Survival outcomes with 12 weeks of adjuvant or neoadjuvant trastuzumab in breast cancer

Background: There is limited access to 1 year of adjuvant trastuzumab in resource-constrained settings. Most randomized studies have failed to prove non-inferiority of shorter durations of adjuvant trastuzumab compared to 1 year However, shorter durations are often used when 1 year is not financially viable. We report the outcomes with 12 weeks of trastuzumab administered as part of curative-intent treatment. Methods: This is a retrospective analysis of patients treated at Tata Memorial Centre, Mumbai, a tertiary care cancer center in India. Patients with human epidermal growth factor receptor (HER2)-positive early or locally advanced breast cancer who received 12 weeks of adjuvant or neoadjuvant trastuzumab with paclitaxel and four cycles of an anthracycline-based regimen in either sequence, through a patient assistance program between January 2011 and December 2012, were analyzed for disease-free survival (DFS), overall survival (OS), and toxicity. Results: A total of 102 patients were analyzed with a data cutoff in September 2019. The median follow-up was 72 months (range 6–90 months), the median age was 46 (24–65) years, 51 (50%) were postmenopausal, 37 (36%) were hormone receptor-positive, and 61 (60%) had stage-III disease. There were 37 DFS events and 26 had OS events. The 5-year DFS was 66% (95% Confidence Interval [CI] 56–75%) and the OS was 76% (95% CI 67–85%), respectively. Cardiac dysfunction developed in 11 (10.7%) patients. Conclusion: The use of neoadjuvant or adjuvant 12-week trastuzumab-paclitaxel in sequence with four anthracycline-based regimens resulted in acceptable long-term outcomes in a group of patients, most of whom had advanced-stage nonmetastatic breast cancer.

Access to HER2?targeted therapy at a tertiary care center in India: An evolution

Background:In a previous retrospective audit from our institution we reported that patients had limited access to HER2-targeted therapy due to financial constraints. Subsequently, the advent of biosimilar versions of trastuzumab and philanthropic support has potentially changed this situation. Herein, we reanalyzed and reported access to HER2-targeted therapy in a more recent cohort of patients. Methods: Medical records of new breast cancer patients registered in one calendar year were retrospectively reviewed, supplemented by online pharmacy data to extract information on receptor status, use of HER2-targeted therapy, and other relevant variables. Since not all HER2 immunohistochemistry (IHC) 2+ tumors underwent fluorescent in-situ hybridization (FISH) testing, we estimated the probable HER2 amplified from this group based on a FISH amplified fraction in those HER2 2+ tumors who did undergo FISH. Results: Between January 2016 and December 2016, 4717 new BC patients were registered at our institution, of whom 729 (20.04%) had HER2 IHC 3+ tumors while 641 (17.62%) had HER2 IHC 2+ tumors. The final number of HER2 overexpressing/amplified tumors was estimated to be 928 (729 HER2 IHC 3+, 105 known FISH amplified, and 94 estimated FISH amplified), of whom 831 received treatment at our institution. Overall 474 (57.03%, 95% confidence interval [CI] 53.6–60.4) of these 831 patients received trastuzumab for durations ranging from 12 weeks to 12 months in the (neo)adjuvant setting or other durations in metastatic setting compared to 8.61% (95% CI 6.2–11.6) usage of HER2-targeted therapy in the 2008 cohort. Conclusion: Access to HER2-targeted therapy has substantially increased among patients treated at a public hospital in the past decade, likely due to the advent of biosimilars, the use of shorter duration adjuvant regimens, and philanthropic support. However, further efforts are required to achieve universal access to this potentially life-saving treatment.

Breast cancer in a tertiary cancer center in India - An audit, with outcome analysis

Background: Surgery is the mainstay in the management of thyroid cancer. Surgical outcomes need to be tempered against the excellent prognosis of the disease. Aims: This study aims to study the surgical outcomes including the 30-day morbidity and 5-year survival of thyroid cancer patients. Settings and Design: Retrospective analysis of a prospectively maintained surgical database in a tertiary cancer center in India. Materials and Methods: We analyzed 221 surgically treated patients in the year 2012. Statistical Analysis: Used IBM SPSS 24.0 (Armonk, NY) with p < 0.05. Results: The median age was 40 years with predominantly papillary thyroid carcinoma (55%). Localized disease in 47% of cases, locoregional disease in 42.5% and distant metastasis in 10.2% of cases at presentation was noted. Treatment naïve patients were 71% and revision surgeries were done in 29% patients. Extended thyroidectomy constituted 11% of the surgeries. Temporary hypocalcemia was seen in 30.8% of patients, 5% requiring intravenous calcium supplementation. Vocal cord palsy as per nerve at risk and chyle leak were seen in 4.5% and 3.1%, respectively. Aggressive histology, extended thyroidectomy, and inadvertent parathyroidectomy were significant factors associated with complications. Five year estimated overall survival with median follow-up of 50 months was 98%, and event-free survival was 84.8%. Advanced age, distant metastasis at presentation and aggressive histology connoted poor outcomes. Conclusion: Thyroid cancer, irrespective of the extent of disease, has good prognosis. Aggressive histology, the extent of thyroid surgery, distant metastasis and age are important factors, which should be factored in the algorithm of thyroid cancer management.

Concomitant follicular lymphoma and histiocytic sarcoma: A rare progression, trans-differentiation or co-occurrence.

Trans‑differentiation of follicular lymphoma (FL) into a histiocytic sarcoma (HS) is a rare event and usually occurs as a sequential event. We report a case where in the same node with two distinct areas one of low‑grade FL and another with HS was observed. This patient was a 58 years old with generalized lymphadenopathy and Ann Arbor Stage III disease. The cervical node biopsy on histological examination revealed two distinct areas, firstly a FL with nodular architecture and the other a smaller focus of sheets of pleomorphic histiocytic cells diffusely arranged at the edge of the section contiguous with FL with few cells in transiting phase. On immunohistochemistry the FL was positive for CD20, CD10, PU.1, PAX5 and Bcl2, while the large histiocytic cells were positive for CD163, CD68, LCA, and PU.1, weakly for PAX5 and negative for CD20, CD10, CD30, CD3, CD1a, Bcl2, S100, and Alk‑1. The therapeutic implications of this diagnosis and postulated theories on trans‑differentiation are discussed.

Primary cutaneous marginal zone lymphoma (immunocytoma like) with lymphoepithelioid or Lennert's lymphoma like involvement of nodes.

Primary cutaneous marginal zone lymphomas (PCMZL) have a wide range of morphology from tumors with monocytoid B cells to those composed entirely of plasma cells and the T-cell rich variants. We report a 60-year-old male with a PCMZL rich in plasma cells of the foot with a lymphoepithelioid-like pattern of dissemination to the lymph nodes posing problems in the diagnosis. The patient had a lesion on the dorsum of the foot which histologically revealed dense perivascular collections of lymphoid cells and plasma cells amidst fibrous tissue. Though the plasma cells did show light chain restriction, CD20 and CD3 did not reveal an overwhelming B/T-cell population and hence a diagnosis of a reactive process was offered. Subsequently the patient developed inguinal nodes with diffuse loss of architecture and replacement by epithelioid histiocytes and reactive T cells with few large B cells (lymphoepithelioid-like pattern). On pathology review it was realized that the two lesions may be related and clonality studies were asked for. The skin lesion showed clonally rearranged IgH receptor while the T-cell receptor rearrangement was negative. The patient developed disseminated disease and received six cycles of chemotherapy with partial response and 6 years after the initial presentation was alive with nonprogressive disease. Thus, the polymorphous background in PCMZL is evolving and an immunocytoma-like tumor can show a T-cell rich or Lennert's like growth pattern of spread and early recognition these odd patterns may aid in appropriate management of patients.

In situ follicular neoplasia/lymphoma: Three illustrative cases exemplifying unique disease presentations.

We report three elderly patients with follicular lymphoma in situ (FLIS) each highlighting a unique pattern of disease presentation and progression. The first patient had incidentally detected FLIS with peripheral blood spill and yet had an 11-year uneventful follow up. The second patient with an overt follicular lymphoma (FL) developed high-grade transformation in jejunum with FLIS extensively involving the Payers patches. The third patient had a FLIS but that qualified as higher grade and was treated in spite of lack of overt FL mainly because of higher grade and patient subsequently did develop overt FL. The first case of typical FLIS confirms that peripheral blood spill does not connote poor prognosis in FLIS, the second case illustrates that FLIS may colonize mucosa-associated lymphoid tissue as part of homing in process of a disseminated FL and the third case validates the aggressive nature of high-grade FLIS.

HER 2 status in invasive breast cancer: Immunohistochemistry, fluorescence in-situ hybridization and chromogenic in-situ hybridization.

Introduction : HER2/neu gene status in breast cancers can be evaluated by targeting protein and gene - immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH). Recent studies have shown chromogenic in-situ hybridization (CISH) as a relatively cheaper alternative. Materials and Methods : Forty-three nonconsecutive, randomly selected primary invasive breast cancer cases were evaluated for c-erbB-2 (HER2 protein) by IHC and gene amplification by FISH and CISH. Results of each of the same were compared. Results : CISH showed approximately 90% and 100% concordance for IHC negative and positive cases, respectively; while approximately 94.4% and 91% concordance with FISH amplified and non-amplified cases, respectively. Conclusion : This study showed feasibility of incorporation of CISH as a low cost option in routine management of breast carcinoma in the Indian setting. Secondly, reconfirmation of IHC negative and positive cases can be done by CISH.

Gastric myeloid sarcoma - A report of two cases addressing diagnostic issues.

Presented herein are two cases of gastric myeloid sarcoma to highlight the diagnostic conundrum and pointers toward accurate diagnosis in such instances. The first case was a 35-year-old man with an ulceronodular mass in the body of stomach. Multiple biopsies were reported as inconclusive chiefly due to the fact that the lamina propria infiltrate was innocuous and failed to mark with CD20 or CD3. Subsequently the patient had extensive disseminated disease which was recognized as myeloid sarcoma but patient succumbed to the disease soon. The second case was a 25-year-old boy who presented with symptoms of gastric outlet obstruction since 6 months. An endoscopy revealed diffuse gastric wall thickening which on biopsy was recognized as myeloid sarcoma but patient developed intestinal obstruction and required ileal resection for symptomatic relief, postoperative patient never recovered and succumbed to the disease. Both patients had marrow involvement by acute myeloid leukemia (AML-M2) with a normal leukocyte count in peripheral blood. Thus gastric myeloid sarcomas are prone to a delayed diagnosis chiefly due to rarity. Pathologist should think of myeloid sarcoma in a hematolymphoid appearing tumor in stomach that is CD20, CD3 negative, has avid Ki67 and shows an infiltrate chiefly centered in lamina propria.

Splenic angiomatoid nodular transformation in child with inflammatory pseudotumor-like areas.

Reports of sclerosing angiomatoid transformation (SANT) in the pediatric age group are rare. We present a case of SANT in an 11-year-old child with a history of trauma presenting with rapidly growing splenic lesion since 2 months. A partial splenectomy revealed a well-demarcated nodular lesion 5 × 4 × 4 cm with central area of fibrosis. Most part of the lesion showed ill-defined nodules or diffuse areas of plump epithelioid appearing endothelial units that marked with CD31, but the internodular stroma was inflammatory pseudotumor (IPT)-like with a mitotic count of 1-2/10 hpf. The angiomatoid nodules were diffusely positive for CD31, CD163, and CD68; however, they were negative for CD34, CD30, smooth muscle actin, and CD8. Epstein-Barr virus-encoded RNA in situ hybridization (EBER-ISH) was negative. The MIB1 labeling was fairly high in the IPT area but low in the angiomatoid areas. After the diagnosis of SANT, the patient has had an uneventful follow-up for more than 3 years since surgery. The morphologic findings in the case being discussed reaffirm the finding that SANT may have an IPT component and it can be seen even in pediatric age group.

Primary cardiac diffuse large B-cell lymphoma with activated B-cell-like phenotype.

Primary cardiac lymphoma (PCL) is a rare and fatal disorder. It may often mimic other common cardiac tumors like cardiac myxoma because of similarities in the clinical presentation. We report a case of PCL of diffuse large B-cell type, in a 38-year-old, immunocompetent male who presented with superior vena cava syndrome that was excised as a myxoma. Histology revealed a large cell population diffusely and strongly expressing CD45, CD20, MUM1/IRF4 and FOXP1 hinting at an activated B-cell (ABC)-like phenotype. After four cycles of Rituximab with CHOP (cyclophosphamide, hydroxydaunorubicin, Oncovin, and prednisolone) the tumor regressed completely but the patient had a relapse and subsequently succumbed to the disease confirming the aggressive nature. The aggressive behavior of PCL may be possibly linked to its ABC-like origin.

Tubulocystic carcinoma of kidney associated with papillary renal cell carcinoma.

Tubulocystic renal cell carcinoma (TCRCC) is a rare variant of renal cell carcinoma, which has distinct histology but there is some controversy about its association with papillary renal cell carcinoma (PRCC) and cell of origin in literature. We report an 18-year-old girl with the rare TCRCC of kidney associated with PRCC with metastases to the para-aortic nodes. The patient presented with hematuria and a right renal mass with enlarged regional nodes for which a radical nephrectomy with retroperitoneal lymph node dissection was done. On gross examination, a solid cystic lesion involving the lower pole and middle pole of the kidney measuring 12x9x9 cm was seen along with an additional cystic lesion in upper pole of kidney. Microscopically the main tumor showed the typical histology of a tubulocystic carcinoma with multiple cysts filled with secretions lined by variably flattened epithelium with hobnailing of cells. The mass in the upper pole was a high-grade PRCC and the nodal metastases had morphology similar to this component. To conclude, at least a small but definite subset of TCRCC is associated with PRCC, and cases associated with PRCC do seem to have a higher propensity for nodal metastasis as in the case we report.

Angioimmunoblastic T-Cell lymphoma: A critical analysis of clinical, morphologic and immunophenotypic features.

Background: Angioimmunoblastic T-cell lymphoma (AITL), a subtype of peripheral T-cell lymphoma (PTCL), is characterized by unique clinical and biological features. Its diagnosis remains a challenge as clinical presentation as well as pathologic findings are frequently misleading. Material and Methods: We retrospectively analyzed the clinical, morphological and immunophenotypic spectrum of 17 cases of histologically proven AITL. Result: The mean age was 54 years and male to female ratio was 2.4. Common clinical features included generalized lymphadenopathy (60%), hepatomegaly (70%), splenomegaly (50%), anemia (80%) and polyclonal hypergammaglobulinemia (100%). Microscopically, three architectural patterns; pattern I (6%), pattern II (41%) and pattern III (53%) were observed. Bone marrow infiltration was seen in 60% cases and 30% cases revealed plasmacytosis. Absence of follicles, polymorphous infiltrate, extra-follicular follicular dendritic cell (FDC) proliferation, high endothelial venules (HEV) prominence and neoplastic T-cells were the diagnostic features of AITL. CD10 positivity (47%), clear cells in the background (59%) admixture with large size CD20+ B-immunoblasts (35%) and bone marrow plasmacytosis (50%) were common observations. Conclusion: Awareness of various morphological and immunophenotypic complexities of AITL and distinction from reactive adenopathies and other types of lymphomas that mimic AITL is underscored in this study.

Assessment of HER-2/neu status in breast cancer using fluorescence in situ hybridization & immunohistochemistry: Experience of a tertiary cancer referral centre in India.

Background & objective: Determination of HER2 status in breast cancer has become important to identify potential candidates for anti-HER2 therapy. In this study we compared fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) for the determination of HER2 status in breast cancer patients referred to a tertiary care referral centre. Methods: A total of 200 cases of invasive breast cancer were evaluated for HER2 status using IHC and FISH and results were compared. Results: The IHC 3+ (93.9%) and IHC negative (85.9%) cases showed good concordance with the corresponding FISH results; while 66.6 per cent of IHC 2+ cases showed gene amplification by FISH. In addition, hormone receptor expression and HER2 gene status showed a statistically significant inverse association (P<0.05). Interpretation & conclusion: These findings reaffirm IHC as a prudent first-step to screen tissue samples for HER2 status and to determine suitability for technically demanding FISH test and the dual coloured FISH as a gold standard for determination of HER2/neu status in IHC equivocal cases of breast carcinoma.

Primary intestinal T cell lymphomas in Indian patients - In search of enteropathic T cell lymphoma.

Objective: This series of six intestinal T cell lymphomas (ITCL) attempts to document enteropathy-associated T cell lymphoma (EATCL) in India. Materials and Methods: A total of six ITCL were selected from 170 gastrointestinal lymphomas in last 10 years. Results: The cases studied included EATCL (4), ITCL with a CD4 positive phenotype (1) and ITCL NK/T cell type (1). Of the four EATCL, two occurred in the ileum, one in right colon and one in duodenum. In three EATCL cases, there was history of celiac disease or lactose intolerance and enteropathic changes were noted in the adjacent mucosa. These tumors had CD3+/CD8+/CD56 (+/-)/CD4-/ Granzyme B+ immunophenotype. One EATCL was monomorphic small cell type (type II EATCL) with a CD3+/CD8-CD56+/CD4-/ Granzyme B+ phenotype. EBER- ISH (Epstein Barr virus coded RNA's- in situ hybridization) revealed positive tumor cells in ITCL NK/T cell type and in bystander cells in three EATCL. Conclusion: ITCL are rare in Indian patients but do occur and comprise a mixture of the enteropathic and non-enteropathic subtypes.

Recurrent mullerian adenosarcoma like tumor of seminal vesicle.

Adenosarcoma like tumor of the seminal vesicle is reported herein. A 35-year-old male presented with mass in the pelvis between bladder and rectum, involving the seminal vesicle and prostate. Mass recurred after enucleation in four years. Histologically, the tumor was multicystic with bland ciliated lining epithelium and sarcomatous stroma. A wide excision was performed followed with chemotherapy and radiotherapy. Adenosarcomas have a low grade recurrent malignant potential and should be recognized.

Monophasic synovial sarcoma of tongue.

Synovial sarcoma is a well defined morphologic entity extensively researched in literature. Synovial sarcoma displays a wide spectrum of clinical presentations and histologic appearances that may give rise to diagnostic dilemmas. One such unusual site in the head and neck area is the tongue. We report a case of monophasic synovial sarcoma of the tongue in a 22-year-old male. Microscopically, this tumor mimicked a poorly differentiated carcinoma which is more common at this site though the patient was young for this type of tumor. On immunohistochemistry, neoplastic cells were positive for cytokeratin, vimentin, calponin, CD99 and bcl2. Molecular studies - viz. reverse transcriptase polymerase chain reaction revealed a SYT-SSX translocation clinching the diagnosis. This paper highlights the immunohistochemistry profile and SYT-SSX translocation which helped arrive at an accurate diagnosis only because the index of suspicion for a monophasic synovial sarcoma is high.

Hormone receptors over the last 8 years in a cancer referral center in India: what was and what is?

This study was carried out to observe the trend in hormone receptors over the last 8 years in a tertiary cancer center in India. A total of 11,780 tumors analyzed for hormone receptors over the last 7 years were compared with the results of hormone receptor expression in a prior published study on 798 cases of breast cancer from the same institute. The patient's ages ranged from 18 to 102 years, Sixty percent of the patients were in the age group of 31-50 years. Seventy percent of the tumors were grade III tumors. The percentage of hormone receptor expression in breast cancer in the last 8 years varied from 52 to 57%. The overall receptor expression in the last 8 years shifted within a 5% range, confirming that the hormone receptor expression in Indian patients with breast cancer is low. However, there was redistribution within the pattern of estrogen receptor (ER) and progesterone receptor (PR) expression among tumors showing hormone receptor expression. Breast cancers showing only PR expression reduced dramatically from 21% in the year 1999 to in the year 2006, with a parallel increase in breast cancers showing combined ER and PR positivity (from 25 to 41.8%) and only ER expression (from 7.4 to 10.6%). The hormone receptor expression in breast cancers in India is and continues to be low but the high incidence of only PR-positive tumors in our population reported earlier was misrepresented.

Secretory carcinoma arising in radial scars of the breast: A case report and review of literature.

Radial scars or complex sclerosing lesions are common benign lesions in the breast with characteristic radiological and pathological features. The pathological diagnosis of carcinoma arising in this setting requires careful amalgamation of clinical, radiological and morphological details. Ancillary techniques like immunohistochemistry aid in the diagnosis. We report an unusual case of a secretory carcinoma arising in the background of a radial scar.

Ultrastructure in resolving a diagnosis of poorly differentiated clear cell sarcoma of soft parts in an adolescent male.

Clear cell sarcoma of soft parts is a rare tumor in children and it requires a high index of suspicion for accurate diagnosis. Early diagnosis leads to radical surgical excision and limits the aggressive behavior of this tumor. We report a case of a 12-year-old boy with a recurrent soft-tissue tumor in the scalp, misdiagnosed on three occasions as epitheloid sarcoma owing to the poorly differentiated appearance of cells. In spite of focal S-100 expression, this tumor was not recognized as a tumor of melanocytic origin till melanosomes were demonstrated on electron microscopy (EM). Detection of melanosomes on electron microscopy helped in clinching the histology diagnosis, reiterating the definite role of EM in diagnosing these tumors. Failure to accurately diagnose this tumor resulted in institution of preoperative chemotherapy, delayed surgical excision, tumor progression and death of patient within a year and half of presentation.

Epithelioid trophoblastic tumor of uterus presenting as an ovarian mass: a diagnostic and therapeutic dilemma.

Epithelioid trophoblastic tumor (ETT) is a rare gestational trophoblastic tumor and often poses a diagnostic and therapeutic challenge to the involved clinicians. We report a case of epithelioid trophoblastic tumor in a young woman which involved the uterus, parametrium and the right ovary. Misdiagnosis as a choriocarcinoma led to improper treatment and progressive disease. Microscopically it revealed a relatively monotonous population of epithelioid cells arranged in nests with hyaline-like matrix surrounding the tumor cells. Differential diagnosis between placental site trophoblastic tumor and carcinoma was ruled out based on histology and immunohistochemistry. The patient developed lung and brain metastasis after 10 months and is alive with disease 1(1/2) years thereafter and is taking palliative chemotherapy. The patient had beta-HCG level of 85.1 mIU/mL at the time of diagnosis; but just before metastasis, the levels rose. Awareness of the histological features of ETT is essential to avoid misdiagnosis, as it represents a tumor which is primarily treated by surgery rather than with chemotherapy.