Intestinal-type Mucinous Tumors Research Articles

Seromucinous Tumors of the Ovary. What's in a Name?

The recent 2014 World Health Organization (WHO) Classification of Tumours of the Female Reproductive Organs introduced a new category of ovarian neoplasm designated "seromucinous tumours". The recognition of this distinctive group of tumors is an important addition to the classification but the term "seromucinous" has serious flaws that obscures the nature of these neoplasms. Morphologically, seromucinous tumors in addition to serous and endocervical-type mucinous epithelium, contain endometrioid, indifferent and squamous type epithelium. Their immunoprofile is characterized by frequent expression of ER, PR, infrequent expression of WT1 and lack of expression of CK20 and CDX2, an immunostaining pattern consistent with a "müllerian" immunophenotype. Unlike serous and intestinal type mucinous tumors, seromucinous tumors are frequently associated with endometriosis making them more analogous to endometrioid and clear cell neoplasms. Indeed, recent studies have shown that a high proportion of seromucinous tumors lost expression of ARID1A, a tumor suppressor gene, that is mutated in approximately 50% of endometrioid and clear cell tumors, in sharp contrast to serous and intestinal-type mucinous tumors which do not contain ARID1A mutations or lose its expression. Therefore, based on their clinicopathologic, immunohistochemical and molecular genetic features we believe a more appropriate designation for this group of tumors is "mixed müllerian tumors" which can be subcategorized as "mixed müllerian cystadenomas", "mixed müllerian atypical proliferative (borderline) tumors" and "mixed müllerian carcinomas".

The value of SATB2 in the differential diagnosis of intestinal-type mucinous tumors of the ovary: primary vs metastatic.

Primary mucinous adenocarcinomas of the ovary are a diagnostic challenge because their histologic and immunohistochemical features usually overlap with metastatic tumors. SATB2 is a recently identified protein with restricted expression in the glandular cells lining the lower gastrointestinal tract. The aim of this study is to examine the differential expression of SATB2 in primary and metastatic tumors of the ovary. Mucinous ovarian tumors of intestinal type were retrieved from the pathology files of the Instituto Nacional de Cancerología de México. A double reading of the hematoxylin and eosin-stained slides was performed to confirm the diagnosis, and a detailed review of the clinical chart was performed to define the primary origin of the tumor (ovarian vs metastatic). Immunohistochemical staining for CK20, CDX2, and SATB2 was performed and evaluated by 2 gynecopathologists. A total of 106 mucinous tumors were identified, 26 of which were considered to be metastatic, and 80 of which were primary ovarian tumors. All of the primary tumors that were not associated with cystic teratomas were negative for SATB2, and the 4 that were associated with a teratoma were positive for SATB2. All 20 of the metastatic tumors of the colon and appendix were positive for CK20, and 4 were positive for CK7. In addition, all 20 of these tumors were positive for SATB2, and 19 were positive for CDX2. SATB2 appears to be a useful marker for the diagnosis of primary vs metastatic mucinous intestinal-type neoplasms and is highly sensitive in detecting lower gastrointestinal tract metastasis.

Ovarian mucinous tumors arising from mature cystic teratomas—a molecular genetic approach for understanding the cellular origin

Mucinous tumors of the ovary are frequently associated with mature cystic teratomas, and it has been speculated that the mucinous tumors arise from teratoma components. The cellular origins of mature cystic teratomas are believed to be post-meiotic ovarian germ cells, and the analysis of microsatellite markers such as short tandem repeats is suitable for determining the cellular origin of tumors. In this study, we analyzed 3 ovarian mature cystic teratomas, all of which were associated with simultaneous ovarian mucinous tumors within the same ovary. Two of the 3 mucinous tumors were intestinal-type and the other was endocervical type. A laser capture microdissection technique was used to separate the epithelial component of the mucinous tumor, the components of the mature cystic teratoma, and control ovarian somatic tissue. Using short tandem repeat analysis based on 6 markers (D20S480, D6S2439, D6S1056, D9S1118, D4S2639, and D17S1290), we could distinguish the germ cell (homozygous) or somatic (heterozygous) origin of a given component in each sample. The epithelial components of the intestinal-type mucinous tumors in cases 1 and 2 were homozygous, and the epithelial component in case 3 (endocervical type) was heterozygous. All teratomatous components were homozygous, and the control components were heterozygous. In addition, we analyzed 3 mature cystic teratomas without mucinous tumors, and all 3 were homozygous in the tumor component. Our data suggest that the origin of mucinous tumors in the ovary may differ among histological subtypes, and intestinal-type mucinous tumors may arise from mature cystic teratomas, although endocervical-type mucinous tumors may not.

Mucinous Tumor of Low Malignant Potential (“Borderline” or “Atypical Proliferative” Tumor) of the Ovary

Mucinous tumors of the ovary are a continuing source of controversy in the field of gynecologic pathology. We examined a series of 171 intestinal-type mucinous tumors of low malignant potential ("borderline" or "atypical proliferative" tumors) to clarify the clinical significance of intraepithelial carcinoma (IECA) and microinvasion (area ≤ 10 mm²). The diagnosis of IECA was based on the presence of marked nuclear atypia (grade 3). Stromal microinvasion was classified as low grade and high grade (with nuclear grade 3). IECA was observed in 67 of 171 cases (39.2%). Microinvasion was identified in 31 (18.1%) cases, low grade in 22 (12.9%) cases, and high grade in 9 (5.3%) cases. Follow-up status was known in 144 cases and tumor recurrence was observed in 6 patients (4.2%). The risk factors for recurrence included International Federation of Gynecology and Obstetrics stage ≥ IC (P=0.002), microinvasion (P=0.013), age less than 45 years (P=0.032), and IECA (P=0.042). The amount of IECA ≥ 10% was also associated with the risk of recurrence (P=0.007). Among tumors with microinvasion, there was no significant association between the clinicopathologic variables and recurrence. When considering tumors with stage ≥ IC, tumor recurrence was significantly associated with IECA ≥ 10% (P=0.031) and age less than 45 years (P=0.047). It is important that mucinous tumors of low malignant potential should be staged and be optimally sampled for pathologic examination to document the status of the external surface or peritoneal involvement and to identify the worst degree of epithelial proliferation. Tumor stage ≥ IC, IECA ≥ 10%, microinvasion, and age less than 45 years were the features that were associated with tumor recurrence. The study results also support the use of nuclear grade 3 as the sole criterion of IECA.

Ovarian Intestinal Type Mucinous Borderline Tumors: Are We Ready for a Nomenclature Change?

At a National Cancer Institute-sponsored workshop it was proposed that the borderline category of ovarian intestinal-type mucinous tumors (OInMTs) could be eliminated if the apparent benign behavior of these tumors could be confirmed. We reviewed 33 cases of borderline OInMT, with either optimal or adequate sampling and with at least 5 years of follow-up, to investigate their behavior. Optimal sampling and adequate sampling were defined as at least 1 section per centimeter of maximum tumor dimension and at least 1 section per 2 cm of maximum tumor dimension, respectively. The patients' age ranged from 16 to 89 years (mean 49 yr). Tumor size ranged from 8 to 39 cm (mean 20 cm). The sampling of the ovarian tumor was optimal in 28 cases and adequate in 5 cases. The patients were treated surgically as follows: cystectomy (1), unilateral oophorectomy or unilateral salpingo-oophorectomy with or without total abdominal hysterectomy (13), and bilateral salpingo-oophorectomy with or without total abdominal hysterectomy (19). Complete or partial staging was obtained in 26 patients. All of them had Federation of Gynecology and Obstetrics stage I disease. Thirty-one patients with a follow-up ranging from 5 to 18 years (mean 10 yr) had no recurrences. Two patients had recurrences 12 and 14 months after their initial surgery. The first patient underwent a left salpingo-oophorectomy and limited staging for a borderline OInMT adherent to the ileum and sigmoid. The tumor was incompletely removed and recurred in the pelvis 1 year later. It was again incompletely excised. Ten months later, the tumor re-recurred in the pelvis and could only be drained because of the patient's advanced age and her poor medical status. She died of other causes 5 years later. The second patient with recurrent tumor had undergone a cystectomy and full staging for a borderline OInMT. Fourteen months later, she developed a recurrence in the residual ovary. She underwent a right salpingo-oophorectomy and total abdominal hysterectomy and has been without evidence of disease for 11 years. In this study of 33 Federation of Gynecology and Obstetrics stage I borderline OInMTs that were optimally or adequately sampled to exclude intraepithelial carcinoma, microinvasion, or invasive carcinoma, there were only 2 cases with recurrence, secondary to incomplete excision or cystectomy, and no deaths from disease. However, borderline OInMTs are usually large and heterogeneous, and the standard sampling protocol for them is not evidence based. As indicated by one of our consultation cases, there remains the potential for a sampling artifact in which a focus of carcinoma is missed. Caution dictates retaining the current nomenclature to ensure the follow-up of patients affected by this disease until uncertainty regarding the extent of sampling needed to exclude the presence of carcinoma is resolved.

Evaluation of diagnostic criteria and behavior of ovarian intestinal-type mucinous tumors: atypical proliferative (borderline) tumors and intraepithelial, microinvasive, invasive, and metastatic carcinomas.

Histologic criteria for the distinction of ovarian mucinous borderline tumors (MBTs) from invasive mucinous carcinomas (MUCCAs) and the definitions of intraepithelial (noninvasive) carcinoma and microinvasion are controversial. Accurate assessment of the behavior of these tumors has been obscured by inclusion of cases of pseudomyxoma peritonei (PMP), an entity of extraovarian origin, and misclassification of the ovarian tumors in PMP and metastatic mucinous carcinomas (METCAs) as either advanced-stage MBTs or primary ovarian MUCCAs. One hundred thirty-six intestinal-type ovarian mucinous tumors without PMP were evaluated for the presence of stromal invasion, marked cytologic atypia, epithelial stratification of more than three cell layers, and necrosis. Criteria for the diagnosis of MBT, MBT with intraepithelial carcinoma, MBT with microinvasion (MIBT), MUCCA, and METCA were established and correlated with behavior. Twenty-three (59%) of 39 patients whose tumors had stromal invasion of more than 5 mm died of disease. Stromal invasion of more than 5 mm was the sole feature that correlated with a poor prognosis. In the absence of this feature, marked cytologic atypia, epithelial stratification of more than three layers, microinvasion (<5 mm), or necrosis did not have an adverse effect on survival. Tumors were classified as MBT (n = 65; 48%) based on absence of stromal invasion, regardless of degree of cytologic atypia or epithelial stratification; of these, 28 (43%) qualified as intraepithelial carcinoma based on epithelial stratification of more than three cell layers or marked cytologic atypia. Tumors with stromal invasion of less than 5 mm were classified as MIBT (n = 8; 6%). Tumors with stromal invasion of more than 5 mm were classified as MUCCA (n = 24; 18%). Tumors with a nodular pattern of stromal invasion, morphology inconsistent with ovarian origin, or a primary site elsewhere were classified as METCA (n = 35; 26%). Four tumors could not be definitively classified. Of the 86 cases with follow-up (median, 33 months) all MBTs (n = 44) and MIBTs (n = 6) were stage I, with 5-year survival rates of 100%. MUCCAs (n = 17) that were stage I had a 5-year survival rate of 91%; all patients with advanced-stage MUCCA died of disease. Five-year survival rate for METCAs (n = 19) was 11%. METCAs were more common than MUCCAs but can mimic MUCCAs and MBTs clinically and histologically. In the absence of a primary site elsewhere, METCA should be strongly suspected when there is bilateral surface involvement and a characteristic nodular pattern of invasion. It is important to recognize this pattern because 5-year survival rate for METCA (11%) was substantially less than that of MUCCA (all stages, 51%) and MBT (100%). Because all MBTs, regardless of degree of atypia or stratification, were stage I and benign, we prefer to designate them as atypical proliferative mucinous tumors. Marked cytologic atypia, epithelial stratification of more than three layers, and microinvasion (<5 mm) had no effect on the behavior of MBT. Noninvasive mucinous tumors with marked cytologic atypia or excessive epithelial stratification can be interpreted as atypical proliferative tumors with intraepithelial carcinoma and those with microinvasion can be designated as atypical proliferative tumors with microinvasion; these tumors appear to represent transitional stages in ovarian mucinous carcinogenesis.