Faculty Bibliography

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.

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.

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.

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.

Ultrasound (US) guided core needle biopsy (CNB) for mass lesions resulting in a diagnosis of ductal carcinoma in situ (DCIS) is often considered radiologically discordant and generates surgical planning difficulty. One hundred cases of US-guided CNB for mass lesions diagnosed as DCIS were collected from 2013 to 2021. Histological features were reviewed and correlated with radiology and surgical excision findings. Thirty (30%) were high-grade (HG), and seventy (70%) were low- to intermediate-grade. Seventy-one (71%) cases had a histological correlate of a mass-forming lesion, including 26 (26%) were associated with benign mass-forming lesions (category 1) such as papilloma, complex sclerosing lesion/radial scar, fibroadenoma, sclerosing adenosis, and ruptured cyst; 23 (23%) were HG with solid pattern, comedo necrosis, and stromal desmoplasia (category 2); and 22 (22%) had predominantly papillary architecture (category 3). Twenty-nine (29%) were discordant with no histologic correlate of a mass lesion (category 4). Follow-up excisions were available in 79 cases. Invasive carcinoma was identified in 14 cases (18%), of which 8 were from the radiologically discordant category (35%), 3 (17%) associated with HG DCIS with desmoplasia, 2 (10%) associated with benign mass lesion and 1(5%) was predominantly papillary architecture. US-guided CNB for mass-forming lesions with a DCIS diagnosis on CNB can be grouped into four categories. Radiology-pathology correlation is essential. This categorization emphasized rad-path correlation and had a clear difference in upgrade rate on follow-up excision. Rad-path discordant biopsy cases were more likely to be associated with a missed invasive carcinoma (p < 0.05).

A 60-year-old female presented with asymptomatic failing mandibular dental implants. Computed tomography (CT) showed a partially calcified, hypointense lesion within the soft tissues, measuring 1.3 x 0.8 x 1.0 cm along the buccal cortex. Incisional biopsy demonstrated a basaloid type of tumor composed of sheets of cells with plump ovoid nuclei, distinct nucleoli, and scant eosinophilic cytoplasm. Mitoses were present, averaging about 2 per 10 high power fields with scattered individual apoptotic cells. Numerous laminated calcified bodies (Liesegang rings) were observed with confluence of these bodies to form larger foci of dystrophic mineralization. These features clearly established the malignant nature of this tumor. Immunohistochemically, the tumor was positive for synaptophysin, focally positivity for CAM 5.2 and had a Ki-67 proliferation index of approximately 25%. This is the first report of a tumor with features of a malignant variant of calcifying epithelial odontogenic tumor and neuroendocrine differentiation.

Plasma cell myeloma (PCM) is defined as a clonal disease of terminally differentiated plasma cells that secrete immunoglobulin. The biologic underpinnings of IgA-type multiple myeloma's (IgAMM) aggressive nature, including its increased morbidity and mortality, have not been elucidated. We describe the clinical, phenotypic, and cytogenetic characteristics of IgA-MM. Flow-cytometry analysis was performed to phenotype clonal plasma cell populations, and interface with fluorescent in situ hybridization (iFISH) to exploit cytogenetics to determine risk stratification; 68.1% of cases were of intermediate or high risk. On flow cytometry, samples from our IgA-PCM cohort revealed less frequent CD56 expression when compared to samples with other PCM subtypes. Our study demonstrated lower frequency of CD56 expression (52.8%). We hypothesize that loss of CD56 may play a significant role in the aggressive behavior of IgA-PCM due to the loss of cell-to-cell adhesion resulting in a higher propensity for extramedullary presentation.

Meningioma is the most common intracranial neoplasm, yet there is no effective therapy for recurrent/refractory meningiomas after surgery and radiation. Prostate-specific membrane antigen (PSMA) is an enzyme upregulated on endothelial cells of multiple neoplasms and is being investigated as a theranostic target. Until now, PSMA has not been studied in meningiomas. We aimed to verify PSMA endothelial expression in meningiomas, detect tumor grade variability, and investigate the relationship of PSMA signal with tumor recurrence. We analyzed 96 archival meningiomas including 58 de novo and 38 recurrent specimens. All specimens were stained routinely and immunostained for CD31 and PSMA. Slides were scanned and analyzed producing raw data for images of PSMA, CD31, PSMA/CD31, and PSMA/vasculature. PSMA expression was seen within 98.9% of meningioma samples. In the total cohort, higher-grade tumors had increased expression of raw PSMA and PSMA/CD31, and PSMA/vasculature ratios compared to grade 1 tumors. PSMA expression and PSMA/vasculature ratios (p = 0.0015) were higher in recurrent versus de novo tumors among paired samples. ROC curves demonstrated PSMA/CD31, PSMA/vasculature, and raw CD31 as indicators of tumor recurrence. Thus, PSMA is expressed within endothelial cells of meningiomas, is increased with tumor grade and recurrence, and persists with prior irradiation.

Breast cancers represent complex ecosystem-like networks of malignant cells and their associated microenvironment. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are biomarkers ubiquitous to clinical practice in evaluating prognosis and predicting response to therapy. Recent feats in breast cancer have led to a new digital era, and advanced clinical trials have resulted in a growing number of personalized therapies with corresponding biomarkers. In this state-of-the-art review, we included the latest 10-year updated recommendations for ER, PR, and HER2, along with the most salient information on tumor-infiltrating lymphocytes (TILs), Ki-67, PD-L1, and several prognostic/predictive biomarkers at genomic, transcriptomic, and proteomic levels recently developed for selection and optimization of breast cancer treatment. Looking forward, the multi-omic landscape of the tumor ecosystem could be integrated with computational findings from whole slide images and radiomics in predictive machine learning (ML) models. These are new digital ecosystems on the road to precision breast cancer medicine.

Whether sentinel lymph node biopsy (SLNB) should be performed in patients with microinvasive breast cancer (MIBC) has been a matter of debate over the last decade. MIBC has a favorable prognosis and while metastasis to the axilla is rare, it can impact treatment recommendations. In this study we evaluated clinical and histological features in both MIBC and background DCIS including ER, PR, and HER-2, number of foci of MIBC, the extent of the DCIS, nuclear grade, presence of comedo necrosis, as well as surgical procedures, adjuvant treatment and follow up to identify variables which predict disease free survival (DFS), as well as the factors which influence clinical decision making. Our study included 72 MIBC patients with a mean patient follow-up time of 55 months. Three patients with MIBC had recurrence, and two deceased, leaving five patients in total with poor long-term outcomes and a DFS rate of 93.1%. Performing mastectomy, high nuclear grade, and negativity for ER and HER-2 were found to be associated with the use of SLNB, although none of these variables were found to be associated with DFS. One positive lymph node case was discovered following SLNB in our study. This suggests the use of SLNB may provide diagnostic information to some patients, although these are the anomalies. When comparing patients who had undergone SLNB to those which had not there was no difference in DFS. Certainly, the use of SLNB in MIBC is quite the conundrum. It is important to acknowledge that surgical complications have been reported, and traditional metrics used for risk assessment in invasive breast cancer may not hold true in the setting of microinvasion.