Serous papillary peritoneal carcinoma: Unknown primary tumour, ovarian cancer counterpart or a distinct entity? A systematic review

https://doi.org/10.1016/j.critrevonc.2009.10.003Get rights and content

Abstract

Introduction

Serous peritoneal papillary carcinoma (SPPC), though managed according to ovarian cancer therapeutic principles, has been variably considered as an ovarian cancer counterpart, a peritoneal malignancy with distinct characteristics or a cancer of unknown primary (CUP).

Patients and methods

We systematically reviewed all publications studying molecular pathophysiology, clinical presentation, management and outcome of at least 10 patients with SPPC from 1980 to 2008 in anglophone medical journals and critically analysed the data.

Results

Molecular profiling of CUP was performed in eight papers reporting on 211 patients with stage III/IV SPPC by means of immunohistochemistry or PCR-based assays. Twenty-five clinical series, mostly retrospetive, reported management and outcome of 579 patiens with SPPC, in several cases matched to advanced ovarian cancer controls. Though we did not identify statistically significant differences in molecular biology, clinical presentation, management and outcome of SPPC and ovarian cancer cases, some subtle differences emerged: patterns of loss of heterozygosity at several chromosomal loci differed from those seen in ovarian cancer, while the overexpression of the HER2 oncogene was encountered more often. Serous peritoneal tumours affected older patients and were more frequently multifocal or exhibited virulent clonal expansion in metastatic sites. Diffuse micronodular spread formed a high total load of malignancy in omental, peritoneal surfaces, difficult to debulk optimally. Despite effective chemotherapeutic cytoreduction and occasional long-term remissions, SPPC patients survived 2–6 months less than ovarian cancer patients.

Conclusions

Patients with SPPC should not be classified in the poor-risk CUP category, in view of the therapeutic and prognostic differences. Still, the assimilation of the SPPC entity by ovarian cancer hindered further research into its genotypic and phenotypic characteristics that may differ from ovarian cancer. Subgroup analyses of large ovarian cancer trials may shed light in this issue.

Introduction

Diffuse carcinomatosis of the peritoneal surfaces is a heterogeneous clinical entity encountered in both male and female patients. Malignant deposits may originate from tumours in the gastrointestinal tract, lung, breast or genital system and tumour histology is serous, mucinous, signet ring, clear cell or endometrioid, depending on the primary [1]. Visceral metastases are present at frequencies that vary according to primary tumour, disease stage and bulk, histology. Still, the most common subset of peritoneal carcinomatosis includes patients with deposits of serous papillary or poorly differentiated adenocarcinomatous histology (60% of all peritoneal carcinomatosis cases). As serous adenocarcinomas constitute the majority of malignant tumours arising from the ovary or fallopian tube, a gynaecologic diagnostic work-up is promptly instituted in a female patient with serous peritoneal deposits or serous malignant ascites. In 80–90% of cases, a clinical, radiological or pathological diagnosis of stage III–IV ovarian adenocarcinoma is established. However in 10–15% of cases, no malignant pathology is evident in the ovaries, fallopian tubes or uterus, in which case a diagnosis of serous papillary peritoneal carcinoma (SPPC) is made [2].

As SPPC tumours are histologically identical to serous ovarian cancer, the Gynecologic Oncology Group (GOG) developed a set of criteria in order to better define the SPPC patient population [3]. Both ovaries must be either normal in size or enlarged by a benign process (4.0 cm in largest diameter) and involvement of extraovarian sites must be greater than on the ovarian surface. Moreover, microscopically the ovarian component must be nonexistent or confined to the ovarian surface epithelium with no evidence of cortical invasion or involving the ovarian epithelium and/or the underlying stroma by less than 5 mm × 5 mm in depth and extent. This strict disease definition created a common standard for diagnostic pathologic work-up and contributed towards the emergence of a homogeneous patient population with papillary peritoneal carcinomatosis in the absence of an ovarian primary. However, from a point of view of epidemiology, terminology, natural history, management and outcome, several investigators still consider serous papillary peritoneal cancer to be any of three disease entities: (a) a counterpart of ovarian cancer, with malignant transformation taking place in the coelomic epithelium of the peritoneum instead of the ovaries, (b) a peritoneal malignancy initiated at the coelomic epithelium but with distinct pathophysiology and natural history from ovarian cancer, (c) a carcinoma of unknown primary site. In fact, more than 30 years ago, before the clinicopathologic entity of SPPC was recognised, these tumours were being classified as cancers of unknown primary.

Clearly, classification of SPPC in any one of these three clinicopathological entities reflects differing conceptions and ideas regarding its origin, the genetic/epigenetic lesions harboured by the malignant clone, and subsequently its biologic behaviour, natural history as well as proper management and outcome. Though SPPC is usually managed as stage III/IV ovarian cancer, some aspects of management may vary as a result of the discordant conceptions of treating physicians regarding its nature. The intensity of gastrointestinal endoscopic search for a primary, the referral to surgical expertise and aggressiveness of surgical debulking of peritoneal implants, the administration of neoadjuvant or adjuvant chemotherapy and the evaluation of long-term remission probability are among the management or prognosis issues that often vary.

A broad consensus on the nature of SPPC, if established on sound molecular and clinical evidence, would be beneficial for patients and physicians as it would result in definition of a universally adopted, optimal management algorithm. In view of the above, we systematically searched and analysed published data on the molecular biology, natural history, management and outcome of patients with SPPC in order to examine the strength of evidence for inclusion of SPPC in any of the three clinicopathologic conceptions: an ovarian cancer counterpart, a distinct peritoneal cancer or an unknown primary cancer.

Section snippets

Patients and methods

We searched PubMed from years 1980 to 2008 for any anglophone medical publications using the search terms: (serous papillary peritoneal cancer or carcinomatosis or tumour) or (extraovarian serous papillary cancer or normal-sized ovary serous papillary cancer) or (serous papillary peritoneal carcinomatosis of unknown primary or unknown primary peritoneal cancer or carcinomatosis). Although we did include published cohorts of poorly differentiated peritoneal tumours, presence of mucinous

Immunohistochemical studies (IHC)

Eight papers were identified in which formalin-fixed paraffin-embedded SPPC tumour blocks from 211 patients with stage III or IV disease were studied by means of immunohistochemistry-based assays for the expression of several biomolecules. In some, immunohistochemical (IHC) expression in stage III/IV serous ovarian cancer patients was also studied for comparison (Table 1).

Wick et al. studied 13 SPPC tumours for IHC expression of differentiation markers, transmembrane glycoproteins and adhesion

Discussion

The prevailing belief in the early twentieth century was that the coelomic epithelium of the ovaries and peritoneum was made up of pluripotent stem cells, a fact that resulted in the term “germinal epithelium” being used. Currently, it is accepted that germ cells do not originate in the coelomic epithelium which is a mesothelial membrane. Strong morphological, functional and molecular data point to a mesonephric origin of the coelomic epithelium [38]. On the other hand, the epithelia of the

Conclusions

Serous papillary peritoneal cancer patients have traditionally been managed similarly to patients with stage III/IV ovarian cancer and have been enrolled in ovarian cancer clinical trials. Despite the histologic, molecular and clinical similarities, the assimilation of this entity by ovarian cancer left no space for investigation of its biology. Today there is a broad consensus on management of SPPC patients that every effort should be made to implement maximal surgical debulking of peritoneal

Conflict of interest

All authors have no conflict of interest to declare.

Reviewer

Dr. F. Anthony Greco, Sarah Cannon Cancer Center, 250, 25th Avenue North, Suite 412, Nashville, TN 37203, United States.

George Pentheroudakis M.D., Ph.D. is a medical oncology consultant and Assistant Professor in Medical Onoclogy at the University of Ioannina, Greece. His clinical and research interests focus on clinical pharmacokinetics, cancer of unknown primary, gastrointestinal, breast and urogenital tumours as well as adolescent/young adult oncology.

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    George Pentheroudakis M.D., Ph.D. is a medical oncology consultant and Assistant Professor in Medical Onoclogy at the University of Ioannina, Greece. His clinical and research interests focus on clinical pharmacokinetics, cancer of unknown primary, gastrointestinal, breast and urogenital tumours as well as adolescent/young adult oncology.

    Nicholas Pavlidis M.D., Ph.D. is Chair of the Department of Medical Oncology in the Ioannina University Hospital and Professor of Oncology in the Medical School of the University of Ioannina, Greece. He chairs the ESMO Minimum Clinical Recommendations working group, his clinic and research interests being cancer and pregnancy, cancer of unknown primary, adolescent/young adult oncology and translational research in breast, lung and gastrointestinal cancer.

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