International Society of Urological Pathology (ISUP)-Grade Grouping in Prostatic Adenocarcinoma and its Prognostic Implications.

In this study, we evaluated the association of ISUP/WHO-grade groups with various pathological prognostic parameters and cancer-specific survival in patients with prostatic adenocarcinoma. We found 27 (15.7%) cases of grade group 1, 22 (12.8%) grade group 2, 30 (17.4%) grade group 3, 40 (23.3%) grade group 4 and 53 (30.8%) grade group 5 prostatic adenocarcinoma. We found that high-grade tumors (grade 3-5) had a higher frequency of perineural invasion and higher tumor volumes (>50%). Moreover, a significant association of tumor grade was noted with cancer-specific survival of patients, signifying prognostic significance of grade grouping in prostatic adenocarcinoma.

Clinicopathological Features of Primary Neuroendocrine Tumors of Gastrointestinal/Pancreatobiliary Tract With Emphasis on High-Grade (Grade 3) Well-Differentiated Neuroendocrine Tumors.

Introduction The two broad subcategories of neuroendocrine neoplasms (NENs) are well-differentiated neuroendocrine tumors (WDNETs) and poorly differentiated neuroendocrine carcinomas (PDNECs), based on tumor architecture and cytology. Grade 3 WDNETs are a subset of WDNETs that not only are high grade by mitotic activity or proliferative index but exhibit a well-differentiated histology. In this study, we evaluated the clinicopathological features of primary neuroendocrine tumors of the gastrointestinal (GI)/pancreatobiliary tract with emphasis on high-grade WDNETs, as it is a newly defined entity. Methods We conducted a retrospective observational study, including a total number of 122 cases of primary GI and pancreatobiliary tract NENs. Slides and blocks of all cases were retrieved from the departmental archives. Immunohistochemical stains including Ki67 were applied to selected tissue blocks of all cases. Tumors were then evaluated for their histological differentiation and tumor grade. Results Our results showed that the mean age of patients was 46.8 ± 17.1 years. Majority of the NENs were GI tract origin (86.9%). The most common site of tumor in gastroenteropancreatic tract was the small bowel (31.1%), followed by the stomach (26.2%). Ninety five percent of the tumors were WDNETs, of which the most common grade was G2. The mean Ki67 index was 15.8 ± 23.8. Grade 3 WDNETs were noted to have an older mean age than grades 1 and 2 WDNETs. Ten out of 102 (9.8%) WDNETs of GI tract were grade 3, compared with four out of 14 (28.6%) of pancreatobiliary tract.  Conclusion In this study, we found that high-grade (grade 3) WDNETs were more frequent in pancreatobiliary tract than GI tract. Moreover, high-grade WDNETs were associated with a higher mean age than low-grade (grade 1-2) WDNETs. It is extremely important to recognize this subset (high grade) of WDNETs and to distinguish it from PDNECs, as the latter are known to be associated with a worse overall survival. Despite high mitotic rate/proliferative index, high-grade WDNETs are characterized by organoid architecture and monomorphic cell population.

p16 Immunohistochemical Expression in Head and Neck Squamous Cell Carcinoma: Association With Prognostic Parameters.

Background p16 is a tumor suppressor gene, over expression of which is considered as a surrogate marker of oncogenic human papillomavirus (HPV) infection. Moreover, p16 over expression correlates with good prognosis in head and neck squamous cell carcinoma (HNSCC). In the present study, we aimed to evaluate the frequency of p16 overexpression in HNSCC in our setup and its association with clinicopathologic parameters. Methods We performed p16 immunohistochemistry (IHC) on 144 cases of HNSCC. Association of p16 overexpression with various clinicopathologic parameters including T-stage, N-stage, grade, recurrence status, and risk factors was evaluated. Results p16 over expression was noted in 22.9% (33 cases), while 21.5% (31 cases) were focal positive and 55.6% (80 cases) were negative for p16 over expression. On the basis of percentage of expression; > 70% p16 expression was noted in 4.9% (7 cases), 9% (13 cases) showed 51% - 70% p16 expression, 9% (13 cases) revealed 11%-50% p16 expression, while 77.1% cases revealed no expression or < 10% p16 expression. Significant association of p16 expression was noted with nodal metastasis and extranodal spread while no significant association of p16 was noted with other prognostic parameters and risk factors. Conclusion Our data revealed that high expression (> 50%) of p16 is low in oropharyngeal squamous cell carcinoma in our setup. These finding suggest a low prevalence of HPV as a cause of HNSCC in our population. Moreover, p16 expression was found to be associated with some good prognostic parameters like lack of nodal metastasis, however, no significant association was noted with overall disease-free survival.

Ki67 index in intrinsic breast cancer subtypes and its association with prognostic parameters.

OBJECTIVES: Ki67 is the most commonly used marker to evaluate proliferative index in breast cancer, however no cutoff values have been clearly defined for high ki67 index. Cancer management should be according to loco-regional profile; therefore, we aimed to determine ki67 index in 1951 cases of intrinsic breast cancer subtypes and its association with other prognostic parameters in our set up. RESULTS: Triple negative breast cancers showed highest ki67 index (mean 50.9 ± 23.7%) followed by Her2neu (mean 42.6 ± 21.6%) and luminal B cancers (mean 34.9 ± 20.05%). Metaplastic and medullary breast cancers significantly showed higher ki67 index as compared to ductal carcinoma, NOS. No significant association of ki67 index was noted with any of the histologic parameters in different subtypes of breast cancer expect for tumor grade. Although, ki67 index is a valuable biomarker in breast cancer, however no independent prognostic significance of ki67 could be established in our study.

Prognostic Significance of High Androgen Receptor Expression in Prostatic Acinar Adenocarcinoma

Background: Quantitative immunohistochemical expression of Androgen receptor (AR) has not been evaluated as a prognostic biomarker of prostate cancer in our population, therefore in the current study we aimed to evaluate the association of AR expression in prostatic acinar adenocarcinoma with various prognostic parameters like tumor quantification, Gleason score, WHO grade group and perineural invasion. Methods: Total 121 cases of biopsy proven prostatic acinar adenocarcinoma were selected from records of pathology department archives from January 2013 till December 2017. Hematoxylin and eosin stained slides and paraffin blocks were retrieved and new sections were cut where necessary. Slides of all cases were reviewed by two senior histopathologists and pathologic characteristics like Gleason score, WHO grade, tumor quantification, perineural and lymphovascular invasion were evaluated. Androgen receptor immunohistochemistry was applied on all cases. Results: Low AR expression was noted in 53 cases (43.8%) while high AR expression was seen in 68 cases (56.2%). Significant association of AR expression was noted with total Gleason score, WHO grade and percentage of tissue involvement (tumor quantification). Univariate binary logistic regression showed patients with low Gleason scores (scores 6,7 or 8) and low WHO grade (grade 1, 2 or 3) were less likely to express high AR expression in comparison to high Gleason score (score 9) and high WHO grade group (grade 5) respectively. Similarly, cases with low tissue involvement by carcinoma (<50%) were less likely to show high AR expression in comparison to cases with >50% tissue involvement by carcinoma. Conclusion: Significant association of AR expression was noted with total Gleason score, WHO grade and percentage of tissue involvement (tumor quantification) which are among the most important markers of tumor progression; therefore we suggest that AR expression should be performed in patients with prostatic adenocarcinoma for prognostic stratification of the patients.

Prognostic utility of epidermal growth factor receptor (EGFR) expression in prostatic acinar adenocarcinoma

Background: Epidermal growth factor receptor (EGFR) is potential prognostic biomarker expressed in many human cancers. Prognostic significance of EGFR immunohistochemical expression has not been established in prostatic acinar adenocarcinoma, therefore we aimed to evaluate the frequency of expression of EGFR in prostatic adenocarcinoma and its association with other prognostic parameters. Methods: The study included 123 cases of biopsy proven prostatic acinar adenocarcinoma treated at Liaquat National hospital, Karachi from January 2013 till December 2017. Paraffin blocks of all cases were retrieved; sections were cut and stained with haematoxylin and eosin. Pathologic characteristics including tumor quantification, WHO grade group, gleason score, perineural and lymphovascular invasion were evaluated. EGFR immunohistochemistry (IHC) was performed on all tissue blocks. Results: Mean age of the patients included in the study was 69.05±8.68years. High gleason scores i.e. 8 & 9 were noted in 22% (27 cases) and 22.8% (28 cases) respectively. Similarly, 22.8% (28 cases) showed WHO grade group 5. 52.8% (65 cases) had > 50% tissue involvement by carcinoma and perineural invasion was seen in 37.4% (46 cases). Positive EGFR expression was noted in 18.7% (23 cases), while 81.3% (100 cases) showed negative EGFR expression. Significant association of EGFR expression was noted with gleason score (p-value = < 0.001), WHO grade (p = < 0.001), tumor quantification (p =0.007) and perineural invasion (p = < 0.001). Moreover, significant association of EGFR expression was also seen with disease recurrence and Her2neu over expression. Patients with low gleason scores (score 6 and 7) and lower grade group (1, 2 & 3) were less likely to have positive EGFR expression as compared to patients with high gleason score (score 9) and higher grade group (5). Similarly, patients with perineural invasion were more likely to have positive EGFR expression. Conclusion: We found a relatively low EGFR expression in our patients with prostatic adenocarcinoma; however, its association with poor prognostic parameters like high gleason score, higher grade group, perineural invasion, higher tissue involvement by cancer and disease recurrence signifies its importance as a prognostic parameter in prostatic acinar adenocarcinoma (AU)

Low p27kip1 expression in head and neck squamous cell carcinoma: association with risk factors and adverse outcomes

Background: Squamous cell carcinoma (SCC) of head and neck is highly prevalent in South-asian countries, owing to high consumption of areca nut/gutka and chewing tobacco. p27kip1 is a tumor suppressor gene, thought to be downregulated in oral squamous cell carcinoma. Therefore, in the present study we used immunohistochemical analysis to investigate an association between low p27kip1 expression in SCC of the head and neck and adverse outcomes/risk factors. Methods: Total 105 cases of SCC of head and neck excision specimens were selected from records of pathology department archives that underwent surgeries at Liaquat National hospital, Karachi from January 2008 till December 2013. Clinical and pathologic characteristics of patients were evaluated and p27kip1 immunohistochemistry was applied on tumor blocks. Results: In our study, low expression of p27kip1 in SCC of head and neck was seen in 39(37.1%) cases while 66(62. 9%) of the cases showed high expression for p27kip1. Significant association of p27kip1 expression with pan/gutka usage (p = 0.004), and recurrence (p = 0.001) was noted; however, no significant association of p27kip1 expression with other clinicopathologic features was seen. Multivariate binary logistic regression showed cases with history of pan/gutka usage were more likely to show low p27kip1 expression. Similarly, we also found that recurrence was more likely to develop in patients with low expression of p27kip1 in comparison to cases showing high p27kip1 expression. Conclusion: Loss of p27kip1 expression is a significant event involved in the pathogenesis of SCC head and neck especially that of oral cavity. Significant association of gutka/areca nut with low p27kip1 expression in our study suggests that loss p27kip1 expression is a major event involved in areca nut induced SCC of head and neck in this part of the world; however, more large scale molecular based studies are required to validate this observation. Moreover, significant association of low p27kip1 expression with tumor recurrence suggests its importance as a prognostic biomarker in SCC of head and neck (AU)

Prognostic significance of p16 & p53 immunohistochemical expression in triple negative breast cancer.

Background: p16 and p53 genes are frequently mutated in triple negative breast cancer & prognostic value of these mutations have been shown; however, their role as immunohistochemical overexpression has not been fully validated. Therefore we aimed to evaluate the association of p16 and p53 overexpression in triple negative breast cancer with various prognostic parameters. Methods: Total 150 cases of triple negative breast cancers were selected from records of pathology department archives that underwent surgeries at Liaquat National hospital, Karachi from January 2008 till December 2013. ER, PR and Her2neu immunohistochemistry were re-performed to confirm triple negative status. p16 & p53 immunohistochemistry was performed on all cases and association with various clinicopathologic parameters was determined. Results: Mean age of the patients involved in the study was 48.9 years. Most of the patients presented at stage T2 with a high mean ki67 index i.e. 46.9%. 42.7% of cases had nodal metastasis. Although 84% cases were of invasive ductal carcinoma; however a significant proportion of cases were of metaplastic histology (9.3%). Fifty-one percent (76 cases) of cases showed positive p53 expression while 49% (74 cases) were negative. Higher percentage of p53 expression was found to correlate with higher T stage, high ki67 index and higher nodal stage. On the other hand, strong intensity of p53 expression was positively correlated with higher tumor grade and ki67 index. Seventy-one percent (98 cases) of cases showed positive p16 expression, whereas 24.8% (34 cases) were negative and 3.6% (5 cases) showed focal positive p16 expression. However, no significant association was found between p16 expression and various clinical and pathologic parameters. Similarly, no significant association of either p16 or p53 over-expression was noted with recurrence status of patients. Conclusion: On the basis of significant association of p53 over-expression with worse prognostic factors in triple negative breast cancer, therefore we suggest that more large scale studies are needed to validate this finding in loco-regional population. Moreover, high expression of p16 in triple negative breast cancer suggests a potential role of this biomarker in triple negative breast cancer pathogenesis which should be investigated with molecular based research in our population.

Immunohistochemical over expression of p53 in head and neck Squamous cell carcinoma: clinical and prognostic significance.

OBJECTIVE: Immunohistochemical over expression of p53 is considered as a marker of poor prognosis in many cancers. Therefore, we aimed to evaluate immunohistochemical overexpression of p53 in 121 cases of head and neck Squamous cell carcinoma and its association with various clinicopathologic features and survival. RESULTS: Total 66.1% (80 cases) expressed positive p53 expression, 34% (29 cases) revealed no p53 expression, while focal positive p53 expression was noted in 9.9% (12 Cases). Moreover, high p53 expression (> 70%) was noted in 26.4% (32 cases), while 19% (23 cases) showed 51-70% p53 expression. On the basis of intensity of p53 staining; strong p53 expression was noted in 39.7% (48 cases), while 24.8% (30 cases) and 10.7% (13 cases) revealed intermediate and weak p53 expression respectively. Significant association of p53 intensity of expression with extranodal extension and higher tumor grade (grades II and III) was noted. p53 is useful prognostic biomarker in head and neck Squamous cell carcinoma and therefore we suggest that more large scale studies are needed to evaluate its prognostic significance in our population.

Clinicopathologic features and prognostic grouping of gastrointestinal stromal tumors (GISTs) in Pakistani patients: an institutional perspective.

OBJECTIVES: Gastrointestinal stromal tumors (GISTs) are rare tumors of gastrointestinal tract, prognosis of which largely depends upon histopathologic characteristics of resection specimens, which were not widely studied in our population. Therefore we aimed to evaluate the histopathologic characteristics of GISTs in our population and their prognostic grouping according to college of American pathologist's guidelines. RESULTS: Mean age of patients was 53.4 years (18-71 years). 92% of cases were of primary GISTs and stomach was the most common site (57.7%). 75% of cases were of spindle cell morphology and 53.8% belonged to high risk prognostic group. Comparison of stomach and intestinal GISTs showed that intestinal GISTs were found to be of high grade (70%) and of high risk prognostic group (75 and 80%) compared to stomach GISTs (43% were of high risk prognostic group), however this finding was not statistically significant. GISTs are infrequent gastrointestinal tumors but early diagnosis and identification of adverse histological features are key to successful treatment. We found a large majority of GISTs to be located in stomach, however intestinal GISTs were found more likely to be associated with adverse prognostic parameters. However more large scale studies are warranted to establish this finding.

Cytokeratin 5/6 and cytokeratin 8/18 expression in triple negative breast cancers: clinicopathologic significance in South-Asian population.

OBJECTIVE: Cytokeratin 5/6 and Cytokeratin 8/18 are basal and luminal markers of breast cancer and they have pathological and prognostic significance in breast cancer. We performed Cytokeratin 5/6 and CK8/18 immunohistochemistry on 150 cases of triple negative breast cancers and association with various clinicopathological features was evaluated. RESULTS: Positive CK5/6 expression was noted in 8% (12 cases) of TNBC while 2.4% (4 cases) showed focal positive (< 10%) and 89.3% (134) were negative with CK5/6. Complete loss of CK8/18 expression was seen in 4.7% (7 cases) while 32.7% (49 cases) revealed focal loss of CK8/18 and 62.7% (94 cases) showed intact normal expression of CK8/18. No significant association of CK5/6 and CK8/18 with various clinicopathological parameters was observed. We found a low expression of basal cytokeratin (CK5/6) in TNBC our studied population, while loss/altered expression of CK8/18 in approximately 38% of TNBC. Although no prognostic relevance of these finding was noted in our study, however these findings are different from those reported in literature in other parts of the world. Therefore we suggest a more through immunohistochemical and genomic profiling of TNBC in our population for better understanding of this disease in this part of the world.

The importance of Evolutionary Medicine in developing countries: A case for Pakistan's medical schools.

Evolutionary Medicine (EM) is a fundamental science exploring why our bodies are plagued with disease and hindered by limitations. EM views the body as an assortment of benefits, mistakes, and compromises molded over millennia. It highlights the role of evolution in numerous diseases encountered in community and family medicine clinics of developing countries. It enables us to ask informed questions and develop novel responses to global health problems. An understanding of the field is thus crucial for budding doctors, but its study is currently limited to a handful of medical schools in high-income countries. For the developing world, Pakistan's medical schools may be excellent starting posts as the country is beset with communicable and non-communicable diseases that are shaped by evolution. Remarkably, Pakistani medical students are open to studying and incorporating EM into their training. Understanding the principles of EM could empower them to tackle growing health problems in the country. Additionally, some difficulties that western medical schools face in integrating EM into their curriculum may not be a hindrance in Pakistan. We propose solutions for the remaining challenges, including obstinate religious sentiments. Herein, we make the case that incorporating EM is particularly important in developing countries such as Pakistan and that it is achievable in its medical student body.

Clinicopathologic features of colorectal carcinoma: features predicting higher T-stage and nodal metastasis.

OBJECTIVES: A rising frequency of colorectal carcinoma has been noted in recent years in Pakistan. In the present study, we aimed to evaluate clinicopathologic features of colorectal carcinoma in our population so that protocols could be developed to stratify patients that may require further biomarker/molecular testing. Furthermore, histological features which predict higher T and N stage were also evaluated. RESULTS: Median age at diagnosis was 54.5 (19-85) years. 79% cases were of conventional adenocarcinoma while 13% cases were of mucinous carcinoma. Most of the cases were at T3 stage (81%), while 27 and 68% of cases revealed lymphovascular invasion and nodal metastasis respectively. Mucinous and signet ring tumors were associated with a higher N stage. Pre-existing polyp was associated with lower T and N stage. We found a high proportion of our cases to present at advanced T-stage. Tumor grade and lymphovascular invasion were found to be associated with higher N-stage while tumor infiltrating lymphocytes was associated with lower T and N-stage. Moreover, a high frequency of mucinous differentiation may be linked to microsatellite instability in our cases of colorectal carcinoma; therefore, we suggest that microsatellite instability testing in colorectal carcinoma should be evaluated in our setup.