Fate of nondiagnostic thyroid fine needle aspirations.

BACKGROUND: Thyroid nodules may be detected during the workup of thyroid hormone abnormalities and as incidental findings during unrelated imaging studies. The diagnosis of a thyroid nodule is mainly established by performing fine needle aspiration (FNA) under ultrasound guidance. Thyroid nodules are classified as nondiagnostic, defined in the Bethesda System for Reporting Thyroid Cytopathology as samples with excess blood, cyst fluid only, and lack of thyroid follicular cells. The current study evaluates a series of nondiagnostic FNAs to assess whether repeat sampling improves yield and what patient management, and outcomes are after a nondiagnostic FNA. METHODS: Thyroid FNAs from 2016 to 2023 were retrieved from our institution archives. All cases were performed under ultrasound guidance and with rapid on-site evaluation. Cases were assigned the Bethesda System Category. Nondiagnostic FNAs were further reviewed for repeat FNA procedures, potential molecular testing, or diagnostic resections. RESULTS: In total 3104 thyroid FNAs were reviewed, with 153 (4.9%) being nondiagnostic. Of the 154 FNAs, there were 129 patients with an average age of 60 and a male-to-female ratio of 1:3.2. Of the 130 patients, there were 50 patients who underwent 55 repeat FNAs. Thirty-seven (67%) of the repeats were benign, 13 (24%) were nondiagnostic again, and 5 (9%) were atypia of undetermined significance (AUS). Molecular testing was performed on repeat FNAs diagnosed AUS. Four cases showed no mutations and had a high likelihood of being benign. One case did have an NRAS Q61R mutation, and resection revealed a noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Seventeen (13% of all cases) with nondiagnostic FNA were resected. Twelve (71%) thyroidectomies showed benign adenomatous nodules. The remainder showed incidental papillary thyroid microcarcinoma (0.1 cm), an infarcted follicular adenoma, a noninvasive follicular thyroid neoplasm with papillary-like nuclear features, and metastatic renal cell carcinoma (2×). CONCLUSION: Thyroid nodules with nondiagnostic cytology are reassuring of being highly likely a benign nodule. Only 5 of the 55 (9%) repeat FNAs yielded abnormalities, with only one of those being truly a follicular neoplasm (confirmed by molecular testing and resection). No primary thyroid malignancies have been identified in follow-up (repeat FNA or surgery). Clinical and ultrasound follow-up may be more appropriate management for nondiagnostic thyroid FNAs.

Esophageal squamous cell carcinoma with pagetoid spread: a clinicopathologic study.

Pagetoid spread in esophageal squamous epithelium associated with underlying esophageal adenocarcinoma (EAC) has been well studied. Case reports describing pagetoid spread of esophageal squamous cell carcinomas (ESCC) also exist in the literature. The latter, however, has not been systematically studied. In this study, we report seven cases of pagetoid spread associated with ESCC. The clinical, morphologic, and immunophenotypic profiles of pagetoid spread in the context of ESCC and EAC are compared. Cases of pagetoid spread of ESCC were identified through computerized search of pathology archives at five institutions. Additional cases were identified through manual review of surgical resection cases of treatment naive ESCC in Mass General Brigham (MGB) pathology archive. Clinical history was collected via chart review. Immunohistochemistry for CK7, CK20, CDX2, p53, p63, and p40 was performed on selected cases. A computerized search of pathology archives of five institutions revealed only two cases. A manual review of 76 resected untreated ESCC revealed five additional cases with unequivocal pagetoid spread of ESCC, indicating the condition was not uncommon but rarely reported. Patient age ranged from 54 to 78 years (median, 65). There were six women and one man. One case had in situ disease, five had pT1 (1 pT1a and 4 pT1b), and one had pT3 disease. One of the patients with pT1 tumor had a positive lymph node, while the remaining six patients were all N0. Four tumors were in the proximal to mid esophagus, and three in the distal esophagus. Patient survival ranged from 25 months to more than 288 months. The pagetoid tumor cells demonstrated enlarged, hyperchromatic nuclei with variable amounts of eosinophilic cytoplasm. The cytoplasm was often condensed to the perinuclear area, creating peripheral clearing. By immunohistochemistry, the pagetoid cells were positive for p40 (6/6) and p63 (7/7) and negative for CDX2 (7/7). The tumor cells showed mutant-type staining for p53 in five of seven cases. One of the patients had pagetoid tumor cells at the resection margin and subsequently had recurrent disease 2 years later. All other patients had negative resection margins and did not have local recurrence. Four cases of pagetoid spread in the context of EAC were used as a comparison group. Previously published studies were also analyzed. These tumors were all located in the distal esophagus or gastroesophageal junction. All cases were associated with underlying invasive EAC. Pagetoid spread associated with EAC often had cytoplasmic vacuoles or mucin. They were more frequently positive for CK7 than pagetoid ESCC (p = 0.01). Both ESCC and EAC may give rise to pagetoid spread of tumor cells within surface squamous epithelium. Pagetoid spread from ESCC and EAC have overlapping morphologic features. P40 and p63 immunostains can facilitate the distinction between ESCC and EAC. P53 immunostain can aid in confirmation of malignancy. Understanding their overlapping pathologic features will help pathologists avoid pitfalls and diagnose these lesions correctly on biopsy specimens.

Nonconventional Dysplasia is Frequently Associated With Goblet Cell Deficient and Serrated Variants of Colonic Adenocarcinoma in Inflammatory Bowel Disease.

Various subtypes of nonconventional dysplasia have been recently described in inflammatory bowel disease (IBD). We hypothesized that goblet cell deficient dysplasia and serrated dysplasia may be the primary precursor lesions for goblet cell deficient (GCDAC) and serrated (SAC) variants of colonic adenocarcinoma, respectively. Clinicopathologic features of 23 GCDAC and 10 SAC colectomy cases were analyzed. All dysplastic lesions found adjacent to the colorectal cancers (n = 22 for GCDACs and n = 10 for SACs) were subtyped as conventional, nonconventional, or mixed-type dysplasia. As controls, 12 IBD colectomy cases with well to moderately differentiated adenocarcinoma that lacked any mucinous, signet ring cell, low-grade tubuloglandular, or serrated features while retaining goblet cells throughout the tumor (at least 50% of the tumor) were evaluated. The cohort consisted of 19 (58%) men and 14 (42%) women, with a mean age of 53 years and a long history of IBD (mean duration: 18 y). Twenty-seven (82%) patients had ulcerative colitis. GCDACs (57%) were more often flat or invisible than SACs (10%) and controls (25%; P = 0.023). The GCDAC and SAC groups were more likely to show lymphovascular invasion (GCDAC group: 52%, SAC group: 50%, control group: 0%, P = 0.001) and lymph node metastasis (GCDAC group: 39%, SAC group: 50%, control group: 0%, P = 0.009) than the control group. Notably, GCDACs and SACs were more frequently associated with nonconventional dysplasia than controls (GCDAC group: 77%, SAC group: 40%, control group: 0%, P < 0.001). Goblet cell deficient dysplasia (73%) was the most prevalent dysplastic subtype associated with GCDACs ( P = 0.049), whereas dysplasias featuring a serrated component (60%) were most often associated with SACs ( P = 0.001). The GCDAC group (75%) had a higher rate of macroscopically flat or invisible synchronous dysplasia compared with the SAC (20%) and control (33%) groups ( P = 0.045). Synchronous dysplasia demonstrated nonconventional dysplastic features more frequently in the GCDAC (69%) and SAC (40%) groups compared with the control group (0%; P = 0.016). In conclusion, goblet cell deficient dysplasia and dysplasias featuring a serrated component could potentially serve as high-risk markers for GCDACs and SACs, respectively.

Müllerian-type carcinosarcoma arising in gastric endometriosis: Case report and review of the literature.

Although endometriosis is a common condition, both extrapelvic endometriosis and endometriosis associated malignancy (EAM) are rare. We describe the first reported case of a patient with Müllerian-type carcinosarcoma arising in gastric endometriosis.

An unusual case of gastric outlet obstruction and melena.

Strongyloidiasis is a parasitic infection caused by nematode helminth Strongyloides stercoralis. Severe infection with S. stercoralis is rare and often missed by clinicians which may cause worsen the outcomes. A 57-year-old Hispanic female with past medical history of HIV and breast cancer was transferred from an outside hospital to a tertiary care facility with complaint of persistent abdominal pain and melena. She underwent Esophagogastroduodenoscopy (EGD) twice before her presentation for the same complaints which showed severe duodenitis with multiple erosions; however, at both occasions, biopsies were deferred. A third EGD done at tertiary care hospital also revealed severe duodenitis. Another notable finding was pseudo-membranous dusky appearing mucosa with duodenal narrowing causing gastric outlet obstruction (GOO). The duodenal mucosa involved was biopsied during EGD. Pathology was consistent with Strongyloidiasis. At that time, a diagnosis of severe Strongyloidiasis causing duodenal ulceration, bleeding, and GOO was made. She was started on Ivermectin. Her hospital course was further complicated by strongyloidiasis hyperinfection syndrome (SHS) leading to her demise. Severe infection with S. stercoralis causing SHS is associated with significant morbidity and mortality. High index of suspicion, timely diagnosis and management is prudent for preventing serious complications.

Epigenetic Dysregulation of 5-hydroxymethylcytosine in Well-Differentiated Pancreatic Neuroendocrine Tumors.

Dysregulation of epigenetic mechanisms, reflected by loss of expression of 5-hydroxymethylcytosine (5-hmC) is being increasingly recognized as a marker of aggressive behavior in several neoplasms; however, the role of such epigenetic modifiers in pancreatic neuroendocrine tumors (PanNETs) has not been studied. Annotated cohort of 60 PanNETs was evaluated for 5-hmC expression using immunohistochemistry. Univariable and multivariable analyses were performed. To determine intratumor heterogeneity of 5-hmC expression, 26 additional synchronous metastatic deposits of PanNETs from 8 patients were evaluated for 5-hmC expression. 5-hmC level showed significant association with the presence of distant metastases (P=0.02), female sex (P=0.04), and Ki-67 proliferation index (P=0.002). A multivariate model created using the stepwise logistic regression analysis showed the presence of nodal metastases (odds ratio=6.15), lymphovascular invasion (odds ratio=4.07) and lack of 5-hmC expression (odds ratio=5.34) were predictive of the risk of distant metastasis in PanNETs with a c-statistic of 0.845. Epigenetic intratumoral heterogeneity of 5-hmC expression was seen in 37.5% cases (3/8). Our work provides evidence that epigenetic regulators are involved in the pathobiology of PanNETs and immunohistochemical analysis of 5-hmC may be able to refine prognostic evaluation of these tumors.

Endoscopic resection is more effective than biopsy or EUS to detect residual rectal neuroendocrine tumor.

Background and study aims Rectal neuroendocrine tumors (NETs) are often discovered incidentally and may be misidentified as adenomatous polyps. This can result in a partial resection at the index procedure, and lesions are often referred for staging or evaluation for residual disease at the resection site. The aim of this study was to identify the ideal method to confirm complete excision of small rectal NETs. Patients and methods Data from patients with a previously resected rectal NET referred for follow-up endoscopy or endoscopic ultrasound (EUS) were retrospectively reviewed. Univariate analysis was performed on categorical data using the Chi-squared test. Results Forty-nine patients with rectal NETs were identified by pathology specimens. Of those, 39 underwent follow-up endoscopy or EUS and were included. Baseline characteristics included gender (71 % F, 29 % M), age (57.2 ±â€Š13.4 yrs) lesion size (7.3 ±â€Š4.2 mm) and location. The prior resection site was identified in 37/39 patients who underwent tissue sampling. Residual NET was found histologically in 14/37 lesions. All residual disease was found during salvage endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) and 43 % had a normal-appearing scar. Every patient undergoing EUS had an unremarkable exam. Initial cold biopsy polypectomy ( P  = 0.006), visible lesions ( P  = 0.001) and EMR/ESD of the prior resection site ( P  = 0.01) correlated with residual NET. Conclusions Localized rectal NETs may be incompletely removed with standard polypectomy. If an advanced resection is not performed initially, repeat endoscopy with salvage EMR or ESD of the scar should be considered. For small rectal NETs, biopsy may miss residual disease when there is no visible lesion and EUS appears to have no benefit.

Histologic patterns of liver injury induced by anti-PD-1 therapy.

BACKGROUND: Nivolumab and pembrolizumab-two monoclonal antibodies that block human programmed cell death-1 (PD-1)-have been successfully used to treat patients with multiple advanced malignancies. The histologic patterns of hepatic toxicity induced by anti-PD-1 treatment have not been well studied and the aim of this study was to explore them. METHODS: Eight patients with advanced malignancies who were treated with either nivolumab or pembrolizumab were identified from five institutions. These patients had no history of underlying liver disease and a viral hepatitis panel was negative in all patients. RESULTS: Seven of eight patients exhibited mild to moderate gastrointestinal symptoms such as abdominal pain, fatigue, nausea, vomiting, and jaundice after anti-PD-1 treatment. Significant elevations in liver-chemistry tests were detected in all patients. Six cases (6/8) demonstrated an acute lobular hepatitis pattern of histologic injury. The remaining two cases showed different histologic patterns of injury: steatohepatitis with mild cholestasis (1/8) and pure acute cholestatic injury (1/8). No case showed typical features of autoimmune hepatitis. The liver function recovered in all eight cases after cessation of anti-PD-1 agents and with immunosuppressive therapy. CONCLUSIONS: Our study suggests that screening patients for abnormal liver-function tests prior to anti-PD-1 therapy as well as periodic monitoring of liver-function tests are necessary to prevent severe liver injury. Rather than causing classical autoimmune hepatitis, PD-1 inhibitors appear to produce an immune-mediated nonspecific acute hepatitis. Drug cessation, without steroid therapy, may therefore be sufficient in some patients.

Next-generation sequencing identifies 2 genomically distinct groups among pyloric gland adenomas.

The molecular alterations identified among pyloric gland adenomas (PGAs) in the published literature are based on polymerase chain reaction of targeted genes, and next-generation sequencing (NGS) has not been performed. In this study, we performed NGS and correlated the molecular alterations with the histologic grade of dysplasia and immunohistochemical findings in a cohort of PGAs. Successful DNA extraction and sequencing were performed in 15 pyloric gland adenomas/adenocarcinoma from 12 patients. Additionally, 4 specimens of autoimmune gastritis were selected to serve as the control group. Ten PGAs with low-grade dysplasia were seen to have mutations in the triad of APC, KRAS, and GNAS genes. Five PGAs with high-grade dysplasia/adenocarcinoma exhibited mutations in several genes including APC, CTNNB1, KRAS, GNAS, TP53, CDKN2A, PIK3CA, and EPHA5 genes but did not exhibit mutations in the triad of APC, KRAS, and GNAS genes. The median tumor mutational burden was higher in PGAs with high-grade dysplasia/adenocarcinoma when compared with PGAs with low-grade dysplasia (5.25 and 4.38, respectively). PGAs with high-grade dysplasia/adenocarcinoma had more chromosomal gains and losses than PGAs with low-grade dysplasia. The molecular findings suggest that there are 2 separate mutator pathways of dysplasia development in PGAs.

Targeted mutational analysis of inflammatory bowel disease-associated colorectal cancers.

Inflammatory bowel disease-associated colorectal carcinomas (IBD-CRCs) develop in a background of chronic inflammation, and thus, the molecular landscape of these tumors likely differs from that of sporadic colorectal cancer. To add to emerging data on molecular alterations present in these tumors, we analyzed our institution's cohort of IBD-CRCs. CRCs resected from patients with IBD underwent molecular analysis via a 50-gene hot-spot solid tumor panel (OncoScreen ST2.0). In-house sporadic CRCs and The Cancer Genome Atlas project data were used for comparison. Fifty-five IBD-CRCs from 48 patients were successfully analyzed. Mutations in TP53 were most common and were present in 69% of IBD-CRCs; a similar percentage of TP53 mutations was detected in sporadic colorectal carcinomas (70%). APC and KRAS mutations were significantly less common in IBD-CRCs than in sporadic CRCs (15% versus 53%, P < .001 and 20% versus 38%, P = .02, respectively). Additionally, the potentially targetable IDH1 R132 mutation was present in 7% of IBD-CRCs but only 1% of sporadic CRCs and The Cancer Genome Atlas CRCs; alterations in other genes with potential targeted therapies were very rare. In conclusion, IBD-CRCs exhibit molecular differences when compared to sporadic CRCs, suggesting different pathways of carcinogenesis, although certain alterations are common to both types of tumors. IDH1 mutations are present in a subset of IBD-CRCs, which may expand therapeutic options in the future.

Smith-Lemli-Opitz Syndrome in a newborn infant with developmental abnormalities and low endogenous cholesterol.

BACKGROUND: Patients with Smith-Lemli-Opitz Syndrome (SLOS) have defective endogenous cholesterol synthesis, and present with decreased cholesterol levels and multiple developmental dysmorphologies. CASE DESCRIPTION: A newborn infant with normal XY karyotype and normal microarray was born with multiple developmental defects and ambiguous genitalia. The patient was diagnosed with SLOS, following biochemical genetic analysis of serum 7-DHC concentrations. The clinical course of the patient was further complicated by the comorbidities associated with SLOS and the bacterial infections. CONCLUSION: We provide a detailed biochemical profile of the SLOS patient. The report can help us further understand the pathological impacts of cholesterol synthesis deficiency and provide relevant clinical management with outcome of this rare genetic disorder.

Desmoid-Type Fibromatosis of the Tongue.

Desmoid-type fibromatosis rarely occurs in the oral tongue. Diagnostic imaging, including ultrasound, is useful for delineating the extent of the lesion and can aid in treatment planning. However, definitive diagnosis is made based on the characteristic histologic features, which include cytologically bland spindle cells with surrounding collagenous matrix and minimal mitotic activity. Immunohistochemical analysis of these lesions reveals that they are classically positive, at least focally, for smooth muscle actin, calponin and muscle-specific actin. These features are exemplified in this sine qua non radiology-pathology correlation article.