Morphological subtypes of ovarian carcinoma: a ... - BPA Pathology

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SUBTYPES OF OVARIAN CARCINOMA 421Table 1 Relative frequencies of subtypes of ovarian carcinoma based on tworecent population based studies68–71% serous3% mucinous9–11% endometrioid12–13% clear cell1% transitional6% mixedvarious tumour types, morphological changes secondary tochemotherapy and tumour grading are covered.RELATIVE FREQUENCIES OF MAJORMORPHOLOGICAL SUBTYPES OF OVARIANCARCINOMAThe major morphological subtypes of ovarian carcinoma areserous, endometrioid, clear cell and mucinous. 6 Other subtypesinclude transitional, undifferentiated and mixed. Primary ovariansquamous carcinomas also occur; these are rare, usuallyarise in a dermoid cyst or more uncommonly in association withendometriosis or a Brenner tumour, and will not be discussedfurther. Two relatively recent population based studies whichhave included central pathology review using modern diagnosticcriteria have provided updated information regarding therelative frequencies of the major subtypes of ovarian carcinoma7,8 (Table 1). It can be seen that serous is the mostcommon, followed by clear cell and endometrioid which occurwith approximately equal frequency. Mucinous carcinomas areless common. This represents a change from most older studieswhere mucinous carcinoma was the second most commonsubtype and accounted for approximately 12% of primaryovarian carcinomas, 9 a much higher frequency than in thetwo recent studies; reasons for this decline in the frequencyof mucinous carcinoma are discussed later. The two studies alsoindicate an increase and decrease in the frequency of serous andendometrioid carcinoma, respectively; this is likely a reflectionof the fact that the distinction between a high grade serous andhigh grade endometrioid carcinoma was previously poorlyreproducible 10–14 and there is now a realisation that manyneoplasms which were previously diagnosed as advanced stage,high grade endometrioid carcinoma were, in fact, of serous type(discussed later). When divided into early stage (stage I–II) andlate stage (stage III–IV), it can be seen that serous, clear celland endometrioid carcinomas are approximately equallyrepresented in early stage, nearly all mucinous carcinomasare early stage and a very high percentage of advanced stageneoplasms are serous in type (Table 2). Put another way, a highpercentage of clear cell, endometrioid and mucinous carcinomasare diagnosed at early stage and in fact these tumourtypes (especially endometrioid and mucinous) are usuallyconfined to the ovary at diagnosis (stage I).Table 2 Early stage (I/II) versus late stage (III/IV) distribution of subtypes ofovarian carcinoma based on two recent population based studiesStage I/IIStage III/IVSerous 36% 88%Clear cell 26% 5%Endometrioid 27% 3%Mucinous 8% 1%MORPHOLOGICAL CHANGES IN OVARIANCARCINOMAS SECONDARY TOCHEMOTHERAPYFor many years, the traditional management of advanced stageovarian carcinoma has been surgical debulking followed byadjuvant chemotherapy. However, in an increasing number ofcases, upfront chemotherapy is administered, especially inpatients who are a poor operative risk or patients with miliarydisease or widespread metastasis where optimal debulking isnot considered feasible; chemotherapy may or may not befollowed by surgery. The morphological features of ovariancarcinomas treated by chemotherapy often differ markedlyfrom native tumour. 15,16 Post-chemotherapy, many ovariancarcinomas (the vast majority will represent serous carcinomassince almost all advanced stage ovarian malignancies are of thismorphological subtype) have abundant clear or eosinophiliccytoplasm and the nuclear features are often bizarre withmultinucleate tumour giant cells 15,16 (Fig. 1). There may beno residual tumour or it may be difficult to identify residualneoplastic cells due to pronounced chemotherapy effect withmarked fibrosis, necrosis, inflammation, cholesterol cleft formation,haemosiderin deposition and dystrophic calcification.Unless there is no or minimal response, it can be very difficultto type an ovarian carcinoma following chemotherapy and thereis a tendency to misdiagnose some as clear cell carcinoma dueto the abundant clear cytoplasm. 15,16 If upfront chemotherapy isbeing administered, a pre-chemotherapy tissue biopsy (usuallya percutaneous radiologically guided biopsy or a biopsy takenat laparoscopy) should be obtained for definitive typing, apartfrom in exceptional circumstances, rather than relying oncytology of the ascitic fluid in combination with serumCA125 levels and imaging. The procurement of a tissue biopsy,as well as facilitating tumour typing and excluding a metastasisfrom other sites, means that material is available for futurestudies and research; for example, targeted therapies may bedeveloped against specific proteins and if tissue is available thiswill be useful in assessing whether the target protein is presentin the tumour cells. Tissue obtained at different stages intreatment may also be useful in assessing tumour progressionand response to therapy.GRADING OF OVARIAN CARCINOMASSeveral grading systems are used for ovarian carcinoma butgrading is often poorly performed by pathologists and in manystudies the grading system used has not been specified. 17–19Most of the grading systems are universal in that they can beapplied to all the major morphological subtypes of ovariancarcinoma; 17–19 for example, the Shimizu-Silverberg system isbased on the Nottingham grading system for breast carcinomaand uses three parameters, namely the degree of nuclear atypia,the mitotic count and the architectural features, specifically theamount of glandular, papillary or solid growth. 17 Eachparameter is given a score of 1–3 and a grade is derived basedon the summation of the scores. However, although manypathologists use this or other universal grading systems, suchas FIGO or World Health Organization (WHO), there is anincreasing tendency to employ different grading systems fordifferent morphological subtypes of ovarian carcinoma; thispractice has been recommended in the Royal College ofPathologists Ovarian Cancer Datasets in the United Kingdom. 20Grading of the different subtypes of ovarian carcinoma isdiscussed with each specific tumour type.Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
422 MCCLUGGAGE Pathology (2011), 43(5), AugustFig. 1 (A) Ovarian serous carcinoma with clear cytoplasm and (B) bizarre nuclear features. These are examples of serous carcinomas with morphological featuressecondary to chemotherapy.SEROUS CARCINOMAThe perceived relationship between benign, borderline andmalignant ovarian serous neoplasms was controversial and asource of confusion for many years. It has always been temptingto speculate that a continuum of ovarian serous neoplasiaexists from benign to borderline to malignant. However, pathologicalevidence for this is lacking and until recently it wasgenerally assumed that there was no firm relationship betweenborderline and malignant serous neoplasms, although occasionallythe two were found to coexist. Recent studies have shedsignificant light on this issue and have convincingly demonstratedthat there are two distinct types of ovarian serouscarcinoma, low grade and high grade. 1–4,21–27 Although termedlow grade and high grade serous carcinoma, it is important toemphasise that these are not two grades of the same neoplasmbut rather two distinct tumour types with different underlyingpathogenesis, molecular events, behaviour and prognosis. Highgrade serous carcinoma is much more common than low grade.Low grade serous carcinoma is thought to arise in many cases ina stepwise fashion from a benign serous cystadenoma through aserous borderline tumour to an invasive low grade serouscarcinoma. Thus, there is a well defined adenoma-carcinomasequence. It has been suggested that a micropapillary architecturein a serous borderline tumour is an intermediate stepbetween a usual serous borderline tumour and an invasive lowgrade serous carcinoma. 1,27–29 However, a micropapillaryarchitecture is not present in many serous borderline tumourswith coexistent low grade serous carcinoma. I also make thepoint that it is relatively uncommon to see areas of invasive lowgrade serous carcinoma within a serous borderline tumour andconversely in many low grade serous carcinomas a borderlinecomponent is not seen. Therefore, it is not proven that all lowgrade serous carcinomas arise from a pre-existing serousborderline tumour and it is possible that some or many donot. In contrast, high grade serous carcinoma is not related toserous borderline tumour and was thought until recently to arisedirectly from the ovarian surface epithelium or the epitheliumof cortical inclusion cysts with no well defined precursor lesion.There is now emerging and quite compelling evidence (discussedlater) that many high grade ovarian serous carcinomasactually originate from the epithelium of the distal fimbrialportion of the fallopian tube. 30–35 Instead of grading ovarianserous carcinoma using a three-tiered system (well, moderate,poor; grade 1, 2 or 3), there is now a growing tendency amongstpathologists and oncologists to classify these as high grade orlow grade and this practice has been adopted in the UnitedKingdom; 20 anecdotally many gynaecological pathologistsnow use this two tiered grading system which was originallyproposed by the MD Anderson Group (Houston, Texas, USA).The classification of a serous carcinoma as low grade or highgrade has been shown to be reproducible amongst pathologists.36,37 Almost all serous carcinomas which would havepreviously been classified as moderately or poorly differentiatedrepresent high grade neoplasms while those which wouldhave been classified as well differentiated may be either lowgrade or high grade using the two tier classification. Forexample, some architecturally well differentiated serous carcinomashave high nuclear grade and represent examples ofhigh grade serous carcinoma. Although representing two distincttumour types, on rare occasions a low grade serouscarcinoma component may coexist with and probably transforminto a high grade serous carcinoma or even an undifferentiatedcarcinoma or a high grade serous carcinoma may arisedirectly from a serous borderline tumour (Dehari et al. 38 andpersonal observations). However, most low grade serouscarcinomas when they recur do so as low grade neoplasms.Some advocate the term invasive micropapillary serous carcinomaas an alternative to low grade serous carcinoma but thisterminology is not recommended since some low grade serouscarcinomas do not exhibit a micropapillary architecture andconversely many high grade serous carcinomas do so. Figure 2illustrates the postulated pathways of development of low gradeand high grade serous carcinoma.Morphological and immunohistochemical features of lowgrade and high grade serous carcinomaThe distinction between low and high grade serous carcinoma isbased on morphology, the chief discriminator being the degreeof nuclear atypia in the worst area of the tumour. The amount ofmitotic activity is also taken into account. 36,37 In low gradeserous carcinoma, the nuclei are uniform with mild or at themost moderate atypia and less than or equal to 12 mitoses per 10high power fields (the mitotic count is usually approximately 2per 10 high power fields or less than this) (Fig. 3). There is nonecrosis or multinucleation. High grade serous carcinomaexhibits moderate to marked nuclear atypia and greater than12 mitoses per 10 high power fields (Fig. 4). Necrosis andmultinucleate cells are often present. It is generally not necessaryto count mitotic figures since these are typically abundantin high grade serous carcinomas and difficult to find in lowgrade neoplasms. In both low grade and high grade serouscarcinomas, there may be a variety of architectural patterns,Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
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