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Background: Subclinical involvement of nerves may sometimes be present much before the overt clinical manifestations become apparent. Protein gene product (PGP) 9.5, a ubiquitin-C-terminal hydrolase, has been widely used as a marker to study the involvement of peripheral nerve fibers in many diseases. Aim and Objectives: To evaluate the change in cutaneous nerve fiber staining and distribution from pre-treatment and post completion of multidrug therapy through the expression of PGP9.5 and to assess PGP9.5 as a marker of treatment response. Materials and Methods: In this prospective single-center observational study, skin biopsy was taken in patients with leprosy, having areas of nerve function impairment (NFI), based on findings of nerve conduction studies (NCSs), but not having lesions or impaired tactile or thermal impairment clinically. The thin nerve fiber density in the clinically normal skin in areas supplied by nerve showing changes of sensory neuropathy was evaluated to study the density of the fibers. A second biopsy was taken at the end of treatment from a site near the previous site to assess the changes in intra-epidermal nerve fiber staining and distribution. Results: Thirty-three patients were recruited in the present study (24 males and 9 females). Pre-treatment, 27 patients had abnormal NCSs, while six patients did not have any evidence of neuropathy on NCSs. Staining for nerve fibers using PGP9.5; in the epidermis was positive in five patients pre-treatment and 11 patients post treatment (P = 0.181). Staining in the dermis revealed positivity in 14 pre-treatment, which increased to 18 post treatment (P = 0.342). Adnexae showed positivity in five patients pre-treatment and increased to 17 post treatment (P = 0.005). Conclusion: A reduced PGP9.5 staining in the epidermal, dermal, and adnexal regions was seen in leprosy patients, which improved post treatment. Thus, PGP9.5 may serve as a marker of NFI and treatment response.

Biliary atresia (BA) is a fibro-obliterative cholestatic disease of infancy. The presence of cartilage in the resected tissue is an uncommon finding. We documented the presence of both mature and immature hyaline cartilage in the portal plate and the wall of the gallbladder in a 2-month-old girl infant with BA who had undergone Kasai portoenterostomy. The presence of cartilage could be part of a heterotopia or an uncommon connective tissue metaplasia. The presence of immature cartilage with the merging of the perichondrium with the soft tissue highlights a metaplastic etiology in the index case.

Background: Nodulocystic acne is a severe type of acne that is known to improve after treatment with isotretinoin. Melnik has hypothesized a unifying concept on the mechanism of acne pathogenesis involving altered expression of Forkhead box O transcription factor (FoxO1) and role of isotretinoin in improving acne via modulating this pathway. Aim: To evaluate the pathway proposed by Melnik in acne pathogenesis by analysing the difference in the expression of FoxO1, peroxisome proliferator-activated receptor (PPARγ), and androgen receptor (AR) between acne patients and non-acne controls and the effect of treatment with isotretinoin on change in expression of these genes in acne patients. Results: The gene expression of FoxO1 was non significantly higher in acne patients as compared to controls. After treatment with isotretinoin, a significant decrease in FoxO1 expression in acne patients at mRNA (P = 0.05) level was observed. There was a significant decrease in grade 3 positivity of FoxO1 at protein level (P = 0.0009). A decrease in androgen receptor positivity (P = 0.055) at protein level was also observed. Conclusion: Reduction in FoxO1 expression appears to be an important mechanism of action of isotretinoin in acne.

Abstract Background Cancer progression can be promoted by chronic inflammation. Local immune response may be associated with favourable or unfavourable prognosis of Papillary Thyroid Carcinoma (PTC). Regulatory T (Treg) cells and T helper 17 (Th17) cells exert opposing function and their balance may have a vital role in promotion of tumor growth. Treg cells in tumor microenvironment (TME) may promote tumor progression and reduced survival of patients. Whereas, Th17 cells can promote or inhibit tumor progression depending on phenotypic characteristics of tumor. In this study, we aimed to analyse the kind of immune response developed and its prognostic impact in future therapeutics. Methods Cytometric Bead Array (CBA) analysis of pro and anti-inflammatory cytokines (IFN-gamma, IL-2, IL-6, IL-17 A, TNF-alpha and IL-4, IL-10) was done in 15 PTC irrespective of Lymphocytic Thyroiditis (LT) and 16 Hashimoto’s Thyroiditis (HT) cases. Immunohistochemical expression of FoxP3 and IL-17 A was studied in 27 cases of PTC with LT. Whereas, quantitative gene expression of both was analysed in 10 cases. Results All the pro-inflammatory cytokines showed mild elevation in PTC with LT. On IHC, IL-17 A expression was observed in 74% PTC with LT. Whereas, FoxP3 was present in only 40% cases. Also, IL-17 A expression was significantly associated with age group (> 45 years), tumor size ≤ 1 cm and disease progression. Conclusions Increased expression of cytokines suggested correlation between inflammatory factors and progression of thyroid tumors. Along with this, the balance between IL-17 A and FoxP3 may play an important role in PTC development, prognosis and future management.

Osteosarcoma is an intramedullary high-grade osteoid-producing sarcoma. It has a preference for sites of the most proliferative growth plates.1 They occur in the metaphysis of long bones, commonly with direct extension into the adjacent epiphysis and diaphysis. It has a bimodal presentation, with most cases between the ages of 14 and 18 years and a second smaller peak in older adults.2 The gross cut surface depends on the type and degree of mineralization of the predominant matrix, which may be dense, solid, tan-white, resembling cortical bone or grey, rubbery or mucoid in the case of cartilaginous component.3 Histomorphological diagnosis of osteosarcoma warrants the demonstration of neoplastic bone formation, which may be in any amount to render the diagnosis. Characteristically, fine or coarse lace-like patterns or broad, large sheets of compact bone formed by coalescing trabeculae are noted. The tumor grows in a permeative pattern, replacing the marrow spaces, encasing and eroding the bony trabeculae. The tumor cells generally show marked pleomorphism with abundant mitosis. Based on the predominant matrix, osteosarcomas are subdivided into osteoblastic (76-80%), chondroblastic (10-13%), and fibroblastic (10%) types. In chondroblastic osteosarcoma, the predominant component is hyaline cartilage with severe cytological atypia. The neoplastic cartilage merges with malignant osteoid and shows condensation and spindling of tumor cells at the periphery of these chondroid nodules.3,4 This feature is beneficial in small biopsy diagnosis, where it needs to be differentiated from chondrosarcoma. The staging is based on the greatest tumor dimension (≤ 8 cm: T1; > 8 cm: T2) and discontinuous involvement of the primary bone site (T3). Pulmonary, followed by skeletal metastasis, are the most frequent sites of systemic disease.3 High-grade osteosarcoma is, therefore, usually treated with preoperative and postoperative chemotherapy, and local control is achieved via surgical resection with wide margins using limb-salvage techniques. Radiation can be used for unresectable tumors.5 The histological response to neoadjuvant chemotherapy remains one of the most important prognosticators of overall and disease-free survival, with ≥ 90% necrosis defined as a good response.6 Figure 1 describes a 15-year-old female with rapidly increasing swelling and pain in her left leg. On examination, there was local tenderness and erythema. Computed tomography showed a destructive lytic lesion involving the diaphysis and epiphysis of the lower femoral end with a periosteal reaction. There was soft tissue extension as well, and the patient was given the diagnosis of osteosarcoma. He underwent chemotherapy with poor response to treatment and was referred to our tertiary care center for limb salvage surgery. The excised specimen of the left femur showed an expanded distal condylar end. On bivalving, a grey-white hard tumor measuring 17.5×11.5×8.8cm was seen with variegated areas of hemorrhage, myxoid change, and calcification (Figure 1A). The tumor was seen extending into the medullary cavity up to the neck. The cortex was breached with periosteal reaction and surrounding soft tissue extension. The articular, soft tissue, muscular, and neurovascular margins were tumor-free. On microscopy, there was sheeting, the lobular and fascicular pattern of cellular tumor infiltrating into the bone and soft tissue (Figure 1B). The tumor cells showed moderate to marked pleomorphism with vesicular nuclei, conspicuous nucleoli, and a moderate amount of cytoplasm. Intervening the tumor cells, a significant amount of lacy-like osteoid material deposition was present. Frequent mitosis was seen; however, no necrosis was identified (Figure 1C). There were nests and lobules of cartilage with increased cellularity and a marked degree of nuclear atypia along with osteoid matrix material (Figure 1D). All the resection margins were not involved in the tumor. Based on clinical, radiological, and histopathological findings, the diagnosis of chondroblastic osteosarcoma [pT2; American Joint Committee on Cancer (AJCC) staging manual; 8th edition] was rendered. Figure 1A – Gross view of the resected femur showing a grey-white infiltrative tumor involving the lower end of the femur, causing periosteal elevation and intramedullary extension. The mucoid to homogenous white areas represent the cartilaginous islands with intervening calcification (scale bar = 12cm); B – Photomicrograph showing permeative cellular tumor (right) condensing at cartilaginous islands (left) (H&E; x100); C – Pleomorphic tumor cells with brisk mitosis (H&E; x200); D – Malignant lacy osteoid permeating the markedly atypical cartilaginous cells (H&E; x200).

IntroductionMedullary thyroid carcinoma (MTC) is a rare thyroid malignancy originating from parafollicular C cells. It accounts for 5%–10% of all thyroid malignancies.MethodsAn ambispective analysis of pathologically proven MTC presented in a tertiary care hospital in northwest India was performed after considering demography, clinical manifestation, RET mutation status, management, and outcome as denominators.ResultsAmong 2,735 thyroid malignancy cases who presented to our institute in the last 10 years (2012–2022), 78 (3%) had MTC with a mean age of presentation of 43 ± 11 years; 60% of them were female. The median duration of symptoms was 23 months (IQR 12–36 months). The most common presenting complaint was goiter with lymphadenopathy (80.8%). Among the atypical presentations, one each had ectopic Cushing’s syndrome, hypertensive crisis in pregnancy due to pheochromocytoma, synchronous chondrosarcoma, and Von Hippel–Lindau disease spectrum. Median calcitonin and carcinoembryonic antigen (CEA) levels at presentation were 1,274 pg/mL (n = 64) and 149 ng/mL (n = 39), respectively. Twenty-two patients were germline RET mutation-positive, and they presented at a younger age. Majority of the patients presented with stage IV disease. Surgery was the primary modality of therapy. Twenty-nine patients received radiotherapy and 25 patients received tyrosine kinase inhibitors (TKIs). Nine patients received peptide receptor radiotherapy (PRRT) with Lu-177 with neoadjuvant capecitabine. Median progression-free survival (PFS) was 60 months. Patients without structurally and biochemically residual disease and stable disease after the first modality of therapy (Log-rank 11.4; p = 0.004) had a better PFS. Female patients (Log-rank: 9.5; p = 0.002) had a better PFS than male patients.ConclusionThis study showed that MTC comprises 3% of thyroid malignancies with a female preponderance. RET mutation-positive patients had a younger age at presentation. Surgery was the first-line therapy. Radiotherapy, TKI, and PRRT were given as a part of second-line or third-line therapy due to persistent disease and/or disease recurrence. The median PFS was better in female patients and in patients who had no residual lesions and stable disease after the primary modality of therapy.

Inclusion body fibromatosis is a benign, often locally recurring myofibroblastic tumor with distinctive intracytoplasmic eosinophilic inclusions. In 1965, Reye1 was the first to document this entity through a series of 6 cases of digital fibrous tumors of childhood, where he observed intracytoplasmic inclusion bodies. This entity was later termed Reye’s tumor.2 As per the recent 2020 World Health Organization (WHO) classification, the other accepted terminologies include infantile digital fibroma/fibromatosis, recurring digital fibrous tumor(s) of childhood, and recurring digital fibroma(s) of childhood/infancy, where the etiology and pathogenesis remain unclear.3 It is a rare and slow-growing tumor that usually affects infants and children (mostly in less than 5 years) with equal gender distribution.4 These lesions most commonly affect the lateral and dorsal aspects of the last four digits, sparing the thumb, hand, or foot. Rarely, extremities, tongue, and breast act as the primary extradigital site. Grossly, the lesion appeared firm to rubbery and polypoidal dermal nodule with intact overlying stretched-out skin surface. Microscopically, the tumor cells contain characteristic intracytoplasmic 1.5 to 24 μm, rounded, pale pink round bodies located mainly in para nuclear location, highlighted better on Masson Trichrome (red color), phosphotungstic acid-hematoxylin (dark purple color), and Movat (pink color) stains. Ultrastructurally, the inclusions correspond to localized collections of non-membrane-bound, granular fibrillary material contiguous with the rough endoplasmic reticulum. These inclusions show strong immunoreactivity with actin and anti-calponin-1 antibody (inclusion containing calponin 1 as its possible content) but an occasional weak expression for caldesmon (the reason is still unknown). The recurrence rate is common with incomplete excision.5 Figure 1 refers to a 2-year-old female child presented with nodular swelling over the dorsal aspect of the proximal phalanx of the right second toe (Figure 1A). The swelling appeared firm, slightly mobile, and non-tender, with a history of gradual increase in size since birth. The overlying skin was erythematous and stretched out. The mass was seen in close approximation with the nail bed. The respective interphalangeal and metatarsophalangeal joints were mobile. The plastic surgeons kept the possibility of fibromatosis and performed a Ray amputation of the right second toe. The specimen was submitted for histopathological examination. Figure 1Inclusion body fibromatosis. A - a nodular swelling over the dorsal aspect of the proximal phalanx of the right second toe measuring 1.6x1.4cm in size (scale bar = 1 cm). The overlying skin was intact, erythematous, and stretched out; B - the spindle-shaped uniform tumor cells show many intracytoplasmic and para-nuclear eosinophilic bodies causing nuclear indentation of one of the poles at places- black arrows (H&E; x200); C - Masson Trichrome stain highlights these inclusions as red-coloured – black arrows (x200); D - ultrastructurally, the tumor cell within the cytoplasm shows a round, dense body (size: 3.12 µm) located in the para-nuclear region with corresponding nuclear indentation.: The specimen grossly included a dislocated right second toe comprising proximal, middle, and distal phalanges, measuring 5.5cm in length and 1cm in width. In close proximity to the nail bed, the dorsal aspect showed a nodular mass measuring 1.6x1.3x0.4cm. The cut surface revealed a relatively well-demarcated lesion that was firm, homogenous, and white. The lesion was not reaching the underlying bone and also the surgical margins. Microscopically, the dermis showed a relatively well-circumscribed tumor with hyperkeratosis, parakeratosis, and flattened rete ridges of the overlying epidermis. The tumor was composed of spindle-shaped cells arranged in intersecting short fascicles and, at places, in whorls. These cells are benign and uniform and contain elongated nuclei, bland chromatin, inconspicuous nucleoli, and pale eosinophilic cytoplasm with indistinct cell membrane. Mitotic activity is infrequent (less than 1/10hpf) with no significant nuclear atypia or necrosis. In addition, many intracytoplasmic and para-nuclear eosinophilic bodies causing nuclear indentation of one of the poles at places were noted (Figure 1B). These inclusions appeared red-colored on the Masson Trichrome stain (Figure 1C), magenta-colored on the Periodic Acid-Schiff stain, and showed weak-to-moderate immunoreactivity for calponin immunostain. The surgical margins and the underlying bone were not involved in the tumor. Taking into account the clinical findings and histopathological aspects, a diagnosis of inclusion body fibromatosis was given. Subsequently, tissue was retrieved from a representative formalin-fixed, paraffin-embedded block and subjected to transmission electron microscopy. Ultrastructurally, the tumor cells showed round, dense bodies of varying sizes (2.97 µm to 4.32 µm) located in the para-nuclear region within the cytoplasm with corresponding nuclear indentation (Figure 1D). The tumor cells also contained bundles of myofilaments. Thus, the characteristic ultrastructural features further confirmed the diagnosis. Postoperatively, the patient was kept on close observation with no adjuvant therapy. At 4 months follow-up, no local recurrence was evident.

Objective: To derive a clinical score from parameters that favor remission of Cushing's disease (CD) after pituitary surgery. Methods: This is an analysis of 11 clinical, hormonal, and post-operative parameters that each favored remission in a cohort of 145 patients with CD treated by trans-sphenoidal surgery (TSS). Each parameter was designated as a categorical variable (presence/absence), and several favorable parameters present for each patient were calculated. From this, a median parameter score (clinical score) of the entire cohort was derived, which was then compared to the event of remission/persistence of CD. Results: The median number of favorable parameters present in the entire cohort was 3 (0–7). The significant count of patients in remission increased with the increasing number of parameters. The receiver-operator characteristic curve showed that the presence of ≥3 parameters was associated with remission in CD with a sensitivity of 84.2% and a specificity of 80%. Patients with a clinical score ≥3 had significantly higher remission rates (88.9%) than those who had persistent disease (27.3%; P = 0.001).Conclusion: A clinical score of ≥3 predicts remission in CD treated by TSS; however, it requires validation in other large cohorts. Rather than assessing individual parameters to predict remission in CD, an integrated clinical score is a better tool for follow-up and patient counseling.

Chronic rheumatic heart disease (RHD) is the most troublesome complication of rheumatic fever. Extensive valvular scarring and ventricular remodeling due to pressure and volume overload occur in chronic RHD. Deformed valves are at potential risk for developing infective endocarditis (IE) with further systemic embolism. We hereby describe a case of a patient diagnosed with chronic rheumatic heart disease and severe ventricular dysfunction, planned for aortic valve replacement. The patient developed septic shock during a hospital stay. The autopsy revealed infective endocarditis in the aortic valve with septic thromboembolism in the peripheral branches of the coronary artery and early multifocal myocardial infarction changes.

BackgroundLymphocytic thyroiditis (LT) is frequently seen in the tumor microenvironment (TME) of papillary thyroid carcinomas (PTCs). However, the characteristic of these tumor-infiltrating lymphocytes (TILs) is not well understood.ObjectiveWe aim to define the TME of PTC cases by characterizing the TILs.DesignThis is a cross-sectional observational study.PatientsWe enrolled 29 PTC (23 having concurrent LT), 14 LT, and 13 hyperplastic nodules with LT (HN) patients from January 2016 to December 2020.MeasurementsImmunohistochemical (IHC) expression of CD8, FoxP3, PD-1, and PD-L1 was studied in PTC with LT and compared with HN. PD-1 and PD-L1 expression was correlated at the mRNA level by quantitative real-time PCR. Immunophenotyping of TILs was done in FNAC samples of PTC and LT by flow cytometry.ResultsIHC revealed the presence of CD8+ cytotoxic T lymphocytes (CTLs) and FoxP3+ T regulatory cells (Tregs) in 83% and 52% of PTC with LT cases, respectively. Flow cytometric analysis of the PTC samples revealed a significant abundance of CTL compared with Treg and a higher CTL with lower Treg counts compared with LT. On IHC, PD-1 positivity was noted in 56.5% of PTC with LT cases, while intermediate PD-L1 positivity was found in 70% of the cases. There was a significant upregulation of PD-1 mRNA in PTC with LT. A significant correlation was noted with PD-L1 expression with lymph node metastasis and presence of Treg cells.ConclusionsIncreased expression of PD-1 and PD-L1 in the TME of PTC may provide a potential molecular mechanism for tumor survival despite the predominance of CTLs, possibly through their inactivation or exhaustion.

Cardiac lipoma is a rare tumor and usually presents as lipomatous hypertrophy of the septum. Cardiac mass in the RV usually occurs due to thrombus from venous thromboembolism or cardiac tumor or vegetation. We present a case of cardiac lipoma in an elderly female who presented with dyspnea on exertion and aspergilloma in the lung, with echocardiogram revealing a cardiac mass. Endomyocardial biopsy identified the mass as lipoma. Multimodality approach may help in identifying the correct diagnosis in case of cardiac tumors. Cardiac tumors should be kept as a differential diagnosis in an undiagnosed right ventricular mass not responding to anticoagulation.

Background/Objectives: Only anecdotal case reports or small case series have attempted to study the histomorphology patterns of leukemic infiltration. This study explored the possible association of leukemia cutis with, temporal course of disease, subtypes of leukemia, blast count, total leukocyte count, lactate dehydrogenase (LDH) levels, and histopathological patterns. Materials and Methods: Clinical and laboratory data were retrieved from the hospital information system. Selected cases were reviewed by two pathologists. Data in terms of demographics, clinical presentation, bone marrow findings, immunophenotype, and temporal course were recorded where available. Results: Twenty-three diagnosed cases of leukemia cutis were reported during the study period. There was no gender predilection with a wide age range (8–82 years). No particular trend was noted in relation to total leukocyte or bone marrow blast count. Common skin manifestations included multiple erythematous papular eruptions, frequently involving the skin of the limbs. All cases showed a consistently high serum LDH level. 11/23 (48%) showed cutaneous manifestation of undiagnosed leukemia or indicated worsening in a diagnosed case. The histological patterns varied from perivascular to diffuse dermal interstitial infiltration. In addition, subtle changes were seen in the form of fibrosis, thrombosis, and epidermotropism in 12%–50% of cases. The judicious use of a panel of immunohistochemistry was vital to establish a diagnosis. Conclusions: Leukemia cutis is a diagnostic challenge on histopathology due to lack of any specific pattern in absence of a clinical suspicion. Its diagnosis may be an indicator of undiagnosed leukemia or worsening in an already known case of leukemia.

Background: Psoriasis is a chronic remitting and relapsing inflammatory disease, with a prevalence of 0.44%–2.5% and is characterized by T-cell-mediated rapid turnover of epithelial cells. Claudin-1 protein is an integral part of the keratinocyte tight junction and has a role in proliferation, differentiation, and cell adhesion. Aim: The aim of the study was to investigate the role of claudin-1 expression in relation to keratinocyte proliferation in psoriasis. Materials and Methods: Fifty cases of psoriasis were included in the study. Skin biopsies were subjected to claudin-1 and Ki67 immunohistochemistry. Claudin-1 expression in the basal and spinous layers was scored. Ki67 proliferation index was assessed. Seven cases of normal skin biopsies were also included as controls. Fisher's exact test was applied for statistical analysis. Results: The cases had a wide age range (14–78 years), with a mean of 46 years with a male preponderance (4:1). The basal cell layer showed a complete loss of expression for claudin-1 in 82% (n = 42). The spinous layer showed a decrescendo pattern of loss of claudin-1 expression in 96% (n = 48). The association of loss of expression of claudin-1 between the basal layer and spinous layer was statistically significant (P = 0.0229). The association of loss of expression of claudin-1 and high Ki67 proliferative index was also statistically significant (P < 0.00001). Conclusion: Our study showed consistent loss of expression of claudin-1 in the lower layers of the epidermis in psoriasis, which is also the site of intense proliferative activity. The cytokine soup released by the T-cells may be responsible for downregulation of claudin-1, which is one of the triggers for proliferation.

Papillary thyroid carcinoma with desmoid-type fibromatosis (PTC-DTF) or nodular fasciitis-like stroma (PTC-NFS) is a rare morphological variant of PTC with a favorable prognosis. There is a paucity of molecular data regarding this entity. We present the case of a 20-year-old female who presented with a palpable mass over the anterior aspect of the neck for the past 3–4 months, which was diagnosed as PTC-NFS. Ultrasonogram of the neck revealed a bulky left lobe of thyroid that contained a well-defined heterogenous lesion measuring around 24 × 26 × 36 mm with involvement of the adjacent isthmus. She underwent a total thyroidectomy with central compartment lymph node dissection. Histological examination revealed a biphasic tumor with epithelial and stromal components resembling nodular fasciitis. Two dissected lymph nodes showed metastasis of the epithelial component only. On immunohistochemistry, BRAF mutant protein expression was evident in the epithelial component only, while β-catenin was negative in both the components. The histopathological diagnosis of papillary thyroid carcinoma with nodular fasciitis-like stroma was offered. Sanger sequencing revealed a BRAFV600E (c.1799T>A, Val600Glu) mutation. Post-operatively, no residual tumor was detected on ultrasound and radioiodine scans. The patient was doing well at follow-up of 9 months. PTC-NFS/DTF is a histological variant of PTC with a favorable prognosis. Our index case was associated with the BRAF mutation, which was restricted to the epithelial component. Thorough sampling of the excised specimen is essential in order not to miss the epithelial component, which, in most reported cases (including ours) appears to be small.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by recalcitrant hypophosphatemia. Reports from the Indian subcontinent are scarce, with most being single center experiences involving few patients. Herein, we conducted a retrospective analysis of 30 patients of TIO diagnosed at three tertiary care hospitals in India. Patients with persistent hypophosphatemia (despite correction of hypovitaminosis D), normocalcemia, elevated alkaline phosphatase, low TmP/GFR and elevated or ‘inappropriately normal’ FGF23 levels were labeled as having TIO. They were sequentially subjected to functional followed by anatomical imaging. Patients with a well-localized tumor underwent excision; others were put on phosphorous and calcitriol supplementation. The mean age at presentation was 39.6 years with female:male ratio of 3:2. Bone pain (83.3%) and proximal myopathy (70%) were the chief complaints; 40% of cases had fractures. The mean delay in diagnosis was 3.8 years. Tumors were clinically detectable in four patients (13.3%). The mean serum phosphate was 0.50 mmol/L with a median serum FGF23 level of 518 RU/mL. Somatostatin receptor-based scintigraphy was found to be superior to FDG-PET in tumor localization. Lower extremities were the most common site of the tumor (72%). Tumor size was positively correlated with serum FGF23 levels. Twenty-two patients underwent tumor resection and 16 of them had phosphaturic mesenchymal tumors. Surgical excision led to cure in 72.7% of patients whereas disease persistence and disease recurrence were seen in 18.2% and 9.1% of cases, respectively. At the last follow-up, serum phosphate in the surgically treated group was significantly higher than in the medically managed group.

Cutaneous lymphoid infiltration is common histology seen in the day-to-day practice of dermatopathology. The reasons for this infiltration can range from a spontaneously remitting pseudolymphoma such as Jessner's infiltration to a sinister and aggressive cytotoxic T-cell lymphoma. Before analyzing the slide, the clinical perspective needs to be borne in mind as a diagnosis can never be made in isolation, especially in dermatopathology. In this article, we discuss in brief the various common cutaneous lymphoid infiltrative entities encountered in routine practice, discuss the differentiating features, and suggest an algorithmic approach to arrive at the possible diagnosis.

Rheumatic heart disease (RHD) is a major cause of cardiovascular morbidity and mortality in developing nations like India. RHD commonly affects the mitral valve which is lined by a single layer of endothelial cells (ECs). The role of ECs in mitral valve damage during RHD is not well elucidated. In here, anti-endothelial cell antibody from RHD patients has been used to stimulate the ECs (HUVECs and HMVECs). ECs proinflammatory phenotype with increased expression of TNFα, IL-6, IL-8, IFNγ, IL-1β, ICAM1, VCAM1, E-selectin, laminin B, and vimentin was documented in both ECs. The promoter hypomethylation of various key inflammatory cytokines (TNFα, IL-6, and IL-8), integrin (ICAM1) associated with leukocyte transendothelial migration, and extracellular matrix genes (vimentin, and laminin) were also observed. Further, the in-vitro data was in accordance with ex-vivo observations which correlated significantly with the etiological factors such as smoking, socioeconomic status, and housing. Thus, the study sheds light on the role of ECs in RHD which is a step forward in the elucidation of disease pathogenesis. Keywords: Anti-Endothelial cell antibodies, DNA methylation, Endothelial cells, Inflammation, Rheumatic heart disease

Lichen planus pigmentosus (LPP) is a rare disorder affecting primarily the people with ethnic skin. It results in hyperpigmentation of sun-exposed sites along with the involvement of flexures. In accordance with clinical patterns, different variants such as diffuse, blotchy, reticulate, and perifollicular have been described. Rare variants such as flexural (inversus), mucosal, linear, and zosteriform have been reported scarcely. Inversus LPP refers to the involvement of major flexures such as inframammary area, axillae, and groins in the absence of involvement of photo-exposed sites. We present an unusual case presenting with coexisting linear and inversus variants of LPP.

Abstract Cyclin D1, a G1-S phase regulator, is upregulated in parathyroid adenomas. Since cyclin-dependent kinase (CDK) inhibitors, CDKN2A and CDKN2B, and RASSF1A (Ras-association domain family 1, isoform A) are involved in G1-S phase arrest and act as potential tumor suppressor genes, we aimed to study potential methylation-mediated inactivation of these genes in parathyroid adenomas. Gene expressions of cyclin D1 (CCND1) and regulatory molecules (CDKN2A, CDKN2B and RASSF1A) was analysed in parathyroid adenoma tissues (n = 30). DNA promoter methylation of cyclin D1 regulators were assessed and correlated with clinicopathological features of the patients. Gene expression analysis showed a relative fold reductions of 0.35 for CDKN2A (p = 0.01), 0.45 for CDKN2B (P = 0.02), and 0.39 for RASSF1A (p

Congenital nevi and fibrolipomatous hamartoma are benign tumors of childhood, the latter being very uncommon. Fibrous hamartoma of infancy typically occurs in

Panniculitis is the inflammation of subcutaneous fat. It poses a diagnostic challenge, both for the clinician as well as the histopathologist owing to its diverse etiologies, overlapping morphological features, and dynamic nature of the lesions. The standard protocol for histopathologic diagnosis is to examine deep skin biopsies after staining with hematoxylin and eosin. Sometimes, however, special stains are also needed to rule out varied etiologies. A thorough histopathologic examination in conjunction with appropriate clinical details is the key to identify different subtypes of panniculitis. In this review, we discuss the classification of panniculitis with salient histopathologic features of the subtypes in each category. We also present a diagnostic algorithm for arriving at a definitive histopathologic diagnosis of different panniculitis subtypes.

Background: Intraocular tuberculosis (IOTB), an extrapulmonary manifestation of tuberculosis of the eye, has unique and varied clinical presentations with poorly understood pathogenesis. As it is a significant cause of inflammation and visual morbidity, particularly in TB endemic countries, it is essential to study the pathogenesis of IOTB. Clinical and histopathologic studies suggest the presence of Mycobacterium tuberculosis in retinal pigment epithelium (RPE) cells.Methods: A human retinal pigment epithelium (ARPE-19) cell line was infected with a virulent strain of M. tuberculosis (H37Rv). Electron microscopy and colony forming units (CFU) assay were performed to monitor the M. tuberculosis adherence, invasion, and intracellular replication, whereas confocal microscopy was done to study its intracellular fate in the RPE cells. To understand the pathogenesis, the transcriptional profile of M. tuberculosis in ARPE-19 cells was studied by whole genome microarray. Three upregulated M. tuberculosis transcripts were also examined in human IOTB vitreous samples.Results: Scanning electron micrographs of the infected ARPE-19 cells indicated adherence of bacilli, which were further observed to be internalized as monitored by transmission electron microscopy. The CFU assay showed that 22.7 and 8.4% of the initial inoculum of bacilli adhered and invaded the ARPE-19 cells, respectively, with an increase in fold CFU from 1 dpi (0.84) to 5dpi (6.58). The intracellular bacilli were co-localized with lysosomal-associated membrane protein-1 (LAMP-1) and LAMP-2 in ARPE-19 cells. The transcriptome study of intracellular bacilli showed that most of the upregulated transcripts correspond to the genes encoding the proteins involved in the processes such as adherence (e.g., Rv1759c and Rv1026), invasion (e.g., Rv1971 and Rv0169), virulence (e.g., Rv2844 and Rv0775), and intracellular survival (e.g., Rv1884c and Rv2450c) as well as regulators of various metabolic pathways. Two of the upregulated transcripts (Rv1971, Rv1230c) were also present in the vitreous samples of the IOTB patients.Conclusions:M. tuberculosis is phagocytosed by RPE cells and utilizes these cells for intracellular multiplication with the involvement of late endosomal/lysosomal compartments and alters its transcriptional profile plausibly for its intracellular adaptation and survival. The findings of the present study could be important to understanding the molecular pathogenesis of IOTB with a potential role in the development of diagnostics and therapeutics for IOTB.

ABSTRACT: Objective: Present a case of an atypical parathyroid adenoma in the mediastinum as a part of multiple endocrine neoplasia type 1 (MEN1).Methods: Clinical, laboratory, imaging, and histolopathogic analyses were performed.Results: A 50-year-old man who was diagnosed with chronic kidney disease secondary to bilateral nephrolithiasis was referred for evaluation of incidentally detected hypercalcemia. He had an acromegaloid facies and lipomas over the forehead. Laboratory evaluation revealed hypercalcemia (3.33 mmol/L), hyperphosphatemia, and elevated intact parathyroid hormone level (215 pmol/L). Serum insulin-like growth factor 1 was elevated and growth hormone was non-suppressible on oral glucose load. Contrast-enhanced magnetic resonance imaging of the sella showed a pituitary microadenoma. A scan using 99mTc-Sestamibi and combined positron emission and computed tomography using fluorocholine F-18 revealed a mediastinal ectopic parathyroid adenoma, thereby attributing hypercalcemia to primary hyperparathyroidism. A clinical diagnosis of MEN1 was made. Genetic analysis revealed an A>T substitution at cDNA 253 in exon 2 of the MEN1 gene. He underwent median sternotomy and a 3 × 3-cm mass was excised, weighing 14 g. Histopathology showed parathyroid tissue with moderate pleomorphism, pushing margins, fibrous trabeculae, atypical mitoses, and low Ki-67 index, suggestive of atypical parathyroid neoplasm. After surgery the patient became normocalcemic. On follow-up, he is asymptomatic without any evidence of recurrence of primary hyperparathyroidism.Conclusion: Parathyroid involvement in MEN1 is almost exclusively in the form of benign hyperplasia. Atypical parathyroid adenomas and parathyroid carcinomas in MEN1 are very rare, limited to only a few anecdotal case reports to which ours contributes a new case.Abbreviations: CKD = chronic kidney disease;iPTH = intact parathyroid hormone;MEN1 = multiple endocrine neoplasia type 1

Background and aimHyperglycemia-mediated oxidative stress impedes cell-reparative process like autophagy, which has been implicated in impairment of β-cell function in type 2 diabetes mellitus (T2DM). However, the role of mitophagy (selective mitochondrial autophagy) in progression of hyperglycemia remains elusive. This study aimed to assess the impact of increasing severity of hyperglycemia on mitochondrial stress and mitophagy.Design and methodsA case–control study included healthy controls, subjects with prediabetes, newly diagnosed T2DM (NDT2DM) and advanced duration of T2DM (ADT2DM) (n = 20 each). Mitochondrial stress indices, transcriptional and translational expression of mitophagy markers (PINK1, PARKIN, MFN2, NIX, LC3-II, and LAMP-2) and transmission electron microscopic (TEM) studies were performed in peripheral blood mononuclear cells.ResultsWith mild hyperglycemia in subjects with prediabetes, to moderate to severe hyperglycemia in NDT2DM and ADT2DM, a progressive rise in mitochondrial oxidative stress was observed. Prediabetic subjects exhibited significantly increased expression of mitophagy-related markers and showed a positive association with HOMA-β, whereas, patients with NDT2DM and ADT2DM demonstrated decreased expression, with a greater decline in ADT2DM subjects. TEM studies revealed significantly reduced number of distorted mitochondria in prediabetics, as compared to the T2DM patients. In addition, receiver operating characteristic analysis showed HbA1C > 7% (53 mmol/mol) was associated with attenuated mitophagy.ConclusionIncreasing hyperglycemia is associated with progressive rise in oxidative stress and altered mitochondrial morphology. Sustenance of mitophagy at HbA1C

The direct immunofluorescence (DIF) of skin in conjunction with histopathology gives the best diagnostic yield. It is invaluable in confirming the diagnosis of small vessel vasculitides and bullous lesions of the skin and can be used as an additional tool to pinpoint the diagnosis of systemic and localized autoimmune diseases involving the skin. This study was undertaken to analyze the strength of DIF vis-à -vis histopathology in the diagnosis of discoid lupus erythematosus (DLE) and at the same time to elaborate the specific immunofluorescence findings in the lesions of DLE. The clinical profile and cutaneous lesions of 75 patients with DLE are described. DIF was positive in 68% and histopathology in 60% of cases. The most common immunoreactant was IgG at the dermoepidermal junction, followed by IgM and IgA. A conclusive diagnosis of DLE could be achieved satisfactorily in 64 cases (85%) by a combination of the two techniques.

Background: Cardiomyopathies are a heterogeneous group of diseases of the myocardium associated with varied pathology. Pathology data from India are scarce. Methods: A retrospective, descriptive study of autopsies, as well as endomyocardial biopsy specimens, was done of patients with cardiomyopathy. The clinical and pathological features are described. Results: There were 32 patients with dilated cardiomyopathy. Two were pediatric, and two had arrhythmogenic right ventricular cardiomyopathy. Myocarditis was seen in 12 cases. In our endomyocardial biopsy data of 32 patients with restrictive cardiomyopathy (RCM), we found amyloid in 13 and idiopathic RCM in the remainder. Our genetic studies in cardiomyopathies suggest that the same genetic mutation may lead to different phenotypic manifestations with restrictive or hypertrophic cardiomyopathies in different families. Conclusions: This study gives insight into the pathology and etiology of some of the cardiomyopathies seen in India. They differ from the west, and now with the availability of genotyping and magnetic resonance imaging, more data should soon be available from more centers.

"Wolf′s isotopic response" refers to the occurrence of a new dermatosis at the site of previously healed dermatosis. A number of factors including viral, neural, vascular, and immunologic factors have been implicated in the causation of this peculiar response but none has been proven conclusively. Here, we report a case where lichen planus developed at the site of dermatofibrosarcoma protruberans that had been previously treated with surgery and radiotherapy. We also put forth a hypothesis on the genesis of isotopic response considering the above mentioned factors.

Nonmelanoma skin cancers (NMSCs), which mainly include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), are infrequent in the Indian subcontinent, compared with white skinned individuals. Although BCC in most cases arises de novo on sun-exposed sites, it may rarely develop in photoprotected areas and in the setting of certain risk factors. In contrast to BCC, SCC in dark skin has a tendency to develop in nonhealing ulcers, chronic scars, and inflammatory and infectious dermatoses. Histopathology is the gold standard in confirming the diagnosis and determining the prognosis. As the existing literature on NMSCs in India is limited mostly to case reports and few reviews only, this article is an attempt to create an awareness regarding the premalignant potential of an expanding list of cutaneous lesions, which would help in timely diagnosis and prompt treatment of NMSCs.

Hypercalcemic states may result in acute pancreatitis. Sarcoidosis has been rarely reported as a cause of acute pancreatitis. A 42-year-old female came with abdominal pain and was found to have acute pancreatitis. Evaluation revealed hypercalcemia and evidence of pulmonary infiltrates and mediastinal lymphadenopathy. Transbronchial lung biopsy revealed noncaseating granulomas consistent with sarcoidosis. In conclusion, sarcoidosis may result in acute pancreatitis by causing hypercalcemia.

Endometriosis is a common benign disease of reproductive age women, and can involve the intestinal tract. Inconsistent clinical presentation, similar features on radiological imaging and colonoscopy with other inflammatory and malignant lesions of the bowel makes the preoperative diagnosis of bowel endometriosis difficult. We present a case of a 42-year-old perimenopausal female clinically presented, investigated and managed in the lines of carcinoma of sigmoid colon. She underwent terminal ileac resection with end to end anastomoses, Hartmann′s procedure and total hysterectomy with bilateral salpingoophorectomy. The histopathological report revealed endometriosis of small intestine, large intestine, mesentery, right ovary and adenomyoma of uterus. Thus, bowel endometriosis should also be considered as differential diagnosis in reproductive age women with gastrointestinal symptoms or intestinal mass of uncertain diagnosis.

Adrenocortical oncocytomas are extremely rare, and most of the tumors are benign and nonfunctioning. To our knowledge, only 30 cases have been reported in English published studies, and most patients are 40 to 60 years of age. So far, in the pediatric age group, only three cases of functioning adrenocortical oncocytoma have been reported. We report a case of functioning adrenocortical oncocytoma in a 3 1/2-year-old female child who presented with premature pubarche, clitoromegaly, and increased serum dehydroepiandrosterone sulfate and testosterone. She was managed successfully with right adrenalectomy, and the tumor histology was consistent with adrenal oncocytoma.

Primary hepatic anaplastic large cell lymphoma (ALCL) of the liver is a rare entity. We present here two cases of primary hepatic anaplastic large cell lymphoma (ALCL) of the null-cell type. Both the cases had jaundice with “B” symptoms and hepatomegaly. The serum billirubin and liver enzymes were raised in both cases. The liver showed sinusoidal infiltration by atypical lymphoid cells with marked nuclear pleomorphism, dispersed chromatin and prominent nucleoli in both the cases. These cells were positive for CD30, negative for CD3, CD20 and EMA, and diagnosed as ALCL of the null-cell type. We hereby report these cases with the review of literature on primary hepatic ALCL with their possible etio-pathogenesis & diagnostic clues which may help in timely diagnosis & management in such cases.

Context: There is limited information on respiratory muscle functions in patients with primary hyperparathyroidism (PHPT). AIM: To assess respiratory muscle dysfunction in patients with PHPT. Setting and Design: This prospective study was carried between January 2005 and December 2006 by the Department of Endocrinology at the Postgraduate Institute of Medical Education and Research, Chandigarh. Materials and Methods: PHPT was defined as elevated parathyroid hormone in the presence of hypercalcemia. Spirometry was performed using a dry rolling seal spirometer and spirometric indices like forced vital capacity (FVC), forced expiratory volume in first second (FEV 1 ), and FEV 1 /FVC ratio were measured using standard guidelines. Results: Thirty patients were studied with a mean age of 37.1 ± 2.4 years and 18 were women. The most common presenting symptoms were fatigue (75.0%) and bone pain (60.70%). The mean (±SD) of percentage predicted FVE 1 , FVC, FEV 1 /FVC ratio, PEF, and FEF were 98.7 ± 16.1, 93.9 ± 14.7, 84.5 ± 3.4, 89.3 ± 22.5, and 99.7 ± 33.6, respectively. Two had obstructive lung disease and two had restrictive lung disease. We did not find correlation with preoperative serum calcium, phosphate, and PTH with FVE 1 , FVC, FEV 1 /FVC ratio, PEF, and FEF. Conclusion: Elevated calcium, low phosphate, and elevated PTH levels in patients with moderate to severe PHPT do not significantly affect respiratory muscle functions.

Adrenal incidentalomas of more than 4 cm size are usually malignant. We describe a 28-year-old woman with a 7-cm, non-functioning, well-demarcated adrenal mass, which was identified as an oncocytoma on histopathological examination. Therefore, a large, non-functioning, unilateral adrenal mass with preserved tumor outline should invoke the suspicion of oncocytoma, which is invariably a benign tumor.

Idiopathic restrictive cardiomyopathy (IRC) is a rare form of heart muscle disease. Genetic studies have revealed that in about half the cases, IRC forms part of the hereditary sarcomeric contractile protein disease spectrum. Mutations in several sarcomere protein encoding genes are detected in 33-66% of cases. Among these, the mutations most commonly involve TNNI3 and MYH7. There is a disproportionately high incidence of TNNI3 mutations in patients with restrictive physiology. De novo mutations are also frequently seen in this group of patients. IRC and hypertrophic cardiomyopathy (HCM) with restrictive phenotype reflect the same or very similar disorders with different names due to arbitrary cut offs in the left ventricular wall thickness rather than two separate distinct diseases. HCM with restrictive physiology should be considered part of a continuous spectrum with IRC. This is because patients with HCM with restrictive phenotype bear far greater clinical and genetic resemblance to IRC than to rest of the HCM cohort.

Leiomyosarcoma of the breast is a rare neoplasm, primarily reported in older women. Only 44 cases have been reported in world literature and to the best of our knowledge, no case has been reported from India till date. We report a case of primary breast leiomyosarcoma in an adolescent girl who underwent a lumpectomy for rapidly increasing lump in the left breast. Here we report the histological findings and immunohistochemical profile of this entity, along with a review of existing literature.