Immunohistochemical biomarkers are prognostic relevant in addition to the ESMO-ESGO-ESTRO risk classification in endometrial cancer.

OBJECTIVE: Pre-operative immunohistochemical (IHC) biomarkers are not incorporated in endometrial cancer (EC) risk classification. We aim to investigate the added prognostic relevance of IHC biomarkers to the ESMO-ESGO-ESTRO risk classification and lymph node (LN) status in EC. METHODS: Retrospective multicenter study within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC), analyzing pre-operative IHC expression of p53, L1 cell-adhesion molecule (L1CAM), estrogen receptor (ER) and progesterone receptor (PR), and relate to ESMO-ESGO-ESTRO risk groups, LN status and outcome. RESULTS: A total of 763 EC patients were included with a median follow-up of 5.5-years. Abnormal IHC expression was present for p53 in 112 (14.7%), L1CAM in 79 (10.4%), ER- in 76 (10.0%), and PR- in 138 (18.1%) patients. Abnormal expression of p53/L1CAM/ER/PR was significantly related with higher risk classification groups, and combined associated with the worst outcome within the 'high and advanced/metastatic' risk group. In multivariate analysis p53-abn, ER/PR- and ESMO-ESGO-ESTRO 'high and advanced/metastatic' were independently associated with reduced disease-specific survival (DSS). Patients with abnormal IHC expression and lymph node metastasis (LNM) had the worst outcome. Patients with LNM and normal IHC expression had comparable outcome with patients without LNM and abnormal IHC expression. CONCLUSION: The use of pre-operative IHC biomarkers has important prognostic relevance in addition to the ESMO-ESGO-ESTRO risk classification and in addition to LN status. For daily clinical practice, p53/L1CAM/ER/PR expression could serve as indicator for surgical staging and refine selective adjuvant treatment by incorporation into the ESMO-ESGO-ESTRO risk classification.

Evaluation of a nationwide Dutch guideline to detect Lynch syndrome in patients with endometrial cancer.

OBJECTIVE: In the Netherlands a nationwide guideline was introduced in 2016, which recommended routine Lynch syndrome screening (LSS) for all women with endometrial cancer (EC) <70 years of age. LSS consists of immunohistochemical (IHC) staining for loss of mismatch repair (MMR) protein expression, supplemented with MLH1 methylation analysis if indicated. Test results are evaluated by the treating gynaecologist, who refers eligible patients to a clinical geneticist. We evaluated the implementation of this guideline. METHODS: From the nation-wide pathology database we selected all women diagnosed with EC < 70 years of age, treated from 1.6.2016-1.6.2017 in 14 hospitals. We collected data on the results of LSS and follow up of cases with suspected LS. RESULTS: In 183 out of 204 tumours (90%) LSS was performed. In 41 cases (22%) MMR protein expression was lost, in 25 cases due to hypermethylation of the MLH1 promotor. One patient was known with a pathogenic MLH1 variant. The option of genetic counselling was discussed with 12 of the 15 remaining patients, of whom three declined. After counselling by the genetic counsellor nine patients underwent germline testing. In two no pathogenic germline variant was detected, two were diagnosed with a pathogenic PMS2 variant, and five with a pathogenic MSH6 variant, in concordance with the IHC profiles. CONCLUSION: Coverage of LSS was high (90%), though referral for genetic counselling could be improved. Gynaecologists ought to be aware of the benefits and possible drawbacks of knowing mutational status, and require training in discussing this with their patients.

A Structured Assessment to Decrease the Amount of Inconclusive Endometrial Biopsies in Women with Postmenopausal Bleeding.

OBJECTIVE: To determine whether structured assessment of outpatient endometrial biopsies decreases the number of inconclusive samples. DESIGN: Retrospective cohort study. SETTING: Single hospital pathology laboratory. POPULATION: Endometrial biopsy samples of 66 women with postmenopausal bleeding, collected during the usual diagnostic work-up and assessed as insufficient for a reliable histological diagnosis. METHODS: Endometrial biopsy samples were requested from the pathology laboratories. The retrieved samples were systematically reassessed by a single pathologist specialized in gynecology. MAIN OUTCOME MEASURE: Disagreement between initial assessment and conclusion after structured reassessment. RESULTS: We retrieved 36 of 66 endometrial biopsy samples from six different pathology laboratories. Structured reassessment of the retrieved samples by a single pathologist specialized in gynecology did not change the conclusion in 35 of the 36 samples. The remaining sample contained a large amount of endometrial tissue and the diagnosis at reassessment was endometrial hyperplasia without atypia. All other samples contained insufficient material for a reliable diagnosis. CONCLUSION: A structured reassessment of endometrial biopsies samples, which were classified as inconclusive due to insufficient material, did not change the conclusion. Although it might be helpful for pathologists to have diagnostic criteria for adequacy and/or inadequacy of an endometrial biopsy sample, the gain in efficiency is likely to be small.

Vulvar mucinous adenocarcinoma with neuroendocrine differentiation: A case report and review of the literature.

BACKGROUND: There are limited cases in literature of patients with mucinous adenocarcinoma of the vulva with neuroendocrine differentiation have. With this new case, we aim to provide an overview of the existing literature and present a tool with relevant markers for the pathologist in the differential diagnosis. CASE DESCRIPTION: A 92-year-old multiparous, Caucasian woman presented with a 8 cm spherical tumor of the left major labium. Since the initial punch biopsy was not conclusive, a local resection was performed. Histopathological examination showed mucus production, large pools of mucin with trabeculae and cribriform glandular structures with strongly atypical columnar epithelium. Additional immunohistochemical analysis demonstrated expression of: CEA, CK7, EMA, and the neuroendocrine markers synaptophysin and chromogranin supporting the diagnosis. CONCLUSION: In this report, we present a new case of a mucinous adenocarcinoma of the vulva with neuroendocrine differentiation based immunohistochemical analysis. Due to the indolent tumor behavior, partial vulvectomy is the therapy of choice.

Lymph node examination among patients with gastric cancer: variation between departments of pathology and prognostic impact of lymph node ratio.

INTRODUCTION: At least 15 lymph nodes should be retrieved for proper TNM-staging in gastric cancer. We evaluated nodal harvest and examined its relation to stage distribution and survival at a population-based level, including the value of N-ratio (metastatic/evaluated) as a staging modality. METHODS: All patients resected for primary M0 gastric cancer diagnosed in 1999-2007 in the Dutch Eindhoven Cancer Registry area were included (N = 880). Determinants of lymph node evaluation and their relationship with stage and survival were assessed in multivariable regression analyses. N-ratio categories were determined (N-ratio 0, 0%; N-ratio 1, 0.1%-19%; N-ratio 2, 20%-29%; N-ratio 3, ≥30%) RESULTS: The median number of lymph nodes examined was 7, dependent on N-category (N0: 7; N+: 8). It varied between departments of pathology from 5 to 9. This variation remained after adjustment for relevant patient- and tumour factors. Stage distribution differed between pathology departments (proportion N0 ranging from 14% to 21%, p = 0.003). Among resected patients with N0M0 disease and <7 nodes examined, 5-year survival was 56%, compared to 69% among patients with ≥7 nodes examined (p = 0.012). Five-year survival for N-ratio 0 was 58%, N-ratio 1 50%, N-ratio 2 18% and N-ratio 3 11% (p < 0.0001), while 5-year survival ranged from 58% for N0, 17% for N1, and 11% for N2/3 (p < 0.0001). CONCLUSION: In this series of patients with a relatively low number of evaluated lymph nodes, a high prognostic accuracy of N-ratio was found. However, improvement in nodal assessment is mandatory.

[Interstitial nephritis attributed to treatment with piperacillin-tazobactam and with ciprofloxacin]. / Interstitiële nefritis toegeschreven aan het gebruik van piperacilline-tazobactam en van ciprofloxacine.

A 26-year-old man was treated with piperacillin-tazobactam because of suspected cholangitis and a 77-year-old man was given ciprofloxacin because of an infected knee-prosthesis. They both developed symptoms of an interstitial nephritis: malaise and laboratory deviations. The symptoms disappeared after the antibiotics were withdrawn. No other explanation for the renal function disorders could be found in either patient. Piperacillin-tazobactam and ciprofloxacin are considered to be relatively safe and serious adverse effects are rare. Acute interstitial nephritis may, however, occur and its clinical presentation may not be very informative. Withdrawal of the culprit usually leads to recovery.

Expression of a marker for colonic crypt base cells is correlated with poor prognosis in human colorectal cancer.

BACKGROUND: There is a need for markers in colorectal cancer which will allow subclassification of stage groups into subgroups with high versus low risk of recurrent disease. AIMS: To develop monoclonal antibodies that recognise antigens or immature crypt base cells, on the assumption that in a neoplasm undifferentiated but not the terminally differentiated cells will be responsible for tumour progression. METHODS: Colon crypt cells which were isolated from human colonic mucosa by EDTA/EGTA incubation were studied. By stepwise harvesting, crypt base cell enriched fractions were obtained, and after incubation with antibodies against dominant antigens, used as immunogens. RESULTS: Of one crypt base cell specific antibody (5E9), the reactive epitope appeared to be a non-terminal carbohydrate in the mucin O-glycans of the colon. The epitope did not seem to be colon specific, but was expressed in a variety of other tissues. In colorectal carcinomas, 5E9 immunoreactivity identified a subgroup of patients with a tendency for worse prognosis. CONCLUSION: A mucin associated maturation epitope was identified in colonic crypt base cells, the expression of which in Dukes' stage B3 colorectal carcinoma may be associated with poor prognosis.

Patterns of alpha- and beta-catenin and E-cadherin expression in colorectal adenomas and carcinomas.

Previous in vitro and in vivo model studies have shown that when E-cadherin expression in carcinoma cells is reduced, invasive behaviour ensues. The situation in human cancer in vivo, however, appears to be more complex, as immunohistochemically determined E-cadherin expression in various carcinomas, including colorectal cancer, does not always correlate with invasive growth. Loss of cell adhesion during invasion in spite of E-cadherin expression might be associated with a defective cadherin-catenin complex. The expression of alpha- and beta-catenin in comparison with E-cadherin was therefore examined in colorectal adenomas and carcinomas and in lymph node and liver metastases. In normal colonic mucosa, alpha- and beta-catenin immunoreactivity occurred along the lateral plasma membranes of the epithelial cells, in a pattern identical to E-cadherin staining. A similar pattern was found in colorectal adenomas and in most malignancies. In general, in neoplastic epithelia, the majority of the cancer cells displayed a normal (matching) pattern of E-cadherin and catenin expression. It is concluded that the patterns of expression of E-cadherin and alpha- and beta-catenin are very similar in colorectal neoplasms. This observation indicates that invasion in colorectal cancer is not paralleled by consistent loss of expression of the components of the cadherin-catenin complex.

Epithelioid haemangioendothelioma of the lung: clinical and pathological pitfalls.

In 1973, a 10 year old boy presented with numerous bilateral lung nodules, diagnosed as histiocytosis X by open lung biopsy. The patient was treated with prednisone until 1984. In 1993, he developed severe pain in the neck. A biopsy of the spine revealed the same tumour morphology as was seen in the lung in 1973. Immunohistological examination of the former and present biopsy led to the definitive diagnosis of epithelioid haemangioendothelioma of the lung with metastases to spine and liver. Epithelioid haemangioendothelioma of the lung is a rare soft tissue tumour of vascular origin, readily mistaken for carcinoma or, as in this case, histiocytosis. The tumour has an intermediate malignant potential. Although metastases of epithelioid haemangioendothelioma of the lung are well-known, metastatic spread to bones, as in our case, has not previously been mentioned in the literature.

L-CAM expression in lymph node and liver metastases of colorectal carcinomas.

L-CAM, also known as E-cadherin, is a cell adhesion molecule expressed on the plasma membranes of epithelial cells at the intercellular interface. From in vitro gene transfection experiments the idea has been conceived that loss of L-CAM expression might be related to the invasive capacity as well as metastatic potential of tumour cells. In several tumours a relation between the grade of differentiation and L-CAM expression has been noticed: loss of differentiation appears to be associated with loss of L-CAM immunoreactivity. Also, in lymph node metastases of poorly differentiated carcinomas loss of L-CAM expression was demonstrated. In this study we describe L-CAM expression in lymphogenous and haematogenous metastases of large bowel adenocarcinomas, using an indirect immunoperoxidase method with the monoclonal anti-L-CAM antibody 6F9. All the metastases studied--lymphogenous as well as haematogenous--demonstrated L-CAM immunoreactivity in a pattern comparable to that of primary tumours. Intratumour heterogeneity in expression was noted, with normal intercellular, apical (non-functional), and focally negative areas in the same tumour. The data indicate that primary tumours and their metastases do not differ strikingly in their pattern of L-CAM expression. This would be consistent with transient rather than constitutive down-regulation of L-CAM in invasive and metastatic cancer cells.

L-CAM expression in normal, premalignant, and malignant colon mucosa.

L-CAM is a cell adhesion molecule which is expressed at the intercellular borders of most epithelial cells. L-CAM has been demonstrated to act as an invasion suppressor in carcinoma cell lines. In order to determine whether or not L-CAM expression might distinguish between invasive and non-invasive or metastatic and non-metastatic colon neoplasms, we studied L-CAM expression in normal colon mucosa, colon adenomas with various degrees of dysplasia, and colon carcinomas by immunohistochemistry, using the 6F9 monoclonal anti-L-CAM antibody. Normal mucosa showed evenly distributed distinct L-CAM immunoreactivity along intercellular borders. In adenomas and carcinomas, a similar though weaker expression was observed. This pattern showed a tendency to decrease in parallel with decreasing differentiation. However, no correlation was found with Dukes stage or area within the tumour. In some carcinomas, L-CAM was expressed at the luminal surface of the cells. In others, L-CAM expression was not found. These results suggest that L-CAM expression is disregulated or lost as an early event in the development of colon neoplasia and indicate that L-CAM expression does not correlate with invasive or metastatic potential.