PMP is an anatomo-clinical entity defined either by mucinous ascites or mucinous deposits in the peritoneal cavity. It is a rare disease whose incidence is approximately 1 to 2 cases per million people per year and which affects more commonly women [2]. Its clinical manifestations are abdominal distention, pain and transit disorder.
PMP is caused by the peritoneal localization of mucin, almost exclusively in the context of a tumor, by two possible mechanisms: tumor rupture in the peritoneal cavity causing the spread of mucinous material containing a variable amount of tumor cells, or metastatic diffusion to the peritoneum of a mucinous adenocarcinoma. Most of the tumors (90%) are of appendiceal origin from LAMN or HAMN associated with a mucocele [2]. Other tumors correspond to mucinous adenocarcinomas of colonic [3], gastric [4], pancreatic [5, 6], urachian [7], pulmonary [8], endocervical [9] or mammary [10] origin, or to rare mucinous ovarian tumors, cystadenomas or cystadenocarcinomas [9]. Some authors reported non-neoplastic intra-peritoneal mucinous deposits caused by alternative processes as mucin retention due to a stercolith or a diverticule, or mucinous metaplasia of fallopian tubes [11, 12, 13], but such situations are very rare and questionable.
Physiopathologically, the mucin deposits, more or less associated with tumor cells, lead by the redistribution phenomenon [14] and epithelio-mesenchymal transition [15] to the spread of mucin into the whole peritoneal cavity. Hematogenic and lymphatic routes of dissemination seem to be infrequent in this complex pathology, still partially understood. However, its clinical evolution leads to consider PMP as a neoplastic condition with variable behaviors, either indolent or aggressive.
Curative treatment of PMP relies on maximal cytoreduction surgery completed by HIPEC, performed by experienced staff in a reference center [16, 17]. This surgical act is indeed associated with numerous potential complications, leading to high morbidity (16 to 65%) and mortality (0 to 18%). Nevertheless, extended survey is possible (59% at 5 years) [18].
Several histological classifications have been established for PMP. In 2017, Carr et al. proposed a PMP classification divided in four categories: mucin without epithelial cells; PMP with low-grade histological features; PMP with high-grade histological features; and PMP with signet ring cells [1]. Recently, the 2019 WHO (World Health Organization) classification adopted a three-tiered system of classification to unify and simplify denomination of the disease. Grade 1 (or low grade appendiceal mucinous neoplasm) is defined by acellular or hypocellular mucinous deposits, with pushing tumor margins, and low grade epithelial cell cytology. Grade 2 (or high grade appendiceal mucinous neoplasm) is characterized by mucinous deposits with numerous epithelial cells often arranged in clusters with marked atypia. Grade 3 (or high grade with signet-ring cells) is represented by neoplasms containing true signet-ring cells defined as intracytoplasmic mucin vacuole indenting the nucleus (degenerating cells floating within mucin pools should not be considered as true signet-ring cells) [19].
The primitive ovarian origin of PMP has been debated for a long time. First descriptions of PMP were from appendiceal or intestinal origins. Thus, when a female patient presented with a clinical situation of PMP with both mucinous lesions of the appendix and the ovaries, she was considered to present either a PMP of appendiceal origin with secondary localization of the ovaries or an appendiceal PMP with a concomitant borderline mucinous ovarian tumor [20–22]. In order to elucidate the origin of PMP in cases of both appendiceal and ovarian mucinous lesions, some authors tried to define morphological criteria comparing the aspects of mucinous tumor of the ovaries with and without PMP and appendiceal tumor.
For Ronett et al., the secondary ovarian localization of a primitive digestive tumor was retained when (i) the ovarian tumor was only superficial; (ii) ovaries were of a quite normal size; (iii) a unilateral ovarian tumor had a digestive phenotype in a context of anteriority of such a digestive tumor; (iv) a bilateral ovarian tumor had a digestive phenotype without any known antecedent; (v) an appendiceal tumor was ruptured with an intact associated ovarian tumor [22].
Stewart et al. observed that secondary ovarian tumor was made by scalloped glands layered by sub epithelial clefts while primary ovarian tumor did not share these features but was instead associated with an abundant stroma reaction and histiocytic infiltration [23].
Immunohistochemistry has also been used to distinguish between primary and secondary ovarian origin. Ferraira et al. showed that CK20 and MUC2 were more often expressed by mucinous ovarian tumors associated with PMP than by mucinous ovarian tumors without PMP, supporting the hypothesis of a secondary ovarian localization of a primitive digestive tumor [24]. However, Saluja et al. reported a case of PMP associated with an ovarian borderline mucinous tumor without any digestive tumor [24]. In this case, the appendix was normal on full microscopic examination, and the ovarian tumor expressed both CK7 and CK20, with MUC2. Finally, studies revealed that the immunohistochemical profile of the tumor did not allow to distinguish between PMP of primary ovarian or digestive origin, both of them being positive for CK20 and CDX2 with variable staining for CK7 [25].
O’Connell et al. investigated the mucin composition of PMP, which is principally made of MUC2 and MUC5AC and revealed that while MUC2 was more abundant in PMP, but also in appendiceal mucinous tumors and normal digestive tissue, MUC5AC was predominant in mucinous ovarian primitive tumors, suggesting that mucin composition could help to distinguish the origin of PMP [26, 27]. However, only a few studies on mucin composition are available.
However, some cases of authentic PMP with an ovarian origin have been described. These cases were associated with various mucinous tumors of the ovary, as benign mucinous adenomas, borderline mucinous tumors and adenocarcinomas [28–31]. Many of these primary ovarian PMP, in which an appendiceal origin was formally excluded, mucinous ovarian tumors were associated with teratoma, suggesting for some authors that primary ovarian origin of a PMP was only possible in a context of a mucinous ovarian tumor arising from an ovarian teratoma [32]. It should be noted that ovarian teratomas associated with mucinous tumors causing PMP did not show particularities from other teratomas without mucinous associated lesion.
The unique and original feature of our case is that the primary ovarian tumor responsible for the PMP was not a classic mucinous tumor of the ovary associated with a teratoma but a teratomatous appendiceal-like mucocele with LAMN. To our knowledge, such teratomatous involvement has never been described.
Molecular sequencing of PMP revealed frequent KRAS and GNAS mutations as in mucinous tumors of the appendix. These mutations are frequent in LAMN and HAMN and slightly rarer in mucinous appendiceal adenocarcinomas, which harbor frequent TP53 mutations as in HAMN but not LAMN [33]. KRAS mutations occur in exon 2. GNAS mutations are located at codon 201 in c.601 or c.602. Mutations in codon 601 are frequently c.601C > T, resulting in p.(R201C), and those in codon 602 are often c.602G > A resulting in p.(R201H) [34]. While the former is more common in LAMN, the latter is more common in HAMN. Molecular data on primary mucinous ovarian carcinomas without the context of PMP showed frequent mutations in KRAS, without GNAS mutation [34]. Choi et al. studied molecular alterations in primary ovarian mucinous tumor associated with teratoma and PMP. They revealed KRAS and GNAS associated mutations [35]. These results, as ours, could indicate that ovarian mucinous tumors associated with teratomas and responsible for PMP are in fact of a teratomatous digestive origin. Molecular data on PMP of other origins than appendiceal and ovarian are not available, those cases being very rare.