Impact of review of histopathology specimens at a tertiary oncology hospital in Eastern India-lessons learnt.

A central review of histopathology specimens at tertiary oncology hospitals is important for optimum patient care in the modern era of personalised medicine. The challenges of healthcare delivery and access to ancillary investigations faced by a pathologist from the Indian subcontinent are different from the western world. We undertook an audit to analyse the differences of opinion between the diagnosis offered at peripheral hospitals and a tertiary oncology hospital in Eastern India. By analysing the differences, common pitfalls and diagnostic discrepancies are identified which need to be addressed in future. This audit also highlights the need of setting up of tertiary oncology diagnostic centres to help both peripheral pathologists and cancer care clinicians like a hub and spoke model. This is most needed for haematopathology, soft tissue and gynaecologic oncology where the need of ancillary investigations is high.

Germline Biallelic Mismatch Repair Deficiency in Childhood Glioblastoma and Implications for Clinical Management.

We report a case of a 9-year-old boy with glioblastoma with a past history of colon cancer. Germline bi-allelic DNA-mismatch repair deficiency was diagnosed by a lack of immunohistochemical staining for PMS2 in the tumor and normal tissue. Family history was lacking. Sequencing confirmed compound heterozygous PMS2 mutations. A second hit in the DNA-polymerase-ε gene led to complete DNA-replication repair deficiency. This contributed to an ultra-hypermutated phenotype. Temozolomide was excluded from the treatment. PD-1 immunotherapy at recurrence contributed to extending post-relapse survival up to 11 months. Challenges included managing initial immune "flare" related to "pseudo-progression" and access to drug. Family screening diagnosed the sibling with Lynch syndrome. This is the first report of a child with a brain tumor treated with immunotherapy from India. Our report supports the routine inclusion of immunohistochemistry for mismatch repair proteins in the evaluation of pediatric high-grade glioma as this may directly impact the clinical care of these children and families.

Evaluating Quality Indicators of Glioblastoma Care: Audit Results From an Indian Tertiary Care Cancer Center.

PURPOSE: There are limited reports of quality metrics in glioblastoma. We audited our adherence to quality indicators as proposed in the PRIME Quality Improvement study. METHODS: This is a retrospective audit of patients treated between 2017 and 2020. After postsurgical integrated diagnosis, patients received radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ). Multiparametric magnetic resonance imaging at predefined times guided management. Numbers with proportions for indices were calculated. Survival was estimated using the Kaplan-Meier method. RESULTS: One hundred six patients were consecutively treated. The median age was 55 years (interquartile range of 47-61 years) with a male preponderance (68%). Ninety-six (90.6%) patients underwent subtotal resection, and 10 (9.4%) biopsy alone. Isocitrate dehydrogenase was wild-type in 96 (91%), and O6-methylguanine-DNA methyltransferase was unmethylated in 70 (66.0%) patients. Telomerase reverse transcriptase promoter was mutated in 64 (60.4%), and TP53 was mutated in 22 (20.8%). Concurrent radiation and TMZ were planned for 104 (98.1%), and radiation alone for 2 (1.9%). The median time to concurrent RT-TMZ was 36 days (interquartile range 30-44 days). All patients planned for RT-TMZ completed treatment, but only 81 (76%) completed adjuvant TMZ. Sixty-three (59%) completed six cycles, 18 (17%) received less than six cycles, and 25 (24%) did not receive adjuvant TMZ. At a median follow-up of 24 months (range 21-31 months), the median (95% CI) progression-free survival and overall survival were 11 (95% CI, 9.4 to 13.0) and 20.0 (95% CI, 15 to 26) months, respectively. CONCLUSION: Our patients met quality indices in most domains; outcomes are comparable with global results. Metrics will be periodically evaluated to include new standards and assess continuous service appropriateness.

Immunohistochemical screening for mismatch repair protein deficiency in paediatric high-grade gliomas - institutional experience and review of literature.

PURPOSE: Immunohistochemical (IHC) testing for mismatch repair (MMR) deficiency (MMRD) is used as a screening tool to identify microsatellite instability in various cancers (especially colon). This not only identifies hereditary cancer syndromes like Lynch and constitutional mismatch repair deficiency (CMMRD) but also aids in prognostication and prediction of sensitivity to checkpoint inhibitor drugs. There are very few reported studies on MMRD status of pediatric high-grade gliomas (pHGG) and none from the Indian subcontinent. The aim of this study is to evaluate the frequency of MMRD in pHGG and to assess if there is a need for universal screening with immunohistochemistry. METHODS: Paraffin blocks of consecutive cases of pHGG (< 18 years) were retrieved from 2 centres, and IHC with four MMR antibodies - MLH1, PMS2, MSH2 and MSH6 - was performed using tissue microarray-based technique. RESULTS: Three out of nine cases (33%) studied showed loss of staining. One case had loss of MSH2 and MSH6 confirmed by gene sequencing. Eight of the cases were glioblastoma. One case of IDH1-mutated anaplastic astrocytoma showed loss of MLH1 and PMS2 staining. Isolated PMS2 loss was noted in 1 case, where the non-tumour cells also showed loss of staining, indicative CMMRD syndrome. This patient had prior colon cancer with isolated PMS2 loss and responded to check-point inhibitor therapy with nivolumab. CONCLUSION: Our study shows that the frequency of MMRD to be about one-third of pHGG. Universal IHC screening for MMRD in all pHGGs may benefit early diagnosis and play a role in therapeutic decisions. A larger multi-institutional study will help better assess the prevalence and treatment implications in MMRD tumours.

18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Finding in a Rare Case of Follicular Carcinoma of Thyroid with Rhabdoid Morphology.

Rhabdoid tumor commonly occurs in the kidney and has an aggressive clinical course with high mortality. Extrarenal rhabdoid tumours can involve a number of organs, but poorly differentiated follicular carcinoma with rhabdoid phenotype is an extremely rare clinical entity. The 18F-FDG PET feature of this thyroid malignancy is not available in the literature to the best of our knowledge. But, this feature has significant clinical relevance in management of such patients. We present such a case.

Nodal yield and topography of nodal metastases from oral cavity squamous cell carcinoma - An audit of 1004 cases undergoing primary surgical resection.

OBJECTIVES: Nodal metastasis is an important prognostic factor in oral squamous cell carcinoma (OSCC). Detailed topographic study of metastasis can guide surgical and adjuvant radiation treatment protocols. METHODS: Retrospective analysis of distribution of nodal spread was done by auditing pathology records of 1004 patients who underwent primary surgical management at our center. RESULTS: The median nodal yield was 41 (range of 9-166) nodes, per patient. Metastasis was present in 42.9% patients, of which 52.3% demonstrated extranodal extension. Reclassification by AJCC8 criteria resulted in up-staging in 35.6% patients (pN1, pN2a, pN2b, pN2c, pN3a and pN3b in 13.1%, 3.7%, 6.9%, 0.9%, 0%, 18.1% respectively). Ipsilateral levels Ib and IIa were involved in a quarter of patients each, while IIb, IV and V were involved in < 4%, 3% and 1% of patients, respectively. Contralateral nodal metastasis was present in 5.4%. Skip metastases to level IV were 2.2% and 1.2% for tongue and gingivobuccal primaries. Tongue primaries had a lower likelihood of involving level Ib, but higher of level IIa and III, compared to gingivobuccal primaries, and a lower likelihood of extranodal extension. Primary site did not influence nodal metastasis to levels IIb, IV or V, but other factors like lymphovascular invasion, pT stage and margin status had an influence. CONCLUSION: This large series with high nodal yield, shows low level of metastasis to level IIb, IV and V, which can help modify future guidelines for extent of surgery and avoid targeted adjuvant radiation to specific levels.

Pathologist's perspectives on reporting of tumour budding in colorectal cancer.

PURPOSE: Tumour budding (TB) is an important adverse prognostic factor in colon cancer, which can also guide adjuvant treatment in stage II colorectal carcinoma. The International Tumor Budding Consensus Conference (ITBCC) recommended a three-tiered scoring system to streamline the scoring of budding across the globe. The goal of this survey is to understand the variation in reporting practice, globally. METHODS: A short survey was designed as an online questionnaire and shared via social media platforms and emails to pathology society groups in various countries. RESULTS: A majority of the 294 respondents (186/294; 63.3%) report budding in colorectal carcinoma. This figure differed significantly from 53.4% in Asia to 97.4% in North America. The most common (56.4%) reason for not reporting TB was because it is yet not a mandatory recommendation in the various datasets (e.g. The College of American Pathologists). The majority (78.9%) of the people who were reporting TB, used the ITBCC scoring system (scoring on a single hotspot 20× field). Most used 10× objective for screening (88.7%) and scored only at the invasive front (88.7%). Immunohistochemistry (8.6%) or deeper cuts (24.2%) were rarely used. TB scoring took 10 minutes or less in most (87.1%). CONCLUSION: Though budding is well accepted among specialist gastrointestinal pathologists, it is still not universally accepted as an important prognostic parameter across the globe. The hesitancy for reporting is due to a combination of lack of clinical demand and extra effort and time involved in counting the ITBCC score.

Relapsed Refractory Hodgkin Lymphoma and Brentuximab Vedotin-Bendamustine Combination Therapy as a Bridge to Transplantation: Real-World Evidence From a Middle-Income Setting and Literature Review.

INTRODUCTION: Despite high cure rates with standard treatment, 30% patients with Hodgkin lymphoma develop relapsed or refractory (R/R) disease. Salvage therapy followed by autologous hematopoietic cell transplantation (HCT) is considered standard of care. Brentuximab Vedotin (Bv) in combination with Bendamustine (B) has been tested in the salvage setting with promising results. MATERIALS AND METHODOLOGY: We conducted a single centre retrospective chart review of patients who received BBv salvage therapy to determine its activity and safety in patients with R/R classical Hodgkin lymphoma (HL). Between May 2011- December 2019, 179 patients were diagnosed with R/R HL. RESULTS: Thirty patients received BBv [median age: 30 (15-59) years, females (n=15)]. Primary refractory disease in 19 patients (63%), and 26 patients (87%) had advanced stage at treatment. Most patients received BBv after 2 prior lines of therapy [n=16 (53%)]. The median number of cycles of BBv were 3 (1-6). The number of BBv cycles delivered as outpatient was 63%. The most common Grade III/IV hematological adverse event was neutropenia [n=21, (70%)], while grade III/IV non-hematological toxicities included infections in 4 (13%), neuropathy in 4(13%), skin rash in 2 (7%), GI toxicities in 3 (10%) and liver dysfunction in 2 (7%) patients. The ORR and CR rates were 79% and 62%, respectively. Seventeen patients (57%) underwent an autologous HCT and 8 (26%) underwent an Allogeneic HCT (all haploidentical). The median follow up time from BBv administration was 12 months. Six patients died: 2 = disease progression, and 4 = non-relapse causes (Infection and sepsis = 2, GVHD=2). In addition to this, one patient progressed soon after HCT and another patient relapsed 22 months post HCT. Three year Overall survival (OS) and Event free survival (EFS) probability post-BBv treatment was 75% and 58%, respectively. OS and EFS analysis based on response (viz., CMR) to BBv demonstrated that patients in CMR had better survival probability [93% (p=0.0022) 3yr-OS and 72% (p=0.038) 3yr-EFS probability]. CONCLUSIONS: BBv is an active and well-tolerated salvage treatment for patients with R/R HL, even in refractory and advanced settings. In middle-income settings, cost constraints and access determine patient uptake of this regimen.