The Effect of Apalutamide on Thyroid Function in Prostate Cancer Patients.

Context: Apalutamide (APT) is a nonsteroidal antiandrogen medication used to treat metastatic castrate-sensitive and nonmetastatic castrate-resistant prostate cancer. Early clinical trials of APT identified thyroid dysfunction as a common adverse effect of therapy, but the clinical presentation and management of APT-induced hypothyroidism has not been studied. Objective: The objective of our study is to elucidate the clinical presentation and treatment approach of APT-associated thyroid dysfunction in prostate cancer patients. Methods: We report a case series of 16 patients with APT-associated thyroid dysfunction during prostate cancer treatment at 2 academic medical centers. Patient clinical parameters, thyroid function laboratory data, and thyroid hormone requirements over the course of APT treatment were analyzed. Results: Among the 16 patients in our case series with APT-associated hypothyroidism, 3 had no prior thyroid disease and 13 had preexisting hypothyroidism. The patterns of thyroid dysfunction included overt and subclinical hypothyroidism. The median time from APT initiation to thyroid function test abnormality was 19 weeks, but occurred in some cases as early as 2 to 4 weeks. Hypothyroidism was effectively managed with thyroid hormone replacement using levothyroxine (LT4), though some patients with preexisting hypothyroidism required a 2- to 3-fold dose increase while on APT to achieve a euthyroid state. In the subset of patients who completed or stopped APT therapy, thyrotropin levels fell at a median of 11 weeks post APT therapy and thyroid hormone requirements decreased to near pre-APT levels. Conclusion: APT-associated thyroid dysfunction presents as new or worsening hypothyroidism and should prompt initiation or increase in thyroid hormone replacement. Monitoring of thyroid function tests is recommended every 1 to 2 months for all patients on APT and 2 to 3 months after completion of APT.

Extraskeletal Ewing Sarcoma of the Gastrointestinal and Hepatobiliary Tract: Deceptive Immunophenotype Commonly Leads to Misdiagnosis.

Ewing sarcoma (ES) is an uncommon mesenchymal neoplasm that typically develops as a bone mass, although up to 30% arise in extraskeletal sites. ES of the gastrointestinal (GI) and hepatobiliary tract is rare and may be misdiagnosed as other, more common neoplasms that occur in these sites. However, the correct classification of extraskeletal ES is important for timely clinical management and prognostication. We reviewed our experience of ES in the GI and hepatobiliary tract in order to further highlight the clinicopathologic features of these neoplasms and document the potential for misdiagnosis in this setting. The archives and consultation files of 6 academic institutions were retrospectively queried for cases of ES occurring in the GI and hepatobiliary tract. The histologic slides and ancillary studies were reviewed and clinical data were retrieved for each case through the electronic medical records, when available. Twenty-three patients with ES in the GI and/or hepatobiliary tract were identified from 2000 to 2022. Of these, 11 were women and 12 were men with a median age of 38 years (range, 2 to 64). Tumor locations included the pancreas (n=5), liver (n=2), stomach (n=3), colorectum (n=3), and small intestine (n=5), as well as tumors involving multiple organs, pelvis and retroperitoneum (n=5). Tumor size varied between 2 cm and 18 cm. Twenty were primary and 3 were metastases. Of the 23 cases, only 17% were initially diagnosed as ES. The most common misdiagnoses involved various forms of neuroendocrine neoplasia due to expression of synaptophysin and other neuroendocrine markers (22%). A wide variety of diagnoses including GI stromal tumor was considered due to aberrant CD117 expression (4%). The diagnosis of ES was ultimately confirmed by detection of the EWSR1 rearrangement in 22 cases. The remaining case was diagnosed using traditional immunohistochemistry. Follow-up information was available in 20 cases, with follow-up time varying between 2 and 256 months. Six patients with follow-up died of disease between 6 and 60 months following initial presentation. Our data indicate ES in the GI and hepatobiliary tract is commonly misdiagnosed leading to a delay in therapy. In light of the attendant therapeutic and prognostic implications, ES should be considered in the differential diagnosis of any GI or hepatobiliary tumor with epithelioid and/or small round cell morphology.

Extra-appendiceal mucinous neoplasms: A tumour with clinicopathologic similarities to low- and high-grade appendiceal counterpart.

AIMS: Appendiceal mucinous neoplasms feature neoplastic mucinous epithelium with pushing borders and densely fibrotic walls. We have identified five examples of analogous colorectal tumours. METHODS AND RESULTS: Slides, pathology reports, and clinical data were reviewed. Whole genome sequencing was performed in two cases. Three were women and the mean age was 70. Associated GI conditions included Crohn's disease [1], diverticulosis [2], and sarcoma of the terminal ileum [1]. Signs/symptoms included obstruction [2], nausea, vomiting, abdominal pain [1], and positive faecal immunohistochemical test [1]. Colonoscopic findings included narrowing [1], "fullness" [1], and caecal lesion concerning for GIST [1]. Tumours involved the rectosigmoid [2], sigmoid [1], transverse colon [1], and cecum [1] and ranged from 1.5 cm to 8.5 cm. All but one tumour arose in the setting of faecal stream abnormalities related to obstruction, diverticulosis, or bowel diversion. All cases showed columnar, variably mucinous epithelium associated with little-to-no lamina propria. All but one case showed fibrosis of the submucosa. Three cases had high-grade areas. Neoplastic glands and/or mucin dissected through the muscularis propria or subserosa in 3 examples. No extracolonic neoplastic cells/mucin, infiltrative invasion, or desmoplastic response were identified. Three patients with available follow-up [5.5-28 months] are alive. Whole genome sequencing identified pathogenic TP53 and ERBB2 variants, as well as ERBB2 copy number amplification in one high-grade example. CONCLUSIONS: Though these tumours share clinicopathologic characteristics with their appendiceal counterparts, our cohort is too small to draw solid conclusions. We propose the term "extra-appendiceal mucinous neoplasm [EAMN]" for these rare lesions.

The Combined Effect of Immune Checkpoint Inhibitors and Tyrosine Kinase Inhibitors on Thyroid Function.

Background: Recent successes with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the treatment of solid malignancies have paved the way for a new era of combined therapy. A common side effect seen with each of these classes of treatment is thyroid dysfunction, with rates estimated at 30-40% for TKI and 10-20% for ICI. However, little is known about the effect of combined ICI+TKI therapy on thyroid function. Therefore, this study evaluated the incidence, clinical features, and risk factors for developing thyroid abnormalities during ICI+TKI therapy and the relationship to cancer outcomes. Methods: We conducted a retrospective cohort study of patients treated with combination ICI+TKI cancer therapy at City of Hope Comprehensive Cancer Center from 2017 to 2023 who had pretreatment normal thyrotropin (TSH) levels. Primary analyses assessed the frequency, timing, and severity of thyroid function test abnormalities during ICI+TKI cancer therapy, and the requirement for thyroid hormone replacement. Secondary analyses evaluated risk factors for the development of thyroid dysfunction, including sex and drug regimen, and the association with cancer progression-free survival or overall survival. Univariable and multivariable models were used. Results: There were 106 patients who received ICI+TKI therapy with a median age of 63.5 years and a median follow-up of 12.8 months (interquartile range [IQR] 5.9-20.9). Notably, 63.2% (67/106) developed thyroid function abnormalities during ICI+TKI therapy, including 11 (10.4%) with hyperthyroidism, 42 (39.6%) with subclinical hypothyroidism (SCHypo), and 14 (13.2%) with overt hypothyroidism. The onset of thyroid dysfunction occurred at a median of 7 weeks (IQR 3.1-9.0) after start of ICI+TKI treatment for hyperthyroidism, 8.0 weeks (IQR 3.0-19.0) for SCHypo, and 8.1 weeks (IQR 5.9-9.1) for overt or worsening hypothyroidism. Hyperthyroidism resolved to hypothyroidism or normal TSH without intervention in all subjects, suggesting thyroiditis, and hypothyroidism was readily treated with thyroid hormone replacement. Conclusions: Thyroid dysfunction is a frequent adverse event in individuals treated with combination ICI+TKI therapy, with our data suggesting a rapid onset and higher incidence than previously seen with ICI or TKI therapy alone. Therefore, close monitoring of thyroid function during initial therapy and multidisciplinary care with endocrinology are recommended to facilitate early detection and initiation of thyroid hormone replacement in these patients.

Comparative Analyses of the Clinicopathologic Features of Short-Term and Long-Term Survivors of Patients with Pancreatic Ductal Adenocarcinoma Who Received Neoadjuvant Therapy and Pancreatoduodenectomy.

Neoadjuvant therapy (NAT) is increasingly used to treat patients with pancreatic ductal adenocarcinoma (PDAC). Patients with PDAC often show heterogenous responses to NAT with variable clinical outcomes, and the clinicopathologic parameters associated with these variable outcomes remain unclear. In this study, we systematically examined the clinicopathologic characteristics of 60 short-term survivors (overall survival < 15 months) and 149 long-term survivors (overall survival > 60 months) and compared them to 352 intermediate-term survivors (overall survival: 15-60 months) of PDAC who received NAT and pancreatoduodenectomy. We found that the short-term survivor group was associated with male gender (p = 0.03), tumor resectability prior to NAT (p = 0.04), poorly differentiated tumor histology (p = 0.006), more positive lymph nodes (p = 0.04), higher ypN stage (p = 0.002), and higher positive lymph node ratio (p = 0.03). The long-term survivor group had smaller tumor size (p = 0.001), lower ypT stage (p = 0.001), fewer positive lymph nodes (p < 0.001), lower ypN stage (p < 0.001), lower positive lymph node ratio (p < 0.001), lower rate of lymphovascular invasion (p = 0.001) and perineural invasion (p < 0.001), better tumor response grading (p < 0.001), and less frequent recurrence/metastasis (p < 0.001). The ypN stage is an independent predictor of both short-term and long-term survivors by multivariate logistic regression analyses. In addition, tumor differentiation was also an independent predictor for short-term survivors, and tumor response grading and perineural invasion were independent predictors for long-term survivors. Our results may help to plan and select post-operative adjuvant therapy for patients with PDAC who received NAT and pancreatoduodenectomy based on the pathologic data.

Sclerosing mesenteritis following immune checkpoint inhibitor therapy.

PURPOSE: Sclerosing mesenteritis (SM), a fibroinflammatory process of the mesentery, can rarely occur after immune checkpoint inhibitor (ICI) therapy; however, its clinical significance and optimal management are unclear. We aimed to assess the characteristics and disease course of patients who developed SM following ICI therapy at a single tertiary cancer center. METHODS: We retrospectively identified 12 eligible adult cancer patients between 05/2011 and 05/2022. Patients' clinical data were evaluated and summarized. RESULTS: The median patient age was 71.5 years. The most common cancer types were gastrointestinal, hematologic, and skin. Eight patients (67%) received anti-PD-1/L1 monotherapy, 2 (17%) received anti-CTLA-4 monotherapy, and 2 (17%) received combination therapy. SM occurred after a median duration of 8.6 months from the first ICI dose. Most patients (75%) were asymptomatic on diagnosis. Three patients (25%) reported abdominal pain, nausea, and fever and received inpatient care and corticosteroid treatment with symptom resolution. No patients experienced SM recurrence after the completion of corticosteroids. Seven patients (58%) experienced resolution of SM on imaging. Seven patients (58%) resumed ICI therapy after the diagnosis of SM. CONCLUSIONS: SM represents an immune-related adverse event that may occur after initiation of ICI therapy. The clinical significance and optimal management of SM following ICI therapy remains uncertain. While most cases were asymptomatic and did not require active management or ICI termination, medical intervention was needed in select symptomatic cases. Further large-scale studies are needed to clarify the association of SM with ICI therapy.

Differential IgG4-Producing Plasma Cell Infiltration in Non- and Post-Transplant Plasma Cell Hepatitis.

Autoimmune hepatitis (AIH), post-transplant recurrent AIH (rAIH), and plasma cell-rich rejection (PCR) are clinical diagnoses with the shared histopathologic hallmark of plasma cell hepatitis (PCH). As these histologically and serologically indistinguishable diagnoses are differentiated by clinical context, it remains uncertain whether they represent distinct immunologic phenomena. Improved understanding of immunoglobulin subclass 4-producing plasma cells (IgG4-PC) has brought attention to IgG4 as an immunophenotypic biomarker. To date, degree and clinical significance of IgG4-PC infiltration in PCH remain elusive. This retrospective, single-center study assessed IgG4-PC infiltration in AIH, rAIH, and PCR via standardized immunohistochemistry analysis. Identified cases from 2005 to 2020 (n = 47) included AIH (treatment-naïve AIH (tnAIH): n = 15 and AIH-flare on treatment (fAIH); n = 10), rAIH (n = 8), and PCR (n = 14) were analyzed and correlated with clinical characteristics. IgG4-Positivity (# IgG4-PC/# pan-IgG-expressing cells) distribution was heterogenous and overlapping [tnAIH: 0.060 (IQR 0.040-0.079), fAIH: 0.000 (0.000-0.033), rAIH: 0.000 (0.000-0.035), PCR: 0.228 (0.039-0.558)]. IgG4-Positivity was inversely correlated with corticosteroid use (p < 0.001). IgG4-Positivity ≥0.500 was associated with rapid AST improvement (p = 0.03). The variable IgG4-Positivity of AIH, rAIH and PCR suggests diverse and overlapping immunopathologic mechanisms and that current diagnostic schemes inadequately capture PCH immunopathology. We propose incorporation of IgG4-Positivity to refine current PCH classification and treatment strategies.

Driving Factors to Pursue Endocrinology Training Fellowship: Empirical Survey Data and Future Strategies.

OBJECTIVE: There is a current and anticipated labor shortage of endocrinologists in the United States. Over the past decade, the number of applications to endocrinology fellowship programs has plateaued despite increased available positions, and interest in endocrinology has declined relative to other internal medicine subspecialty fields. The examination of driving factors for pursuit of endocrinology as a subspecialty career is needed. METHODS: A 12-question online survey was developed to identify the primary reasons for current endocrinology fellows/trainees to pursue the field. This survey was sent to 152 U.S. endocrinology fellowship program directors for completion by their fellows between July and August 2021. RESULTS: A total of 176 of 629 fellows (28.0%) completed the survey. The majority (57.4%) had decided to pursue endocrinology as a career during residency, while 27.3% had decided during medical school. The endocrinology rotation during residency was ranked by 79 fellows (44.9%) as the most influential factor, followed by having positive experiences with a clinical mentor (27.3%). Endocrinology exposure during medical school was sparse, with only 2.8% noting the availability of an endocrinology student interest group, while 59.7% reported inadequate endocrinology exposure during their medical school curriculum. CONCLUSION: The majority of current endocrinology fellows/trainees report that exposure to the field during medical school was limited, and that their endocrinology elective and mentorship experiences during residency were the most influential factors for pursuing endocrinology as a subspecialty. Improved integration of endocrinology experiences between medical school and residency may enhance career interest in endocrinology.

Hepatitic Variant of Graft-vs-Host Disease.

OBJECTIVES: Graft-vs-host disease (GVHD) of the liver is a complication of allogeneic hematopoietic stem cell transplantation with hepatitic and classic variants. We determined the percentage of hepatitic variant cases, compared clinicopathologic features of the two groups, and assessed prognostic factors. METHODS: Fifty liver biopsy specimens from 40 patients with GVHD were studied. RESULTS: Fifteen (30%) cases had moderate to marked lobular inflammation and were classified as a hepatitic variant. Bile duct damage was present in all cases. Ductular reaction, apoptosis. and endotheliitis were more commonly seen in the hepatitic variant. Hepatocyte ballooning was an independent poor prognostic factor. The median aspartate aminotransferase and alanine aminotransferase were higher in the hepatitic variant while alkaline phosphatase and bilirubin were higher in the classic group. Forty (80%) GVHD cases were more than 100 days after transplant, correlating to immunosuppression taper. There was response to treatment with increased immunosuppression in both groups, but time to normalization of liver function tests was higher in the hepatitic variant. CONCLUSIONS: Bile duct damage was the most consistent pathologic finding in our cohort and was present in all cases of GVHD. Moderate to marked lobular inflammation can be seen in GVHD in up to 30% of cases without any other coexisting cause. Hepatocyte ballooning is an independent poor prognostic factor.

Primary hepatic carcinoma with inhibin positivity in a young male patient: a rare tumor previously only reported in females-case report and review of literature.

Primary hepatic carcinoma with inhibin positivity is a rare aggressive liver tumor with seven cases described. The tumor presents at a younger age than primary hepatic carcinoma with all cases being females. RNA albumin ISH positivity suggests the tumor to be a primary hepatic carcinoma. The tumor is different from hepatocellular carcinoma as well as intrahepatic cholangiocarcinoma because of its distinct morphology, lack of hepatocellular differentiation, strong inhibin staining, and lack of typical mutations. A 26-year-old male presented with a 20-cm liver mass. The tumor progressed on therapy with development of multiple lung metastasis. Currently, the patient is enrolled in phase II clinical trial utilizing nivolumab and ipilumumab. While the tumor has a female preponderance, it is not exclusively found in females. Additional studies are necessary to determine the cause of inhibin staining, driving molecular alterations, natural history of this rare tumor, and to come up with consensus nomenclature.