignant mixed mesodermaltumours are not metaplastic carcinomasbut are composed of histogenetically dif-ferent elements.

Department ofHistopathology,Derriford Hospital,PlymouthT J ClarkeCorrespondence to:Dr T J Clarke, AreaDepartment of Pathology,Royal Devon and ExeterHospital, Exeter EX2 5DY

Accepted for publication19 October 1989

Ovarian malignant mixed mesodermal tumoursare rare neoplasms that arise typically innulliparous, postmenopausal women.1Recently they have been referred to as "mixedMullerian tumours of high grade malignancy"or as "carcinosarcomas". The prognosis isbleak and most patients die within 12 months ofpresentation.235 Theories concerning the his-togenesis of malignant mixed mesodermaltumours of the female genital tract have beendescribed as "a matter of art rather than ofscience".6 The same theoretical problems con-

cerning histogenesis are encountered with"carcinosarcomas" at other sites such asbreast,' lung,89 colon,'0 and urinary bladder." 12

It has been suggested that ovarian malignantmixed mesodermal tumours are "metaplasticcarcinomas" in which the sarcomatous com-

ponent (homologous and heterologous) arisesdirectly from the carcinomatous component(usually glandular in type). The concept ofmetaplastic carcinomas differs from that ofcarcinosarcomas, which are regarded as

heterogeneous tumours of combination, com-

position, or collision in type.'3 This study was

undertaken to investigate whether there were

morphological, cytoarchitectural, andimmunohistochemiccal transitions from car-

cinoma to sarcoma in ovarian malignant mixedmesodermal tumours.

MethodsSections of formalin fixed, paraffin wax

287

embedded tumour tissue were cut at 4 im andstained with haematoxylin and eosin, periodicacid Schiff (PAS) before and after diastasetreatment, Caldwell and Rannie's reticulinstain, and phosphotungstic acid haematoxylin(PTAH). Sequential sections were stained bythe indirect immunoperoxidase techniqueusing monoclonal antibodies directed againstcytokeratin (PKK1 which reacts with lowmolecular weight cytokeratins of 44, 46, 52 and54 kilodaltons), vimentin, a-l-antitrypsin andmyoglobin. Appropriate positive and negativecontrols, with omission of specific antisera inthe latter, were performed. Haematoxylin andeosin stained sections were examined forsecondary fluorescence using a Leitz Dialux20ES microscope and mercury vapour lightsource epifluorescence.Four patients, aged 68, 71, 72 and 73 presen-

ted with abdominal distension and discomfortand were found to have an ovarian malignantmixed mesodermal tumour of at least FIGOstage III.'" Three of the women werenulliparous and the parity of the fourth was notknown. Three died within one year of opera-tion and one was alive and free from diseasenine years after surgery. None of the patientsreceived radiotherapy or chemotherapy aftersurgery. Necropsy was performed in onepatient who died eight days after operation.This case has been reported previously.'"

HistopathologyThe tumours were all large at initial presenta-tion, ranging from 15 to 22 cm in maximumdiameter. Three were typical, solid, and cysticovarian malignant mixed mesodermal tumourscomposed of a haphazard mixture of adenocar-cinoma and undifferentiated sarcoma (fig 1),with heterologous elements of rhabdomyosar-coma in one and chrondosarcoma in another.The tumour in the fourth case was a unilocularserous cystadenocarcinoma containing severaldiscrete intramural sarcomatous nodules up to2-5 cm in diameter and a 5 5 cm in diameterfibroma. At necropsy a separate metastaticspread of carcinoma and sarcoma was found;para-aortic lymph nodes contained metastaticsquamous cell carcinoma and the liver con-tained deposits of sarcoma including rhab-domyosarcoma. There was no evidence ofendometriosis or teratomatous differentiationin any of the four tumours.

Multiple sections of each tumour wereexamined for evidence ofmorphological transi-tion between carcinoma and sarcoma and nonewas found. Reticulin stains showed a crisp

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Figure I Ovarian malignant mixed mesodermal tumourcomposed of adenocarcinoma and sarcoma.(Haematoxylin and eosin.)

demarcation in cytoarchitecture between theperiglandular pattern of adenocarcinoma andthe pericellular pattern of sarcoma which wasinvariable in each tumour (fig 2). Immunohis-tochemical techniques showed carcinomatouselements positive for cytokeratin set in undif-ferentiated sarcoma positive for vimentin (fig3). The intramural sarcomatous nodules in theserous cystadenocarcinoma were vimentinpositive and entirely separate from the cyto-keratin positive, malignant epithelial lining.

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Figure 2 Contrast in retzculin patterns betweenadenocarcinoma and sarcoma. (Rannie's reticulin.)

Coexpression of cytokeratin and vimentinwithin the same cell, determined by stainingserial sections alternately, was not found in anyof the four tumours.The rhabdomyoblasts in one primary

tumour (fig 4) and in the hepatic metastases ofanother did not show cross-striations withPTAH but they did contain myoglobin. In twocases PAS positive, diastase resistant eosino-philic hyaline droplets of varying size (5-50 pmin diameter) were found mainly in the spindle

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Figure 3 Consecutive sections stained with anti-cytokeratin (3a) and anti-vimentin (3b). (Indirectimmunoperoxidase.)

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Histogenesis of ovarian malignant mixed mesodermal tumours

Figure 4Rhabdomyoblasts stainedwith anti-myoglobin(Indirectimmunoperoxidase.)

cell sarcomatous component. They staineddeep blue with PTAH but did not showsecondary fluorescence in sections stained withhaematoxylin and eosin or contain ac-l-antitrypsin.

DiscussionThree tumours corresponded with the typicaldescriptions of ovarian malignant mixedmesodermal tumours, being composed of adisorganised mixture of carcinoma and sar-

coma with a predominance of adenocarcinomaof serous type.2 In one case, however, thetumour was a "forme fruste" ovarian malig-nant mixed mesodermal tumour from whichthe separate metastatic spread ofcarcinoma andsarcoma nevertheless fulfilled the necessarydiagnostic criterion. The presence of rhab-domyosarcoma in metastases alone has beennoted before.2 Ovarian endometriosis hasoccasionally been described in association withovarian malignant mixed mesodermaltumours,''`20 but none was found in thisseries. The eosinophilic hyaline droplets were

tinctorially similar to those in previousreports2'2- but did not show secondary fluores-

23 21-23cence or contain c-l-antitrypsin.It has been suggested that ovarian malignant

mixed mesodermal tumours are metaplasticcarcinomas, and morphological transitionshave been described. 12 The intraperitoneal andlymphatic spread of ovarian malignant mixedmesodermal tumours is consistent with thismode of spread of a carcinoma,24 but themetastases are frequently sarcomatous.2Masuda grew a carcinoma cell line derivedfrom an ovarian malignant mixed mesodermaltumour in low cell density tissue culture andfound that there was a- loss of epithelial charac-teristics.25 This phenomenon has been des-cribed, however, in tissue culture using other

epithelial cell lines.26 It is due to decreased cellto cell contact27 and is, therefore, not proof ofmetaplasia. When examined by electronmicroscopy, two ovarian malignant mixedmesodermal tumours showed no evidence oftransitional cell forms or discontinuity in thebasal lamina separating carcinoma from sar-coma."8 Electron microscopy was not used inthis series but the difference in reticulin pat-terns between the two components supportsthe previously reported ultrastructural find-ings. The biphasic pattern of cytokeratin andvimentin expression has been describedbefore29 but immunohistochemical transitionsbetween the two elements were not inves-tigated.The light, electron microscopic, and

immunohistochemical findings suggest thatovarian malignant mixed mesodermal tumoursare not metaplastic carcinomas-that is,tumours in which the sarcomatous componentderives from the carcinomatous. Meyer clas-sified carcinosarcomas into collision, combina-tion, and composition types."3 There is noevidence to suggest that ovarian malignantmixed mesodermal tumours are collisiontumours formed following coalescence of twoseparate tumours; moreover, ovarian carcin-omas are common and sarcomas are rare."6 In acombination tumour the carcinosarcoma isthought to arise from a precursor stem cell(Ahnzelle) which differentiates along twodivergent pathways. There is evidence fromtissue culture experiments using cells frommalignant mixed mesodermal tumours to sup-port"' and refute3' this; but, again, extrapola-tion from tissue culture work is fraught withdifficulties. In a composition tumour there issynchronous malignant change in adjacentepithelium and stroma. This change wasevident in the forme fruste ovarian malignantmixed mesodermal tumour in this series. Theother three tumours may have been either ofcombination or composition in type.

In conclusion, examination of the generalmorphology, cytoarchitecture, and immuno-histochemistry of four ovarian malignantmixed mesodermal tumours produced noevidence to suggest that such neoplasms aremetaplastic carcinomas, and it is suggested thatcarcinosarcomas at other sites be reexamined inthe manner described in this study.

This paper is based on work presented at the Association ofClinical Pathologists' Junior Members Research Award inLondon on October 14, 1988.

I thank Mrs Carol Stoddard for technical assistance. Mrs GMarshall for typing the manuscript, and Professor P P Anthonyfor constructive criticism.

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