Faculty Bibliography

We report a collection of lung findings in a patient with a remote history of cigarette smoking, but now engaged in heavy nicotine vaping with daily edible and combustible cannabis use. Computed tomography (CT) imaging demonstrated numerous, small, and bilateral nodules with ground-glass appearance. The largest nodule is demonstrated in the right upper lung lobe. Clinically the differential diagnosis at this time included hypersensitivity pneumonitis and sarcoidosis. Atypical infection, particularly of a fungal etiology, and metastatic malignancy were also considered. Initial pathology of the right lung needle biopsy revealed alveolar septal thickening with associated atypical pneumocyte proliferation, suggestive of atypical adenomatous hyperplasia (AAH). Subsequently the patient underwent wedge resection of the right upper, middle and lower lobes. Pathology examination revealed pulmonary Langerhans cell histiocytosis (PLCH) in the upper and lower lobes, with CD1a staining highlighting the aggregates of Langerhans cells. Vascular changes were also present including intimal thickening of muscular pulmonary arteries, consistent with pulmonary hypertensive changes. Background lung parenchyma demonstrated respiratory bronchiolitis, smoking-related interstitial fibrosis, an organizing thrombus in muscular artery and associated pneumocyte hyperplasia.

Background: Despite investigation, 95% of thyroid nodules are ultimately benign. Radiomics is a field that uses radiological features to inform individualized patient care. We aimed to evaluate the diagnostic utility of radiomics in classifying undetermined thyroid nodules into benign and malignant using ultrasonography (US). Methods: A diagnostic test accuracy systematic review and meta-analysis was performed in accordance with PRISMA guidelines. Sensitivity, specificity, and area under curve (AUC) delineating benign and malignant lesions were recorded. Results: Seventy-five studies including 26,373 patients and 46,175 thyroid nodules met inclusion criteria. Males accounted for 24.6% of patients, while 75.4% of patients were female. Radiomics provided a pooled sensitivity of 0.87 (95% CI: 0.86−0.87) and a pooled specificity of 0.84 (95% CI: 0.84−0.85) for characterizing benign and malignant lesions. Using convolutional neural network (CNN) methods, pooled sensitivity was 0.85 (95% CI: 0.84−0.86) and pooled specificity was 0.82 (95% CI: 0.82−0.83); significantly lower than studies using non-CNN: sensitivity 0.90 (95% CI: 0.89−0.90) and specificity 0.88 (95% CI: 0.87−0.89) (p < 0.05). The diagnostic ability of radiologists and radiomics were comparable for both sensitivity (OR 0.98) and specificity (OR 0.95). Conclusions: Radiomic analysis using US provides a reproducible, reliable evaluation of undetermined thyroid nodules when compared to current best practice.

Mass-forming ductal carcinoma in situ (DCIS) detected on core needle biopsy (CNB) is often a radiology-pathology discordance and thought to represent missed invasive carcinoma. This brief report applied supervised machine learning (ML) for image segmentation to investigate a series of 44 mass-forming DCIS cases, with the primary focus being stromal computational signatures. The area under the curve (AUC) for receiver operator curves (ROC) in relation to upgrade to invasive carcinoma from DCIS were as follows: high myxoid stromal ratio (MSR): 0.923, P = <0.001; low collagenous stromal percentage (CSP): 0.875, P = <0.001; and low proportionated stromal area (PSA): 0.682, P = 0.039. The use of ML in mass-forming DCIS could predict upgraded to invasive carcinoma with high sensitivity and specificity. The findings from this brief report are clinically useful and should be further validated by future studies.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread worldwide. Most of the infected patients present with respiratory symptoms and acute lung damage. Here, we present three cases of patients with COVID-19 disease whose main clinical manifestations are gastrointestinal symptoms. In our first case, we present a COVID-19 patient with histologic findings associated with ischemic necrosis of the small bowel. In the second and third cases, we demonstrate acute cholecystitis and histology showing microvascular thrombosis. These three cases highlight the ischemic and thrombotic changes seen in the setting of COVID-19 infection without classic respiratory symptoms, with resulting severe gastrointestinal and hepatobiliary disease requiring surgical management. Although the bile or stool viral load was not tested in these patients, the small intestine and gallbladder were infected with SARS-CoV-2, most likely via the epithelial angiotensin-converting enzyme 2 (ACE2) receptor.

BACKGROUND:The aim of this study is to assess the efficacy of cytology in omental or peritoneal lesions. METHODS:A retrospective review of the pathology database for cytology cases of peritoneal or omental nodules over a 3-year period (2016-2018) was conducted. The cases consisted of either FNA only (FO); FNA and Core biopsy (FCB) or Touch prep and core biopsy (TCB). Cases were further divided based on the prior history of carcinoma. Concordance rates of cytologic diagnosis with histologic diagnosis were studied. RESULTS:Out of 104 cytology cases reviewed, 60 (57.7%) had prior history of cancer (PHC) and 44 (42.3%) had no prior history of cancer (NPHC). Of the cases with PHC, 43(71.66%) were recurrence, 10 (16.66%) were second cancer, and 7 (11.66%) were non-neoplastic lesions. Of the cases with NPHC, 38 (86.4%) had a second cancer diagnosis, while 6 (13.6%) were non-neoplastic. For FO only cases, 11 of 35 (31.4%) had follow up and 9 of 11 (81.8%) were concordant. For FCB cases, 6 out of 39 (15.4%) had follow up and 6 (100%) were concordant. For TCB cases, 9 out of 30 (30%) had follow up and 9 (100%) were concordant. A definite diagnosis was reached in 30/35, 39/39, and 29/30 cases in FO, FCB, and TCB, respectively. CONCLUSION/CONCLUSIONS:In summary, cytologic evaluation of omental lesions is an effective tool in providing accurate diagnosis and guiding further management. Also, the results based on our study show that the combined techniques are superior at reaching a definitive diagnosis.

Uterine undifferentiated (UC)/dedifferentiated (DEAC) carcinomas are rare malignant neoplasms. They tend to pursue an aggressive clinical course with an advanced stage at presentation. It has been found that androgen receptor (AR) might play a role as a prognostic and therapeutic marker in endometrial carcinoma. However, its expression in UC/DEAC has not been investigated. Herein, the aim of this study was to evaluate the expression of AR along with estrogen receptor (ER), progestin receptor (PR), and HER2 in UC/DEAC and also in other subtypes of high-grade endometrial carcinomas. Review of our pathology database over the period of 2011 to 2019 identified 16 UC/DEAC cases (N=16). We also randomly selected other high-grade endometrial carcinomas including FIGO 3 endometrioid carcinoma (N=9), serous carcinoma (N=8), clear cell carcinoma (N=12) and carcinosarcoma (N=10) for comparison. Immunohistochemical stains for AR, ER, PR, and HER2 were performed on all 55 cases. The protein expression was evaluated both quantitatively and qualitatively. In DEAC cases both the undifferentiated component and the well-differentiated component were recorded separately. Overall, variable degrees of AR reactivity (by Allred scoring method) was present in 63% of UC/DEACs(10/16), 67% of FIGO 3 endometrioid carcinomas (6/9), 88% of serous carcinomas (7/8), 80% of carcinosarcomas (8/10), and 9% of clear cell carcinoma (1/12). AR expression was most often seen with PR (70%) or ER (60%) staining in UC/DEACs. Thirteen cases of UC/DEACs were positive for at least 1 hormone receptor. HER2 was negative in all UC/DEACs. Almost all other high-grade carcinoma cases were negative for HER2 except 20% of carcinosarcoma (2/10) and 13% of serous carcinoma (1/8) which showed 3+ HER2. Loss of AR appears to be associated with worse clinicopathologic parameters in UC/DEAC. AR is highly expressed in UC/DEAC, and in the majority of FIGO 3 endometrioid carcinomas, serous carcinomas, and carcinosarcoma. These findings suggest a potential role for androgen inhibitors in the management of patients with these tumors.

The role of stromal differentiation (SD), program death-ligand 1 (PD-L1), and v-domain Ig suppressor of T cell activation (VISTA) in gastrointestinal stromal tumor (GIST) is largely unknown. Looking forward, the assessment of SD and immune check point inhibition will become more ubiquitous in surgical pathology. Immature, myxoid stroma has been found to be a poor prognostic signature in many cancer subtypes (colon, breast, cervix, esophagus, stomach); although little is known regarding its significance in GIST. For immune check-point inhibition, studies have demonstrated expression to be associated with patient outcomes in numerous cancer subtypes. The present body of work aims to evaluate SD, PD-L1 and VISTA; both in terms of its nature and significance in a clinical setting. Here we found PD-L1 expression in immune cells (IC) and immature SD to be associated with worse cancer free survival, while positive VISTA expression was found to be associated with improved outcomes. High-grade, immature SD had the highest propensity for death/recurrence and was the only variable found to have prognostic significance on multivariate analysis. Our findings support the evaluation of SD, PD-L1 and VISTA in GIST, with clinical practice implications for pathologists. Ultimately, we hope our findings lead to improved prognostication, further optimization of therapeutics, and improved outcomes in a true clinical environment. For GIST, PD-L1 and VISTA could be both clinically relevant and targetable, while SD may be the answer to clinical heterogeneity.

Colorectal cancer (CRC) incidence is rising globally. Hence, preventing this disease is a high priority. With this aim, we determined the CRC prevention potential of the TRAIL-inducing small molecule ONC201/TIC10 using a preclinical model representing high-risk familial adenomatous polyposis (FAP) patients, Apc ^min/+ mice. Prior to the efficacy study, optimal and non-toxic doses of ONC201 were determined by testing five different doses of ONC201 (0-100 mg/kg body weight (BW); twice weekly by oral gavage) in C57BL/6J mice (n=6/group) for 6 weeks. BW gain, organ weights and histopathology, blood profiling, and the plasma liver enzyme profile suggested no toxicities of ONC201 at doses up to 100 mg/kg BW. For efficacy determination, beginning at six weeks of age, groups of Apc ^min/+ male and female mice (n≥20) treated with colon carcinogen azoxymethane (AOM) (AOM-Apc ^min/+) were administered ONC201 (0, 25, and 50 mg/kg BW) as above up to 20 weeks of age. At termination, efficacy was determined by comparing the incidence and multiplicity of intestinal tumors between vehicle- and drug-treated groups. ONC201 showed a strong suppressive effect against the development of both large and small intestinal tumors in male and female mice. Apc ^min/+ mice treated with ONC201 (50 mg/kg BW) showed >50% less colonic tumor incidence (P<0.0002) than controls. Colonic tumor multiplicity was also significantly reduced by 68% in male mice (0.44 ± 0.11 in treated vs. 1.4 ± 0.14 in controls; P<0.0001) and by 75% in female mice (0.30 ± 0.10 in treated vs. 1.19 ± 0.19 in controls; P<0.0003) with ONC201 treatment (50 mg/kg BW). Small intestinal polyps were reduced by 68% in male mice (11.40 ± 1.19 in treated vs. 36.08 ± 2.62 in controls; P<0.0001) and female mice (9.65 ± 1.15 in treated vs. 29.24 ± 2.51 in controls; P<0.0001). Molecular analysis of the tumors suggested an increase in TRAIL, DR5, cleaved caspases 3/7/8, Fas-associated death domain protein (FADD), and p21 (WAF1) in response to drug treatment. Serum analysis indicated a decrease in pro-inflammatory serum biomarkers, such as IL1β, IL6, TNFα, G-CSF, and GM-CSF, in the ONC201-treated mice compared with controls. Our data demonstrated excellent chemopreventive potential of orally administered ONC201 against intestinal tumorigenesis in the AOM-Apc ^min/+ mouse model.