Trupti Pai

Pulmonary adenofibroma: clinicopathological study of 3 cases of a rare benign lung lesion and review of the literature

Pulmonary adenofibroma is a rare benign biphasic tumor of the lung composed of epithelial and stromal components. We report 3 cases of this unusual lesion of lung in a male (25 years old) and 2 female (40 and 55 years old) patients. Breathlessness on exertion and mild left-sided chest pain of 1 months duration were the main concerns in 2 patients, whereas the third had cough and hemoptysis for 3 months. Chest radiograph and computed tomography scan revealed a well-circumscribed, subpleural homogenous mass in left lower chest fields in 2 cases and solid-cystic lesion in left upper lobe in the third patient. All 3 patients underwent lobectomy, following biopsy in 2 cases. Histology revealed a well-circumscribed lesion composed of complex glandlike spaces lined by cuboidal to columnar epithelium surrounded by a hyalinized spindle-cell fibroblastic proliferation reminiscent of adenofibroma of the female genital tract or fibroadenoma of the breast. Immunohistochemical examination supported the diagnosis of a benign pulmonary adenofibroma. All 3 patients were are alive and doing well with no evidence of recurrent or metastatic disease. Diagnosis on biopsy can be challenging and may be misinterpreted as well-differentiated adenocarcinoma with extensive fibrosis or low-grade sarcoma. Frozen-section consultation will be a valuable adjunct in planning for limited lung resection of this benign lung lesion. Although we described 3 cases of pulmonary adenofibroma, still this is the largest published series of this rare entity till date. The possible histogenesis and various differential diagnoses are discussed along with literature review.

Evidence for the association of Epstein‐Barr Virus in breast cancer in Indian patients using in‐situ hybridization technique

Epstein‐Barr Virus (EBV) is etiologically linked to Burkitt lymphoma (BL), nasopharyngeal carcinoma, post‐transplant lymphomas, Hodgkin disease, and possibly other tumors. However, the association of oncogenic EBV with breast carcinoma (BC) is still controversial and a matter of debate. We aimed to study the presence of EBV genome in BC cases in Indian patients and its association with the clinicopathological features. The formalin fixed paraffin embedded tissues from 83 women with primary invasive BC were studied for the presence of EBV by in‐situ hybridization (ISH) technique for Epstein‐Barr Virus Encoded RNA (EBER) with appropriate controls. Correlation of EBER‐ISH positivity with clinicopathological features was performed using Fisher exact test and P<.05 was considered as significant. Eighty‐three BC cases were comprised of 47 (56.5%) triple negative breast cancers (TNBC), 17 (20.5%) hormone positive and 19 (22.9%) HER2 positive cases. Of 83 cases, 25 cases (30.1%) were positive for EBER‐ISH test. The positivity was restricted to the tumor cells and not seen in the surrounding breast lobules. EBER‐ISH positivity was statistically associated with larger tumor size (52.6% in >5 cm tumors vs 19.3% in ≤5 cm; P=.014) and with TNBCs (21/47 [44.7%] in TNBCs vs 4/36 [11.1%] in non‐TNBCs; P=.001). A possible causal association of EBV in BC cases in Indian patients is suggested by high frequency of EBER‐ISH positivity noted in our study. This might have therapeutic significance because of the possible role of EBV specific cytotoxic T cells in targeting EBV associated tumor cells and can be considered as a potential targeted therapy. To the best of our knowledge, this is the first study from India to address this issue using EBER‐ISH technique.

Lymphoepithelioma-like carcinoma of breast—evaluation for Epstein-Barr virus–encoded RNA, human papillomavirus, and markers of basal cell differentiation

This is a largest series of 5 cases of lymphoepithelioma-like carcinoma (LEC) of the breast attempting to look at the expression of basal cytokeratins (CKs), human papillomavirus, and Epstein-Barr virus-encoded RNAs in these tumors. Five cases were selected after stringent evaluation of all breast carcinomas showing dense lymphoid infiltration. Histologically, all these tumors showed the typical histology except 1 tumor that showed an unusual granulomatous response. All tumors were negative for estrogen and progesterone receptors and HER2 (triple negative). Three tumors expressed CK5/6 and high-molecular-weight CK, whereas only the case with nodal metastasis expressed CK14. Analysis for in situ hybridization for Epstein-Barr virus-encoded RNAs and human papillomavirus DNA on paraffin-processed tissues was negative in all tumors. All of these patients received adjuvant therapy. One patient with tumor expressing basal marker, CK5/6, had contralateral breast malignancy after a duration of 53 months of treatment completion. The rest were disease free with the follow-up period in the range of 6 to 105 months. The lymphoepithelioma-like carcinoma of breast expressed basal CK profile that is more CK5/6 positive than CK14. Analysis of basal markers within these tumors may help in refining the definition of these tumors and in classifying them into prognostically relevant groups.

Histological spectrum of oligodendroglial tumors: Only a subset shows 1p/19q codeletion

Background: Canonical oligodendroglial tumors (ODGs) are characterized genetically by chromosomes 1p/19q codeletion. Aims: This study was essentially aimed at the detection of frequency of 1p/19q codeletion in the different histological spectrum of ODG tumors in a large cohort of Indian patients. Materials and Methods: All the ODG tumors evaluated for 1p/19q by fluorescence in-situ hybridization (FISH) during 2009–2015 were correlated with histology, immunohistochemical expression for p53 protein and clinical features. Results: A total of 676 cases included both pediatric (n = 18) and adult (n = 658) patients. Histologically, 346 pure ODGs [oligodendroglioma (OD) and anaplastic oligodendroglioma (AOD)] and 330 mixed ODGs [oligoastrocytomas (OA), anaplastic oligoastrocytomas (AOA) and glioblastoma with oligodendroglioma component (GBM-O)] were included. 1p/19q co-deletion was noted in 69% (60/87), 55.9% (145/259), 18.2% (18/99), 10.5% (18/172), and in 5.1% (3/59) cases of OD, AOD, OA, AOA, and GBM-O, respectively. In the pediatric age-group, 1p/19q codeletion was seen in 25% (2/8) of pure ODGs and in 10% (1/10) of mixed ODGs. In adults, it was observed in 60% (203/338) cases of pure ODGs and in 11.9% (38/320) cases of mixed ODGs. In adults, pure ODG histology (P = 0.00), frontal location (P = 0.004), calcification [in pure ODGs] (P = 0.03), and lack of p53 protein overexpression (P = 0.00) showed significant statistical correlation with 1p/19q codeletion. Conclusions: This study is unique in being one of the largest on ODGs for 1p/19q co-deletion including both pediatric and adult age groups of Indian patients. The results showed co-deletion in 60% of adult ODGs and 25% of pediatric pure ODGs. This reemphasizes the occurrence of 1p/19q codeletion, even though rare, in the pediatric age group.

Unraveling the spectrum of KIT mutations in gastrointestinal stromal tumors: An Indian Tertiary Cancer Center Experience

Background: Primary mutations in the KIT gene are the driving force for gastrointestinal stromal tumors (GIST) tumorigenesis. Predictive role of KIT mutation status aids oncologists in patient management. There is a paucity of comprehensive data on the frequency of mutations in the KIT gene in GIST affecting Indian patients. The aims of this study were to determine the frequency and spectrum of molecular alterations affecting the KIT gene and assess their association with clinicopathologic features in a cohort of patients of GIST. Materials and Methods: Morphological and immunohistochemically confirmed GIST cases (n = 114) accessioned from August 2014-June 2015 were analyzed for mutations in KIT exons 9, 11, 13, and 17 and subjected to Sanger sequencing onto the ABI 3500 Genetic Analyzer. The sequences were analyzed using sequence analysis software: SeqScape® and Chromas Lite. Results: KIT mutations were seen in 70% of cases and the majority of KIT mutations involved exon 11 (57%), followed by exon 9 (10%), exon 13 (3%), and exon 17 (1%). Most common exon 11 mutations were in-frame deletions (61.4%) followed by substitution mutations (19.3%). Exon 9 mutations showed identical duplication of Ala-Tyr at codons 502–503. Simultaneous mutations affecting exon 11 and 13 were discovered. Novel variations, namely, p.Q556E (c.1666C>G), p.Q556dup (c.1666_1668dupCAG), p.K558_V559delinsS (c.1672_1677delAAGGTTinsAGT), p.Y503_F504insTY (c.1509_1510insACCTAT), and p.K642R (c.1925A>G) involving exons 11, 9, and 13, respectively, were observed. Interpretation and Conclusions: First study with complete analysis of all 4 exons of KIT (exons 9, 11, 13, and 17) in Indian GIST patients. Along with well-described KIT mutations, several rare double mutations as well as novel alterations were reported in this series.

Triple-Negative Breast Cancer A Comprehensive Study of Clinical, Histomorphological, and Immunohistochemical Features in Indian Patients

Triple-negative breast cancers (TNBCs) are characterized by negative expression for estrogen (ER), progesterone (PR), and human epidermal growth factor 2 (HER2) receptors. Although the majority of basal-like breast cancers (BLBCs) diagnosed based on gene expression profiling belong to the TNBC group, both entities are not synonymous. Core BLBCs are TNBCs, which are positive for basal cytokeratin (CK) and/or epidermal growth factor receptor (EGFR). We aimed to study and correlate a TNBC cohort for various histomorphological features and immunohistochemical (IHC) profile in Indian patients. We studied 205 naïve TNBCs for histopathological features, which were further evaluated for basal CKs—namely, CK5/6, CK14, CK17—and EGFR expression to classify them as core BLBCs, using criteria of any basal CK and/or EGFR positivity and 7-negative phenotype (7NP). Among 205 TNBCs, 91% of cases were core BLBCs, and absence of ductal carcinoma in situ (DCIS) was significantly associated (P = .014) with core BLBC. Geographic necrosis was correlated with expression of CK17 (P = .002) and EGFR (P = .038). A ribbon-like trabecular pattern and absence of DCIS were associated with CK17 (P = .0002 and P = .043, respectively) and CK14 (P = .04 and P = .0008, respectively). TNBC is a heterogeneous subgroup with adverse clinicopathological features, and many of them show significant correlation with basal CKs. TNBCs cannot be classified as core BLBC or 7NP based on morphological features, except absence of DCIS. However, this study illustrates the heterogeneity in TNBCs on the basis of IHC markers.

Metastatic nasopharyngeal carcinoma presenting as an isolated breast mass: A diagnostic pitfall and a review of literature

Metastases to breast are much rarer than primary breast tumors. We now present a case of 45-year-old female, who presented with an isolated breast mass. A positron emission tomography-computed tomography (PET-CT) done revealed hypermetabolic right breast nodules, soft tissue deposits, and multiple nodal involvement. The biopsy from the breast and axillary lymph node showed dense lymphoid infiltrate and was interpreted initially as granulomatous inflammation. However, the lumps were hard and suspicious for primary breast cancer, so an immunohistochemistry for cytokeratin was performed which highlighted the epithelial cell clusters masked within the inflammatory infiltrate and the diagnosis of undifferentiated carcinoma, lymphoepithelioma-like was made. After the diagnosis was made, it was realized that the patient had been treated earlier for a nasopharyngeal carcinoma (NPC). The in situ hybridization (ISH) test for Epstein–Barr virus-encoded RNA ISH was positive in the tumor cells, and hence, a diagnosis of metastatic NPC was finally made. The patient subsequently developed extensive nodal, skeletal, and soft tissue metastatic disease but was alive till September 2015. Although extremely rare, metastatic NPC can occur in the breast and the above case highlights that it mimics an inflammatory lesion. This case highlights the importance of the multidisciplinary approach for appropriate tumor diagnosis and patient management.

Pilomatrix carcinoma masquerading as breast carcinoma

Pilomatrix carcinoma is an exceedingly rare skin adnexal neoplasm derived from piliferous follicles, usually occurring in the head and neck region. Localization of this tumor in the breast is a rarity. We now report an unusual case of a 49-year-old female who presented with a palpable mass in the left breast for 2 years. Mammogram revealed a large, lobulated opacity with calcification, and positron emission tomography–computed tomography showed a metabolically active soft tissue mass measuring 15 cm involving all the quadrants of the left breast. Subsequently, the patient underwent radical mastectomy, and histopathologic diagnosis of pilomatrix carcinoma of the breast was offered. Pilomatrix carcinoma, although exceedingly rare, can have an intramammary location and can be misdiagnosed as breast carcinoma on limited material. A high index of suspicion is required to arrive at an accurate diagnosis so as to obviate neoadjuvant chemotherapy.

Epidermal growth factor receptor (EGFR) gene amplification in high-grade gliomas: Western Indian tertiary cancer center experience

BACKGROUND EGFR gene amplification is the hallmark of primary glioblastomas; however, its frequency in patients of Indian origin remains sparsely investigated. AIMS The aim of this study was to explore the frequency of EGFR amplification in high grade gliomas (HGGs) in Indian patients and to study its correlation with p53 protein overexpression. METHODS AND MATERIALS 324 cases of HGGs, where EGFR gene amplification was evaluated by fluorescence in-situ hybridization formed the study group. Ratio of >2 was considered as EGFR gene amplification. Immunohistochemically, p53 overexpression was evaluated and graded as positive for strong intensity staining in more than 50% of tumour cells. RESULTS 249 patients were male and 75 female (M: F-3.3:1); their age range was 8-91 years [paediatric glioblastoma (pGBM; 8-18yrs; n = 24)], adult HGGs [>18yrs; n = 300]}. 258 patients were having a GBM [including 31 with a GBM with oligodendroglioma component (GBM-O)], 31 with a gliosarcoma, 13 with an anaplastic astrocytoma (AA), 12 with an anaplastic oligodendroglioma (AO), and 10 with an anaplastic oligoastrocytoma (AOA). 79/233 cases (34%) with an adult GBM, (including 10/31 with a GBM-O [32.2%]), 1/31 (3.2%) with a GS and 1/10 (10%) with an AOA showed EGFR gene amplification. None of the pGBMs (n = 24) showed amplification. Amplification was seen in 19/81 (23.4%) of diffuse p53 protein positive cases and 53/143 (37%) of cases with focal or negative p53 protein expression. CONCLUSIONS 34% of our adult GBM patients showed EGFR gene amplification. The amplification was uncommonly associated with a strong diffuse p53 protein expression.

Impact of Squamous Differentiation in Breast Carcinoma

This study attempted to review the impact of extent of squamous differentiation in 56 infiltrating duct carcinomas (IDC) with squamous differentiation (metaplastic squamous carcinomas [MSC]). Tumors showing 100% squamous elements were labeled as primary squamous carcinomas (PSC; n = 28) and compared with 28 MSC showing lesser squamous components. A clinicopathological comparison revealed that lymphovascular emboli were never seen in any PSC but were noted in 7/28 of other MSC, while perineural invasion was seen only in PSC and not in MSC. Nodal metastasis was significantly more in other MSC as opposed to PSC. Most MSC presented with 2- to 5-cm sized tumors while PSC were 5 to 10 cm in size. PSC showed cystic change while MSC did not. Disease free survival (DFS) for MSC versus PSC was 64% versus 39.8%, while overall survival (OAS) was 72.7% in MSC versus 66.7% in PSC. Tumor stage affected DFS in MSC while none of the factors affected DFS/OAS in PSC. The extent of squamous differentiation affected DFS with best behavior for metaplastic carcinomas showing <40% squamous elements and worse for those with >90% squamous component (P = .024). PSC of breast is an aggressive disease and show distinct clinicopathological features from other MSC, and though the current definition of MSC does not advocate quantifying the squamous element, clearly this affects prognosis.