Saral Desai

Crizotinib: A comprehensive review

Anaplastic lymphoma kinase (ALK) gene rearrangements are present in a small subset of non-small-cell lung cancers. ALK-positivity confers sensitivity to small-molecule ALK kinase inhibitors, such as crizotinib. The integration of crizotinib into standard treatment practice in NSCLC will rest on the widespread implementation of an effective screening system for newly diagnosed patients with NSCLC which is flexible enough to incorporate new targets as treatments are developed for them. Phase I and II studies of crizotinib in ALK-positive lung cancer have demonstrated significant activity and impressive clinical benefit, which led to its early approval by USFDA in 2011. Although crizotinib induces remissions and extends the lives of patients, there have been reports of emerging resistance to Crizotinib therapy. In this review, we discuss the history, mechanism of action, uses, adverse effects, dose modifications and future challenges and opportunities for patients with ALK-positive lung cancers.

Frequency of EGFR Mutations in 907 Lung Adenocarcioma Patients of Indian Ethnicity

Background During the past decade, the incidence of EGFR mutation has been shown to vary across different ethnicities. It occurs at the rate of 10–15% in North Americans and Europeans, 19% in African-Americans, 20–30% in various East Asian series including Chinese, Koreans, and Japanese. Frequency of EGFR mutations in India however remains sparsely explored. Methodology/Principal Findings We report 23% incidence of Epidermal growth factor receptor (EGFR) mutations in 907 Non small cell lung cancer (NSCLC) patients of Indian ethnicity, in contrast to 10–15% known in Caucasians and 27–62% among East Asians. In this study, EGFR mutations were found to be more common in never-smokers 29.4% as compared to smokers 15.3%. Consistent with other populations, mutation rates among adenocarcinoma-males were predominantly lower than females with 32% incidence. However unlike Caucasians, EGFR mutation rate among adenocarcinoma-never-smoker females were comparable to males suggesting lack of gender bias among never smokers likely to benefit from EGFR targeted therapy. Conclusions/Significance This study has an overall implication for establishing relevance for routine EGFR mutation diagnostics for NSCLC patients in clinics and emphasizes effectiveness for adoption of EGFR inhibitors as the first line treatment among Indian population. The intermediate frequency of EGFR mutation among Indian population compared to Caucasians and East Asians is reminiscent of an ancestral admixture of genetic influence from Middle Easterners, Central Asians, and Europeans on modern- Indian population that may confer differential susceptibility to somatic mutations in EGFR.

Pathology of Ewing’s sarcoma/PNET: Current opinion and emerging concepts

Ewing’s sarcoma/PNET are small round cell tumors showing a varying degree of neuroectodermal differentiation. They are one of the commonest tumors of childhood and occur in bone and within soft tissues. Traditionally, light microscopy with the aid of immunohistochemical stains was suitable for diagnosis. But now translocation analyses are being used not only for the diagnosis and classification of small round cell tumors, but to ascertain their prognostic significance, detect micrometastasis, and monitor minimal residual disease, with potential for targeted therapy. This article analyzes the pathology, biology, and molecular aspects of Ewing’s sarcoma/PNET and discusses their clinical and therapeutic implications.

A study of histopathological features of medullary carcinoma of the thyroid: Cases from a single institute in India

BACKGROUND The microscopic features of medullary carcinoma have been described in world literature, together with its behavior and molecular biology. However, no large study has been reported from India. AIMS This study aims to analyse the clinical, and especially the pathological features of medullary carcinoma of the thyroid, and the surrounding thyroid. MATERIALS AND METHODS In this study a total of 234 cases of medullary thyroid carcinoma (MTC) were gathered over a period of 3 decades. The clinical presentation, the microscopic features and the clinical outcome were analyzed. RESULTS MTC was found to be twice as common in men as in women and for some reason it occurred 10 years earlier in women. The histology revealed certain interesting features like the presence of apoptosis in over half of the tumors, in addition to the other common and not so common histological findings (encapsulated variant, small cell variants, follicular pattern, rosettes, oncocytic change, osteosarcoma-like pattern, and cribriform pattern). The adjacent thyroid in about 19% of the cases showed optically clear nuclei in the follicles that were close to the tumor cells. These features were similar to those seen in papillary thyroid carcinoma. CONCLUSIONS The thyroid adjacent to MTC showed nuclear changes, which are also found in papillary carcinoma of the thyroid. The occasional concurrent occurrence of these two tumors and the involvement of the RET gene in both medullary and papillary carcinomas, makes this observation worth discussing and studying further.

Florid reactive periostitis of the hands

Reactive periostitis of the hand can be a confounding lesion on both radiological and histological grounds. An erroneous diagnosis of a malignant tumor, particularly an osteosarcoma, is a possibility. Two cases of florid reactive periostitis of the hand mistaken for osteosarcoma are reported here to illustrate this entity and caution against a diagnostic pitfall.

EGFR Mutations in Indian Lung Cancer Patients: Clinical Correlation and Outcome to EGFR Targeted Therapy

Screening for EGFR mutation is a key molecular test for management of lung cancer patients. Outcome of patients with mutation receiving EGFR tyrosine kinase inhibitor is known to be better across different ethnic populations. However, frequency of EGFR mutations and the clinical response in most other ethnic populations, including India, remains to be explored. We conducted a retrospective analysis of Indian lung cancer patients who were managed with oral tyrosine kinase inhibitors. Majority of the patients in the study had adenocarcinoma and were non-smokers. 39/111 patients tested positive for EGFR kinase domain mutations determined by Taqman based real time PCR. The overall response to oral TKI therapy was 30%. Patients with an activating mutation of EGFR had a response rate of 74%, while the response rate in patients with wild type EGFR was 5%, which was a statistically significant difference. Progression free survival of patients with EGFR mutations was 10 months compared to 2 months for EGFR mutation negative patients. Overall survival was 19 months for EGFR mutation patients and 13 months for mutation negative patients. This study emphasizes EGFR mutation as an important predictive marker for response to oral tyrosine kinase inhibitors in the Indian population.

Recurrent giant cell tumor of bone with simultaneous regional lymph node and pulmonary metastases

Giant cell tumors of bone are known for their unpredictable behavior characterized occasionally even by metastases. Most metastases lodge in the lungs but other rare sites are regional lymph nodes, mediastinum, skin, scalp and the pelvis. In this case report we document a case of giant cell tumor of the patella in which, associated with local recurrence, there were simultaneous metastases to lymph nodes and lungs.

Chemotherapy compliance in patients with osteosarcoma

Histological response (HR) to neoadjuvant‐chemotherapy (NACT) is considered as a robust prognostic marker in treated osteosarcomas. Chemotherapy compliance can affect both, dose intensity and density and may affect the final outcome in these cases. This vital aspect has been inadequately addressed and therefore merits further investigation.

Desmoplastic Small Round Cell Tumor-Clinicopathological Spectrum, Including Unusual Features and Immunohistochemical Analysis of 45 Tumors Diagnosed at a Tertiary Cancer Referral Centre, with Molecular Results t(11; 22) (p13; q12) (EWS-WT1) in Select Cases

Desmoplastic small round cell tumor (DSRCT) is a distinct soft tissue tumor of uncertain histogenesis, mostly composed of small round cells; is characterized by polyphenotypic differentiation and a translocation t(11; 22)(p13; q13), resulting in formation of a specificEWS-WT1 fusion gene transcript [1]. This tumor was initially described by Sesterhenn et al. [2] as an undifferentiated malignant epithelial tumor involving serosal surfaces of scrotum and abdomen in young males. In 1989, Gerald and Rosai [3] published the first case that they designated as a desmoplastic small round cell tumor (DSRCT) with divergent differentiation. In the following year, Gonzalez-Crussi et al. [4] documented three additional cases of an intra-abdominal DSRCT. Subsequently, Gerald et al. [5] published the first large series of IADSRCT stating its predilection for adolescent males; an almost intra-abdominal location with rare secondary organ involvement and its classical histopathological features. Sawyer et al. [6] identified t (11; 22) (p13; q13) translocation for the first time in an IADSRCT. Ordonez et al. [7] identified a single case of ‘IADSRCT’ in the scrotum in their series of 22 cases. Thereafter, this tumor has been documented in form of series and case reports in intra and extra-abdominal sites like ovary, paratesticular region, pleura, soft tissues, including head and neck and finally recognized as a DSRCT [1, 8–16]. It is a highly malignant tumor that displays variable epithelial, mesenchymal and neural differentiation, demonstrated by immunohistochemical stains; mostly involves abdominal sites of young male patients, spreads along serosal surfaces; has an aggressive clinical course with frequent recurrences, rarely metastasis and is refractory to conventional, individual treatment modalities like surgery, chemotherapy (CT) and radiotherapy (RT). Apart from its classical histopathological features, including small round cells embedded in a desmoplastic stroma, a spectrum of features has been described, including tumors B. Rekhi (*) : S. Ahmed : S. S. Desai :M. Ramadwar : S. B. Desai :N. A. Jambhekar Department of Pathology, Tata Memorial Hospital, Dr E.B. Road, Parel, Mumbai, India 400012 e-mail: rekhi.bharat@gmail.com

Primary leiomyosarcoma of bone—a clinicopathologic study of 8 uncommon cases with immunohistochemical analysis and clinical outcomes

Primary leiomyosarcoma of bone is a rare and a diagnostically challenging tumor entity. Over a 7-year period, we identified 8 such cases that fulfilled the diagnostic criteria in 6 men and 2 women, with age ranging from 25 to 59 years (mean, 42.7 years). All cases were noted in the lower limbs, including femur and tibia as the commonly involved bones in 4 and 3 cases, respectively. On radiography, the most consistent feature was a solitary osteolytic lesion with cortical destruction, unassociated with matrix formation. On histopathology, all cases showed spindly sarcomatous cells, mostly arranged in fascicles and whorls. Of 8 cases, 6 (75%) were of high grade. Prominent vasculature was noted in 5 cases. Two cases displayed focal mineralization, including calcification and heterotropic woven bone formation in 1 case each, but lacked malignant osteoid or chondroid matrix. One case showed osteoclast-like giant cells. On immunohistochemistry, smooth muscle actin was diffusely positive in all cases (100%), desmin was positive in 6 (75%) of 8 cases, and h-caldesmon was positive in 5 (83.3%) of 6 cases. Five cases underwent surgery, including 3 amputations and 2 wide excisions. One case underwent chemotherapy. On follow-up, 5 cases developed metastasis, including 1 case with another, who died within 17 and 5 months. Leiomyosarcoma of bone is uncommon and diagnostically challenging. An index of suspicion is necessary for this diagnosis, especially in cases of lytic, destructive bone lesions, unassociated with matrix production, that show spindly sarcomatous cells on histopathology. Immunohistochemical analysis, including an optimum panel formed by smooth muscle actin (diffuse positivity), desmin, and h-caldesmon, is necessary for substantiating this diagnosis. Surgery forms the treatment mainstay. The prognosis appears to be dismal.