BACKGROUND Neuroendocrine carcinomas (NECs) arise from neuroendocrine cells present throughout th... more BACKGROUND Neuroendocrine carcinomas (NECs) arise from neuroendocrine cells present throughout the body, and often present with metastases even with small and undetectable primary tumors. Additionally, neuroendocrine differentiation can be seen in carcinomas of non-neuroendocrine origin further complicating the landscape of metastatic NECs. Organ specific immunohistochemical markers such as TTF1, CDX2 and PAX8 are often lost in high grade tumors and may be non-contributory in localizing the primary site. Though NECs share a common cellular origin, they exhibit great variability in biologic behavior, prognosis and treatment based on the primary organ of origin. DESIGN Twenty one cases of metastatic NECs were retrieved from our archives and were classified based on location of the primary tumor derived from clinical and radiological findings. Next generation sequencing data was retrieved and analyzed for recurrent genetic abnormalities in these cases. Statistical analysis was performed using IBM SPSS25 software. RESULTS RB1 mutations were exclusive to NECs metastasizing from lung primary and were detected in 5 of 12 (41.6 %) cases (p = 0.04). CDKN gene family (CDKN1B and 2 A) mutations were limited to metatstatic NECs of non-pulmonary origin and were detected in 4 of 9 (44.4 %) cases (p = 0.02). CONCLUSION The location of the primary tumor in metastatic NECs appears to have significant prognostic and therapeutic implications. But due to the morphological homogeneity, higher grade of tumor, variable sensitivity of immunohistochemical markers, and small, often undetectable primary tumors, the localization of the primary tumor in cases of metastatic NECs is a challenge. In this study, RB1 and CDKN gene family mutations are identified as possible markers for differentiating pulmonary and non-pulmonary origin in metatstatic NECs.
Strongyloides stercoralis is an intestinal nematode endemic to tropical and subtropical locations... more Strongyloides stercoralis is an intestinal nematode endemic to tropical and subtropical locations, such as most of Latin America, and in the United States, the Appalachian mountain region. Clinical manifestations vary greatly and are non-specific; as a result, cases in regions that do not regularly screen for strongyloides often go undiagnosed. Current research estimates a prevalence of 370 million cases worldwide. Chronically infected patients that become immunosuppressed, particularly from exposure to corticosteroids, are at risk for developing a hyperinfection syndrome or disseminated strongyloidiasis, which carries a mortality rate of up to 87%. We present two cases of fatal disseminated strongyloidiasis. The first case is that of a 66 year old man, originally from Nicaragua, with ulcerative colitis receiving corticosteroids for three months that developed fatal disseminated strongyloidiasis which was complicated by gram-negative bacteremia, a complication associated with the highest mortality rates. The hospital course was additionally complicated by cytomegalovirus infection, Clostridium difficile colitis, severe gastrointestinal bleeding, disseminated intravascular coagulopathy, deep venous thromboses, pulmonary emboli, fungemia, bacterial meningitis, multifocal pneumonia with aspergillosis and toxic megacolon. The second case is that of an 87 year old man, originally from Cuba, with chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis on corticosteroids for an unknown duration that developed fatal disseminated strongyloidiasis. The hospital course was complicated by respiratory failure, anemia and thrombocytopenia, atrial fibrillation with heart failure, acute renal failure, lactic acidosis, alveolar hemorrhage and Mycoplasma pneumoniae pneumonia. Both patients were originally from Latin American countries where strongyloides is endemic. Because chronic infections are typically asymptomatic, both were likely unaware they were infected. Furthermore, use of corticosteroids suppresses the eosinophilic response to infection, which is often the only clinical evidence that prompts clinicians to search for strongyloides. These cases highlight the importance of screening patients from endemic areas prior to initiation of immunosuppressive therapy.
The American Journal of Surgical Pathology, Jul 26, 2022
Dermatopathic lymphadenopathy (DL) is a distinctive type of lymph node hyperplasia that typically... more Dermatopathic lymphadenopathy (DL) is a distinctive type of lymph node hyperplasia that typically occurs in the setting of chronic dermatologic diseases. DL generally self-resolves following disappearance of the underlying skin stimulus and does not require any specific therapy. We recently observed multiple myeloma oncogene 1/interferon regulatory factor 4 (MUM1/IRF4) expression in a case of DL using immunohistochemical methods. The goal of this study was to systematically assess DL cases for MUM1/IRF4 expression and to survey other histiocytic and Langerhans cell lesions. We particularly focused on Langerhans cell histiocytosis (LCH) because the differential diagnosis of DL versus LCH in lymph nodes can be challenging. We identified high expression of MUM1/IRF4 in all 22 cases of DL tested. Specifically, MUM1/IRF4+ dendritic cells comprised 50% to 90% (median, 80%) of all dendritic cells in the paracortex of dermatopathic lymph nodes, always showing moderate or strong intensity. Among 10 DL cases stained for MUM1/IRF4 and langerin/CD207 using dual immunohistochemistry, MUM1/IRF4+ and langerin+ Langerhans cells represented 5% to 60% (median, 30%) of paracortical dendritic cells. MUM1/IRF4 was also positive in reactive Langerhans cells in skin biopsy specimens of all cases of spongiotic dermatitis (n=10) and normal skin (n=15), and was negative in all cases of LCH (n=24), Rosai-Dorfman disease (n=10), follicular dendritic cell sarcoma (n=5) and histiocytic sarcoma (n=4). In aggregate, our findings support the utility of MUM1/IRF4 to highlight the dendritic cells of DL and to distinguish DL from other histiocytic and Langerhans cells lesions.
BACKGROUND Fibrosis, calcification, and ossification are histopathologic hallmarks of calcific ao... more BACKGROUND Fibrosis, calcification, and ossification are histopathologic hallmarks of calcific aortic valve disease (CAVD), a leading cause of morbidity and mortality in the aging population. Cellular senescence contributes to a functional decay in chronic diseases by intensifying tissue remodeling and impairing tissue regeneration. We evaluated the expression of P16INK4A and P53 as surrogate markers of senescence in CAVD. METHODS Aortic valves from 27 individuals with severe CAVD requiring aortic valve replacement were selected for routine histologic processing. Immunohistochemical expression of P16INK4A and P53 was quantified using computerized image analysis on fields matching compartments with varying degrees of tissue remodeling. RESULTS All aortic valves demonstrated P16INK4A and P53-positive cells. The percentage of P16INK4A -positive cells, but not of P53, was higher in areas of calcification/ossification (57.21% ± 26.31, n=40) and severe fibrosis (54.79% ± 27.19, n=25) than in areas with minimal to mild tissue remodeling (13.69% ± 11.88, n=16, P<0.0001). P16INK4A expression was observed in interstitial valve cells within all compartments proportional to the degree of fibrosis and did not correlate with age, severity of aortic stenosis, or P53 expression. Multiple linear regression analysis by backward elimination revealed P16INK4A expression was lower among statin users (P<0.01). CONCLUSIONS P16INK4A- expression is ubiquitous in calcified aortic valves and correlates with severity of tissue remodeling, suggesting a role of cellular senescence in the progression of CAVD. Further research is needed to identify possible treatment modalities as disease modifying agents for CAVD.
Activating mutations in the MAPK/ERK pathway have been shown in nearly half of cases of Rosai-Dor... more Activating mutations in the MAPK/ERK pathway have been shown in nearly half of cases of Rosai-Dorfman disease (RDD). Cyclin D1, a key cell cycle regulator, constitutes a major downstream target of the MAPK/ERK pathway. In this study, we aim to further understand the pathogenesis of RDD by assessing the lesional histiocytes for cyclin D1, p-ERK, Ki-67 and BCL2 by immunohistochemistry We assessed 35 samples of RDD and a control group of histiocyte-rich reactive lesions. Cyclin D1 was expressed in about 90% of cases of RDD. Cyclin D1 was positive in 25-95% (median, 85%) of lesional histiocytes, was moderately/strongly expressed in 97% of cyclin D1-positive cases, and was significantly higher than in control specimens. p-ERK was positive in 16 of 30 (53%) cases of RDD and was negative in all controls. Whereas all p-ERK-positive RDD cases had concurrent cyclin D1 expression, over a third of cyclin D1-positive cases were negative for p-ERK. Ki-67 was low in RDD (median, 3%). BCL-2 was positive in lesional histiocytes in nine of 10 RDD cases assessed and was negative Overall, these findings point to unexpected, potential roles of these molecules in the pathogenesis of RDD. Overexpression of cyclin D1 in the absence of ERK phosphorylation in a subset of RDD cases opens the possibility of oncogenic mechanisms bypassing ERK, and supports the notion that cyclin D1 overexpression in RDD is multifactorial. Moreover, the observed lack of correlation between cyclin D1 with Ki-67 proliferative index suggests that prosurvival actions of cyclin D1 are, at least in part, cell-cycle independent. Finally, expression of BCL-2 and the low Ki-67 index suggest that RDD might be driven by anti-apoptotic rather than pro-proliferative oncogenic mechanisms.
BACKGROUND: Breast cancer, one of the leading causes of cancer-related mortality in women worldwi... more BACKGROUND: Breast cancer, one of the leading causes of cancer-related mortality in women worldwide, exhibits wide-ranging histo-morphologic, clinical and molecular diversity. OBJECTIVE: This study compares the genetic alterations of breast tumors with the histo-morphological, hormone receptor status and metastatic “organotropism”. MATERIALS AND METHODS: Twenty-two cases of primary invasive breast carcinoma with local/distant metastasis were retrieved from the pathology archives. The status of estrogen and progesterone receptors by immunohistochemistry was recorded along with other pertinent case data. Next generation sequencing was performed on formalin-fixed paraffin embedded blocks of tumor. RESULTS: The mean age of the study subjects was 57.9 ± 13.3 years. TP53 mutation was the most common gene alteration in this study and was seen in 40.9% cases. ROS1 gene was mutated in 44.4% PR negative breast cancers while being wild type in the twelve PR positive tumors. (p = 0.021). STRING interaction network constructed with ROS1 and PR revealed a significantly higher number of interactions in this network than expected (p-value 0.000973). CONCLUSION: This study highlights the significantly higher incidence of ROS1 gene alterations in metastatic PR− breast cancers, with STRING network analysis revealing higher nodal interaction in the nodal network comprised of PR and ROS1 exclusive of ER.
American Journal of Forensic Medicine and Pathology, Aug 14, 2020
In modern medicine, there is an increasing dependence on noninvasive imaging modalities, for diag... more In modern medicine, there is an increasing dependence on noninvasive imaging modalities, for diagnosis and management of diseases. Though there are definite advantages to this, they are at times offset by diagnostic pitfalls especially in entities with elusive clinical presentation.Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) is an aggressive subtype of T-cell lymphomas that does not meet criteria for a specific subtype. Peripheral T-cell lymphoma usually has varied clinical presentations depending on the site of involvement. Vast majority of PTCL patients present with systemic disease, generalized lymphadenopathy and constitutional symptoms. Pulmonary involvement is relatively rare and is seen in approximately 10% of patients.Here in we highlight a rare case of PTCL, masquerading as pneumonia due to extensive pulmonary involvement that went undiagnosed and was discovered at autopsy. This case of malignant lymphoma of T-cell origin involving the lung, which is very rare, highlights the continued importance of medical autopsies not only as a teaching tool but also as an important adjunct to investigative medicine in uncovering lapses that can subsequently be avoided to improve patient care and decrease mortality.
: Cutaneous malignant melanoma is an aggressive cancer that contributes significantly to cancer-r... more : Cutaneous malignant melanoma is an aggressive cancer that contributes significantly to cancer-related mortality. Over the years, a deeper scrutiny of melanoma biology has led to identification of diverse evolutionary patterns involving various genetic pathways. This study attempts to further understand the genetic landscape of cutaneous malignant melanoma in terms of loco-regional variations and malignant potential. Thirty-five cases of cutaneous malignant melanoma were retrieved from the archives and were classified based on location of the primary tumor and presence or absence of metastatic disease. Next-generation sequencing data consisting of base substitutions, copy number variations, indels, and rearrangements in a total of 324 genes were analyzed for recurrent genetic alterations. Statistical analysis was performed using IBM SPSS26 software. Mutations in KDM gene family were found in 62.5% of the melanomas in the head and neck as compared with 10% in melanomas of the extremity and trunk (P = 0.03). Mutations in the RAS gene family were found in 70% of melanomas in the extremities as compared to 12.5% in melanomas of the head and neck (P = 0.003). BTK gene mutations were found exclusively in melanomas of the head and neck (P = 0.032). CREBBP mutations were seen in 50% of the nonmetastatic melanomas as compared with 3.57% of metastatic melanomas (P = 0.005). This study highlights the loco-regional variations in cutaneous malignant melanoma for genetic alterations involving the KDM, RAS, and BTK gene family. In addition, the CREBBP mutational status is identified as a potential prognostic marker for predicting metastatic potential in cutaneous malignant melanomas.
Fluid overload-associated large B-cell lymphoma (FO-LBCL) is a new entity described in the fifth ... more Fluid overload-associated large B-cell lymphoma (FO-LBCL) is a new entity described in the fifth edition of the World Health Organization (WHO) Classification of Hematolymphoid Tumors (WHO-HAEM5). It refers to malignant lymphoma present with symptoms of serous effusions in body cavities (pleural, peritoneal, and/or pericardial) in the absence of an identifiable tumor mass. We present a case of an 82-year-old man with a history of atrial fibrillation and atrial flutter, status post-ablation, essential hypertension (HTN), hyperlipidemia (HLD), and diabetes mellitus (DM) type 2 who was referred to our hospital for shortness of breath due to recurrent pleural effusion. Right video-assisted thoracoscopy with right pleural biopsy was performed. Histopathological examination of the pleural biopsy revealed dense fibrous tissue, chronic inflammation, lymphoid aggregates, and granulation tissue, with no evidence of lymphoma. Cytology of the right pleural fluid revealed large lymphoid cells, w...
Amyloidosis is a term describing the extracellular deposit of fibrils composed of subunits of sev... more Amyloidosis is a term describing the extracellular deposit of fibrils composed of subunits of several different normal serum proteins in various tissues. Amyloid light chain (AL) amyloidosis contains fibrils that are composed of fragments of monoclonal light chains. Many different disorders and conditions can lead to spontaneous splenic rupture, including AL amyloidosis. We present a case of a 64-year-old woman with spontaneous splenic rupture and hemorrhage. A final diagnosis of systemic amyloidosis secondary to plasma cell myeloma was made with infiltrative cardiomyopathy and possible diastolic congestive heart failure exacerbation. We also provide a narrative review of all documented cases of splenic rupture associated with amyloidosis from the year 2000 until January 2023, along with the main clinical findings and management strategies.
Objectives The aim of this study is to analyze the prevalence of somatic mutations in BRCA1 and B... more Objectives The aim of this study is to analyze the prevalence of somatic mutations in BRCA1 and BRCA2 in malignant mesothelioma and their putative impact on protein properties. Methods Eighteen cases of malignant mesothelioma were retrieved from the archives and for next generation sequencing analysis of BRCA1 and BRCA2 genes. Variants were analyzed using Ensembl VEP17, Polyphen 2.0 software, SIFT software, MutpredV2, and SWISS-MODEL homology-modeling pipeline server. Results BRCA2 variants were found in significantly higher percentage (22%) of cases (p=0.02). Five missense variants were identified. These were p.A2351P, p.T2250A, p.A895V, pG1771D, and p.R2034C. The SIFT scores of all except one were ≥ 0.03. The Polyphen scores of these four alterations were ≤0.899. In case of p.A2315, the SIFT score was 0.01, while the Polyphen 2 score was 0.921. MutPred2 scores were ≤0.180 for all. Loss of intrinsic disorder was predicted (Pr=0.32, p=0.07) for p.R2034C, while gain of intrinsic diso...
BACKGROUND Neuroendocrine carcinomas (NECs) arise from neuroendocrine cells present throughout th... more BACKGROUND Neuroendocrine carcinomas (NECs) arise from neuroendocrine cells present throughout the body, and often present with metastases even with small and undetectable primary tumors. Additionally, neuroendocrine differentiation can be seen in carcinomas of non-neuroendocrine origin further complicating the landscape of metastatic NECs. Organ specific immunohistochemical markers such as TTF1, CDX2 and PAX8 are often lost in high grade tumors and may be non-contributory in localizing the primary site. Though NECs share a common cellular origin, they exhibit great variability in biologic behavior, prognosis and treatment based on the primary organ of origin. DESIGN Twenty one cases of metastatic NECs were retrieved from our archives and were classified based on location of the primary tumor derived from clinical and radiological findings. Next generation sequencing data was retrieved and analyzed for recurrent genetic abnormalities in these cases. Statistical analysis was performed using IBM SPSS25 software. RESULTS RB1 mutations were exclusive to NECs metastasizing from lung primary and were detected in 5 of 12 (41.6 %) cases (p = 0.04). CDKN gene family (CDKN1B and 2 A) mutations were limited to metatstatic NECs of non-pulmonary origin and were detected in 4 of 9 (44.4 %) cases (p = 0.02). CONCLUSION The location of the primary tumor in metastatic NECs appears to have significant prognostic and therapeutic implications. But due to the morphological homogeneity, higher grade of tumor, variable sensitivity of immunohistochemical markers, and small, often undetectable primary tumors, the localization of the primary tumor in cases of metastatic NECs is a challenge. In this study, RB1 and CDKN gene family mutations are identified as possible markers for differentiating pulmonary and non-pulmonary origin in metatstatic NECs.
Strongyloides stercoralis is an intestinal nematode endemic to tropical and subtropical locations... more Strongyloides stercoralis is an intestinal nematode endemic to tropical and subtropical locations, such as most of Latin America, and in the United States, the Appalachian mountain region. Clinical manifestations vary greatly and are non-specific; as a result, cases in regions that do not regularly screen for strongyloides often go undiagnosed. Current research estimates a prevalence of 370 million cases worldwide. Chronically infected patients that become immunosuppressed, particularly from exposure to corticosteroids, are at risk for developing a hyperinfection syndrome or disseminated strongyloidiasis, which carries a mortality rate of up to 87%. We present two cases of fatal disseminated strongyloidiasis. The first case is that of a 66 year old man, originally from Nicaragua, with ulcerative colitis receiving corticosteroids for three months that developed fatal disseminated strongyloidiasis which was complicated by gram-negative bacteremia, a complication associated with the highest mortality rates. The hospital course was additionally complicated by cytomegalovirus infection, Clostridium difficile colitis, severe gastrointestinal bleeding, disseminated intravascular coagulopathy, deep venous thromboses, pulmonary emboli, fungemia, bacterial meningitis, multifocal pneumonia with aspergillosis and toxic megacolon. The second case is that of an 87 year old man, originally from Cuba, with chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis on corticosteroids for an unknown duration that developed fatal disseminated strongyloidiasis. The hospital course was complicated by respiratory failure, anemia and thrombocytopenia, atrial fibrillation with heart failure, acute renal failure, lactic acidosis, alveolar hemorrhage and Mycoplasma pneumoniae pneumonia. Both patients were originally from Latin American countries where strongyloides is endemic. Because chronic infections are typically asymptomatic, both were likely unaware they were infected. Furthermore, use of corticosteroids suppresses the eosinophilic response to infection, which is often the only clinical evidence that prompts clinicians to search for strongyloides. These cases highlight the importance of screening patients from endemic areas prior to initiation of immunosuppressive therapy.
The American Journal of Surgical Pathology, Jul 26, 2022
Dermatopathic lymphadenopathy (DL) is a distinctive type of lymph node hyperplasia that typically... more Dermatopathic lymphadenopathy (DL) is a distinctive type of lymph node hyperplasia that typically occurs in the setting of chronic dermatologic diseases. DL generally self-resolves following disappearance of the underlying skin stimulus and does not require any specific therapy. We recently observed multiple myeloma oncogene 1/interferon regulatory factor 4 (MUM1/IRF4) expression in a case of DL using immunohistochemical methods. The goal of this study was to systematically assess DL cases for MUM1/IRF4 expression and to survey other histiocytic and Langerhans cell lesions. We particularly focused on Langerhans cell histiocytosis (LCH) because the differential diagnosis of DL versus LCH in lymph nodes can be challenging. We identified high expression of MUM1/IRF4 in all 22 cases of DL tested. Specifically, MUM1/IRF4+ dendritic cells comprised 50% to 90% (median, 80%) of all dendritic cells in the paracortex of dermatopathic lymph nodes, always showing moderate or strong intensity. Among 10 DL cases stained for MUM1/IRF4 and langerin/CD207 using dual immunohistochemistry, MUM1/IRF4+ and langerin+ Langerhans cells represented 5% to 60% (median, 30%) of paracortical dendritic cells. MUM1/IRF4 was also positive in reactive Langerhans cells in skin biopsy specimens of all cases of spongiotic dermatitis (n=10) and normal skin (n=15), and was negative in all cases of LCH (n=24), Rosai-Dorfman disease (n=10), follicular dendritic cell sarcoma (n=5) and histiocytic sarcoma (n=4). In aggregate, our findings support the utility of MUM1/IRF4 to highlight the dendritic cells of DL and to distinguish DL from other histiocytic and Langerhans cells lesions.
BACKGROUND Fibrosis, calcification, and ossification are histopathologic hallmarks of calcific ao... more BACKGROUND Fibrosis, calcification, and ossification are histopathologic hallmarks of calcific aortic valve disease (CAVD), a leading cause of morbidity and mortality in the aging population. Cellular senescence contributes to a functional decay in chronic diseases by intensifying tissue remodeling and impairing tissue regeneration. We evaluated the expression of P16INK4A and P53 as surrogate markers of senescence in CAVD. METHODS Aortic valves from 27 individuals with severe CAVD requiring aortic valve replacement were selected for routine histologic processing. Immunohistochemical expression of P16INK4A and P53 was quantified using computerized image analysis on fields matching compartments with varying degrees of tissue remodeling. RESULTS All aortic valves demonstrated P16INK4A and P53-positive cells. The percentage of P16INK4A -positive cells, but not of P53, was higher in areas of calcification/ossification (57.21% ± 26.31, n=40) and severe fibrosis (54.79% ± 27.19, n=25) than in areas with minimal to mild tissue remodeling (13.69% ± 11.88, n=16, P<0.0001). P16INK4A expression was observed in interstitial valve cells within all compartments proportional to the degree of fibrosis and did not correlate with age, severity of aortic stenosis, or P53 expression. Multiple linear regression analysis by backward elimination revealed P16INK4A expression was lower among statin users (P<0.01). CONCLUSIONS P16INK4A- expression is ubiquitous in calcified aortic valves and correlates with severity of tissue remodeling, suggesting a role of cellular senescence in the progression of CAVD. Further research is needed to identify possible treatment modalities as disease modifying agents for CAVD.
Activating mutations in the MAPK/ERK pathway have been shown in nearly half of cases of Rosai-Dor... more Activating mutations in the MAPK/ERK pathway have been shown in nearly half of cases of Rosai-Dorfman disease (RDD). Cyclin D1, a key cell cycle regulator, constitutes a major downstream target of the MAPK/ERK pathway. In this study, we aim to further understand the pathogenesis of RDD by assessing the lesional histiocytes for cyclin D1, p-ERK, Ki-67 and BCL2 by immunohistochemistry We assessed 35 samples of RDD and a control group of histiocyte-rich reactive lesions. Cyclin D1 was expressed in about 90% of cases of RDD. Cyclin D1 was positive in 25-95% (median, 85%) of lesional histiocytes, was moderately/strongly expressed in 97% of cyclin D1-positive cases, and was significantly higher than in control specimens. p-ERK was positive in 16 of 30 (53%) cases of RDD and was negative in all controls. Whereas all p-ERK-positive RDD cases had concurrent cyclin D1 expression, over a third of cyclin D1-positive cases were negative for p-ERK. Ki-67 was low in RDD (median, 3%). BCL-2 was positive in lesional histiocytes in nine of 10 RDD cases assessed and was negative Overall, these findings point to unexpected, potential roles of these molecules in the pathogenesis of RDD. Overexpression of cyclin D1 in the absence of ERK phosphorylation in a subset of RDD cases opens the possibility of oncogenic mechanisms bypassing ERK, and supports the notion that cyclin D1 overexpression in RDD is multifactorial. Moreover, the observed lack of correlation between cyclin D1 with Ki-67 proliferative index suggests that prosurvival actions of cyclin D1 are, at least in part, cell-cycle independent. Finally, expression of BCL-2 and the low Ki-67 index suggest that RDD might be driven by anti-apoptotic rather than pro-proliferative oncogenic mechanisms.
BACKGROUND: Breast cancer, one of the leading causes of cancer-related mortality in women worldwi... more BACKGROUND: Breast cancer, one of the leading causes of cancer-related mortality in women worldwide, exhibits wide-ranging histo-morphologic, clinical and molecular diversity. OBJECTIVE: This study compares the genetic alterations of breast tumors with the histo-morphological, hormone receptor status and metastatic “organotropism”. MATERIALS AND METHODS: Twenty-two cases of primary invasive breast carcinoma with local/distant metastasis were retrieved from the pathology archives. The status of estrogen and progesterone receptors by immunohistochemistry was recorded along with other pertinent case data. Next generation sequencing was performed on formalin-fixed paraffin embedded blocks of tumor. RESULTS: The mean age of the study subjects was 57.9 ± 13.3 years. TP53 mutation was the most common gene alteration in this study and was seen in 40.9% cases. ROS1 gene was mutated in 44.4% PR negative breast cancers while being wild type in the twelve PR positive tumors. (p = 0.021). STRING interaction network constructed with ROS1 and PR revealed a significantly higher number of interactions in this network than expected (p-value 0.000973). CONCLUSION: This study highlights the significantly higher incidence of ROS1 gene alterations in metastatic PR− breast cancers, with STRING network analysis revealing higher nodal interaction in the nodal network comprised of PR and ROS1 exclusive of ER.
American Journal of Forensic Medicine and Pathology, Aug 14, 2020
In modern medicine, there is an increasing dependence on noninvasive imaging modalities, for diag... more In modern medicine, there is an increasing dependence on noninvasive imaging modalities, for diagnosis and management of diseases. Though there are definite advantages to this, they are at times offset by diagnostic pitfalls especially in entities with elusive clinical presentation.Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) is an aggressive subtype of T-cell lymphomas that does not meet criteria for a specific subtype. Peripheral T-cell lymphoma usually has varied clinical presentations depending on the site of involvement. Vast majority of PTCL patients present with systemic disease, generalized lymphadenopathy and constitutional symptoms. Pulmonary involvement is relatively rare and is seen in approximately 10% of patients.Here in we highlight a rare case of PTCL, masquerading as pneumonia due to extensive pulmonary involvement that went undiagnosed and was discovered at autopsy. This case of malignant lymphoma of T-cell origin involving the lung, which is very rare, highlights the continued importance of medical autopsies not only as a teaching tool but also as an important adjunct to investigative medicine in uncovering lapses that can subsequently be avoided to improve patient care and decrease mortality.
: Cutaneous malignant melanoma is an aggressive cancer that contributes significantly to cancer-r... more : Cutaneous malignant melanoma is an aggressive cancer that contributes significantly to cancer-related mortality. Over the years, a deeper scrutiny of melanoma biology has led to identification of diverse evolutionary patterns involving various genetic pathways. This study attempts to further understand the genetic landscape of cutaneous malignant melanoma in terms of loco-regional variations and malignant potential. Thirty-five cases of cutaneous malignant melanoma were retrieved from the archives and were classified based on location of the primary tumor and presence or absence of metastatic disease. Next-generation sequencing data consisting of base substitutions, copy number variations, indels, and rearrangements in a total of 324 genes were analyzed for recurrent genetic alterations. Statistical analysis was performed using IBM SPSS26 software. Mutations in KDM gene family were found in 62.5% of the melanomas in the head and neck as compared with 10% in melanomas of the extremity and trunk (P = 0.03). Mutations in the RAS gene family were found in 70% of melanomas in the extremities as compared to 12.5% in melanomas of the head and neck (P = 0.003). BTK gene mutations were found exclusively in melanomas of the head and neck (P = 0.032). CREBBP mutations were seen in 50% of the nonmetastatic melanomas as compared with 3.57% of metastatic melanomas (P = 0.005). This study highlights the loco-regional variations in cutaneous malignant melanoma for genetic alterations involving the KDM, RAS, and BTK gene family. In addition, the CREBBP mutational status is identified as a potential prognostic marker for predicting metastatic potential in cutaneous malignant melanomas.
Fluid overload-associated large B-cell lymphoma (FO-LBCL) is a new entity described in the fifth ... more Fluid overload-associated large B-cell lymphoma (FO-LBCL) is a new entity described in the fifth edition of the World Health Organization (WHO) Classification of Hematolymphoid Tumors (WHO-HAEM5). It refers to malignant lymphoma present with symptoms of serous effusions in body cavities (pleural, peritoneal, and/or pericardial) in the absence of an identifiable tumor mass. We present a case of an 82-year-old man with a history of atrial fibrillation and atrial flutter, status post-ablation, essential hypertension (HTN), hyperlipidemia (HLD), and diabetes mellitus (DM) type 2 who was referred to our hospital for shortness of breath due to recurrent pleural effusion. Right video-assisted thoracoscopy with right pleural biopsy was performed. Histopathological examination of the pleural biopsy revealed dense fibrous tissue, chronic inflammation, lymphoid aggregates, and granulation tissue, with no evidence of lymphoma. Cytology of the right pleural fluid revealed large lymphoid cells, w...
Amyloidosis is a term describing the extracellular deposit of fibrils composed of subunits of sev... more Amyloidosis is a term describing the extracellular deposit of fibrils composed of subunits of several different normal serum proteins in various tissues. Amyloid light chain (AL) amyloidosis contains fibrils that are composed of fragments of monoclonal light chains. Many different disorders and conditions can lead to spontaneous splenic rupture, including AL amyloidosis. We present a case of a 64-year-old woman with spontaneous splenic rupture and hemorrhage. A final diagnosis of systemic amyloidosis secondary to plasma cell myeloma was made with infiltrative cardiomyopathy and possible diastolic congestive heart failure exacerbation. We also provide a narrative review of all documented cases of splenic rupture associated with amyloidosis from the year 2000 until January 2023, along with the main clinical findings and management strategies.
Objectives The aim of this study is to analyze the prevalence of somatic mutations in BRCA1 and B... more Objectives The aim of this study is to analyze the prevalence of somatic mutations in BRCA1 and BRCA2 in malignant mesothelioma and their putative impact on protein properties. Methods Eighteen cases of malignant mesothelioma were retrieved from the archives and for next generation sequencing analysis of BRCA1 and BRCA2 genes. Variants were analyzed using Ensembl VEP17, Polyphen 2.0 software, SIFT software, MutpredV2, and SWISS-MODEL homology-modeling pipeline server. Results BRCA2 variants were found in significantly higher percentage (22%) of cases (p=0.02). Five missense variants were identified. These were p.A2351P, p.T2250A, p.A895V, pG1771D, and p.R2034C. The SIFT scores of all except one were ≥ 0.03. The Polyphen scores of these four alterations were ≤0.899. In case of p.A2315, the SIFT score was 0.01, while the Polyphen 2 score was 0.921. MutPred2 scores were ≤0.180 for all. Loss of intrinsic disorder was predicted (Pr=0.32, p=0.07) for p.R2034C, while gain of intrinsic diso...
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Papers by Vathany SriGaneshan