sarcoma-like mural nodules cystic serous tumours · the origin for either the ovarian mural nodules...

J Clin Pathol 1987;40:1443-1448

Sarcoma-like mural nodules in cystic serous ovarian

tumoursT J CLARKE

From the Department ofHistopathology, Derriford Hospital, Plymouth

SUMMARY The morphology, immunohistochemistry, ultrastructure and natural history of sarcoma-like mural nodules in two serous cystic ovarian tumours are described.

Primary ovarian sarcomas are rare; they comprisedonly 43 of a series of 2400 ovarian tumours (1 8%).'Sarcomatous and epithelial elements can be foundtogether in ovarian tumours, most commonly inan immature teratoma or a malignant mixedmesodermal tumour (MMMT).' Sarcomas arising inepithelial ovarian tumours are rare and those foundin serous tumours are extremely rare, with onlytwo recorded cases: a leiomyosarcoma in a serouscystadenoma,2 and a leiomyosarcoma in a serouscystadenocarcinoma.3 In this paper two further cases,diagnosed as cystic serous ovarian tumours withsarcoma-like mural, nodules are reported.

Material and methods

Sections were stained with haematoxylin and eosin,periodic acid Schiff with and without diastase pre-treatment, alcian blue (pH 2.5) and Caldwell andRannie reticulin stain. The indirect peroxidase-antiperoxidase method was used with antibodiesagainst cytokeratin, vimentin, carcinoembryonic anti-gen (CEA), CA 125, monoclonal antibody OC125(from CIS UK) and myoglobin. OC125 is a mono-clonal murine antibody raised against the antigenCA125 derived from the human ovarian serous papil-lary cystadenocarcinoma cell line OVCA433.4 CA125is expressed in most non-mucinous human ovarianepithelial tumours.56 Portions of the ovarian muralnodules were reprocessed from formalin fixed mate-rial and examined using a JEM-1200EX transmissionelectron microscope.

Case reports

CASE 1A 49 year old, multiparous, postmenopausal womanpresented with a two month history of weight loss,

Accepted for publication 25 June 1987

anorexia, and malaise. On examination she was foundto have an enlarged right supraclavicular lymph nodeand a firm pelvic mass. At laparotomy a Tru-cutbiopsy of the cervical lymph node was taken and alarge, cystic left ovary and an enlarged para-aorticlymph node were removed. The left ovary was rup-tured on removal but was considered to be clinicallybenign, and the right ovary, which appeared normal,was left in situ. The uterus and liver appeared normaland there was no ascites. A right iliac crest bone mar-row trephine biopsy specimen was taken becauselymphoma was suspected.

CASE 2A 72 year old nulliparous woman presented with athree month history of anorexia, constipation, andvomiting. A fixed pelvic mass and ascites were pal-pable. At laparotomy ascites, peritoneal and omentalmetastases, and a large cystic right ovarian mass werefound. A bilateral salpingo-oophorectomy, hysterec-tomy, and omentectomy was performed. She diedeight days later. At necropsy, metastatic tumour wasfound in the liver, para-aortic and mediastinal lymphnodes, and encircling the small intestine in severalplaces. The bone marrow was normal.

Pathology

CASE 1On histological examination, the left ovary was foundto be replaced by a thin walled, unilocular cyst 9 cm indiameter. A rough surfaced grey mural nodule mea-suring 3 x 3 x 1-5 cm projected into the cyst cavity.The external surface of the cyst was smooth except forslight roughening over the mural nodule.The cyst was found to be a serous tumour of low

grade ("borderline") malignancy; the columnar epi-thelium lining the cyst showed focal moderate cellularpleomorphism, loss of orientation, multilayering,occasional mitoses and tuft formation. The epi-

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thelium had ulcerated over the inner aspect of themural nodule, which was covered by inflammatoryexudate. The nodule was composed of sheets of large,round, and spindle cells with hyperchromatic nuclei,and there was no differentiation into recognisableconnective tissue or epithelial elements. Mitoses werecommon and many were atypical (fig 1). The diffuseinflammatory cell infiltrate of neutrophils andeosinophils that permeated the nodule was unrelatedto the occasional small areas of haemorrhage andnecrosis that were present. The borders of the nodulewere poorly defined, and undifferentiated neoplasticcells extended into the cyst wall adjacent to thenodule.

Reticulin stains showed a loose alveolar pattern inthe mural nodule. There was no evidence of endo-metriosis, teratomatous organoid differentiation,osteoclast-like multinucleate giant cells, or heterolo-gous elements. Vascular invasion by tumour cells wasnot seen.

CASE 2The right ovary was replaced by a smooth surfaced,thin walled, unilocular cyst 22 cm in diameter with thefallopian tube stretched across it. The cyst had rup-

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Clarketured at operation. Several well circumscribed, yel-lowish and tan coloured mural nodules (0-2cm to2-5 cm in diameter) were present on the inner surfaceof the cyst. A solid pale grey mass 5-5 cm in diameter,with a whorled cut surface, was present in the wall ofthe cyst. The omentum bore several grey nodules oftumour. The uterus contained a cystic endometrialpolyp 2cm in diameter.The right ovarian cyst was for the most part a

serous tumour of low grade ("borderline") malig-nancy, but there were also small foci of superficial,well differentiated invasive papillary serous ade-nocarcinoma containing psammoma bodies. The tancoloured mural nodules were composed ofundifferentiated spindle and round cell tumour similarto that seen in case 1, and were covered by serousepithelium (fig 2). A delicate pericellular reticulinpattern was present, in contrast to case 1, and therewas no evidence of endometriosis or teratomatousdifferentiation. The solid grey ovarian mass notedmacroscopically was a typical ovarian fibroma. Theleft ovary was atrophic.The endometrium was atrophic and bore a benign

microcystic endometrial polyp with glands lined byflat, inactive epithelium. The omental deposits consis-

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Fig 2 Case 2: sarcoma-like nodule covered by serousepithelium (Haematoxylin and eosin.)

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Fig 3 Case 2: omental nodule containing metastatic serous cystadenocarcinomaand eosin.)

ted mainly of metastatic undifferentiated spindle celltumour similar to the ovarian mural nodules, though Alin some areas there was metastatic papillary serouscystadenocarcinoma (fig 3).

Immunohistochemistry

CASElThe serous epithelium showed apical CA125 and cyto- jplasmic cytokeratin positivity and there was no CEA texpression. The cells in the nodule were positive forScytokeratin and did not express vimentin, CA125,CEA, or myoglobin, nor was there intracellular neu-tral mucin. Ultrastructurally, the neoplastic cells con-tained moderate numbers of mitochondria, scantyrough endoplasmic reticulum, and occasionaldesmosomes with convergent tonofilaments (fig 4).Microvilli and intracellular lumina were absent andpericellular basal laminar material was scanty.The cervical and para-aortic lymph nodes and iliac

crest trephine biopsy specimen all contained meta-static undifferentiated tumour morphologically and - *immunohistochemically identical with that in theovarian nodule. Despite chemotherapy with cis-platinum, adriamycin, cyclophosphamide, andnumerous blood transfusions, the patient gradually Fig 4 Case 1: ultdeteriorated and died five months after laparotomy. nodule. Note two aAn abdominal ultrasound examination shortly before and lead citrate.)

and spindle cell tumour. (Haematoxylin

trastructure of undifferentiated cells indesmosomes (arrowed). (Uranyl acetate

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Fig 6 Case 2: hepatic metastasis containing myoglobin-positive rhabdomyoblasts. (Antimyoglobin peroxidase-antiperoxidase.)

death showed hepatic metastases. Consent for nec-ropsy was not obtained.

CASE 2The serous lining epithelium was positive for cyto-plasmic cytokeratin and apical CA125, and negativefor CEA. The cells in the nodules were uniformlypositive for vimentin with no expression of cyto-keratin, CA125, CEA, or myoglobin. Electronmicroscopy of the nodules showed cells containingmoderate amounts of rough endoplasmic reticulumand scanty mitochondria, surrounded by abundantbasal laminar material; there was no evidence of epi-thelial differentiation such as microvilli, intracellularlumina, or desmosomes.The metastases sampled at necropsy were mainly

sarcomatous positive (for vimentin) with some areasof spindle cell carcinoma positive (for cytokeratin).There were also areas suggestive of squamous car-cinoma (fig 5). Small numbers of tadpole shaped rhab-domyoblasts were found that had dense eosinophiliccytoplasm and no visible cross striations; these werepositive for vimentin and myoglobin (fig 6).

Discussion

Sarcoma-like mural nodules have been reported inmucinous ovarian tumours, usually of low grade("borderline") malignancy.7 Microscopically, they

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Sarcoma-like mural nodules in cystic serous ovarian tumours 1447consist predominantly of pleomorphic spindle andoval cells exhibiting frequent and atypical mitoses.Their margins are well circumscribed and vascular,and stroma invasion is absent; variable numbers ofosteoclast-like multinucleate giant cells are present. Inspite of a sarcoma-like morphology the nodules showno tendency to metastasise (mean follow-up 7-5 years)and are considered to be biologically benign.7`9 Theymight possibly result from an unusual reaction to cystcontents7 or to intramural haemorrhage.9 10 Theovarian mural nodules in the cases reported here,though they shared several morphological featureswith sarcoma-like nodules in mucinous cysts, wereclearly malignant. The ovarian cysts in which theywere found were undoubtedly of serous type and hadimmunohistochemical reactions characteristic of suchtumours."1 12The electron microscopical structure and immuno-

histochemical reactions were different in the twocases. In case 1 they were those of an undifferentiatedcarcinoma; in case 2 they were those of anundifferentiated sarcoma. The expression of cyto-keratin, absence of vimentin staining,13 and presenceof desmosomes ultrastructurally in the mural nodulein case 1 were typical of an epithelial tumour. Thesarcoma-like morphology persisted in the metastasesin case 1 as did the expression of cytokeratin in themetastases. There was no evidence of biphasic car-cinosarcomatous differentation in either the ovariantumour or its metastases in case 1 (as was seen incase 2). It was established that the sarcoma-like muralnodule in case 1 was a primary anaplastic carcinomaarising in a serous cystadenoma of borderline malig-nancy. The early paraxial lymphatic spread of metas-tases seen in case 1, in an apparently FIGO stage 114ovarian carcinoma, is characteristic of undifferen-tiated ovarian carcinoma. 15 The malignant behaviourof the nodules in both cases was in contrast to thebenign nature of reactive proliferative stromal reac-tions in ovarian epithelial tumours.`6

In case 2 the ovarian tumour showed discretedevelopment of sarcoma-like mural nodulesprojecting into a serous cystadenocarcinoma. Theimmunohistochemistry and ultrastructure of thesarcoma-like nodules were consistent withundifferentiated sarcoma arising from the cyst wall, incontrast to the epithelial characteristics of thesarcoma-like nodule in case 1. The metastases in case2 were composed of carcinomatous and sarcomatouselements with rhabdomyoblasts positive formyoglobin1 7and were typical of those arising from anovarian malignant MMMT.`8 The uterus, in whichMMMTs arise more commonly, was shown not to bethe origin for either the ovarian mural nodules ormetastases in case 2.The epithelial element most commonly found in

ovarian MMMTs resembles papillary serous cys-tadenocarcinoma.18 The metastases from an ovarianMMMT are usually predominantly sarcomatous,18and rhabdomyoblasts may be found only in themetastases. 1 8Although the ovarian tumour in case 2 lacked the

intermingling of carcinomatous and sarcomatouselements typically found in an ovarian MMMT,18 19it appeared to have been an early form of ovarianMMMT with separate development ofcarcinomatousand sarcomatous elements. The ovarian tumour andmetastases in case 2 exhibited other features com-monly found in ovarian MMMTs.The histogenesis of the carcinomatous and sarco-

matous elements in typical ovarian MMMTs isunknown, though an ovarian MMMT has beendescribed in the wall of an endometriotic cyst.20 Tis-sue from a human ovarian MMMT, when passaged innude mice, has shown development of discrete epi-thelial and mesenchymal cell lines.21 The separatedeveloped of carcinoma and sarcoma in the ovariantumour in case 2 reflects this finding and is the firstdescription of a MMMT arising in an ovarian tumourof serous type that I know of.

Benign sarcoma-like nodules in serous cysticovarian tumours have not been described. Thesarcoma-like mural nodules reported here were ana-plastic carcinoma and undifferentiated sarcoma(forming part of an ovarian MMMT), and differedfrom sarcoma-like mural nodules in ovarian mucin-ous tumours, both in morphology and in behaviour.This suggests that, unlike the occurrence in mucinoustumours, sarcoma-like mural nodules in a serousovarian tumour should probably be regarded asmalignant.

I thank Dr J Brindle for permission to report clinicalmaterial and Mrs J West for secretarial help.

References

I Azoury RS, Woodruff JD. Primary ovarian sarcomas; report of43 cases from the Emil Novak Ovarian Tumor Registry. ObstetGynecol 1971;37:920-41.

2 von Numers C, Mikkonen R. Leiomyosarcoma arising in serouscystadenoma of ovary: report of a case. Annules Chirugiae etGynaecologiae Fenniae 1960;49:240-4.

3 Walts AE, Lichtenstein I. Primary leiomyosarcoma associatedwith serous cystadenocarcinoma of the ovary. Gynecol Oncol1977;5:81-6.

4 Bast RC Jr, Feeney M, Lazarus H, Nadler LM, Colvin RB,Knapp RC. Reactivity of a monoclonal antibody with humanovarian carcinoma. J Clin Invest 1981;68:1331-7.

5 Kabawat SE, Bast RC Jr, Bhan AK, Welch WR, Knapp RC,Colvin RB. Tissue distribution of a coelomic-epithelium-related antigen recognised by the monoclonal antibody OC 125.Int J Gynecol Pathol 1983;2:275-85.

6 Koelma TA, Nap M, Rodenburg CJ, Flenren GJ. The value of



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7 Prat J, Scully RE. Ovarian mucinous tumors with sarcoma-likemural nodules: a report of seven cases. Cancer1979;44:1332-44.

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9 Fujii S, Konishi I, Kobayashi F, Okamura H, Yamabe H,Mori T. Sarcoma-like mural nodules combined with a micro-focus of anaplastic carcinoma in mucinous ovarian tumor.Gynecol Oncol 1985;20:219-33.

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11 Kabawat SE, Bast RC, Welch WR, Knapp RC, Colvin RB.Immunopathologic characterisation of a monoclonal antibodythat recognises common surface antigens of human ovariantumors of serous, endometrioid, and clear cell types. Am J ClinPathol 1983;79:90-104.

12 Charpin C, Bhan AK, Zurawski VR, Scully RE. Carcino-embryonic antigen (CEA) and carbohydrate determinant 19-9(CA19-9) localisation in 121 primary and metastatic ovariantumors: an immunohistochemical study with the use of mono-clonal antibodies. Int J Gynecol Pathol 1982;1:231-45.

13 Leader M, Collins M, Patel J, Henry K. Vimentin: an evaluation

of its role as a tumour marker. Histopathology 1987;11:63-72.14 International Federation of Gynaecology and Obstetrics.

Classification and staging of malignant tumors of the femalepelvis. Acta Obstet Gynaecol Scand 1971;50:1-7.

15 Knapp RC, Friedman EA. Aortic lymph node metastases in earlyovarian cancer. Am J Obstet Gynecol 1974;119:1013-7.

16 Ortega I, Nogales FF, Amerigo J, Fernandez-Sanz J. Carcino-sarcomas and mixed mesodermal tumors of the ovary: a clin-icopathologic study of six cases. Int J Gynecol Obstet1978;15:561-5.

17 Mukai K, Varela-Duran J, Nochomovitz LE. The rhab-domyoblast in mixed mullerian tumors of the uterus and ovary.Am J Clin Pathol 1980;74:101-4.

18 Fenn ME, Abell MR. Carcinosarcoma of the ovary. Am J ObstetGynecol 1971;110:1066-74.

19 Dehner LP, Norris HJ, Taylor HB. Carcinosarcomas and mixedmesodermal tumors of the ovary. Cancer 1971;27:207-16.

20 Cooper P. Mixed mesodermal tumor and clear cell carcinomaarising in ovarian endometriosis. Cancer 1978;42:2821-31.

21 Centola GM. Long-term growth of a heterologous mixed muller-ian tumor of the ovary. Invasion Metastasis 1986;6:123-32.

Requests for reprints to: Department of Histopathology,Derriford Hospital, Derriford Road, Plymouth PL6 8DH,England.



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