Report of a Case With Clinical and Pathologic Features of Castleman Disease That Predates Castleman's Report by More Than 50 Years.

CONTEXT.­: In 1954, Benjamin Castleman, MD, described what was then believed to be a new entity in lymph node pathology. Initially labeled "Hyperplasia of the mediastinal node" and then "Localized mediastinal lymph node hyperplasia resembling thymoma," we now recognize the condition with the eponym "Castleman disease." We document a paper that describes the same condition, a half century before Castleman did. OBJECTIVE.­: To report the striking resemblance between Castleman disease and the lymph node reported in the paper published by Edwin R. LeCount, MD, titled "Lymphoma, a benign tumor representing a lymph gland in structure," published in Journal of Experimental Medicine in 1899. We also provide an overview of the remarkable achievements of LeCount. DESIGN.­: We compared the elucidation in the original paper by LeCount with the morphologic details in the papers published by Castleman et al. Material on the life of LeCount was compiled from the scientific literature, the Internet, and the files of the University of Chicago. RESULTS.­: LeCount's description and illustrations of the lymph node are uncannily similar to the onion-skinning and vascularity that Castleman documented. CONCLUSIONS.­: LeCount deserves credit for his depiction of a hitherto-unreported entity.

Role of SMARCA4 (BRG1) and SMARCB1 (INI1) in Dedifferentiated Endometrial Carcinoma With Paradoxical Aberrant Expression of MMR in the Well-Differentiated Component: A Case Report and Review of the Literature.

INTRODUCTION: Dedifferentiated endometrial carcinoma is an uncommon highly aggressive uterine tumor. It comprises 2 components: a well-differentiated, low-grade epithelial carcinoma and an undifferentiated carcinoma. The undifferentiated carcinoma frequently exhibits rhabdoid cytologic features. Many of these tumors are characterized by an aberrant switch/sucrose non-fermenting (SWI/SNF) complex. They may also exhibit aberrant expression of mismatch repair (MMR) proteins. Together, these play an important role in the pathogenesis and aggressive nature of the tumor. MATERIAL AND METHODS: We present a case of dedifferentiated endometrial carcinoma in a 63-year-old female showing loss of expression of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4/BRG1), and aberrant expression of MMR proteins. We also review the literature starting from the earliest recognition of this entity and the various studies done to explain its molecular pathogenesis and prognostic importance. RESULTS AND CONCLUSIONS: Recognition of SWI/SNF complex-deficient dedifferentiated endometrial carcinoma is important as these tumors do not respond to platinum-based chemotherapy, and consideration of alternative therapies is often necessary. We also want to emphasize that though most of the studies have found MMR deficiency in the undifferentiated carcinoma component, it may be seen only in the low-grade, well-differentiated component, as observed in this case.

Chromosomal Alterations and Gene Expression Changes Associated with the Progression of Leukoplakia to Advanced Gingivobuccal Cancer.

We present an integrative genome-wide analysis that can be used to predict the risk of progression from leukoplakia to oral squamous cell carcinoma (OSCC) arising in the gingivobuccal complex (GBC). We find that the genomic and transcriptomic profiles of leukoplakia resemble those observed in later stages of OSCC and that several changes are associated with this progression, including amplification of 8q24.3, deletion of 8p23.2, and dysregulation of DERL3, EIF5A2, ECT2, HOXC9, HOXC13, MAL, MFAP5 and NELL2. Comparing copy number profiles of primary tumors with and without lymph-node metastasis, we identify alterations associated with metastasis, including amplifications of 3p26.3, 8q24.21, 11q22.1, 11q22.3 and deletion of 8p23.2. Integrative analysis reveals several biomarkers that have never or rarely been reported in previous OSCC studies, including amplifications of 1p36.33 (attributable to MXRA8), 3q26.31 (EIF5A2), 9p24.1 (CD274), and 12q13.2 (HOXC9 and HOXC13). Additionally, we find that amplifications of 1p36.33 and 11q22.1 are strongly correlated with poor clinical outcome. Overall, our findings delineate genomic changes that can be used in treatment management for patients with potentially malignant leukoplakia and OSCC patients with higher risk of lymph-node metastasis.

Enteropathy associated T cell lymphoma-monomorphic variant, presenting as bilateral ovarian masses.

Enteropathy associated T cell lymphoma (EATL) is a rare type of T-cell lymphoma, often associated with a history of celiac disease. It usually arises in the jejunum, but can involve other gastrointestinal tract sites such as stomach and colon. Monomorphic variant of EATL often occurs without a history of celiac disease, has variable histologic evidence of enteropathy, and is usually CD56 +. We report a case of EATL in a 49-year-old female presenting as bilateral ovarian masses. The morphology and immunophenotypic features were compatible with monomorphic variant of EATL.

Understanding the role of keratins 8 and 18 in neoplastic potential of breast cancer derived cell lines.

BACKGROUND: Breast cancer is a complex disease which cannot be defined merely by clinical parameters like lymph node involvement and histological grade, or by routinely used biomarkers like estrogen receptor (ER), progesterone receptor (PGR) and epidermal growth factor receptor 2 (HER2) in diagnosis and prognosis. Breast cancer originates from the epithelial cells. Keratins (K) are cytoplasmic intermediate filament proteins of epithelial cells and changes in the expression pattern of keratins have been seen during malignant transformation in the breast. Expression of the K8/18 pair is seen in the luminal cells of the breast epithelium, and its role in prognostication of breast cancer is not well understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we have modulated K8 expression to understand the role of the K8/18 pair in three different breast epithelium derived cell lines: non-transformed MCF10A, transformed but poorly invasive MDA MB 468 and highly invasive MDA MB 435. The up-regulation of K8 in the invasive MDA MB 435 cell line resulted in a significant decrease in proliferation, motility, in-vitro invasion, tumor volume and lung metastasis. The down-regulation of K8 in MDA MB 468 resulted in a significant increase in transformation potential, motility and invasion in-vitro, while MCF10A did not show any changes in cell transformation assays. CONCLUSIONS/SIGNIFICANCE: These results indicate the role of K8/18 in modulating invasion in breast cancer -its presence correlating with less invasive phenotype and absence correlating with highly invasive, dedifferentiated phenotype. These data may have important implications for prognostication of breast cancer.

Alterations in keratins and associated proteins during 4- Nitroquinoline-1-oxide induced rat oral carcinogenesis.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is the sixth largest group of malignancies globally and the single largest group of malignancies in the Indian subcontinent. Despite the advances in treatment and therapeutic modalities the five year survival rate of OSCC has not changed in the last few decades, and remains less than 40%. Several studies have focused on defining molecular markers that can either detect cancer at an early stage or can predict patient's outcome. However, such markers are still undefined. Keratins (K) are epithelia predominant intermediate filament proteins which are expressed in a differentiation dependent and site specific manner. Keratins are being used as biomarkers in different epithelial disorders including cancer. They are associated with desmoplakin and α6ß4 integrin which are components of desmosomes and hemidesmosomes respectively. MATERIALS AND METHODS: 4-Nitroquinoline 1-Oxide (4NQO) was used as a carcinogen for the development of various stages of oral carcinogenesis in rat lingual mucosa. Two-Dimentional gel electrophoresis was performed for the separation of Keratins followed by western blotting for their specific identification. Western blotting and RT PCR was carried out for desmoplakin and α6ß4 integrin respectively to understand their levels. Immunohistochemical analysis was carried out to further study the localization of desmoplakin and α6 integrin. RESULTS: In this study we have analysed the alterations in Keratins and associated proteins during sequential stages of 4NQO induced rat oral carcinogenesis. Our results showed that the alterations primarily begin after the dysplastic changes in the lingual epithelium like the elevation of Keratins 5/6a, ectopic expression of Keratin 8, increase in suprabasal expression of α6 integrin and increase in desmoplakin levels. Most of these alterations persisted till the development of SCC except desmoplakin, the levels of which were downregulated in papillomatous lesions and SCC. Many of these alterations have also been documented in human oral carcinogensis. CONCLUSION: Thus, 4NQO model of rat lingual carcinogenesis reproduces majority of the changes that are seen in human oral carcinogenesis and it can be exploited for the development of biomarkers.

Clinicopathological and prognostic implications of genetic alterations in oral cancers.

This study evaluated the clinicopathological and prognostic implications of genetic alterations characterizing oral squamous cell carcinoma(OSCC). Comparative genomic hybridization(CGH) was used to identify chromosomal alterations present in primary OSCCs obtained from 97 pateints. In this population, tobacco use was a significant risk factor for OSCC. By contrast, all 97 of our samples are negative for human papillomavirus (HPV) DNA integration, which is another known risk factor for OSCC in certain populations. Results of the Fisher's exact test followed by Benjamini-Hochberg correction for multiple testing, showed a correlation of 7p gain and 8p loss with node-positive OSCC (p≤0.04 for both genetic alterations) and association of 11q13 gain with high-grade OSCC (p≤0.05). Univariate Cox-proportional hazard models, also corrected for multiple testing, showed significant association of 11q13 gain and 18q loss with decreased survival (p≤0.05). These findings were supported by multivariate analysis which revealed that 11q13 gain and 18q loss together serve as a strong bivariate predictor of poor prognosis. In conclusion, our study has identified genetic alterations that correlate significantly with nodal status, grade, and poor survival status of OSCC. These potential biomarkers may aid the current TNM system for better prediction of clinical outcome.

Angiogenic ability of metastatic squamous carcinoma in the cervical lymph nodes from unknown primary tumours.

OBJECTIVES: To study angiogenesis in metastasis of unknown primary (MUP) to support the authors' hypothesis that MUPs are of a low angiogenic phenotype and are able to undergo metastasis in spite of an unknown primary. PATIENTS AND METHODS: A retrospective analysis was performed on paraffin blocks obtained from 50 cases of MUP and 52 cases of metastasis of known primary (MKP) from 1 January 2000 to December 2003. A prospective analysis was performed on fresh tissues from 22 cases of MUP and 26 cases of MKP. Immunohistochemical staining for VEGF was performed on the paraffin blocks. The fresh frozen tissue was analysed by RT-PCR and Western blotting for VEGF isoforms (VEGF121, VEGF165, VEGF189) and VEGF protein, respectively. RESULTS: Immunohistochemistry showed that MUPs had a higher percentage of lower scores of VEGF189 expression than MKPs. MKPs had increased scores of VEGF expression. RT-PCR analysis showed that MKPs had increased expression of VEGF121 and VEGF165 isoforms as compared with MUPs. MKPs showed a higher VEGF protein expression than MUPs. CONCLUSION: The study shows that metastases of squamous carcinoma from unknown primary have decreased VEGF expression at the immunohistochemical and protein level. They also display decreased expression of the VEGF121 and VEGF165 isoforms. Hence, these tumours are of a low angiogenic phenotype. They are able to develop a metastatic phenotype and grow at the metastatic site, since angiogenesis is redundant for lymph-node metastasis.

Genomic profiling of advanced-stage oral cancers reveals chromosome 11q alterations as markers of poor clinical outcome.

Identifying oral cancer lesions associated with high risk of relapse and predicting clinical outcome remain challenging questions in clinical practice. Genomic alterations may add prognostic information and indicate biological aggressiveness thereby emphasizing the need for genome-wide profiling of oral cancers. High-resolution array comparative genomic hybridization was performed to delineate the genomic alterations in clinically annotated primary gingivo-buccal complex and tongue cancers (n = 60). The specific genomic alterations so identified were evaluated for their potential clinical relevance. Copy-number changes were observed on chromosomal arms with most frequent gains on 3q (60%), 5p (50%), 7p (50%), 8q (73%), 11q13 (47%), 14q11.2 (47%), and 19p13.3 (58%) and losses on 3p14.2 (55%) and 8p (83%). Univariate statistical analysis with correction for multiple testing revealed chromosomal gain of region 11q22.1-q22.2 and losses of 17p13.3 and 11q23-q25 to be associated with loco-regional recurrence (P = 0.004, P = 0.003, and P = 0.0003) and shorter survival (P = 0.009, P = 0.003, and P 0.0001) respectively. The gain of 11q22 and loss of 11q23-q25 were validated by interphase fluorescent in situ hybridization (I-FISH). This study identifies a tractable number of genomic alterations with few underlying genes that may potentially be utilized as biological markers for prognosis and treatment decisions in oral cancers.

Metastasis of squamous cell carcinoma of the oral tongue is associated with down-regulation of epidermal fatty acid binding protein (E-FABP).

Squamous cell carcinoma (SCC) of the tongue is one of the most common cancers encountered in India, due to the prevalent habits of tobacco chewing and smoking. Up to 40% of the early stage tumours (clinical N0 M0) presenting at the Tata Memorial Hospital have occult cervical lymph node metastasis. Therefore, features in the primary tumour that would predict metastasis would be very useful for designing therapeutic approaches. Hence, we aimed at detecting genotypic markers of the metastatic sub-clones within the heterogeneous primary tumour population. We studied the differential expression of mRNAs between the primary tumour samples of SCC of the oral tongue and their metastasis by differential display analysis and identified a gene, FABP5, coding for Epidermal fatty acid binding protein (E-FABP-GenBank Accession ). Its expression was up to 4-fold higher in the primary tumours (67%) as compared to the corresponding metastatic lymph nodes by northern blot analysis.

Melanin bearing myoepithelial cells in a pigmented salivary gland carcinoma: a new avatar of myoepithelial cell? A case report.

Melanocytes can be found in the stroma of salivary glands and their tumors. However, the presence of melanin pigment in the tumor cells of salivary gland origin is exceedingly rare. A 42-year-old man presented with a nasal tumor that was black in color. The histology was that of a minor salivary gland carcinoma with foci resembling an adenoid cystic carcinoma. The myoepithelial cells of this tumor contained melanin pigment. The possible histogenesis of this lesion and an explanation for the occurrence of melanin pigment in a salivary gland tumor are discussed.

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.

Recurrent melanotic neuroectodermal tumour of infancy of the epididymis and testis: a case report.

Melanotic neuroectodermal tumor of infancy or melanotic progonoma is an uncommon tumor, presenting in infants. The epididymis and testis are rare sites of occurrence. This tumor can be confused with round cell tumor (RCT). Since the treatment modality and prognosis of melanotic progonoma and RCT are very different, it is imperative to make a correct diagnosis.

Modified H & E staining technique for fine needle aspiration cytology (FNAC) smears.

Papanicolaou (Pap) staining procedure has achieved worldwide acceptance in cytology practice due to its crisp cytological details. There are many centres or private laboratories in our country which cannot fulfill the economic requirement of Pap staining and hence employ comparatively cheaper haematoxylin and eosin (H & E) stain. Although routine H & E cannot replace Pap, this study is an attempt to modify H & E staining that would offer comparable diagnostic results. The present study is restricted to FNAC material from palpable lesions i.e.breast and lymph nodes. For this purpose 50 lymph nodes ( LN) and 18 breasts were aspirated. Out of two fixed smears, 1 was stained by Pap technique for routine reporting and other by modified H & E method which was examined and reported by other pathologist, Dr. Sangeeta B. Desai ( SBD) The diagnosis of both the techniques were compared. Emphasis was also given on cytomorphological characteristics. Out of fifty lymph node aspirates from various sites, no diagnostic discrepancy was observed in 46 cases. Three out of 4 had sampling errors whereas, poor nuclear staining was noticed in a single case. Out of eighteen breast aspirates concordant diagnosis was achieved in 16 cases. Out of two discrepant diagnosis 1 was due to sampling error, and the other was an interpretative error. All the cases were confirmed histologically. In conclusion, modified H & E staining is useful for common sites of aspirations of superficial lesions.

Aggressive behaviour of solid arrangement pattern in differentiated papillary carcinoma of thyroid.

The prognosis and overall outcome of solid growth pattern in differentiated papillary carcinoma of thyroid is controversial. While general consensus suggest outcomes similar to typical papillary carcinomas others demonstrate a more aggressive biology. We present a case of differentiated papillary carcinoma of thyroid with solid growth pattern presenting with neck swelling and widespread skeletal metastases. The areas of bone lesions showed avid 131I concentration on a postoperative large dose 131I whole body scan and was treated with 131I subsequently. The present case suggest that the solid architecture in a papillary thyroid carcinoma may be indicative of an aggressive clinical course, contrary to the common opinion that it does not adversely influence its biologic behaviour and thus emphasize the need to reexplore the prognostic significance of histopathologic subclassification along with an assessment of histologic grade and expression of molecular risk factors in this particular tumour subtype.

The prevalence of high-grade prostatic intraepithelial neoplasia in surgical resection specimens: an Indian experience.

BACKGROUND: To the authors' knowledge there is a paucity of literature regarding the prevalence of high-grade prostatic intraepithelial neoplasia (HGPIN) in the Indian subcontinent. The objective of the current study was to document the prevalence of HGPIN in a low-risk Indian population. METHOD: SA total of 110 prostate specimens (61 taken from the test group and 49 taken from the control group) were studied to document the prevalence of HGPIN in a low-risk Indian population. RESULTS: None of the benign prostate samples were found to harbor HGPIN, whereas 85.24% of the samples from malignant prostates did so. CONCLUSION: SA strong correlation between HGPIN and invasive carcinoma was observed, a finding that reinforces the view that HGPIN is a strong indicator of concurrent invasive prostate carcinoma.