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

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SUBTYPES OF OVARIAN CARCINOMA 423Postulated development of low-grade and high-gradeovarian serous carcinomaFimbria of fallopian tubeOvarian surface epitheliumBenign serous cystadenomaSerous tubalintraepithelialcarcinoma (serousTIC)OvarianintraepithelialneoplasiaCorticalinclusioncystsUsual serous borderlineneoplasmMicropapillary variant of serousborderline neoplasmHigh gradeserous carcinomaLow gradeserous carcinomaFig. 2Postulated developmental pathways of low grade and high grade serous carcinoma.including nested, papillary (micropapillary or macropapillary),glandular (slit-like or round spaces), cribriform, solid and singlecells. The glands and papillae in low grade serous carcinomasare often surrounded by clefts or non-epithelial lined spaces andintracytoplasmic mucin is often a feature. 39 Psammoma bodiesare common in both tumour types. Psammocarcinoma is a termused for a tumour with extensive psammoma body formationand is usually morphologically a low grade serous carcinoma,although occasional examples have high grade nuclear cytology,in keeping with high grade serous carcinoma.Both low grade and high grade serous carcinomas typicallyexpress WT1. High grade serous carcinoma exhibits significantlygreater expression of p53, MIB1, bcl-2, c-kit, Her-2 neu,HLA-G and p16 than low grade serous carcinoma. 40,41 p16 istypically diffusely positive in high grade serous carcinoma andfocally positive or negative in low grade. Low grade serouscarcinomas are almost always diffusely positive with oestrogenreceptor (ER), as are a high percentage of high grade serouscarcinomas (70–80%). High grade serous carcinomas mostcommonly exhibit diffuse intense nuclear immunoreactivitywith p53 but totally absent staining (‘all or nothing’) is also anaberrant pattern of p53 staining and suggestive of an underlyingTP53 abnormality (see next section). So-called ‘wild-type’ p53staining, with a focal, weak and heterogenous pattern, is notindicative of a TP53 abnormality and is characteristic of lowgrade serous carcinoma. 42Molecular events in low grade and high grade serouscarcinomaThe underlying molecular events differ between low grade andhigh grade serous carcinoma. Low grade serous carcinoma isassociated with k-ras or b-raf mutation in approximately twothirdsof cases. 21–27 These mutations occur early in the evolutionof low grade serous carcinoma since they are also found inborderline and benign areas within the same neoplasm. K-rasand b-raf mutations appear mutually exclusive; in other wordsone, but not both, may be present in a particular neoplasm. TheERBB2 gene is also frequently mutated. 27 Low grade serouscarcinoma is not associated with TP53 mutations. 21–27 Incontrast, high grade serous carcinomas harbour, in most cases,a TP53 mutation or exhibit p53 dysfunction and this appears tooccur early in neoplastic development; 20–26 they are not, exceptin occasional cases, associated with k-ras, b-raf or ERBB2mutation. A recent study using stringent techniques identifiedTP53 mutations in 97% of ovarian high grade serous carcinomas;most of the mutation negative cases exhibited TP53Fig. 3 (A) Low grade serous carcinoma with a micropapillary architecture and clefts surrounding the groups of tumour cells. (B) On high power of another low gradeserous carcinoma, the tumour cells are bland with little mitotic activity.Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
424 MCCLUGGAGE Pathology (2011), 43(5), Augustserous carcinoma was 9% with a median survival of 1.7 years 36while low grade serous carcinomas had a median survival of4.2 years and a 5 year survival of 40%. 36 In another study of lowgrade serous carcinomas, the median overall survival with stageIII or IV disease was 6.8 years. 44 Low grade serous carcinomasoften prove fatal but in some cases the course is indolent and ina few cases the patient survives for a considerable period oftime, for example in excess of 10 or 20 years.Fig. 4 High grade serous carcinoma with slit-like spaces and abundant mitoticactivity.dysfunction, illustrating that p53 is abnormal in almost 100% ofhigh grade serous carcinomas. 43 High grade serous carcinomasare also associated with BRCA1 and BRCA2 abnormalities,including germline mutations and somatic abnormalities.Behaviour of low grade and high grade serous carcinomaMost low grade and high grade serous carcinomas are stage IIIor IV when diagnosed. At present, management is similarbetween these two tumour types and consists, in most cases,of total surgical debulking if possible followed by adjuvantchemotherapy. In cases where surgical debulking is not consideredfeasible, upfront chemotherapy may be the method oftreatment and this may or may not be followed by surgicaldebulking. However, adjuvant chemotherapy is usually notadministered for a stage I low grade serous carcinoma.Additionally, there is a growing realisation amongst oncologiststhat low grade serous carcinomas do not respond well totraditional chemotherapeutic agents and if the tumour is optimallydebulked with no gross residual disease, some oncologistsdo not administer adjuvant chemotherapy. High gradeserous carcinoma is an aggressive neoplasm which usuallyresponds well initially to chemotherapy but which commonlyrecurs. Few studies have directly compared the outcomebetween low grade and high grade serous carcinoma. In onestudy, the survival of patients with low grade neoplasms wassignificantly better than that of patients with high gradetumours. 36 In this study, the 5 year survival for high gradeEVIDENCE FOR ORIGIN OF HIGH GRADEPELVIC SEROUS CARCINOMA FROM DISTALFALLOPIAN TUBEThere is recent convincing and accumulating evidence thatmany currently classified high grade serous carcinomas of theovary, fallopian tube and peritoneum (collectively referred to ashigh grade pelvic serous carcinoma) are derived from thefimbria of the fallopian tube. 30–35 Most of the work hasemanated from Christopher Crum and colleagues in the Brighamand Women’s Hospital, Boston, USA. The initial evidencefor this came from prophylactic salpingo-oophorectomy specimensin patients with germline BRCA1 or BRCA2 mutation,these patients having a high risk of developing ovarian highgrade serous carcinoma. In initial studies, small high gradeserous carcinomas were occasionally identified in the ovary butthis was rare. However, when pathologists began examining thefallopian tubes in their entirety, it was found that there wasmore likely to be a small in situ or invasive high grade serouscarcinoma involving the mucosa of the fimbria of the fallopiantube; the in situ lesions are referred to as serous tubal intraepithelialcarcinoma (serous TIC). This is relatively uncommonbut is occasionally seen in prophylactic salpingo-oophorectomyspecimens in patients with BRCA1 or BRCA2 germlinemutation. Further studies systematically examined the fallopiantubes in patients with sporadic high grade ovarian serouscarcinoma and found similar lesions involving the fimbria ina significant percentage of cases (Fig. 5). 30,33 Furthermore,identical TP53 mutations were demonstrated within the ovarianand tubal lesions. While this does not unequivocally prove thatthe origin is within the fallopian tube (this could represent atumour originating within the ovary and spreading to thefallopian tube), there is accumulating evidence that many highgrade pelvic serous carcinomas arise from the tubal fimbriafrom serous TIC. A p53 signature has also been demonstrated inthe fallopian tube. 45 This takes the form of small foci of intensep53 nuclear staining involving consecutive secretory cells,most commonly of the fimbria, in the absence of morphologicalFig. 5 (A) Serous tubal intraepithelial carcinoma (serous TIC) involving fimbria of fallopian tube and exhibiting diffuse nuclear p53 positivity; (B) the adjacent tubalepithelium is p53 negative.Copyright © Royal College of pathologists of Australasia. Unauthorized reproduction of this article is prohibited.
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Morphological subtypes of ovarian carcinoma: a ... - BPA Pathology

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