—  SPECIALTY CONFERENCE  —

Gynecologic Pathology

Case 3 - Once Low Grade Serous Tumors Have Been Eliminated, Serous LMP Tumors are Benign - Pro

Robert Kurman
Johns Hopkins University School of Medicine
Baltimore, MD





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Clinical History
A 34 year old woman was found to have a pelvic mass and a serum CA-125 of 800. A TAH, BSO, and omentectomy were performed. A virtual slide of the 5 cm diameter right ovary is provided for your review as well as images of the ovary and omentum.


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The category of "serous borderline tumor (SBT)" or "low malignant potential (LMP)" was carved out of conventional serous carcinomas by FIGO in 1971 and WHO in 1973 to draw attention to a group of tumors that had a significantly better outcome and that therefore required less aggressive management [1]. Because the outcome for tumors with extra ovarian spread was far better than anticipated, even when inadequately treated, it was recommended that extra ovarian disease associated with SBTs be designated "implants" rather than metastases [1]. Subsequent clinicopathologic studies showed that when SBTs were confined to the ovary survival was nearly 100% but that survival for patients with advanced stage disease was approximately 70% [2]. Numerous efforts to distinguish the small group of tumors that behaved in a malignant fashion from those that behaved in a benign fashion were unsuccessful. In 1996 two studies of noninvasive serous tumors demonstrated that those with a micropapillary architecture behaved in a malignant, albeit indolent, fashion compared to those with a more typical (hierarchical branching) pattern that were benign. These investigators proposed that the former group be classified as "noninvasive micropapillary serous carcinoma (MPSC)" and the latter as "atypical proliferative serous tumor (APST)" to more accurately describe their behavior thereby permitting triage of patients into different prognostic groups [3, 4]. These studies also demonstrated that a subset of MPSCs were closely associated with invasive low-grade serous carcinoma (LGSC). Accordingly, it was proposed that there was a progression of SBT to noninvasive MPSC and subsequently invasive LGSC [3, 4] . Prior to this molecular genetic and clinicopathological studies maintained that SBTs were unrelated to conventional serous carcinomas. The relationship of SBT to LGSC had not been previously appreciated because LGSC was not recognized as a distinct entity, probably because it is relatively uncommon accounting for only 10% of all serous carcinomas [5, 6, 7, 8] .

This led to an intense debate about the clinical significance of MPSCs. Although several studies demonstrated that MPSCs, in contrast to APSTs, were more frequently associated with invasive peritoneal implants, bilateral and advanced stage disease and increased tumor recurrence, higher mortality was not confirmed in all the studies and therefore it was argued that the designation "carcinoma" for the micropapillary tumors was unwarranted and that MPSC was merely a morphological variant of SBT [9, 10, 11, 12, 14, 15, 16, 17, 18]. Another related issue of considerable importance was clarifying the diagnosis and clinical significance of implants. In the late 1980s it was reported that implants that invaded underlying tissue were associated with a poorer outcome than those that were not invasive with the implication that the invasive implants were malignant and the noninvasive implants were benign [19]. A review of nearly 500 cases reported in the literature confirmed that impression [2]. A persistent problem, however, has been the observation that some women with noninvasive implants die of their disease.

Molecular genetic studies comparing the frequency of mutations of KRAS, BRAF and TP53 in SBTs, invasive LGSCs and invasive high-grade serous carcinoma (HGSC) demonstrated that SBTs and LGSC displayed a similar mutational profile in that about two thirds of both tumor types contained KRAS or BRAF mutations and rarely harbored TP53 mutations. This contrasted dramatically with HGSC, which rarely contained KRAS and BRAF mutations but had a very high frequency of TP53 mutations [20, 21]. The mutational data were confirmed by gene expression profiling studies demonstrating similar expression patterns between SBTs and LGSC, which were very different from HGSC [22, 23, 24] . These studies, however, did not compare APSTs to noninvasive MPSCs. Recently, compelling data based on gene expression profiling of APSTs, noninvasive MPSCs and invasive LGSC demonstrated that MPSC is closer molecularly to invasive LGSC than to SBT [25] . Furthermore, these investigators demonstrated that genes involved in the mitogen-activated protein kinase (MAPK) signaling pathway showed higher expression in MPSC than in APSTs supporting the biological role of the KRAS-BRAF-MEK-MAPK pathway in the development of LGSC [26] .

These findings have several important implications. First, taken together with previous molecular genetic studies showing that MPSC is clonally related to invasive LGSC [20] , this gene expression profiling study supports the view that MPSC is the noninvasive precursor of invasive LGSC. Moreover, the finding that the gene expression profiles of MPSC and APST are different and a previous study reporting that MPSC harbors a pattern of chromosomal imbalance distinct from that of APST [8] suggests that APST and MPSC are molecularly distinct and confirms the proposal that LGSC develops in a stepwise fashion from cystadeno(fibro)ma to APST and noninvasive MPSC . Second, the diagnosis of a MPSC should alert the surgeon that this tumor might have a greater risk of being associated with extra ovarian disease, specifically metastatic LGSC. In this regard it should be noted that studies have shown that the morphology of invasive implants is identical to LGSC. Moreover, it is evident that some noninvasive implants are identical morphologically to invasive implants and therefore appear to represent LGSC that has not yet invaded. Accordingly, we recommend that "invasive implants" and similar appearing "noninvasive implants" be classified as "metastatic LGSC" whereas implants lacking these features should be designated "implants" [27] . Third, in view of the above molecular and morphologic findings the category of SBT is no longer relevant. Instead these noninvasive ovarian tumors should be designated APST or noninvasive MPSC as these terms provide more specific and useful prognostic information [2] . Fourth, since MPSC represents a stage of tumor progression rather than a morphological variant of SBT, future research should focus on the molecular changes that occur during the progression from APST to MPSC, and then to invasive LGSC. Finally, the increased expression levels of TANK, PARP, PEA15, and CDK2 proteins that potentially participate in MAPK signaling in APST-MPSC suggest that the development of MPSC and invasive LGSC depend on activation of the MAPK pathway. In this regard, it is noteworthy that a recent GOG clinical trial (GOG0239) using a MEK inhibitor (AZD6244) has been active in recurrent LGSC patients. Targeted therapy for women with advanced stage LGSC is an area that requires investigation since these tumors do not respond to conventional cytotoxic chemotherapy [28] .

The question being debated in this Symposium is that once noninvasive MPSCs are removed from the group of noninvasive serous tumors, are the remainder (APSTs) benign? It is generally reported that SBTs without micropapillary architecture are associated with invasive implants in about 5% of cases and that these can behave in a malignant fashion. As noted above it has also been reported that noninvasive tumors with a micropapillary pattern do not behave more aggressively than SBTs. We maintain that SBTs without a MP pattern are benign based on several considerations. To begin with, because SBTs are relatively uncommon, virtually all published studies of these neoplasms come from tertiary care centers. The advantage of such studies is that there is a uniform and expert pathology review but there are several limitations, which seriously undermine the conclusions that SBTs can behave aggressively and that MPSCs are merely variants of SBTs. These limitations include lack of standardized surgical staging, lack of comprehensive tissue collection and sampling and lack of long-term follow up. Thus, a study from MD Anderson presented at this meeting in 2008 is particularly illuminating. That study, unlike others that were previously reported, included a relatively large number of patients with advanced stage disease (n=56) and had long-term follow-up (43-432 months with a mean of 179 months). The investigators found that noninvasive serous tumors with >10% MPSC behaved the same as invasive LGSC whereas those with <10% of MPSC behaved the same as pure APST supporting the view that MPSC is a distinct entity apart from the typical SBT and is similar to invasive LGSC in its behavior [29]. Another problem that we have encountered that can account for malignant behavior by an SBT is the erroneous diagnosis of a noninvasive HGSC as a "borderline" tumor since there is no evidence of invasion (Kurman RJ, Vang R, unpublished data). Not surprisingly, such tumors may act aggressively. Finally, SBTs reported as being associated with invasive implants may harbor occult areas of invasion that were not sampled. Thus, when a series of low grade serous tumors with metastatic LGSC (invasive implants) was analyzed for the presence of invasion based on the number of sections taken, it was found that when the number of sections increased from 1 section/cm of greatest tumor dimension to >2 sections/cm, 3 of 10 APSTs on initial review were upgraded to invasive LGSC [30].

In summary, clinicopathologic and molecular genetic studies support the view that MPSC is a distinct tumor entity rather than a variant of SBT and clarify the "intermediate" and enigmatic behavior of SBTs by pointing out that the borderline category is not pure but heterogeneous, composed of a majority of benign tumors (APSTs) and a small group of noninvasive low grade carcinomas (MPSCs). Combining these two discrete tumors into one category explains their "intermediate" behavior and obscures their different behavior. Accordingly, there is now ample evidence to eliminate the category of "borderline."

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