Circumferential resection margin positivity due to direct or indirect tumour involvement in rectal cancer - a call for better stratification.

BACKGROUND: A positive circumferential resection margin (CRM) after rectal cancer surgery, which can be the result of direct or indirect tumour involvement, has consistently been associated with increased local recurrence and poorer survival. However, little is known of the differential impact of the mode of tumour involvement on outcomes. METHODS: 1460 consecutive patients undergoing rectal cancer resection between 2003 and 2018 were retrospectively assessed. Histopathology reports for patients with a positive CRM were reviewed to determine cases of direct (R1-tumour) or indirect tumour involvement (R1-other). Disease-free survival (DFS) and overall survival (OS) were assessed by Kaplan-Meier analysis. The role of the mode of CRM positivity was examined by univariate and multivariate Cox proportional hazards models. RESULTS: Eighty-five patients had an R1 resection due to CRM involvement (5.8%). Of those, 69 were due to direct tumour involvement, while 16 were from indirect causes. Kaplan-Meier analysis revealed that R1-other was associated with increased OS (hazard ratio 0.40, log-rank P = 0.006) and DFS (P = 0.043). Multivariate regression confirmed that the mode of CRM positivity was an independent predictor of OS. More interestingly, the patterns of recurrence were different between the two groups, with R1-tumour leading to significantly more local recurrence (P = 0.04). CONCLUSIONS: Our data strongly suggests that direct tumour involvement of the CRM confers worse prognosis after rectal cancer surgery. Importantly, differences in the site and frequency of recurrences make a case for better stratification of patients with a positive CRM to guide treatment decisions.

Inter- and intra-observational variability in immunohistochemistry: a multicentre analysis of diffuse large B-cell lymphoma staining.

AIMS: Although many immunohistochemical (IHC) cancer biomarkers have been identified, very few have translated into routine clinical practice, primarily because of technical and observational inconsistencies between studies. However, despite the obvious need to address such variability, very few studies have done so. METHODS AND RESULTS: Using bcl-6, CD10, MUM1, GCET1 and FOXP1 antibody staining on diffuse large B-cell lymphoma cases (n = 138) as a model, we employed Cronbach α analysis to quantify interobserver and intraobserver variability between four independent observers (two per institution), scoring two tissue microarrays (TMAs) stained at both institutions using differing staining procedures. The overall concordance between all observations irrespective of staining procedure or TMA source was high (average α = 0.951), with the highest level being reached for CD10 staining (average α = 0.967) and the lowest for bcl-6 (average α = 0.924). Interslide and interinstitutional reproducibility were similarly high (average α = 0.952 and average α = 0.934, respectively). Interobserver/intrainstitutional and interobserver/interinstitutional comparisons showed lower levels of concordance (average α = 0.870 and average α = 0.877, respectively), and intraobserver/interinstitutional comparisons showed the lowest levels of concordance (average α = 0.810), particularly for bcl-6 staining (α = 0.658). CONCLUSIONS: This study suggests that most variability in IHC studies between centres results from inherent limitations of the biomarkers investigated rather than procedural or observational differences.

Image of the month: Mauriac variant: a rare complication of poorly controlled diabetes.

We present a case of Mauriac syndrome in a young woman with poorly controlled type 1 diabetes mellitus. Liver complications are well known in the context of type 2 diabetes mellitus, it is associated metabolic complications and with the non-alcoholic fatty liver disease spectrum. This case brings to light a less well-known liver complication associated with type 1 diabetes mellitus.

A pathologist's survey on the reporting of sessile serrated adenomas/polyps.

AIM: The purpose of this survey was to ascertain reporting habits of pathologists towards sessile serrated adenomas/polyps (SSA/P). METHODS: A questionnaire designed to highlight diagnostic criteria, approach and clinical implications of SSA/P was circulated electronically to 45 pathologists in the UK and North America. RESULTS: Forty-three of 45 pathologists agreed to participate. The vast majority (88%) had a special interest in gastrointestinal (GI) pathology, had great exposure to GI polyps in general with 40% diagnosing SSA/P at least once a week if not more, abnormal architecture was thought by all participants to be histologically diagnostic, and 11% would make the diagnosis if a single diagnostic histological feature was present in one crypt only, while a further 19% would diagnose SSA/P in one crypt if more than one diagnostic feature was present. The vast majority agreed that deeper sections were useful and 88% did not feel proliferation markers were useful. More than one-third did not know whether, or did not feel that, their clinicians were aware of the implications of SSA/P. CONCLUSIONS: 98% of pathologists surveyed are aware that SSA/P is a precursor lesion to colorectal cancer, the majority agree on diagnostic criteria, and a significant number feel that there needs to be greater communication and awareness among pathologists and gastroenterologists about SSA/P.

Meningeal and brainstem infiltration by a malignant mesothelioma.

Malignant mesothelioma is an uncommon neoplasia which primarily involves the pleura or peritoneum. Central nervous system involvement is rare. A rare presentation of metastatic pleural mesothelioma, which had infiltrated the meninges and brainstem, is described. The patient presented with diplopia following a 2-week history of malaise, myalgia, mild headache and diarrhoea. Clinical examination found global areflexia, cerebellar ataxia and bilateral sixth nerve palsies. Differential diagnoses included the Miller-Fisher variant of Guillain-Barre syndrome, malignant meningitis and infectious meningitis. The patient was treated with immunoglobulins, plasmaphoresis and corticosteroids; however, he deteriorated and died 31 days after admission. Retrospective examination of the MRI of the brain found diffuse low attenuation changes within the pons and cerebral peduncles. Postmortem examination favoured a diagnosis of an early sarcomatoid malignant mesothelioma of pleural origin with leptomeningeal metastatic deposits.

Mitotic count is not predictive of clinical behavior in hidradenoma papilliferum of the vulva: a clinicopathologic study of 19 cases.

Although it is generally recognized that some benign sweat gland neoplasms may show appreciable mitotic activity, there are few reports of its quantitative analysis in specific tumor types or of its correlation with clinical behavior. The presence of a large number of mitoses in a sweat gland tumor for which the histologic criteria of malignancy are not well defined, particularly in association with nuclear abnormalities, may produce a considerable diagnostic challenge. We recently encountered such a problem in a putative case of hidradenoma papilliferum. Therefore, we have undertaken a retrospective clinicopathologic study of 19 cases originally diagnosed as hidradenoma papilliferum or probable hidradenoma papilliferum, with a particular emphasis on the relationship of the mitotic index to clinical behavior. The age range of the cases was 41 to 92 years (mean 56.8 years). In all cases in which the margins could be evaluated, the tumors were well circumscribed (15/15), but in 4 cases circumscription could not be assessed because the specimen was fragmented. All showed focal mild nuclear pleomorphism. Mitoses were present in both epithelial and myoepithelial cells. The mitotic index varied from 0 to 5.3 mitoses/mm2 (0 to 13 mitoses per 10 high power fields (hpf); 1 hpf=0.246 mm2), with a mean of 2.4/mm2 (6/10 hpf) and a median of 0.8/mm2 (2/10 hpf). No atypical mitoses were identified. The proliferative fraction (MIB-1 index) correlated with the mitotic index (correlation coefficient 0.94; P<0.0001) and varied from 1% to 10.5% (mean 3.9%, median 3.0%). There were no recurrences or metastases over a mean period of 8 years. Consequently, we have shown that the mitotic index in these lesions can be variable and often high, but it does not predict a more aggressive outcome.

Minichromosome maintenance protein in myxofibrosarcoma.

Histopathological assessment of myxofibrosarcoma may be difficult, especially on the basis of a small core biopsy, which enables only a crude evaluation of grade and prognosis. We have tested the hypothesis that determination of cell cycle state may assist in the diagnostic assessment of myxofibrosarcoma. We have studied 51 cases of high-grade (n=20), intermediate-grade (n=21), and low-grade (n=10) myxofibrosarcomas, as well as nine cases of benign myxoma. Cell cycle state within tumors was determined by immunostaining for the recently described marker minichromosome maintenance protein 2 (MCM2), together with Ki67. Labelling indices for both markers were correlated with tumor grade, mitotic index, and time to first recurrence. The MCM2 labelling indices were significantly higher than the Ki-67 labelling indices. Both indices showed a significant correlation with the mitotic index and both showed significant increases with increasing grade of myxofibrosarcoma. The MCM2 labelling index (but not the Ki67 labelling index) showed a significant inverse exponential correlation with the time to first recurrence. Myxoid and cellular areas showed no difference in the MCM2 and Ki-67 labeling index, suggesting that clinically useful information could be obtained from any component of a myxofibrosarcoma sampled in a needle biopsy and/or cytological specimen. We therefore suggest that assessment of cell cycle state may be a useful diagnostic adjunct in the histopathological assessment of myxofibrosarcoma, by enabling more accurate determination of grade and prediction of outcome.