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The p16 gene belongs to INK4 family of genes and is made up of four members: p16 INK4A , p15 INK4B , p18 INK4C and p19 INK4D , all of which share biological properties, namely, inhibition of cell growth and tumour suppression. After p53, p16 is the second most common tumour suppressor gene. It has been regarded as the familial melanoma gene. Immunohistochemistry for p16 has a well-defined role in distinct pathological scenarios. It is used to distinguish desmoplastic melanoma from reactive fibrous proliferation, with former showing strong nuclear positivity. In other types of melanoma, p16 protein expression is lost. Spitz nevi show retention of nuclear staining for p16. Benign mesothelial proliferations tend to retain nuclear p16 immunoreactivity, while malignant mesotheliomas lose expression. However, p16 fluorescent in-situ hybridisation analysis is recommended in the workup of malignant mesothelioma. Another common application of p16 immunohistochemistry is as an indicator for human papillomavirus (HPV) infection and p16 protein is overexpressed in HPV-associated tumours. In this context, p16 immunopositivity should be strong, diffuse, nuclear or nuclear and cytoplasmic in location. Another use for p16 is demonstration of p16 immunopositivity in well-differentiated and dedifferentiated liposarcoma.

Smad4 or DPC4 belongs to a family of signal transduction proteins that are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to transforming growth factor beta (TGF-β) signaling via several pathways. The gene acts as a tumour suppressor gene and inactivation of smad4/DPC4 is best recognised in pancreatic cancer. However, smad4/DPC4 is also mutated in other conditions and cancers such as juvenile polyposis syndrome with and without hereditary haemorrhagic telangiectasia, colorectal and prostate cancers.Immunohistochemistry for smad4/DPC4 protein is most useful in separating benign/reactive conditions from pancreatic cancer in needle/core biopsies. In normal and reactive states, the protein is localised to the cytoplasm and nucleus, while the protein is lost in high-grade pancreatic intraepithelial neoplasia/carcinoma in situ and pancreatic cancer.

Immunodeficient individuals are prone to develop a number of opportunistic infections and unique neoplasms. Epstein-Barr virus–associated smooth muscle tumor is an uncommon neoplasm associated with immunodeficiency. It has been described in patients infected with human immunodeficiency virus, in the posttransplant setting, and in those with congenital immunodeficiency. Different anatomic sites can be involved by Epstein-Barr virus–associated smooth muscle tumor, and even multiple locations can contain these unique lesions within the same patient. The presence of variable numbers of intratumoral lymphocytes and primitive round cell areas are the unique defining features for this tumor. Histopathologic features may vary considerably in terms of cellular atypia, mitotic activity, and necrosis, with no correlation to the clinical behavior. Demonstration of Epstein-Barr virus infection by in situ hybridization within tumor cell remains critical for the diagnosis. The mechanism for Epstein-Barr virus infection of progenitor cells and neoplastic transformation has been an area of interest and conjecture. Different treatment strategies are proposed according to underlying disease status. This paper reviews the clinicopathologic features of this uncommon neoplasm with detailed discussion of the role of Epstein-Barr virus in the pathogenesis.

Sclerosing pneumocytoma (SP) is a rare benign low-grade tumour of the lung, and typically presents as single discrete coin lesions on imaging. Multiple SP is an exceedingly rare entity and thus reported sparingly. We review the literature on multiple SP, their clinical presentations, histopathology, relevant differential diagnoses and molecular histogenesis of this entity. SP has a predilection for East Asian origin females who have never smoked. Patients are either asymptomatic or have symptoms such as cough, haemoptysis that may be persistent, chest pain if involving the pleura and presents as discrete coin lesion on chest X-ray. Histologically, they are papillary, solid, angiomatoid or sclerotic, or combinations of these four basic patterns. Multiple lesions have the same or slightly different histological patterns. They can be distributed in either lung, in any lobe and can even be bilateral. AKT-1 molecular pathways are pivotal in their molecular pathogenesis. In this review, we further propose a classification based on five types of distribution of multiple SP.

RNF43 (E3 ubiquitin-protein ligase RNF43 or RING-type E3 ubiquitin transferase RNF43) functions as a tumor suppressor, by exerting a predominant negative feedback mechanism in the Wnt/β-catenin signaling pathway. RNF43 inhibits Wnt/beta-catenin signaling by ubiquitinating Frizzled receptor and targeting it to the lysosomal pathway for degradation. Loss of function of RNF43 results in decrease/lack of degradation of Frizzled with enhancement of Wnt/β-catenin signaling pathway. Mutations of RNF43 have been reported in different cancers. We describe the structure of RNF43, its function and most frequent mutations in different cancers.

‘Apoptotic colopathy’ is an umbrella term signifying a pattern of injury where the gastrointestinal biopsy shows a colitic picture with apoptosis as the predominant histological feature. Although the entities within apoptotic colopathy share a common histological feature— ‘apoptosis’, there is a list of varied clinical differential diagnoses that produce this similar histological pattern of injury. These include graft-versus-host disease, drug-induced injury due to multiple drugs (in particular, mycophenolate mofetil, check point inhibitor therapy and some others), infections (particularly cytomegalovirus, adenovirus and some others), immune disorders and other miscellaneous causes. However, the management of these varied differentials is strikingly different, thus necessitating an algorithmic approach for accurate diagnosis and optimal patient management. A definitive diagnosis requires interpretation of varied histological findings in the appropriate clinical context including clinical history, drug history and laboratory findings. This review will focus on the histopathological findings of varied entities that can manifest as ‘apoptotic colopathy’ on assessment of colonic biopsies.

The authors report a mechanistic basis for intestinal polyp formation in patients with hereditary mixed polyposis syndrome that involves the aberrant epithelial expression of morphogens and leads to the formation of ectopic intestinal crypts by progenitor cells outside the stem cell niche, a mechanism that seems to also be involved in human ectopic serrated polyps. Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1 . Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5 -negative progenitor cells that have exited the stem cell niche. These cells form ectopic crypts, proliferate, accumulate somatic mutations and can initiate intestinal neoplasia, indicating that the crypt base stem cell is not the sole cell of origin of colorectal cancer. Furthermore, we show that epithelial expression of GREM1 also occurs in traditional serrated adenomas, sporadic premalignant lesions with a hitherto unknown pathogenesis, and these lesions can be considered the sporadic equivalents of HMPS polyps.

Neoadjuvant chemoradiation (NACR) is now standard of care in stage II and III rectal cancer. The advent of this modality of treatment has impacted on the way the pathological evaluation of resection specimens that have been subjected to preoperative chemoradiation is conducted. The gross description, sectioning and microscopic examination have had to be adapted to accommodate the changes induced by NACR. Attempts at introducing a uniform approach to the gross triaging and reporting of these specimens have been met with muted response. There still exists much variation in approach. The purpose of this overview is to highlight some of the newer developments and issues around NACR-treated rectal cancers from a pathological point of view. The NACR-treated resection specimens should be handled in a consistent manner, at least within individual institutions, if not universally. There should be generous sampling with multiple sections taken as tumour is often sequestered deep in the bowel wall. Microscopic examination should be extra vigilant as residual cancer can be present as single cells or small clusters, often deep in the muscularis propria or serosa. Acellular pools of mucin or non-viable tumour cells in mucin within the bowel wall or lymph nodes are not regarded as positive and do not upstage the tumour. The issue of grading of regression has been the subject of much debate, and several approaches have been published. It is recommended that a system that has clinical meaning and use to oncologists be used. Lymph node counts will be reduced after NACR, but reasonable attempts to accrue 12 nodes should be made.

Immunohistochemistry (IHC) for mismatch repair (MMR) proteins is used to identify MMR status: being diffusely positive (intact/retained nuclear staining) or showing loss of nuclear tumour staining (MMR protein deficient). Four colonic adenocarcinomas and a gastric adenocarcinoma with associated dysplasia that displayed heterogenous IHC staining patterns in at least one of the four MMR proteins were characterised by next‐generation sequencing (NGS). In order to examine a potential molecular mechanism for these staining patterns, the respective areas were macrodissected, analysed for microsatellite instability (MSI) and investigated by NGS and multiplex ligation‐dependent probe amplification (MLPA) analysis of MLH1, MSH2, MSH6 and PMS2 genes, including MLH1 methylation analysis. One colonic adenocarcinoma showed heterogenous MSH6 IHC staining and molecular analysis demonstrated increasing allelic burden of two MSH6 frameshift variants (c.3261delC and c.3261dupC) in areas with MSH6 protein loss compared to areas where MSH6 was retained. Two colonic adenocarcinomas with heterogenous MLH1 staining showed no differences in sequence variants. In one of these cases, however, MLH1 was hypermethylated in the area of MLH1 loss. Another colon carcinoma with heterogenous PMS2 staining (but with retained MSH6) showed both MSH6 c.3261dupC and 3260_3261dupCC where PMS2 protein was lost and only c.3261dupC where PMS2 was retained. The gastric carcinoma showed complete loss of MSH6 in dysplastic foci, while the underlying invasive carcinoma showed retention of MSH6. Both these areas, however, were MSI‐high and showed the same MSH6 variant: c.3261delC. The gastric dysplasia additionally showed MSH6 c.3261dupC. In four of the five cases where MMR protein was lost, these areas were MSI‐high. Heterogenous MMR IHC (focal and/or zonal within the same tumour or between invasive and dysplastic preinvasive areas) is not always due to artefact and is invariably related to MSI‐high status in the areas of loss. An interesting aspect to this study is the presence of MSH6 somatic mutations irrespective of whether MSH6 IHC staining was intact or lost.