Kedar Deodhar

Down-staging following neoadjuvant chemo-radiotherapy for locally advanced rectal cancer: Does timing of surgery really matter?

Background: Neoadjuvant chemoradiotherapy (NACTRT) improves local recurrence rate in locally advanced (LA) rectal cancer with no survival benefit. Pathological complete response (pCR) post-NACTRT is associated with improved outcome. Debate is ongoing as to when would be the opportune time to operate. Aim: To determine if greater down-staging can be achieved by a longer time interval from NACTRT to surgery (tumor regression score [TRS]) and whether this would impact sphincter saving surgery rates and early relapse rates. Materials and Methods: A retrospective analysis of a prospectively maintained database of patients with LA rectal adenocarcinoma treated from January 2012 to August 2013 was carried out. One hundred and ten patients who completed NACTRT (50 Gy/25 fractions with capecitabine 825 mg/m2 twice daily) followed by surgical resection were included. For response evaluation patients were divided into two groups, Group 1 (TRS ≤60 days, n = 42) and 2 (TRS >60 days, n = 68). Tumor down-staging, pCR rate, tumor regression grade (TRG) post-NACTRT and relapse rates were correlated with TRS. Results: Of 110 patients (median age: 49 years (21-73), 71% males; 18 (16.5%) with signet ring histology) 96% patients underwent an R0 resection. Post-NACTRT, CR was attained in 5 (4.5%), partial response in 98 (89%) and stable disease in 7 (6.4%) patients. Median time from completion of NACTRT to surgery was 64.5 days (6-474). Median lymph nodes harvested were 10 (1-50). Overall, 22 (20%) patients achieved pCR. 26 (62%) patients in Group 1 compared to 36 (53%) in Group 2 underwent sphincter sparing surgery (SSS) (P = 0.357). Six patients (14%) in Group 1 and 16 (24%) in Group 2 achieved pCR (P = 0.24). Median TRG in both groups was three. Conclusion: Timing of surgery following NACTRT for LA rectal cancer does not influence pathological response, ability to perform SSS or disease-free survival. There is no incremental benefit of delaying the surgery though this needs to be confirmed in a prospective randomized trial.

Solid pseudopapillary tumor of the pancreas: ‘Experiences’ and ‘Lessons’ at a tertiary‐care oncology center

Solid pseudopapillary tumor of the pancreas (SPT) is a rare and fascinating entity of elusive histogenesis and unpredictable biology. It has a peculiar proclivity to afflict young females and involve the pancreatic body‐tail region. Cytology diagnosis of these rare neoplasms remains a challenge. We analyzed the cytology features of all SPT cases diagnosed on fine needle aspiration cytology (FNAC) from 2003 to 2009 along with their histopathology slides. Nineteen consecutive cases were diagnosed as SPT on FNAC. Fifteen out of nineteen cases were confirmed as true SPT on histopathology. Amongst the true SPT, all except one occurred in females. Age ranged from 14 to 50 years. Pseudopapillae bearing stout branches terminating in bulbous tips and enclosing transgressing vessels, separated from a collar of tumor cells by a clear zone of myxohyaline coat were pathognomonic of SPT. Singly dispersed monomorphic tumor cells with bland chromatin formed the second diagnostic component of SPT. Nuclear grooves and hyaline globules were in addition helpful in segregating SPT from its close differentials. In four cases diagnosed as SPT on FNAC, histopathology revealed a different final diagnosis (one case each of paraganglioma, extragastrointestinal stromal tumor, metastatic papillary renal cell carcinoma and inflammatory myofibroblastic tumor). Conversely, one case of SPT had been erroneously diagnosed as neuroendocrine tumor on FNAC. Six cases (40%) developed metastasis; commonest site being liver. In conclusion, cytology in conjunction with clinico‐radiologic findings plays a key role in making a correct diagnosis. Awareness of unique cytomorphological features is important in distinguishing this tumor from its diverse mimics. Diagn. Cytopathol. 2013.

Factors influencing response to neoadjuvant chemoradiation and outcomes in rectal cancer patients: tertiary Indian cancer hospital experience

BACKGROUNDnIn the treatment of rectal cancers several randomized trials have demonstrated benefits of neoadjuvant chemoradiotherapy (NACRT) in downstaging as well as survival among these patients. We investigated the patient and tumor related variables dictating the outcomes in these patients.nnnMETHODSnBiopsy proven treatment naive 182 rectal cancer patients underwent NACRT from June 2006 to December 2010. The entire patients received long course conventionally fractionated external beam radiotherapy with concurrent oral Capecitabine. At 6 weeks from completion of NACRT clinico-radiological assessment was carried out for surgical feasibility. All patients were given postoperative adjuvant chemotherapy either single agent or multi drug regimen depending upon biopsy report.nnnRESULTSnAmong 182 patients, 131 (72%) underwent surgery and initial T stage and signet ring cell morphology were major determinant of operability. Among the 131 operated patients at median follow up of 36 months, 94 (72%) are alive and disease free. With a median follow up of 42 months the 5-year disease free survival (DFS) and overall survival (OS) was 60% and 77%. The majority of the failures were distal but with more advanced disease at presentation both local and distal failures were similar. While assessing survival by multivariate analysis patients having positive nodes post-surgery had a significantly poorer DFS (P=0.001), while signet ring cell morphology and pre-treatment carcino-embryonic antigen (CEA) levels strongly influenced OS (P=0.03).nnnCONCLUSIONSnThe outcome of our patients were similar to World Literature and signet ring cell morphology, pre-treatment CEA level, and pathological nodal staging all were influential in determining survival. Besides this, the study also highlights the fact that tumours with signet ring cell morphology appearing in younger population with poor survival needs prospective evaluation for more intense CRT regimen and aggressive surgical resections.

Somatic Variations in Cervical Cancers in Indian Patients.

There are very few reports that describe the mutational landscape of cervical cancer, one of the leading cancers in Indian women. The aim of the present study was to investigate the somatic mutations that occur in cervical cancer. Whole exome sequencing of 10 treatment naïve tumour biopsies with matched blood samples, from a cohort of Indian patients with locally advanced disease, was performed. The data revealed missense mutations across 1282 genes, out of 1831 genes harbouring somatic mutations. These missense mutations (nonsynonymous + stop-gained) when compared with pre-existing mutations in the COSMIC database showed that 272 mutations in 250 genes were already reported although from cancers other than cervical cancer. More than 1000 novel somatic variations were obtained in matched tumour samples. Pathways / genes that are frequently mutated in various other cancers were found to be mutated in cervical cancers. A significant enrichment of somatic mutations in the MAPK pathway was observed, some of which could be potentially targetable. This is the first report of whole exome sequencing of well annotated cervical cancer samples from Indian women and helps identify trends in mutation profiles that are found in an Indian cohort of cervical cancer.

Neoadjuvant imatinib: longer the better, need to modify risk stratification for adjuvant imatinib

BACKGROUNDnMultimodality treatment of gastrointestinal stromal tumor (GIST) with surgery and adjuvant imatinib mesylate (IM), along with an emerging role for neoadjuvant IM prior to evaluation for resectability has resulted in high survival rates.nnnMETHODSnWe conducted a retrospective analysis of prospectively collected data of patients who underwent surgery for GIST, prior to or followed by IM therapy. A total of 112 patients underwent surgery between January 2009 and March 2015 at our centre. This included 27 patients with upfront resectable disease, 76 patients with locally advanced GIST who received neoadjuvant IM followed by surgery and 9 patients with metastatic disease who had excellent response to IM and were taken for surgery.nnnRESULTSnThe primary tumor in the non metastatic patients was in the stomach (53%), duodenum (16%), rectum (12%), jejunum (11%), ileum (7%), and others (2%). Median duration of neoadjuvant IM was 5 months with 4 patients showing disease progression during neoadjuvant IM. Ninety-three percent of all patients had R0 resections, while 7% had R+ resections. The estimated 3- and 5-year DFS in non-metastatic patients was 86.1% and 67% respectively with a 3- and 5-year median OS of 95.4% and 91.7% respectively. Five-year PFS and OS for the metastatic patients was 88.8% and 100% respectively. Lack of adjuvant IM was the only factor related to inferior PFS and OS.nnnCONCLUSIONSnLonger duration of neoadjuvant IM should be considered in locally advanced GIST prior to surgery and resection may be considered in responding metastatic patients.

Tumour origin and R1 rates in pancreatic resections: towards consilience in pathology reporting

To evaluate differences in the R1 rates of ampullary (AC), pancreatic (PC), and distal bile duct (DBD) cancers in pancreatoduodenectomies (PD) using standardised pathology assessment. Data of PD (2010–2011) analysed in accordance with the Royal College of Pathologists (UK) protocol, were retrieved. Clinicopathologic features, including frequency, topography, and mode of margin involvement in AC (nu2009=u200987), PC (nu2009=u200918), and DBD (nu2009=u20095) cancers were evaluated. The R1 rate was 7%, 67%, and 20% in the AC, PC, and DBD cancers (pu2009<u20090.001). Within the PC cohort, R1 rate was heterogeneous (chemo-naïve, 77%; post-neoadjuvant, 40%). Commonest involved margins were as follows: posterior in overall PD (35%), AC (43%), overall PC (33%), and post-neoadjuvant PC (100%); superior mesenteric artery margin in chemo-naïve PC (38%) and common bile duct margin in DBD (100%) cancers. In AC, majority (66%) of R1 were signet ring cell type. Indirect margin involvement due to tumour within lymph node, perineural sheath or lymphovascular space was observed in 26% cases, and altered R1 rate in AC, PC, and DBD cohorts by 1%, 12%, and 0%, respectively. Although not statistically significant, patients with R1 had lower disease-free survival than those with R0 (mean, 25.4xa0months versus 44.4xa0months). Tumour origin impacts R1 data in PD necessitating its accurate classification by pathologists. Indirect involvement, histology, and neoadjuvant therapy influence the R1 rate, albeit in a minority of cases. Generating cogent R1 data based on standardised pathology reporting is the foremost need of the hour.

Correction to: Tumour origin and R1 rates in pancreatic resections: towards consilience in pathology reporting

The authors regret that one of the author’s given name was missing and a typographical error was present in Reference 26 of the above article. These are presented correctly in this article.

National Cancer Grid of India Consensus Guidelines on the Management of Cervical Cancer

Standard guidelines for the management of early and locally advanced cervical cancer are available from various academic consortiums nationally and internationally. However, implementing standard-of-care treatment poses unique challenges within low- and middle-income countries, such as India, where diverse clinical care practices may exist. The National Cancer Grid, a consortium of 108 institutions in India, aims to homogenize care for patients with cervical cancer by achieving consensus on not only imaging and management, but also in addressing potential solutions to prevalent challenges that affect the homogenous implementation of standard-of-care treatment. These guidelines therefore represent a consensus statement of the National Cancer Grid gynecologic cancer expert group and will assist in homogenization of the therapeutic management of patients with cervical cancer in India.

Cancer Stem cells, CD44 and outcomes following chemoradiation in locally advanced cervical cancer: Results from a prospective study

PURPOSEnAlthough cancer stem cells (CSCs) have been reported across solid tumors, there is a dearth of data regarding CSC and its impact on outcomes of cervical cancer.nnnMETHODS AND MATERIALSnFrom October 2013 to December 2015, patients with squamous cancer of the cervix (stage IB2-IVA) were included. Pretreatment and posttreatment biopsy was obtained and immunohistochemistry was performed for SOX-2, OCT-4, Nanog, CD44, and Podoplanin. All patients received concurrent radiation and brachytherapy to an equivalent dose of 80 to 84xa0Gy to point A with concurrent weekly cisplatin. Correlation of CSC expression was performed with known prognostic factors. The effect of stem cell expression on disease outcomes was tested within multivariate analysis.nnnRESULTSnOne hundred fifty patients were included. The median dose to point A was 83xa0Gy (46-89xa0Gy) and a median of 4 cycles (range, 0-6 cycles) of chemotherapy was administered. At baseline, moderate to strong immunohistochemical expression of SOX-2, OCT-4, Nanog, CD44, and Podoplanin was observed in 12.8%, 4.8%, 24.4%, 15.5%, and 1.3% of patients, respectively. At median follow-up of 30xa0months (range, 3-51xa0months), locoregional and distant relapse was observed in 12.2% and 23.1% of patients, of whom 4.7% had both local and distant relapse. The 3-year disease-free survival rate was 87%. On multivariate analysis, moderate to high CSC expression and CD44 low status (hazard ratio [HR]xa0=xa08.8; 95% confidence interval [CI], 1.0-77.2; Pxa0<xa0.04) independently predicted for locoregional relapse-free survival. International Federation of Gynecology and Obstetrics stage (HRxa0=xa02.6; 95% CI, 1.3-5.4; Pxa0=xa0.004) and presence of residual tumor after external radiation (HRxa0=xa03.5; 95% CI, 1.8-6.5; Pxa0=xa0.0001) predicted for a detriment in disease-free survival.nnnCONCLUSIONSnThe presence of stem cell proteins and loss of CD44 independently predicts for reduced locoregional control in locally advanced cervical cancer. Further investigation into the interaction of stem cell and CD44 biology is warranted.

Napsin A and WT 1 are useful immunohistochemical markers for differentiating clear cell carcinoma ovary from high-grade serous carcinoma

Clear cell carcinoma (CCC) of the ovary is an uncommon, but an aggressive epithelial ovarian cancer (EOC), which has overlapping histopathologic features with other ovarian tumours. Lately, Napsin A has been identified as its useful diagnostic immunohistochemical (IHC) marker. Fifty‐eight prospectively diagnosed ovarian CCCs, 53 high‐grade serous carcinomas (HGSCs), 16 endometrioid adenocarcinomas (EMACs), six mixed carcinomas, containing components of CCC and EMAC, seven metastatic mucinous adenocarcinomas and six ovarian yolk sac tumours (YSTs) were tested for Napsin A immunostaining. Fifty ovarian CCCs, 50 HGSCs, seven ovarian EMACs and five mixed carcinomas were tested for WT1 immunostaining. Napsin A was positively expressed in all 58 (100%) CCCs; was focally positive in 1 of 6 YSTs; in 1/16 EMACs and in six cases of mixed carcinomas, while it was negative in all 53 HGSCs and in seven metastatic mucinous adenocarcinomas. Other IHC markers expressed in cases of CCC ovary were CK7 (31/31) (100%), WT1 (0/50), p53 (20/26, ‘wild type’), ER (4/31, focal) (12.9%), PAX8 (14/14) (100%), glypican‐3 (4/10, focal) (44.4%), p16INK4 (5/5, focal) and CK20 (0/5). Various IHC markers expressed in HGSCs were WT1 (48/50) (96%), p53 (31/31, mostly ‘mutation type’), CK7 (9/9) (100%) ER (13/16, variable) (81.2%) and PAX8 (14/14) (100%). IHC markers expressed in EMACs were ER (15/16) (93.7%), CK7 (2/2) (100%) and WT1 (0/7). IHC markers expressed in mixed carcinomas were CK7 (2/2) (100%), WT1 (0/2), focal Napsin A (6/6) and focal ER (5/6). The sensitivity and specificity of Napsin A for the diagnosis of CCC ovary was 100% and 90.9%, respectively. The sensitivity and specificity of WT1 for diagnosis of HGSC ovary was found to be 96% and 100%, respectively. Napsin A and WT1 are highly sensitive and specific IHC markers for diagnosing ovarian CCCs and HGSCs, respectively, and in differentiating these tumours from their mimics. Napsin A is useful in identification of component of CCC in certain EMACs.