Relation between retinoblastoma and p53 proteins in human papilloma viruses 16/18 positive and negative cancers of the uterine cervix.

AIM: To ascertain the extent of retinoblastoma protein (pRB) expression in comparison to p53 protein and human papilloma viruses (HPV) 16/18 status in cervical carcinomas. METHODS: Fifty cases of invasive cervical carcinoma were HPV typed for genotypes 16 and 18 using consensus primers by polymerase chain reaction (PCR). Immunohistochemistry for pRB and p53 was done on formalin fixed tissue using microwave antigen retrieval and commercially available antibodies. RESULTS: Forty five cases were squamous carcinomas, three were adenocarcinomas, and two were adenosquamous carcinomas. Thirty one cases were HPV 16 positive and one was HPV 18. Sixteen cases showed +4 pRB expression and a further 11 were +3 positive. Seven cases were negative. Only five cases (10%) showed +4 p53 immunostaining, while seven were negative and 15 were +1. Of the 16 pRB +4 positive cases, one was negative for p53 and a further seven were +1 positive. This inverse pattern of staining between pRB and p53 had a p value of < 0.001. No correlation was observed between HPV 16/18 status and p53 and/or pRB staining. CONCLUSIONS: pRB is expressed in the majority of cases of cervical cancer (86%), with more than 75% (+4) of the tumour cell population being positive in 16 cases (32%). There appears to be a general inverse pattern of staining between pRB (high) and p53 (low) in cervical cancer. The expression of both pRB and p53 proteins is independent of the HPV 16/18 status of the tumour.     

Wnt disruption in colorectal polyps – the traditional serrated adenoma enters the fray

The adenoma–carcinoma sequence describes the development of colorectal carcinoma (CRC) from benign colorectal precursor lesions. Molecular classification of established CRC has demonstrated considerable disease heterogeneity; however, as an emerging cancer frequently outgrows and destroys the initial precursor lesion, CRC molecular taxonomy can only be partially reconciled with histologically classified polyps. Thus, the molecular pathogenesis of some colorectal polyp types, including the traditional serrated adenoma (TSA), is still unclear. Now, candidate driver gene analysis of a cohort of different polyps reveals characteristic, but highly variable, mutations disrupting the Wnt signalling pathway across different histological polyp subtypes. How and when different precursor lesions acquire Wnt disruption reflects important distinctions in polyp biology, dependent on a combination of the dominant molecular pathway and the cell of origin of individual lesions. TSAs preferentially acquire ligand‐dependent Wnt activating mutations, which means that the cancers that arise from these aggressive polyps may be sensitive to targeted Wnt inhibition. This paper demonstrates that applying next‐generation sequencing technology to improve our understanding of colorectal precursor lesion molecular pathogenesis could also give important and translationally relevant insights into colorectal cancer biology. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Spindle cell pancreatic endocrine tumor associated with cushing’s syndrome

A 59-yr old female presented with Cushing’s syndrome due to ectopic ACTH production. At the time of initial diagnosis an obvious source for the Cushing’s syndrome was not found and the patient was treated with bilateral adrenalectomy. Three years later she presented with hyperpigmentation and evidence of ACTH overproduction. This time a CT scan localized a mass to the tail of the pancreas and a distal pancreatectomy was performed. The mass was composed of compact plump spindle cells arranged in interlacing fascicles, was well circumscribed, and did not display angioinvasion. Although isolated punctate foci of necrosis were noted, the overall mitotic count was 1 per 10 high power fields. Immunohistochemistry showed the tumor to be positive for chromogranin, synaptophysin, and ACTH. This case highlights an unusual histological variant of pancreatic endocrine tumor (PET), namely, one composed almost exclusively of interlacing spindle-shaped cells. This raises a wide differential diagnosis and the use of immunohistochemistry is required to arrive at the correct diagnosis. ACTH-producing PET are usually aggressive lesions with metastases at the time of presentation and aggressive biological behavior. However, this case was characterized by an indolent clinical course.     

Cytokeratins 7 and 20 Immunoexpression Profile in Goblet Cell and Classical Carcinoids of Appendix

Goblet cell carcinoid (GCC) of the vermiform appendix is an uncommon neoplasm and its histogenesis is controversial. Whether GCC represents a morphological variant of classical appendiceal carcinoid or a mucin-producing adenocarcinoma is still conjectural. Little is known about the immunohistochemical expression of cytokeratins 7 (CK7) and 20 (CK20) in appendiceal neuroendocrine tumors. In this study, we compared the expression of CK7 and CK20 in 17 cases of appendiceal GCC and 25 cases of classical carcinoid. The tumors were also evaluated for Ki-67 proliferation index, mitotic activity, tumor necrosis, extracellular pools of mucin, obvious intestinal type adenocarcinomatous foci, angiolymphatic permeation, perineural/neural infiltration, and the depth of invasion of the appendix wall. Mesoappendiceal extension was present in 14 of 17 (82.3%) cases of GCC, whereas angiolymphatic and perineural/intraaneural involvement were found in 10 of 17 (58.8%) and 14 of 17 (82.3%) cases, respectively. The mitotic count ranged from 0 per 10 high power fields to 6 per 10 high power fields, with an average of 1.4 per 10 high power fields. Necrosis was not seen in any case and pools of extravasated mucin were present in 5 of 17 (29.4%) cases. Immunohistochemically, all 17 (100%) of GCC exhibited strong and diffuse immunopositivity for CK20, whereas expression of CK7 was present in 12 cases (70.5%), ranging from 5 to 50% of tumor cells being labeled. The Ki-67 labeling index ranged from 0 to 75% and showed no correlation to mitotic activity, angiolymphatic invasion or perineural/intraneural permeation. On the other hand, 25 cases of classical carcinoid tumors were consistently negative for CK7; however, 4 cases (16%) showed immunolabeling for CK20 in 25-50% of the tumor cells. The Ki-67 labeling index in classical carcinoids ranged from 0 to 5%. This study shows that in addition to the morphological differences, GCC (CK7/CK20-positive) and classical carcinoid (CK7/CK20-negative) differ in their expression of CK7 and CK20. In addition, GCC shows the same CK7/CK20 immunoexpression as colorectal adenocarcinoma. Goblet cell carcinoid should be regarded as a crypt cell or an amphicrine carcinoma rather than a variant of carcinoid tumor, a lesion that has benign connotations.     

Loss of DOG-1 expression associated with shift from spindled to epithelioid morphology in gastric gastrointestinal stromal tumors with KIT and platelet-derived growth factor receptor α mutations

Most gastric gastrointestinal stromal tumors (GISTs) display spindle cell morphology and coexpress CD117 (KIT), DOG-1, and CD34. Secondary loss of DOG-1 has not been reported. We present two gastric GISTs which showed loss of DOG-1 in the epithelioid component but retained its expression in the minor spindle cell component. Patients were a 67-year-old man and an 80-year-old woman with 4.8-cm and 3.5-cm gastric GISTs harboring mutations in KIT exon 11 (c.1729_1758dup30; p.P577_R586dup) and platelet-derived growth factor receptor α (PDGFRA) exon 18 (c.2527_2538del12; p.I843_D846del), respectively. Both were predominantly epithelioid with a minor microscopic spindle cell component (3-12 mm). The spindle cell component was CD117⁺CD34⁺DOG-1⁺ in both cases. The epithelioid component in case 1 was CD117⁺CD34⁺DOG-1^?. In case 2, the epithelioid component strongly expressed PDGFRA (dot-like) but lost CD117, CD34, and DOG-1. These cases confirm the immunophenotypic heterogeneity as secondary events in GIST. Loss of DOG-1 in KIT-negative PDGFRA mutants should not preclude diagnosis.     

Developmental lead neurotoxicity: alterations in brain cholinergic system

Developing brain has been shown to be susceptible to the neurotoxic effects of lead (Pb). Our earlier studies (Reddy GR, Riyaz Basha Md, Devi CB, Suresh A, Baker JL, Shafeek A, Heinz J, Chetty CS. Lead induced effects on acetylcholinesterase activity in cerebellum and hippocampus of developing rat. Int J Devl Neurosci 2003;21:347-52) have shown decrease in acetylcholinesterase (AChE) activity in the crude homogenates of cerebellum and hippocampus of rat brain exposed to Pb. In this study, we have further examined in detail, the alterations in AChE activity and acetylcholine (ACh) levels in different brain regions using histochemical and spectrophotometric methods. Rats were lactationally exposed to low level (0.2%) and high level (1%) Pb. The studies were conducted in young (1 month) and adult (3 months) rats. Pb exposure significantly decreased the specific activity of AChE and increased the levels of ACh in the synaptosomal fractions of cerebellum, hippocampus and cerebral cortex in a dose- and age-dependent manner. These alterations in AChE and ACh were more predominant in young rat brain as compared to adult brain. Maximum AChE activity and ACh level as well as maximum alterations following Pb exposure were observed in synaptosomes of hippocampus. Histochemical studies also showed higher AChE activity in the hippocampal region compared to other areas of brain as revealed by the intensity of AChE staining. Though high level Pb exposure remarkably decreased the intensity of AChE staining in the dentate gyrus, CA2 and CA3 areas of hippocampus, and different cell layers of cortex and cerebellum, highly significant loss of AChE activity was observed in the CA3 region of hippocampus, molecular layer of cerebellum and cortical cell layers. These data suggest that Pb exposure may selectively affect cholinergic system in brain areas controlling learning and cognitive behavior.     

Quality Indicators for Gastric Cancer Surgery: A Survey of Practicing Pathologists in Ontario

Background  Adequate lymph node (LN) assessment and R0 resection are critical to the staging and management of gastric cancer. The American Joint Committee on Cancer/International Union Against Cancer recommend at least 15 LN be assessed, and the literature suggests a gross disease-free margin of 5–6 cm be achieved. Results of an Ontario general surgeons’ survey indicated these standards were not widely known. Because disease management is highly collaborative, we surveyed pathologists to assess their knowledge of LN assessment and margins for processing gastric cancer specimens. Methods  Pathologists were identified by the College of Physicians and Surgeons of Ontario and MD Select databases. Participants were surveyed online or by mail. Results  Pathologists indicated a goal of assessing <5 LN (2%), 5–10 LN (27%), 10–15 LN (40%), 15–20 LN (20%), or >20 LN (11%). Most self-reported an actual assessment of 5–10 LN (49%), with 88% reporting a number below current standards. Additionally, 54% of responding pathologists identified >1 cm as an adequate gross margin, and 89% of pathologists indicated a response below current standards. Ninety-four percent of pathologists agreed that more education on gastric cancer is valuable. Conclusions  To improve the quality of gastric cancer management, our findings suggest the need for clear, consistent guidelines for adequate gross margin resection length. Furthermore, there is a critical need for education aimed at closing the knowledge gap among practicing pathologists and surgeons regarding current recommended guidelines for LN assessment and adequate margin length. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Intraductal tubular adenoma (pyloric gland-type) of the pancreas: a reappraisal and possible relationship with gastric-type intraductal papillary mucinous neoplasm

Aims:  Intraductal tubular adenoma (ITA) is an uncommon intraluminal polypoid lesion that occurs in the main pancreatic duct and involves the main pancreatic duct in the region of head or body. Three cases of ITA are presented, the literature reviewed and their association with intraductal papillary mucinous neoplasm (IPMN) is postulated.
Methods and results:  ITA is composed of tightly packed tubular structures with focal cystic dilation and papillary areas lined by gastric/pyloric epithelium showing minimal to mild cytological atypia. Pancreatic intraepithelial neoplasia (PanIN) 1A and B was present in smaller ducts of all cases. In addition, in the cases in this report and 50% of cases reported in the literature, an associated gastric-type IPMN was present in the same duct as the ITA or in adjacent ducts. The coexistence of ITA and IPMN and the similarities of their epithelial lining (gastric/pyloric mucosa) suggest a possible pathogenic link.
Conclusions:  ITA can occur without (type A) or with (type B) an associated gastric-type IPMN. ITA could represent a localized, polypoid form of gastric-type IPMN.It is a benign lesion with no evidence of invasion and no direct tumour-related deaths. Its relationship to intraductal tubular carcinoma remains to be elucidated.