Primary Hepatic Melanoma: A Diagnostic Surprise.

Melanoma is a relatively rare malignancy with a highly aggressive biological behavior. Metastases to other sites, like lymph nodes and liver are common, but primary hepatic melanoma is a rarity with poor survival ranging from months to few years. Diagnosis of primary hepatic melanoma via clinical features and imaging technology is difficult because of its ambiguous features. Here, we present a 26-year-old North Indian woman admitted in the department of gastrointestinal surgery at our tertiary care hospital with the complaint of pain in the abdomen for a month associated with the loss of appetite and subsequent weight loss. The liver function tests were within normal limits and viral markers were negative. The triple-phase computed tomography scan of abdomen showed significant hepatomegaly and two well-defined lesions in both lobes of the liver. Histopathological evaluation was performed on the core liver biopsies submitted from the liver lesions. A malignant tumor with abundant black intracytoplasmic pigment was identified. Immunohistochemistry proved the tumor to be melanoma. The detailed clinical history, laboratory, and radiological investigations were acquired and analyzed to rule out a metastatic lesion of the same. A final diagnosis of primary hepatic melanoma was thus rendered. Primary hepatic melanoma is extremely uncommon and has been rarely reported. Preoperative diagnosis is challenging due to low index of suspicion and nonspecific clinical features. In this case report, we discuss the clinicopathological features of primary hepatic melanoma and review the literature so as to increase the awareness and improve our understanding of the disease.

Early-onset diabetes mellitus as a presenting feature of Werner's syndrome in an Indian family.

BACKGROUND: Diabetes mellitus (DM) in children and adolescents is typically caused by type 1 DM, followed by type 2 DM and maturity-onset diabetes of the young (MODY). We report an unusual Asian Indian family in which three members presented with DM at ages 15, 20, and 30, but not fitting the typical clinical picture of type 1 DM, type 2 DM, or MODY. The primary objective was to elucidate the molecular genetic basis of DM in this family. METHODS: The proband, a 22-year-old man, had short stature, gray hair, osteoporosis, and markedly reduced subcutaneous fat on the body, especially on the extremities along with acanthosis nigricans, and developed myxoid malignant peripheral nerve sheath tumor. Detailed family history revealed multiple loops of consanguinity. The proband underwent whole-genome sequencing, and seven relatives underwent whole-exome sequencing. RESULTS: The proband and three additional family members were found to have the homozygous c.561A>G nucleotide variant of WRN RecQ-like helicase (WRN) gene consistent with the diagnosis of Werner's syndrome. The c.561A>G variant induces a new splicing site on exon 6 resulting in a truncated WRN protein, p.Lys187Trpfs*13. CONCLUSION: Our report brings to attention the onset of DM during childhood or early adulthood in patients with Werner's syndrome who typically develop type 2 DM around the age of 30-40 years. Presence of consanguinity among parents, dysmorphic features, and malignancy should prompt consideration of diagnosis of Werner's syndrome.

Xanthogranulomatous cholecystitis with histologic features suggestive of IgG4 related cholecystitis - A morphologic overlap with IgG4 related disease.

AIMS: Both xanthogranulomatous cholecystitis (XGC) and IgG4-related cholecystitis (IgG4-CC) are rare chronic fibroinflammatory tumefactive diseases of the gallbladder, which cause a strong confusion with resectable malignancy in view of their mass forming tendency with extension into the liver. We aim to study the histopathologic features of xanthogranulomatous cholecystitis with regard to IgG4-related cholecystitis in extended cholecystectomy specimens. METHODS AND RESULTS: Sixty cases of extended cholecystectomy with liver wedge resection, diagnosed as XGC on histopathology from January 2018 to December 2021 were retrieved from the archives. Representative sections were reviewed by two pathologists independently. Immunohistochemistry was performed for IgG4 and IgG4/IgG was derived. The cases were dichotomized in two groups on the basis of IgG4 positive plasma cells. Six cases with >50 IgG4 positive plasma cells had storiform fibrosis, IgG4/IgG ratio >0.40 and extra-cholecystic extension. Of these, 50 % had obliterative phlebitis and 66.7 % had perineural plasma cell wrapping. CONCLUSIONS: A small subset of XGC cases (~10 %) had morphologic overlap with IgG4-CC, but should not be overcalled as the diagnosis of IgG4-RD requires an integrative approach based on clinical, serologic and imaging criteria and not solely on histopathology.

Autoantibodies to Perilipin-1 Define a Subset of Acquired Generalized Lipodystrophy.

Acquired lipodystrophy is often characterized as an idiopathic subtype of lipodystrophy. Despite suspicion of an immune-mediated pathology, biomarkers such as autoantibodies are generally lacking. Here, we used an unbiased proteome-wide screening approach to identify autoantibodies to the adipocyte-specific lipid droplet protein perilipin 1 (PLIN1) in a murine model of autoimmune polyendocrine syndrome type 1 (APS1). We then tested for PLIN1 autoantibodies in human subjects with acquired lipodystrophy with two independent severe breaks in immune tolerance (including APS1) along with control subjects using a specific radioligand binding assay and indirect immunofluorescence on fat tissue. We identified autoantibodies to PLIN1 in these two cases, including the first reported case of APS1 with acquired lipodystrophy and a second patient who acquired lipodystrophy as an immune-related adverse event following cancer immunotherapy. Lastly, we also found PLIN1 autoantibodies to be specifically enriched in a subset of patients with acquired generalized lipodystrophy (17 of 46 [37%]), particularly those with panniculitis and other features of autoimmunity. These data lend additional support to new literature that suggests that PLIN1 autoantibodies represent a marker of acquired autoimmune lipodystrophies and further link them to a break in immune tolerance.

Classification of endoscopic ultrasound guided fine needle aspiration cytology of pancreatic space occupying lesions by Papanicolaou Society of Cytopathology System: A five year study.

BACKGROUND: Majority of the pancreatic cancer patients present at an advanced stage and have poor 5 year survival rate. Thus, there is a need for early detection of pancreatic cancer with the initiation of the therapy. MATERIALS & METHODS: This is a retrospective study including all the endoscopic ultrasound guided (EUS) guided pancreatic FNAs from 2016 to 2020. The aspirate smears were analyzed and classified according to The Papanicolaou Society of Cytopathology System for Reporting Pancreaticobiliary Cytology (PSCPC). RESULTS: A total of 245 EUS guided FNAs from pancreatic lesions were included. Cyto-histological correlation was done wherever available. Category I (non diagnostic) accounted for 40 cases (16%) cases, Category II (negative) comprised of 44 cases (18%); and Category III (Atypical) had 5 cases (2%). Category IV neoplastic-benign category included 3 cases of serous cystadenoma, while neoplastic-others category included pancreatic neuroendocrine tumors (n = 21), solid pseudo-papillary neoplasms (SPEN) (n = 12) and mucinous cystic neoplasms (n = 4). A total of 7 cases (2.8%) were reported in Category V (Suspicious). A diagnosis of adenocarcinoma (Category VI) was rendered in 105 cases (42.8%) cases. Rarer types included non Hodgkins lymphoma (n = 3) and one case of primary undifferentiated carcinoma with osteoclastic giant cells. Cyto-histological correlation in all categories was available in 58 cases with 8 false negative cases. Thus overall sensitivity of EUS guided FNAC was found to be 87.8% with a diagnostic yield of 83.6% while sensitivity in diagnosing adenocarcinoma was 96.9%. CONCLUSION: The present study highlights the spectrum of EUS guided FNA of pancreatic lesions in a subset of North Indian population and classified them according to PSCPC. EUS guided FNAC is a sensitive investigation which plays a crucial role in confirming the diagnosis of pancreatic space occupying lesions (SOLs) in advanced stage.

Giant hyperplastic gastric polyp: A diagnostic dilemma!!

Gastric hyperplastic polyps (GHP) account for a majority of benign gastric polyps. Most of the GHPs are <2 cm, asymptomatic, and incidentally detected on endoscopy or radiologically. With increasing size, these polyps manifest as upper gastrointestinal bleeding, iron deficiency anemia, and gastric outlet obstruction (GOO). We report an unusual case of giant GHP simulating gastric carcinoma and posing as a diagnostic challenge for the surgeons emphasizing the diagnostic role of histopathology. A 46-year-old female presented with clinical features of progressive GOO for 1 year. Endoscopy revealed an eccentric proliferative lesion in the antrum. Computed tomography showed a polypoidal, enhancing mural thickening involving distal body and antro-pyloric region measuring 8.4 cm × 6.6 cm × 1.8 cm. Subtotal gastrectomy was done in view of clinical features of GOO and having a clinical suspicion of malignancy. Gross examination showed a giant sessile hyperplastic polyp with lobulated surface. Microscopy revealed features of a large, sessile hyperplastic polyp without any evidence of dysplasia. The patient was symptomatically relieved and is on follow-up. To conclude, giant GHPs can mimic gastric carcinoma on endoscopy and radiology. The possibility of giant GHP should be kept in mind in the presence of an intensely contrast-enhancing polypoidal lesion in the gastric antrum. Long-term endoscopic follow-up is recommended.

Discovery of MDV6058 (PF-06952229), a selective and potent TGFßR1 inhibitor: Design, synthesis and optimization.

Compound 1 is a potent TGF-ß receptor type-1 (TGFßR1 or ALK5) inhibitor but is metabolically unstable. A solvent-exposed part of this molecule was used to analogue and modulate cell activity, liver microsome stability and mouse pharmacokinetics. The evolution of SAR that led to the selection of 2 (MDV6058 / PF-06952229) as a preclinical lead compound is described.

Face-sparing Congenital Generalized Lipodystrophy Type 1 Associated With Nonclassical Congenital Adrenal Hyperplasia.

CONTEXT: Congenital generalized lipodystrophy, type 1 (CGL1), due to biallelic pathogenic variants in AGPAT2, is characterized by the near total loss of body fat from the face, trunk, and extremities. Patients develop premature diabetes, hypertriglyceridemia, hepatic steatosis, and polycystic ovary syndrome. However, sparing of the facial fat and precocious pubertal development has not been previously reported in CGL1. CASE DESCRIPTION: We report a 21-year-old woman of European descent with CGL1 who had sparing of the facial fat and premature thelarche at birth with premature pubarche and menstrual bleeding at age 3 years. Her serum 17-OH progesterone level rose to 1000 ng/dL (30.26 nmol/L) after cosyntropin stimulation test, suggestive of nonclassical congenital adrenal hyperplasia (NCAH) due to 21-hydroxylase deficiency. Hydrocortisone replacement therapy from age 3.5 to 10 years resulted in cessation of menstruation and growth of pubic hair, and a reduction of breast size. Sanger and whole-exome sequencing revealed compound heterozygous variants c.493-1G>C; p.(Leu165_Gln196del), and c.del366_588+534; p.(Leu123Cysfs*55) in AGPAT2 plus c.806G>C; p.(Ser269Thr) and c.844G>T; p.(Val282Leu) in CYP21A2. She developed diabetes at age 13 requiring high-dose insulin and had 7 episodes of acute pancreatitis due to extreme hypertriglyceridemia in the next 5 years. Metreleptin therapy was initiated at age 18 and after 3 years, she had remission of diabetes and hypertriglyceridemia; however, menstrual irregularity and severe hirsutism did not improve. CONCLUSION: Concomitant NCAH in this CGL1 patient was associated with precocious pubertal development and sparing of facial fat. Metreleptin therapy drastically improved her hyperglycemia and hyperlipidemia but not menstrual irregularity and hirsutism.

Gallbladder reporting and data system (GB-RADS) for risk stratification of gallbladder wall thickening on ultrasonography: an international expert consensus.

The Gallbladder Reporting and Data System (GB-RADS) ultrasound (US) risk stratification is proposed to improve consistency in US interpretations, reporting, and assessment of risk of malignancy in gallbladder wall thickening in non-acute setting. It was developed based on a systematic review of the literature and the consensus of an international multidisciplinary committee comprising expert radiologists, gastroenterologists, gastrointestinal surgeons, surgical oncologists, medical oncologists, and pathologists using modified Delphi method. For risk stratification, the GB-RADS system recommends six categories (GB-RADS 0-5) of gallbladder wall thickening with gradually increasing risk of malignancy. GB-RADS is based on gallbladder wall features on US including symmetry and extent (focal vs. circumferential) of involvement, layered appearance, intramural features (including intramural cysts and echogenic foci), and interface with the liver. GB-RADS represents the first collaborative effort at risk stratifying the gallbladder wall thickening. This concept is in line with the other US-based risk stratification systems which have been shown to increase the accuracy of detection of malignant lesions and improve management.

Reappraisal of the Role of Ascitic Fluid Adenosine Deaminase for the Diagnosis of Peritoneal Tuberculosis in Cirrhosis.

BACKGROUNDS/AIMS: Although peritoneal tuberculosis (TB) is one of the important differential diagnoses among cirrhotic patients with ascites, a peritoneal biopsy is not always available. High ascitic fluid adenosine deaminase (ADA) has been indicative of peritoneal TB. On the other hand, studies to assess its diagnostic utility based on the confirmation of peritoneal biopsy in cirrhotic patients are scarce. METHODS: Patients with new-onset ascites were enrolled prospectively from a tertiary hospital. Peritoneal biopsy was applied according to clinical judgment when required. Based on pathology diagnosis of the peritoneum, the diagnostic efficacy of ascitic fluid ADA for peritoneal TB was evaluated in total and cirrhotic patients, respectively. RESULTS: Among 286 patients enrolled, 78 were diagnosed with peritoneal TB. One hundred and thirty-two patients had cirrhosis, and 30 of those were diagnosed with peritoneal TB. The mean ADA was 72.2 U/L and 22.7 U/L in the peritoneal and non-peritoneal TB group, respectively, among the total study population, and 64.0 U/L and 19.1 U/L in the peritoneal and non-peritoneal TB group, respectively, among the subgroup with cirrhosis. The area under the curve for ADA to diagnose peritoneal TB was 0.96 in the total study population with a cutoff value of 41.1 U/L, and 0.93 in cirrhotic patients with a cutoff value of 39.9 U/L. CONCLUSIONS: The ascitic fluid ADA measurements showed high diagnostic performance for peritoneal tuberculosis in patients with ascites regardless of cirrhosis at a similar cutoff value.