Comparative analysis of mutational patterns in triple negative breast cancer before and after neoadjuvant chemotherapy in patients with residual disease.

Triple-negative breast cancer (TNBC) is a heterogeneous disease with poor survival compared to other subtypes. Patients with residual disease after neoadjuvant chemotherapy (NAC) face an increased risk of relapse and death. We aimed to characterize the mutational landscape of this subset to offer insights into relapse pathogenesis and potential therapeutic targets. We retrospectively analyzed archived paired (pre- and post-NAC) tumor samples from 25 patients with TNBC with residual disease using a targeted 72-gene next-generation sequencing panel. Our findings revealed a stable mutational burden in both pre- and post-NAC samples, with a median count of 12 variants (IQR 7-17.25) per sample. TP53, PMS2, PTEN, ERBB2, and NOTCH1 variants were observed in pre-NAC samples predominantly. Notably, post-NAC samples exhibited a significant increase in AR gene mutations, suggesting potential prognostic and predictive implications. No difference in mutational burden was found between patients who did and did not receive platinum (p = 0.94), or between those with and without recurrence (p = 0.49). We employed K-means clustering to categorize the patients based on their variant profiles, aiding in the prediction of possible patterns associated with recurrence. Our study was limited by its small sample size and retrospective design, suggesting the need for further validation in larger prospective cohorts.

Dose-Dense Docetaxel-Cyclophosphamide and Epirubicin-Cisplatin(ddDCEP): Analysis of an Alternative Platinum-Containing Regimen in 116 Patients with Early Triple Negative Breast Cancer.

We assessed the efficacy, tolerability, and cost-effectiveness of a novel neoadjuvant regimen comprising docetaxel-cyclophosphamide alternating with epirubicin-cisplatin (ddDCEP) administered biweekly for 16 weeks in 116 patients with early triple-negative breast cancer. This regimen achieved a high pathological complete response (ypT0/TisN0) rate of 55.2% and favorable survival outcomes (30-month event-free survival, 91.2%; overall survival, 97%). Febrile neutropenia was observed in 4.3% of patients, and 98% completed at least six of eight cycles. ddDCEP was more cost-effective than contemporary carboplatin-based regimens. This novel approach offers an economically viable and effective alternative to current chemoimmunotherapy regimens, and merits further investigation.

Molecular characterization of triple-negative myeloproliferative neoplasms by next-generation sequencing.

The role of next-generation sequencing (NGS) in identifying mutations in the driver, epigenetic regulator, RNA splicing, and signaling pathway genes in myeloproliferative neoplasms (MPNs) has contributed substantially to our understanding of the disease pathogenesis as well as disease evolution. NGS aids in determining the clonal nature of the disease in a subset of these disorders where mutations in the driver genes are not detected. There is a paucity of real-world data on the utility of this test in the characterization of triple-negative myeloproliferative neoplasms (TN-MPN). In this study, 46 samples of TN-MPN (essential thrombocythemia (ET) = 17; primary myelofibrosis (PMF) = 23; & myeloproliferative neoplasm unclassified (MPN-u) = 6) were screened for markers of clonality using targeted NGS. Among these, 25 (54.3%) patients had mutations that would help determine the clonal nature of the disease. Eight of the 17 TN-ET (47%) and 13 of the 23 TN-PMF (56.5%) patients had noncanonical mutations in the driver genes and mutations in the genes involved in epigenetic regulation. Identification of mutations categorized as high molecular markers (HMR) in 2 patients helped classify them as PMF with high risk according to the MIPSS 70 scoring system. A novel mutation in the MPIG6B (C6orf25) gene associated with childhood myelofibrosis was detected in a 14-year-old girl. The presence of clonal hematopoiesis could be confirmed in four of the six MPN-u patients in this cohort. This study demonstrates the utility of NGS in improving the characterization of TN-MPN by establishing clonality and detecting noncanonical mutations in driver genes, thereby aiding in clinical decision-making.

ALK-positive large B-cell lymphomas: A clinicopathologic study.

Background and Aim: Anaplastic lymphoma kinase (ALK)-positive large B-cell lymphomas (ALK+-LBCLs) are aggressive CD20-negative lymphomas, accounting for <1% of diffuse LBCLs. Being rare and with peculiar immunophenotypic characteristics, these can be easily misdiagnosed. We present 11 cases of ALK+-LBCLs diagnosed over a period of 11 years at a tertiary care hospital in South India to analyze the clinical, morphological, and immunophenotypic profile of these tumors. Subjects and Methods: ALK+-LBCL cases diagnosed from September 2009 to August 2020 were included. Clinical details were obtained from stored electronic records and summarized. Available hematoxylin and eosin (H and E) stained slides and immunohistochemistry slides were reviewed and observations tabulated. Results: Eleven patients (nine males and two females) were diagnosed with ALK+-LBCLs in the study period with seven presenting primarily with extranodal disease manifestations. Tumors in the lymph nodes showed diffuse architecture effacement and variable sinusoidal invasion. All tumors showed immunoblastic and plasmablastic-type large lymphoid cells with scattered anaplastic/multinucleate large cells, including rare Reed-Sternberg-like cells. Cytoplasmic granular ALK-1 staining, CD20 negativity, and immunohistochemical features of plasmablastic differentiation were noted in all. Of eight patients treated, only one achieved remission with multi-agent chemotherapy but relapsed after 6 months. Two patients died of disease and five others had progressive/persistent disease and were lost to follow-up. Conclusion: Although rare, these tumors should always be in the differential diagnoses of tumors with plasmablastic and immunoblastic morphology, especially in extranodal sites to avoid diagnostic delay/misdiagnosis.

Comparison of primary follicular lymphoma of gastrointestinal tract and secondary involvement: A study from South India.

Primary follicular lymphoma of the gut (PFL-GI) is a rare entity. This study aims to compare the clinicopathologic features of PFL-GI with cases of gastrointestinal involvement by disseminated nodal follicular lymphoma. This is a retrospective study with 6 cases of primary follicular lymphoma and 8 cases of secondary involvement of the gut, over a period of 9 years. The slides and blocks were retrieved and reviewed. Clinical data was obtained from hospital records. Clinicopathologic features were compared. PFL-GI cases had a slightly higher median age group (p value 0.23) and no gender predilection when compared to cases with secondary involvement which showed a female preponderance. Para-aortic lymphadenopathy was seen in all secondary cases whereas none of the primary cases showed significant lymphadenopathy. The only microscopic feature that was different was the presence of hollowed out pattern of immunostaining for follicular dendritic cells seen in all cases of PFL-GI but in none of the secondary cases.

Neoadjuvant chemotherapy with biosimilar trastuzumab in human epidermal growth factor receptor 2 overexpressed non-metastatic breast cancer: patterns of use and clinical outcomes in India.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer is associated with poor prognosis and access to anti-HER2 treatment is still a challenge in lower-middle income countries. The availability of the biosimilar trastuzumab has improved access by lowering the costs. We report the pattern of use of neoadjuvant ± adjuvant trastuzumab and outcomes in patients with HER2-positive non-metastatic breast cancer treated with regimens incorporating shorter durations of therapy and the use of the biosimilar trastuzumab compared to the innovator. METHODS: We conducted a retrospective analysis of patients with non-metastatic HER2-positive breast cancer treated with neoadjuvant ± adjuvant trastuzumab (innovator (n = 34 (33%)) and biosimilar (n = 70 (67%)) manufactured by Biocon Biologics) with chemotherapy. Information regarding chemotherapy regimens, duration of trastuzumab use (≤12 weeks and >12 weeks), pathological response (Miller Payne grade), disease free survival (DFS), overall survival (OS) and safety data were collected from electronic medical records. RESULTS: A total of 135 patients were analysed with a median age of 51 years (range: 23-82); of these, 57% were postmenopausal, 31.8% were hormone receptor positive and 62.9% had stage III disease. The overall pathological complete response (p-CR) in both breast and axilla increased to 37.6% in patients treated with trastuzumab preoperatively as compared to 22.2% in patients who did not receive any trastuzumab. Patients receiving innovator trastuzumab and biosimilar trastuzumab showed a p-CR of 28.5% and 41.7%, respectively. At a median follow-up of 42 months (range: 3-114), there were 18 relapses and 11 deaths. The 3-year DFS was 87.1% and OS was 92.2%. Cardiac dysfunction developed in 4 of 78 (5.1%) evaluable patients. CONCLUSION: Access to anti-HER2 therapy in the treatment of non-metastatic HER2-positive breast cancer in resource-constrained settings has improved significantly with the availability of the biosimilar trastuzumab. Imbalances in patient profiles at baseline in routine clinical practice led to inconclusive outcomes of ≤12 weeks versus >12 weeks trastuzumab treatment. However, on the basis of historical data, patients could be offered shorter duration of trastuzumab when a standard 1-year treatment of adjuvant trastuzumab is not feasible in resource-constrained settings. The p-CR using the biosimilar trastuzumab in neoadjuvant treatment has been observed to be comparable to the innovator trastuzumab.

Role of Ultrasound Acoustic Radiation Force Impulse in Differentiating Benign from Malignant Superficial Lymph Nodes.

OBJECTIVE: The purpose of this study was to evaluate the diagnostic performance of acoustic radiation force impulse (ARFI) imaging in differentiating benign from malignant peripheral lymphadenopathy. MATERIALS AND METHODS: This was a prospective study approved by the Institutional Review Board with financial grant for the same. Ultrasound and ARFI imaging of peripheral lymph nodes were performed and correlated with pathological results, which were used as the reference standard. The virtual touch tissue imaging and virtual touch tissue quantification parameters of ARFI were analyzed in 86 lymph nodes, of which 78 were included in the study. Using receiver operating characteristic curve analysis, the diagnostic usefulness of ARFI values were evaluated with respect to their sensitivity, specificity, and area under the curve. RESULTS: The mean area ratio of benign lymph nodes was 0.88 (±0.2) and that of malignant lymph nodes was 1.17 (±0.14). The mean shear wave velocities (SWV) of benign and malignant lymph nodes were 2.02 m/s (±0.94) and 3.7 m/s (±2.27), respectively. The sensitivity and specificity of virtual touch imaging area ratio in differentiating benign from malignant lymph nodes was 97% and 77%, of SWV was 71% and 70%, and of SWV ratio was 68% and 79%, respectively. CONCLUSION: As ARFI was found to have a superior diagnostic performance over conventional ultrasound and color Doppler in the characterization of lymph nodes, we recommend its routine use in differentiating benign from malignant nodes.

A fatal case of levamisole induced bone marrow failure.

A 20-year-old college student presented with high grade, intermittent fever for 10 days associated with blood stained loose stools after taking tablet levamisole for 17 days for vitiligo vulgaris. He was febrile, had a toxic appearance and appeared pale. Investigations showed neutropaenia with thrombocytopaenia. Blood cultures were sterile and stool cultures did not grow any enteric pathogens. His bone marrow examination was suggestive of an aplastic anaemia. He was administered empirical antibiotics, granulocyte colony stimulating factor and platelet transfusions. However, his fever and blood stained stools persisted. A repeat bone marrow examination after 2 weeks still revealed a hypoplastic marrow. Hence, a diagnosis of a levamisole induced bone marrow failure was made. While being worked up for an allogeneic stem cell transplantation, he developed neutropaenic enterocolitis and refractory septic shock with carbapenem resistant Klebsiella pneumoniae and succumbed to his illness.

Visceral leishmaniasis with haemophagocytic lymphohistiocytosis.

A 27-year-old man presented with high-grade intermittent fever for 4 months, generalised fatigue for 2 months, intermittent gum bleeds for 1 month and loss of weight of 15 kg. He appeared cachectic with generalised wasting, had pallor and features of reticuloendothelial system proliferation. His liver span was 17 cm. He had massive splenomegaly. His cardiovascular, respiratory and neurological examination were normal. He was diagnosed to have visceral leishmaniasis (VL) based on bone marrow (BM) examination that showed Leishmania donovani (LD) bodies and was treated with liposomal amphotericin (LA). During the course of therapy, he developed bleeding from various mucosal and venepuncture sites. His further evaluation, which included a repeat BM aspirate, showed haemophagocytes. Final diagnosis made was VL with secondary haemophagocytic lymphohistiocytosis. He was continued on LA with intravenous hydrocortisone. He developed refractory distributive shock with multiorgan dysfunction and succumbed to his illness.

Pathological prognostication of paediatric adrenocortical tumours: Is a gold standard emerging?

BACKGROUND: Criteria for the pathological classification of adult adrenocortical tumours (ACTs) have been found to overestimate the malignant potential of childhood ACTs. We sought to evaluate the accuracy and utility of criteria developed for paediatric ACT compared to current criteria for adults. METHODS: ACTs treated between January 2006 and December 2016 in two paediatric institutions were evaluated. Patients classified clinically as malignant (CM) had locally invasive disease at surgery requiring extensive en bloc resection to achieve clear margins, had local recurrence or distant metastasis. Slides were reviewed by pathologists blinded to the clinical outcome. A grade was assigned to each tumor according to the Weiss, Aubert, Wieneke and Dehner-Hill criteria. The pathological grade was compared to the clinical outcome. RESULTS: The median follow-up was 60 months (interquartile range 25-80 months). Based on clinical criteria, of 22 patients 14 (64%) had a benign course and eight (34%) behaved malignant. The malignant potential was overestimated by Weiss criteria in 23% and Aubert criteria in 27%. Wieneke and Dehner-Hill criteria showed good clinicopathological correlation; no child who had a benign course was classified as malignant. The Dehner-Hill criteria, however, classified five (23%) children as intermediate risk of which three had a clinically benign and two a CM course. CONCLUSION: The Wieneke criteria accurately predicts the clinical course in childhood ACTs and could be considered the gold standard in their pathological characterization.

Peripheral T cell lymphoma: Clinico-pathological characteristics & outcome from a tertiary care centre in south India.

Background & objectives: Peripheral T cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin's lymphomas (NHLs), with universally poor outcome. This study was undertaken to provide data on demographics and outcomes of patients with PTCL who underwent treatment in a single tertiary care centre in southern India. Methods: Retrospective study was done on all patients (age ≥18 yr) diagnosed with PTCL from January 2007 to December 2012. The diagnosis of PTCL was made according to the WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. Results: A total of 244 adult patients were diagnosed with PTCL (non-cutaneous). The most common subtype was PTCL-not otherwise specified (35.7%), followed by anaplastic large cell lymphoma (ALCL), ALK negative (21.3%), natural killer/T cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), ALCL, ALK positive, hepatosplenic T cell lymphoma (HSTCL) and adult T cell leukaemia/lymphoma followed in frequency with 13.1, 11.5, 8.6, 8.2 and 1.6 per cent cases, respectively. The three-year Kaplan-Meier overall survival (OS) and event-free survival (EFS) for the patients who received chemotherapy (n=122) were 33.8±5.0 and 29.3±4.7 per cent, respectively. Various prognostic indices developed for T cell lymphomas were found to be useful. Interpretation & conclusions: Except for ALCL, ALK positive, all other PTCLs showed poor long-term outcome with CHOP-based chemotherapy. Novel therapies are needed to improve the outcome.

Lymphomatoid granulomatosis: A case series from South India.

CONTEXT: Lymphomatoid granulomatosis (LYG) is a rare B-lymphoproliferative disorder characterised by an angiocentric and angiodestructive pattern along with Epstein - Barr virus (EBV) association. It is one of the diagnostic challenges in lymphoma pathology. Deregulation of EBV immune surveillance is one of the narrated hypotheses in the literature. Extrapulmonary manifestations are rare with LYG. Morphological grading is done based on the number of EBV-positive B cells, which is useful to strategize treatment protocol. AIMS: We report here a series of nine cases of LYG to discuss the clinical, histological, and immunohistochemistry findings. SETTINGS AND DESIGN: This is the first case series from India in published literature. SUBJECTS AND METHODS: We reviewed cases of LYG diagnosed at our center for the past 11 years (2006-2016). A total of nine cases were included in this study. Histomorphology was studied in conjunction with immunohistochemistry and clinical details. Cases without classical morphology and negative for EBV immunostain were excluded from the study. RESULTS: There were nine patients in our study (7 males and 2 female; M:F ratio 3.5:1). The age of these patients ranged from 4 years to 57 years (mean age: 30 years). The most common site involved was the lung (4, 44%), followed by the skin (2, 22%), central nervous system (2, 22%) and lymph node (1, 11%). One patient had primary immunodeficiency. Another patient had undergone renal transplant 11 years before the development of the lesion. Angiocentricity and angioinvasion were appreciated in all nine cases (9/9) with necrosis in four cases (44%) and ill-defined histiocytic aggregates in three cases (33%). The histological features were as follows: Grade 1(4 cases, 44%), Grade 2(2 cases, 22%), and Grade 3(3 cases, 33%). CONCLUSION: LYG is a rare EBV driven angiodestructive disease with predominantly lung involvement as well as isolated extrapulmonary sites as seen in our study. It is often progressive and ultimately fatal in the absence of appropriate treatment. Grading of the lesion helps to initiate the appropriate treatment of choice.

Methotrexate-associated Epstein-Barr virus mucocutaneous ulcer: A case report and review of literature.

Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) comprises part of the spectrum of B-cell lymphoproliferative disorders, reported in settings of immunosenescence and iatrogenic immunosuppression, affecting the oropharyngeal mucosa, skin, and gastrointestinal tract. We report a case of a 59-year-old female, known case of rheumatoid arthritis on methotrexate (MTX) for 15 years, who presented with an ulcer in the inner aspect of her cheek region for 2 years. Clinical examination revealed an infiltrative lesion involving the lower gingivobuccal sulcus of size 2 cm × 3 cm extending to the alveolus with level I lymph nodes, suspicious for carcinoma buccal mucosa. Anti-EBV-capsid antigen-immunoglobulin M and qualitative EBV polymerase chain reaction of peripheral blood were negative. Histopathological examination revealed atypical lymphoid cells with enlarged vesicular nuclei, prominent nucleoli, and moderate eosinophilic cytoplasm, few with binucleation (CD20 focally positive, CD79a focally positive, CD30+, EBV LMP-1+, MIB-I 60%) consistent with EBVMCU, MTX-associated. This is the first case report from India.

Extramedullary plasmacytoma: an unusual neoplasm in a HIV-positive patient.

There is a wide range of plasma cell abnormalities in people living with HIV (PLHIV). Extramedullary plasmacytomas are not common in HIV infection, unlike plasmablastic lymphomas. An HIV-positive 44-year-old man on antiretroviral therapy presented with a rapidly progressing swelling on the face. Imaging revealed underlying bone destruction. Histologically, there was a tumour composed of small to medium-sized plasmacytoid cells admixed with many mature plasma cells and plasmablasts. These were positive for CD138 and MUM 1. Extramedullary multiple myeloma was ruled out as CD56 and cyclin D-1 were negative. EBV was negative. As the tumour cells were mostly mature, plasmablastic lymphoma was also excluded. The presence of a monoclonal protein (1 g%), IgG kappa type, was detected. Neoplasia of plasma cells acquires special clinical characteristics in PLHIV. These patients are younger, with a greater tendency to develop solitary extramedullary plasmacytomas with atypical clinical evolution and greater aggressiveness of the neoplastic process. All of these features, along with a high proliferation index (MIB1 60%) was found in our patient. We report this case for its rarity, histopathological dilemma and its atypical features in HIV infection.

Primary pineal malignant melanoma - illustrated review.

AIM: Primary pineal melanoma is a rare tumor. We herein review the histogenesis, pathology, radiology and therapeutic options of this rare tumor. MATERIAL AND METHODS: We conducted a PUBMED search using a combination of keywords such as "primary pineal melanoma", "CNS melanoma", and "pineal tumor" and identified 16 cases of primary pineal melanoma. Clinical features, pathologic characteristics and treatment details of these patients were noted from respective case reports. We also describe a case of a 45-year-old Indian woman with primary pineal melanoma treated with a combination of surgery and post-op radiation. RESULTS: The median age at presentation is 50 years. Median duration of symptoms is 6 weeks. Common symptoms at presentation include headache (58.8%), personality changes (41.2%), gait disturbance (35.3%) and Parinaud's syndrome (29.4%). Surgery, radiotherapy and chemotherapy have been used in 29.4%, 47.1% and 23.5% of patients respectively. Median overall survival is 56 weeks. Leptomeningeal dissemination and ventricular ependymal spread were noted in 70.6% and 35.3% patients, respectively. CONCLUSION: Combined modality treatment comprising maximal safe surgery and post-operative radiation should be preferred in patients with localized pineal melanoma without leptomeningeal dissemination. Taking a cue from other subsites of melanoma, chemotherapy can perhaps be deferred until recurrence.

Prognostic value of MIB-1, p53, epidermal growth factor receptor, and INI1 in childhood chordomas.

BACKGROUND: Chordomas are slow-growing tumors and most commonly involve the sacrum and clivus. Multiple recurrences are frequent. Childhood chordomas are rare and often show exceptionally aggressive behavior, resulting in short survival and a high incidence of metastatic spread. OBJECTIVE: This study examined the histologic features and immunohistochemical profile of pediatric chordomas and compared them with their adult counterparts. METHODS: Nine pediatric and 13 adult cases were included in the study. Childhood chordomas were classified into conventional, atypical, and poorly differentiated types. Immunohistochemistry was performed for cytokeratin, epithelial membrane antigen, vimentin, S100, brachyury, p53, INI1, epidermal growth factor receptor (EGFR), and CD117. Cytogenetic analyses were performed in a subset of tumors for SMARCB1/INI1 locus on 22q chromosome by fluorescent in situ hybridization (FISH) and analysis of the SMARCB1/INI1 gene sequence. RESULTS: All tumors showed expression of cytokeratin, epithelial membrane antigen, S100, vimentin, brachyury, and EGFR. Atypical morphology, p53 expression, higher MIB-1 labelling index (LI), and INI1 loss were more frequently seen in pediatric chordomas as compared with adults. None of the tumors showed CD117 expression. No point mutation in the SMARCB1/INI1 gene was noted in the tumors examined; however, 4 pediatric and 1 adult chordoma showed loss of this locus on FISH analysis. CONCLUSIONS: A subset of pediatric chordomas with atypical histomorphologic features needs to be identified, as they behave in an aggressive manner and require adjuvant therapy. Pediatric chordomas more frequently show p53 expression, INI1 loss, and higher MIB-1 LI as compared with adults, whereas EGFR expression is common to both.