Breast lymphoma: General review.

BACKGROUND: Lymphoma of the breast can be classified as either primary breast lymphoma (PBL) or secondary to systemic lymphoma (SBL). PBL is a rare disease with Diffuse Large B cell Lymphomas (DLBCL) being the most common subtype. OBJECTIVES: In the current study, we represented eleven cases diagnosed with breast lymphoma in our trust; two of them had PBL and nine had SBL. We focused mainly on the clinical presentation, diagnosis, management and outcomes. METHODS: We did this retrospective review for all breast lymphoma patients who were diagnosed in our trust during the periods from 2011-2022. Patients' data were obtained from the hospital recording system. We followed up these patients thus far to identify the outcome of treatment in each patient. RESULTS: Eleven patients were included in our review. All patients were females. Average age of diagnosis was 66.1 ± 13 years of age. Eight patients were diagnosed with DLBCL, two patients were diagnosed with follicular lymphomas, and the last one had lymphoplasmacytic lymphoma. Chemotherapy +∕- radiotherapy was the standard treatment regimen in all patients. Four patients passed away within one year of chemotherapy, five patients achieved complete remission, one patient had two relapses and is still under treatment, while the last patient was diagnosed recently and still awaiting treatment. CONCLUSION: Primary breast lymphoma is an aggressive disease. The treatment for PBL is mainly systemic with chemoradiotherapy. The role of surgery is now limited to the diagnosis of the disease. Early diagnosis and proper treatment are crucial for the management of such cases.

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.

A Pilot Study to Determine the Utility of Automated Tissue Dissociator for Flowcytometry Based Evaluation of Hematolymphoid Tumor Tissue Biopsies.

Routine diagnostic biopsy tissue processing, conventional histology/immunohistochemistry (IHC) method is a multi-step and time consuming practice. With the advanced tissue dissociation protocols and panel designing, flow cytometric immunophenotyping (FCI) can be performed on diagnostic hematolymphoid tissue samples using single cell suspensions that economize steps and the time taken. Diagnostic tissue samples from lymph node, mediastinal mass, testicular biopsies and similar sites were dissociated using gentle MACS Octo-dissociator and FCI was performed thereafter. Oral tissue biopsy samples were also processed as a validation set for the protocol. 21 prospective tissue biopsy samples with suspected involvement by a known hematolymphoid neoplasm were processed and evaluated. These included B lymphoblastic lymphoma (n = 12), T lymphoblastic lymphomas (n = 3), Burkitts lymphoma (n = 3) and one case each of granulocytic sarcoma, Hodgkin lymphoma and granulomatous disease. Tissue FCI and IHC were found concordant with identified profile FCI obtained from blood/bone marrow analyses. FCI can produce a highly sensitive and reliable report, within hours, by processing fresh tumor tissue samples from suspected hematolymphoid malignancies. This method can be considered as an effective adjunct to IHC and can be applicable in routine clinical diagnostics, especially in cases that needs quick diagnosis and immediate clinical treatment.

Assessment of skin response in T4b breast carcinoma patients post-neoadjuvant chemotherapy.

BACKGROUND: Breast cancer patients with skin ulcerations, satellite nodules or Peau d'orange at presentation are classified with stage 4 breast cancer (T4b). Neoadjuvant chemotherapy (NACT), followed by mastectomy, is the commonly accepted treatment in such patients for fear of adverse outcomes with breast conservation surgery (BCS) and uncertainty over sparing initially involved skin irrespective of the response to chemotherapy. Identifying patients with skin resolution post-NACT can help surgeons in decision-making. AIM: To assess skin response in T4b breast cancer patients post-NACT and find the correlation between various clinical and pathological factors associated with no skin involvement on final histology. METHODOLOGY: Records of breast cancer patients managed at the Tata Medical Center, Kolkata, with NACT for T4b breast carcinoma patients who underwent mastectomy were reviewed between January 2014 and December 2018. Final histology was checked for dermal involvement with the tumour. The Mann-Whitney U test was used for continuous variables for descriptive data, and Pearson's chi-squared and Fischer's exact tests were applied for categorical data. p-value < 0.05 was taken as significant. RESULTS: A total of 285 records mentioning skin involvement were reviewed, out of which 111 patients fulfilled the AJCC criterion. The median age at diagnosis of T4b breast cancer was 50 years. The median clinical size pre-chemotherapy was 7 cm. Residual median tumour size on final histology was reported as 1 cm. 78/111 patients showed a post-NACT response of 50% or more, and 43/111 showed a response of more than 90%. 57 (51.4%) patients showed skin involvement on final histopathology, while 54 (48.6%) patients did not.ER negative tumours were more likely to show no dermal involvement (p = 0.006). Residual tumour size of less than 1 cm on final histology (p < 0.05) and nodal stage were significant predictors of dermal response. CONCLUSION: Approximately half of the T4b breast cancer patients showed resolution of dermal skin involvement post-NACT. ER negative and those with residual tumour size less than 1 cm post-NACT are more likely to show dermal resolution. This can help surgeons plan a BCS or skin sparing mastectomy for such patients who usually end up having a mastectomy.

Outcomes of diffuse large B-cell lymphoma in elderly patients-real-world experience from a middle-income country setting.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is the commonest subtype of lymphoma in the elderly and poses unique challenges in this group of patients. There is a need for more information on real-world outcomes across economic disparities. METHODS: Electronic Medical Record of 3,087 lymphomas (>18 years) were evaluated retrospectively, of which 842 (27%) patients were ≥65 years. Two hundred and twelve patients who were ≥65 years received first line treatment for DLBCL between May 2011 and Dec 2016. Demography, clinical features, associated co-morbidities, first line treatment outcomes and hospital costs were analysed. Patients were followed up till March 2020. RESULTS: The median age at presentation was 71 years. Gender ratio was 2.5:1. 38% patients presented with early-stage disease, 37% with low and low-intermediate International prognostic index, 49% with nodal disease. One or more co-morbidities were present in 58%. The commonest extra nodal site was gastro-intestinal (29%). Two-thirds of the patients presented with non-Germinal centre B subtype. The overall response (OR) to treatment was 72.5%. Patients who received anthracycline-based therapy (n = 124) and rituximab-based therapy (n = 159) had a median progression free survival (PFS), not reached and 47.0 months, respectively, versus 10 months and 7.9 months, respectively, for patients receiving non-anthracycline and non-rituximab therapies. At a median follow-up of 24 months, the 5-year overall survival and PFS are 44% and 41%, respectively, for the entire cohort. CONCLUSIONS: DLBCL is a curable lymphoma in elderly patients with standard anthracycline and rituximab-based therapies. Improvement in outcomes largely depends on social and financial support to complete the scheduled treatments.

Systematic Optimization of Potent and Orally Bioavailable Purine Scaffold as a Dual Inhibitor of Toll-Like Receptors 7 and 9.

Several toll-like receptors (TLRs) reside inside endosomes of specific immune cells-among them, aberrant activation of TLR7 and TLR9 is implicated in myriad contexts of autoimmune diseases, making them promising therapeutic targets. However, small-molecule TLR7 and TLR9 antagonists are not yet available for clinical use. We illustrate here the importance of C2, C6, and N9 substitutions in the purine scaffold for antagonism to TLR7 and TLR9 through structure-activity relationship studies using cellular reporter assays and functional studies on primary human immune cells. Further in vitro and in vivo pharmacokinetic studies identified an orally bioavailable lead compound 29, with IC50 values of 0.08 and 2.66 µM against TLR9 and TLR7, respectively. Isothermal titration calorimetry excluded direct TLR ligand-antagonist interactions. In vivo antagonism efficacy against mouse TLR9 and therapeutic efficacy in a preclinical murine model of psoriasis highlighted the potential of compound 29 as a therapeutic candidate in relevant autoimmune contexts.

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.

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.

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.

Density of CD3+ and CD8+ cells in gingivo-buccal oral squamous cell carcinoma is associated with lymph node metastases and survival.

The tumor immune microenvironment is emerging as a critical player in predicting cancer prognosis and response to therapies. However, the prognostic value of tumor-infiltrating immune cells in Gingivo-Buccal Oral Squamous Cell Carcinoma (GBOSCC) and their association with tumor size or lymph node metastases status require further elucidation. To study the relationship of tumor-infiltrating immune cells with tumor size (T stage) and lymph node metastases (N stages), we analyzed the density of tumor-infiltrating immune cells in archived, whole tumor resections from 94 patients. We characterized these sections by immune-histochemistry using 12 markers and enumerated tumor-infiltrating immune cells at the invasive margins (IM) and centers of tumors (CT). We observed that a higher density of CD3+ cells in the IM and CT was associated with smaller tumor size (T1-T2 stage). Fewer CD3+ cells was associated with larger tumor size (T3-T4 stage). High infiltration of CD3+and CD8+ cells in IM and CT as well as high CD4+ cell infiltrates in the IM was significantly associated with the absence of lymph node metastases. High infiltrates of CD3+ and CD8+ cells in CT was associated with significantly improved survival. Our results illustrate that the densities and spatial distribution of CD3+ and CD8+ cell infiltrates in primary GBOSCC tumors is predictive of disease progression and survival. Based on our findings, we recommend incorporating immune cell quantification in the TNM classification and routine histopathology reporting of GBOSCC. Immune cell quantification in CT and IM may help predict the efficacy of future therapies.