Strategies for distinguishing low-grade endometrioid and serous carcinomas of endometrium

Distinction between endometrioid and serous carcinomas of the endometrium has important prognostic and therapeutic implications. Misdiagnosing a serous carcinoma as endometrioid can have significant consequences for the patient and pathologist. Although many cases are straightforward and easy to classify, there are occasional problematic cases. This review focuses on strategies that help differentiate between low-grade endometrioid carcinoma and serous carcinoma of the endometrium. We will discuss clinical, morphologic, and immunohistochemical differences between the 2 entities and provide practical tips for practicing pathologists when confronted with this differential diagnosis.     

Two cases of peritoneal serous papillary adenocarcinoma.

Two cases of peritoneal papillary carcinoma are reported. The patient in the first case was a 71-year-old woman with symptoms of obstructive ileus. Laparotomy revealed a tumor in the omentum involving the transverse colon, and several small tumors in the peritoneum and pelvic wall. However, no primary site of the tumor was seen in the ovary, pancreas, or gastrointestinal tract. The patient in the second case was a 44-year-old woman with carcinomatous peritonitis. Postmortem examination revealed multiple tumors in the peritoneum, omentum, and pelvic wall. Tumors were also found in the cortex with mild invasion of the underlying parenchyma of the bilateral ovaries, although these lesions were thought to be metastatic. The histologic features of the tumor in both cases were those of tubulopapillary adenocarcinoma containing scattered psammoma bodies. The cells were positive with the PAS-D technique, but negative with alcian blue staining. In both cases, the serum levels of CA-125 were considerably elevated, and the tumor cells showed positivity for CA-125, S-100 protein, cytokeratin and EMA by immunohistochemistry. The present cases were most likely peritoneal serous papillary adenocarcinoma derived from extraovarian peritoneal mesothelium with müllerian potential, being different from the usual type of diffuse malignant mesothelioma.     

In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low-grade serous tumours

Genes of the RAF family, which mediate cellular responses to growth signals, encode kinases that are regulated by RAS and participate in the RAS/RAF/MEK/ERK/MAP-kinase pathway. Activating mutations in BRAF have recently been identified in melanomas, colorectal cancers, and thyroid and ovarian tumours. In the present study, an extensive characterization of BRAF and KRAS mutations has been performed in 264 epithelial and non-epithelial ovarian neoplasms. The epithelial tumours ranged from adenomas and borderline neoplasms to invasive carcinomas including serous, mucinous, clear cell, and endometrioid lesions. It is shown that BRAF mutations in ovarian tumours occur exclusively in low-grade serous neoplasms (33 of 91, 36%); these included serous borderline tumours (typical and micropapillary variants), an invasive micropapillary carcinoma and a psammocarcinoma. KRAS mutations were identified in 26 of 91 (29.5%) low-grade serous tumours, 7 of 49 (12%) high-grade serous carcinomas, 2 of 6 mucinous adenomas, 22 of 28 mucinous borderline tumours, and 10 of 18 mucinous carcinomas. Of note, two serous borderline tumours were found to harbour both BRAF and KRAS mutations. The finding that at least 60% of serous borderline tumours harbour mutations in two members of the ERK-MAP-kinase pathway (BRAF 36%, KRAS 30%) compared with 12% of high-grade serous carcinomas (BRAF 0%, KRAS 12%) indicates that the majority of serous borderline tumours do not progress to serous carcinomas. Furthermore, no BRAF mutations were detected in the other 173 ovarian tumours in this study.     

Combined large cell neuroendocrine carcinoma and papillary serous carcinoma of the endometrium with pagetoid spread

Neuroendocrine carcinomas of the endometrium are rare tumors that can be pure, combined with endometrioid adenocarcinoma, or a component of malignant mixed müllerian tumor. Recently, a case of combined small cell carcinoma and papillary serous carcinoma of the endometrium was described for the first time. We report the first case, to our knowledge, of combined large cell neuroendocrine carcinoma and papillary serous carcinoma of the endometrium, with an unusual pagetoid spread of the neuroendocrine component into normal endometrial and endocervical glands. The endometrial carcinoma had a small serous component, but most of the tumor was characterized by solid sheets of medium to large cells with abundant mitotic figures, numerous apoptotic bodies, and foci of necrosis. This component was diffusely positive for neuroendocrine markers. Following surgery, the patient was treated with radiation therapy and chemotherapy. She was without evidence of progression at 5 months of follow-up.     

Lymphovascular space invasion does not predict vaginal relapses in stage I endometrioid adenocarcinoma of the endometrium

This study was conducted to determine whether, in a pure population of patients with International Federation of Gynecology and Obstetrics stage I endometrioid endometrial (S1EE) carcinoma that is confined to the uterus and without lymph node metastases, the presence of lymphovascular space invasion (LVSI) is positively associated with vaginal relapses. Pathologic reports for all S1EE diagnosed in a hysterectomy specimen during a 9-year period (1997-2005) were reviewed. Cases with LVSI were selected and immunohistochemical staining for CD34, factor VIII-related antigen and pancytokeratin were performed on the relevant slides for confirmation. Various established prognostic/predictive clinicopathologic parameters were documented for the whole cohort and were correlated with the presence or absence of LVSI. One-way analysis of variance with Bonferroni correction and Fisher exact/chi(2) tests were used in the respective comparisons of continuous and categoric variables among the different groups. A total of 345 patients were diagnosed with S1EE during this period. The mean patient age for the cohort was 61.9 (+/-12.2) years (range, 28-89 years) and median follow-up was 80 months. Among these 345 patients, LVSI was present in 52 (15%), representing 1 (0.8%) of 121 stage 1A, 23 (14.5%) of 159 stage 1B, and 28 (43%) of 65 stage 1C cases (P < .001). Pelvic and/or para-aortic lymph node dissection was performed in 216 cases, and none had positive lymph nodes. We noted that LVSI correlated significantly with nuclear grade, with LVSI being present in 48% (10/21), 18% (32/175), and 5% (7/140) of cases with nuclear grades 3, 2, and 1 cases, respectively (P < .001). It was also more likely to be present in cases with architectural grades 2 and 3 (35/105) than grade 1 (16/234) (P < .01). Vaginal recurrences occurred in 2 (3.8%) of 52 patients with LVSI and 8 (2.7%) of 293 patients without LVSI (P = .65). In addition, on univariate analysis, LVSI did not correlate significantly with patient age, body mass index (using 50-year and 30 body mass index thresholds, respectively), or diabetic status. We conclude that LVSI is seen in approximately 15% of S1EE, and correlates with established prognostic parameters such as the level of myometrial invasion (substage), nuclear grade, and architectural grade. However, LVSI does not denote an increased likelihood of vaginal recurrences in S1EE. The presence of LVSI should not, in of itself, alter clinical staging, or trigger unnecessary therapeutic intervention.     

KRAS (but not BRAF) mutations in ovarian serous borderline tumour are associated with recurrent low‐grade serous carcinoma

BRAF and KRAS mutations in ovarian serous borderline tumours (OSBTs) and ovarian low‐grade serous carcinomas (LGSCs) have been previously described. However, whether those OSBTs would progress to LGSCs or whether those LGSCs were developed from OSBT precursors in previous studies is unknown. Therefore, we assessed KRAS and BRAF mutations in tumour samples from 23 recurrent LGSC patients with a known initial diagnosis of OSBT. Paraffin blocks from both OSBT and LGSC samples were available for five patients, and either OSBTs or LGSCs were available for another 18 patients. Tumour cells from paraffin‐embedded tissues were dissected out for mutation analysis by conventional polymerase chain reaction (PCR) and Sanger sequencing. Tumours that appeared to have wild‐type KRAS by conventional PCR–Sanger sequencing were further analysed by full COLD (co‐amplification at lower denaturation temperature)‐PCR and deep sequencing. Full COLD‐PCR was able to enrich the amplification of mutated alleles. Deep sequencing was performed with the Ion Torrent personal genome machine (PGM). By conventional PCR–Sanger sequencing, BRAF mutation was detected only in one patient and KRAS mutations were detected in ten patients. Full COLD‐PCR deep sequencing detected low‐abundance KRAS mutations in eight additional patients. Three of the five patients with both OSBT and LGSC samples available had the same KRAS mutations detected in both OSBT and LGSC samples. The remaining two patients had only KRAS mutations detected in their LGSC samples. For patients with either OSBT or LGSC samples available, KRAS mutations were detected in seven OSBT samples and six LGSC samples. Surprisingly, patients with the KRAS G12V mutation have shorter survival times. In summary, KRAS mutations are very common in recurrent LGSC, while BRAF mutations are rare. The findings indicate that recurrent LGSC can arise from proliferation of OSBT tumour cells with or without detectable KRAS mutations. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Frameshift mutations in the bax gene are not involved in development of ovarian endometrioid carcinoma.

The purpose of this study was to determine whether mutations in the Bax gene play a role in the development of ovarian endometrioid carcinoma with a microsatellite instability phenotype. We analyzed a total of 60 tumor specimens, 49 ovarian endometrioid carcinomas and 11 concurrent endometrial endometrioid carcinomas from 49 patients. Fourteen ovarian endometrioid carcinomas and 6 endometrial endometrioid carcinomas showed a microsatellite instability-high phenotype. Tumor and normal-tissue specimens from eight patients with a microsatellite instability-high phenotype colorectal carcinoma were included in this study as controls. The presence or absence of a mutation in the poly (G) 8 tract of the Bax gene was determined by polymerase chain reaction followed by direct DNA sequence analysis. A 1-base pair deletion at the poly (G) 8 tract and no expression of Bax and Bcl-2 proteins were identified in one microsatellite instability-high endometrial endometrioid carcinoma. Immunohistochemical staining for Bax and Bcl-2 proteins was negative on the tumor specimen that had this 1-base pair deletion. No mutations were found in the synchronous microsatellite instability-high ovarian endometrioid carcinoma from the same patient. In contrast, four (50%) of the eight microsatellite instability-high sporadic colorectal carcinomas had a mutation in the poly (G) 8 tract. Although Bax plays an important role in carcinogenesis of the colorectum with microsatellite instability-high phenotype, Bax may not play a direct role in the genesis of ovarian endometrioid carcinoma, regardless of microsatellite instability status.     

Meniscus repair five-year results are influenced by patient pre-injury activity level but not age group

BackgroundThe purpose of the study is to determine whether patient age group (≥ 40 years versus < 40 years) and pre-injury activity level are independently predictive of symptomatic failure rates and patient-reported outcomes after meniscus repair with or without concomitant anterior cruciate ligament reconstruction (ACLR) at mean five years of follow-up.MethodsTwo hundred and twenty-five patients (n = 61, age ≥ 40 years; n = 164, age < 40; 11% sedentary, 63% recreational athletes, 26% competitive athletes; 72% cutting-pivoting sports, 28% non-cutting or non-pivoting sports) who underwent meniscal repair were assessed for symptomatic failure and subjective knee function at mean 5.4 years of follow-up. Symptoms were assessed with Knee Osteoarthritis Outcome Score (KOOS) and International Knee Documentation Committee Subjective (IKDC-S) scores.ResultsRepair failure was 20% overall with no association with age group (< 40 vs. ≥ 40 years) or level of activity. When compared with sedentary patients, IKDC-S scores were not associated with age group but were lower among sedentary patients (mean: 59.6, SE: 4.9) compared with recreational (mean: 78.9, SE: 2.5; p = 0.007) or competitive athletes (mean: 79.2, SE: 3.8; p = 0.02). KOOS-ADL scores were independently associated with age and were higher among patients < 40 years. KOOS-pain, KOOS-sport, or KOOS-QOL were not associated with age group. Sedentary status was independently associated with lower KOOS scores for all sub-scores.ConclusionsMeniscal repair failure rates and patient-reported outcomes do not differ substantially between older or younger patients of similar pre-injury activity level. Sedentary patients regardless of age have worse self-reported subjective outcomes compared with active patients.     

Clinicopathological analysis of recurrence and progression of low-grade papillary urothelial carcinoma of the urinary bladder: Predicting the outcome

BackgroundUrothelial carcinoma of the urinary bladder is the most common malignancy of the urinary system. Patients with low grade papillary urothelial carcinoma (LGPUC) usually have a low risk for tumor recurrence and progression; yet a subset of patients develop recurrence or grade/stage progression to high-grade papillary urothelial carcinoma (HGPUC). The clinicopathological and molecular factors that contribute to this progression are yet to be determined.ObjectivesIn our study, we aimed to assess the incidence and clinicopathological factors associated with tumor recurrence/progression of LGPUC.MethodsUsing a pathological database of surgical specimens from patients who underwent bladder biopsies and/or transurethral resection of bladder tumors (TURBTs) between August 01, 2011, and July 31, 2021, at a large academic medical center, a single-center retrospective cohort analysis was performed, and medical charts of patients were reviewed.ResultsOf the total 258 patients included, 157 (60.9 %) had “no recurrence”, 85 (32.9 %) had ≥1 “recurrence of LGPUC”, and 16 (6.2 %) had “grade progression to HGPUC”. The mean follow-up time was 31.5 ± 32 months. Patients with “grade progression” and “recurrence of LGPUC” had larger mean tumor size on initial biopsy and multiple lesions on initial cystoscopy compared to those with “no recurrence.” Interestingly, former smokers had 2.5- and 8.5-times higher risk of recurrence of LGPUC and grade progression, respectively.ConclusionSince the majority of our patients did not develop recurrence, we question whether there is tendency to overclassify the papillomas as LGPUC based on the 2004 WHO/ISUP consensus grading classification.     

Terminal duct carcinoma of minor salivary glands. A nonpapillary subtype of polymorphous low-grade adenocarcinoma

The clinicopathologic features of five terminal duct carcinomas arising in minor salivary glands are presented. These nonpapillary, low-grade adenocarcinomas are part of the spectrum of polymorphous low-grade adenocarcinoma. The patients ranged in age from 47 to 77 years. Symptoms were nonspecific and related to a mass that usually was present for several years. Histologically, the tumors had a ductal pattern with areas of solid and cribriform architecture. Cytologically, they were composed of uniform, cuboid cells with round to oval nuclei and fine chromatin. One patient developed a recurrence after 13 years, but none of the tumors has metastasized. One lesion in this series was studied ultrastructurally and demonstrated both glandular and pseudoglandular structures analogous to those of adenoid cystic carcinoma. Nonetheless, terminal duct carcinoma is cytologically distinctive from adenoid cystic carcinoma and appears to have a more favorable prognosis.     

Establishment and characterization of a serous papillary adenocarcinoma cell line of the human ovary in a serum-free culture.

In order to clarify the biologic characteristics of serous papillary adenocarcinoma of the human ovary, we tried to establish a continuous cell line using four primary tumor specimens derived from four patients with such tumors. We also evaluated c-myc, MYCN and c-erbB2 gene amplification in the cultured cells, and the xenografts, as well as in these four primary tissue specimens by a Southern blot analysis. One continuous cell line, named as FU-OV-1, was established in a serum-free culture system and this line propagated continuously for 96 serial passages over a 2-year-period in vitro. FU-OV-1 reproduced and still maintained the characteristics of the original tumor. C-myc gene amplification was found in the FU-OV-1 cells, and the xenografts, as well as in only the primary tumor of FU-OV-1 out of the four primary serous papillary adenocarcinomas. However, neither MYCN amplification nor c-erbB2 amplification was observed in any tumor specimens including FU-OV-1 cells. In conclusion, FU-OV-1 is thus considered to be a useful system for studying the biological behavior of serous papillary adenocarcinoma in the human ovary. The results of this study suggest that c-myc gene amplification might thus be associated with the progression of this tumor both in vitro and in vivo.     

Somatic but not germline mutation of the APC gene in a case of cribriform-morular variant of papillary thyroid carcinoma

We report a case of cribriform-morular variant (C-MV) of papillary thyroid carcinoma (PTC) in a 27-year-old woman. In addition to conventional cytologic features of typical PTC, the fine-needle aspirate showed numerous epithelial cells with abundant, eosinophilic, very elongated cytoplasm. Microscopically, the tumor was encapsulated and highly cellular and exhibited a mixture of cribriform, follicular, papillary, trabecular, solid, and spindle cell patterns of growth, with morular foci showing peculiar nuclear clearing (biotin-rich nuclei). The cells were cuboidal or tall, with frequent nuclear pseudostratification and abundant eosinophilic cytoplasm. The nuclei were usually hyperchromatic, with grooving, pallor, and pseudoinclusions. Angioinvasion and foci of capsular invasion were observed. Immunohistochemically, the neoplastic cells showed reactivity for thyroglobulin, epithelial membrane antigen, low- and high-molecular-weight cytokeratins, vimentin, neuron-specific enolase, CD15, estrogen and progesterone receptors, and bcl-2 protein. Molecular genetic analysis of the APC gene revealed a mutation in exon 15 at codon 1309 in tumoral tissue but not in peripheral lymphocytes. These findings support a relationship between the morphologic pattern of the C-MV of PTC and the APC gene and the existence of this variant as a sporadic counterpart of familial adenomatous polyposis-associated thyroid carcinoma.     

High telomerase activity is associated with cell cycle deregulation and rapid progression in endometrioid adenocarcinoma of the uterus.

Telomerase activity, a mechanism granting cellular immortality, has been detected in most cancer entities, but its association with clinical, histopathologic, and prognostic parameters is not fully understood. We investigated whether quantitative telomerase levels are correlated to established prognostic factors, telomere lengths, cell cycle kinetics, and the clinical course in endometrioid adenocarcinoma of the uterus (EC). A modified telomeric repeat amplification protocol (TRAP) was used to quantify the relative telomerase activity in a series of 53 primary tumors. Mean telomere length was determined by Southern blot analysis. Cell cycle kinetics were studied immunohistochemically on paraffin sections using monoclonal antibodies to 2 distinct proliferation-specific proteins: Ki-67, which is expressed throughout the cell cycle, and a novel cell cycle-associated protein, repp86, the expression of which is restricted to the cell cycle phases S, G2, and M. The ratio of the 2 immunolabeling indices defines the rate of transition through the restriction point. Telomerase activity was detected in 50 of 53 ECs (94%). Its levels correlated significantly with FIGO stage (P =.01) and FIGO grade (P =.003) but not with myometrial invasion. They were weakly associated with the overall proliferative activity (Ki-67, r =.48) but significantly with the repp86 index (r =.64) and even more strongly with the repp86:Ki-67 ratio (r =.77). There was no correlation with mean telomere length. In the group of tumors with high telomerase activity, 5 patients had relapses and 2 died of the disease within a median follow-up period of 29 months. Recurrence showed no relation to FIGO grade and stage. No events were observed in the group with low telomerase activity. In a multivariate model including tumor stage, histopathologic grade, depth of myometrial invasion, and Ki-67 indices, telomerase activity emerged as the only independent predictor of disease progression (P =.0002). It is concluded that beyond a link to proliferation, high telomerase activity reflects a deregulation of the cell cycle associated with an increased rate of cells entering S phase and a higher degree of malignancy. Therefore, quantitative analysis of telomerase activity may be useful for identifying EC patients at high risk for recurrence.