Poorly-differentiated Carcinoma Research Articles

Abstract 3499: Non-small cell lung cancer (NSCLC) histology classification using DNA methylation data captured from liquid biopsies

Abstract Background: Non-small cell lung cancer (NSCLC) makes up ~85% of lung cancers, and its major subtypes are adenocarcinoma (AD) and squamous cell carcinoma (SC). The histology classification of NSCLC has significant therapeutic and prognostic implications. As liquid biopsies are rapid and non-invasive, computational methods to classify NSCLC subtypes using cell-free DNA (cfDNA) are desired. Methods: Using The Cancer Genome Atlas (TCGA) NSCLC methylation data, we developed a method to classify AD and SC subtypes from cfDNA samples. We mapped TCGA methylation data to Guardant Infinity’s promoter regions and transformed them to allow for the transfer of the TCGA trained model to Infinity cfDNA epigenomic data. An advantage of this approach is that TCGA training data originates from the primary tumor, while cfDNA samples have low tumor fraction (TF) and may also contain signals from metastatic tumors. We trained a penalized Logistic Regression model with LASSO. To better fit the model to Infinity cfDNA data, we performed region filtering. Results: Our model effectively classified AD and SC subtypes from TCGA samples (AUC 0.97) (10-fold cross validation; Table 1). When evaluating on cfDNA samples with epigenomic TF ≥ 1%, the final model shows reasonable performance (AUC 0.94) (Table 1); the performance decreases when reduced to TF > 0.05% (AUC 0.89) as expected (Table 1). When evaluating cfDNA from uncategorized lung samples, the predicted AD probabilities have significant association with KRAS mutations (p-value = 0.027). Conclusion: Our results show that the penalized Logistic Regression model trained with tissue TCGA methylation data through mapping, transformation, and region selection can classify NSCLC subtypes from cfDNA samples. This method may offer a fast, non-invasive tool to inform subtype-based clinical decisions, especially in the setting of poorly-differentiated carcinomas, and to identify subtype switches upon resistance to targeted therapies. Table 1: Model evaluation on tissue TCGA samples and cfDNA Infinity samples (different TF cutoffs) Sample type N samples AUC Accuracy Sensitivity Specificity Precision F1 score tissue TCGA 907 0.97 0.93 0.94 +/- 0.02 0.93 +/- 0.02 0.94 +/- 0.02 0.94 +/- 0.01 cfDNA Infinity 17 (TF ≥ 1%) 0.94 0.88 0.83 +/- 0.3 0.91 +/- 0.17 0.83 +/- 0.3 0.83 +/- 0.21 cfDNA Infinity 29 (TF > 0.05%) 0.89 0.83 0.88 +/- 0.23 0.81 +/- 0.17 0.64 +/- 0.28 0.74 +/- 0.2 Citation Format: Laura Tung, Denis Tolkunov, Catalin Barbacioru, Deepika Kale, Scott Shell, Jill Tsai, Leylah Drusbosky, Kaushal Parikh, Han-Yu Chuang. Non-small cell lung cancer (NSCLC) histology classification using DNA methylation data captured from liquid biopsies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3499.

A complex of cadherin 17 with desmocollin 1 and p120-catenin regulates colorectal cancer migration and invasion according to the cell phenotype

BackgroundCadherin-17 (CDH17), a marker of differentiation in intestinal cells, binds and activates α2β1 integrin to promote cell adhesion and proliferation in colorectal cancer (CRC) metastasis. Furthermore, CDH17 associates with p120- and β-catenin in a manner yet to be fully elucidated. In this report, we explored the molecular mediators involved in this association, their contribution to CRC dissemination and potential therapeutic implications.MethodsProteomic and confocal analyses were employed to identify and validate CDH17 interactors. Functional characterization involved the study of proliferation, migration, and invasion in cell lines representative of various phenotypes. Immunohistochemistry was conducted on CRC tissue microarrays (TMA). In vivo animal experiments were carried out for metastatic studies.ResultsWe found that desmocollin-1 (DSC1), a desmosomal cadherin, interacts with CDH17 via its extracellular domain. DSC1 depletion led to increased or decreased invasion in CRC cells displaying epithelial or mesenchymal phenotype, respectively, in a process mediated by the association with p120-catenin. Down-regulation of DSC1 resulted in an increased expression of p120-catenin isoform 1 in epithelial cells or a shift in cellular location in mesenchymal cells. Opposite results were observed after forced expression of CDH17. DSC1 is highly expressed in budding cells at the leading edge of the tumor and associates with poor prognosis in the stem-like, mesenchymal CRC subtypes, while correlates with a more favorable prognosis in the less-aggressive subtypes. In vivo experiments demonstrated that DSC1 silencing reduced tumor growth, liver homing, and metastasis in CRC mesenchymal cells. Furthermore, a synthetic peptide derived from CDH17, containing the NLV motif, effectively inhibited invasion and liver homing in vivo, opening up new possibilities for the development of novel therapies focused on desmosomal cadherins.ConclusionsThese findings shed light on the multifaceted roles of CDH17, DSC1, and p120-catenin in CRC metastasis, offering insights into potential therapeutic interventions for targeting desmosomal cadherins in poorly-differentiated carcinomas.

EGFR and HER-2 oncogenes expression in an experimental model of two-stage chemically induced carcinogenesis in mouse skin

The aim of the study was to investigate the expression of EGFR and HER-2 oncogenes using an experimental two stage chemically induced carcinogenesis protocol on the dorsal skin in FVB/N mice.Forty female FVB/N mice 4 weeks old, were grouped into one control (n = 8) and two experimental groups (Group A: n = 16, Group B: n = 16) following a randomization process. Two-stage carcinogenesis protocol, was implicated, including an initial treatment with 97.4 nmol DMBA on their shaved dorsal skin and subsequent treatments of 32.4 nmol TPA applications after 13 weeks for Group A and after 20 weeks for Group B. The control group C, received no treatment. Skin was examined weekly for tumor development. Post-experiment, animals were euthanized for tissue analysis.The histological status of the skin lesions in the experimental groups corresponded well with tumour advancement (from dysplasia to poorly-differentiated carcinoma). Tumour sections were evaluated histologically and immunohistochemically. EGFR expression was found significantly higher in precancerous and malignant tumours (p = 042 and p = 008 respectively), while tended to be higher in benign tumours (p = 079), compared to normal histology. Moreover, mean percentage of EGFR positive expression in malignant tumours was significantly higher than in benign tumours (p < 001). HER-2 expression was found significantly higher in precancerous and malignant tumours (p = 042 and p = 015 respectively), while tended to be higher in benign tumours (p = 085), compared to normal histology. Furthermore, mean percentage of HER-2 positive expression in malignant tumours was significantly higher than in benign tumours (p = 005).The study demonstrated that in FVB/N mice subjected to a two-stage chemically induced carcinogenesis protocol, there was a significant increase in the expression of EGFR and HER-2 oncogenes in precancerous and malignant skin lesions compared to normal tissue. This suggests a potentially early role of these oncogenes in the progression of skin tumours in this model.

DICER1-Mutant Thyroid Carcinoma of Unusual Morphology: A Follicular Carcinoma with Bizarre Nuclei or a Novel Entity?

Abstract Introduction/Objective DICER1 mutations are associated with a host of benign and malignant neoplasms, of which the thyroid ranks among those with the highest prevalence. We present a case of a DICER1-mutant thyroid carcinoma with unusual morphologic features not described in the existing literature. Methods/Case Report A 29-year old 33 weeks pregnant female presented with swelling of the left neck. The patient subsequently underwent an ultrasound, which revealed a thyroid lesion measuring 6.2cm in greatest dimension. Labs including TSH and free T4 wree within normal 3rd trimester limits. Following an unremarkable delivery, FNA revealed loosely clustered cells with marked hyperchromasia and nuclear pleomorphism and variable microfollicular architecture in a colloid-containing background. Though definitively malignant, the anomalous cytomorphology of this neoplasm prompted molecular testing by Afirma Genomic Sequencing Classifier and Xpression Atlas next-generation sequencing, which was significant for a DICER1 hotspot mutation (p.E1705K c.5113G&amp;gt;A). Follow-up total thyroidectomy was pertinent for a tan-red, nodular mass involving 95% of the thyroid. Histomorphology revealed a neoplasm of primarily macrofollicular architecture with scattered microfollicles and intervening zones that appeared poorly-to-undifferentiated. Cells demonstrated bizarre hyperchromatic, pleomorphic nuclei with multinucleation and Azzopardi effect. Capsular invasion was identified. Inconsistent with a poorly-differentiated or anaplastic carcinoma, the mitotic rate and Ki-67 index were low at &amp;lt; 1/2mm2 and 1-2%, respectively. The tumor was consequently theorized to represent a follicular carcinoma with bizarre nuclei or other entity associated with DICER1 mutations not previously described. To date, no recurrence or metastasis has occurred. Results (if a Case Study enter NA) NA Conclusion We report an enigmatic morphology of a thyroid cancer associated with a DICER1 mutation. DICER1 mutations have been hitherto described in follicular carcinoma, papillary carcinoma, poorly-differentiated carcinoma and thyroblastoma, none of which are consistent with the present case. Thus, we conjecture that this morphomolecular profile may constitute a "follicular carcinoma with bizarre nuclei" or other novel entity not previously reported. Further investigation should be pursued to determine the nature of this entity, its pathophysiology, epidemiology, possible association with germline DICER1 syndrome, and relationship between morphology and prognosis in patients with DICER1 mutations.

Isolated Castrate-resistant Prostate Cancer Metastasis to Both Adrenal Glands Detected on 68Ga PSMA PET/CT.

A 61-year-old male patient, who had undergone radical prostatectomy, underwent 68Ga labeled prostate-specific membrane antigen (PSMA) positron emission tomography/computerized tomography (PET/CT) for evaluation of suspected biochemical recurrence of prostate cancer (PCa). PET/CT scan showed increased 68Ga PSMA expressions in hypodense mass lesions in both adrenal gland localizations. An adrenal gland tru-cut biopsy was performed for the right side, which showed poor-differentiated carcinoma metastases associated with the patient's high-grade PCa. As far as we could determine based on an extensive literature search, this is the second case in which isolated adrenal metastasis was detected by 68Ga PSMA PET/CT study in a patient with PCa.

The potential oncogenic effect of tissue-specific expression of JC polyoma T antigen in digestive epithelial cells.

JC polyoma virus (JCPyV), a ubiquitous polyoma virus that commonly infects people, is identified as the etiologic factor for progressive multifocal leukoencephalopathy and has been closely linked to various human cancers. Transgenic mice of CAG-loxp-Laz-loxp T antigen were established. T-antigen expression was specifically activated in gastroenterological target cells with a LacZ deletion using a cre-loxp system. Gastric poorly-differentiated carcinoma was observed in T antigen-activated mice using K19-cre (stem-like cells) and PGC-cre (chief cells), but not Atp4b-cre (parietal cells) or Capn8-cre (pit cells) mice. Spontaneous hepatocellular and colorectal cancers developed in Alb-cre (hepatocytes)/T antigen and villin-cre (intestinal cells)/T antigen transgenic mice respectively. Gastric, colorectal, and breast cancers were observed in PGC-cre/T antigen mice. Pancreatic insulinoma and ductal adenocarcinoma, gastric adenoma, and duodenal cancer were detected in Pdx1-cre/T antigen mice. Alternative splicing of T antigen mRNA occurred in all target organs of these transgenic mice. Our findings suggest that JCPyV T antigen might contribute to gastroenterological carcinogenesis with respect to cell specificity. Such spontaneous tumor models provide good tools for investigating the oncogenic roles of T antigen in cancers of the digestive system.

Cancers of unknown primary: Survival by histologic type, demographic features, and treatment in the U.S. Military Health System

BackgroundCancers of unknown primary (CUP), a group of heterogenous metastatic cancers lacking a known primary site, have poor prognosis. This study compared survival of CUP by histologic type, patient characteristics, and treatment in the U.S. Military Health System (MHS), which provides universal care to its members. MethodsPatients histologically diagnosed with CUP were identified from the U.S. Department of Defense (DoD)’s Automated Central Tumor Registry. Median survival with 95 % confidence intervals was calculated for demographic and treatment variables by histologic type. A multivariable accelerated failure time model estimated time ratios and 95 % confidence intervals. ResultsThe study included 3358 CUP patients. The most prevalent CUP in this study was well- and moderately-differentiated adenocarcinomas. Median survival varied by histologic type with squamous cell carcinoma having the longest at 25.1 months and poorly-differentiated carcinomas having the shortest at 3.0 months. For each histologic type, survival was generally similar by sex and active-duty status although women with well- and moderately-differentiated adenocarcinoma had longer survival than their male counterparts. Younger patients tended to have longer survival than those aged 65 years or older. Generally, there were no racial differences in survival except poorer survival for Black patients than White patients in the group of other histologic types. Patients with chemotherapy and radiation treatment generally had improved survival whereas patients with squamous cell carcinoma who received chemotherapy had shorter survival than those without. ConclusionSurvival generally did not differ between racial groups, which may be related to equal healthcare access despite racial background. Further studies are warranted to better understand how survival in the MHS compares with that in the general U.S. population.

Molecular Classification of Extrapulmonary Neuroendocrine Carcinomas With Emphasis on POU2F3-positive Tuft Cell Carcinoma.

Extrapulmonary neuroendocrine carcinomas (EP-NECs) are associated with a poor clinical outcome, and limited information is available on the biology and treatment of EP-NECs. We studied EP-NECs by applying the recent novel findings from studies of pulmonary neuroendocrine carcinomas, including POU2F3, the master regulator of tuft cell variant of small cell lung carcinomas. A cohort of 190 patients with surgically resected EP-NECs or poorly differentiated carcinomas (PDCs) were established. Immunohistochemistry (IHC) for POU2F3 along with ASCL1, NEUROD1, YAP1, and conventional neuroendocrine markers was performed on tissue microarrays. Selected cases with or without POU2F3 expression were subjected to targeted gene expression profiling using nCounter PanCancer Pathway panel. POU2F3-positive tuft cell carcinomas were present in 12.6% of EP-NEC/PDCs, with variable proportions according to organ systems. POU2F3 expression was negatively correlated with the expression levels of ASCL1, NEUROD1, and conventional neuroendocrine markers ( P <0.001), enabling IHC-based molecular classification into ASCL1-dominant, NEUROD1-dominant, POU2F3-dominant, YAP1-dominant, and not otherwise specified subtypes. Compared wih POU2F3-negative cases, POU2F3-positive tuft cell carcinomas showed markedly higher expression levels of PLCG2 and BCL2 , which was also validated in the entire cohort by IHC. In addition to POU2F3, YAP1-positive tumors were a distinct subtype among EP-NEC/PDCs, characterized by unique T-cell inflamed microenvironment. We found rare extrapulmonary POU2F3-positive tumors arising from previously unappreciated cells of origin. Our data show novel molecular pathologic features of EP-NEC/PDCs including potential therapeutic vulnerabilities, thereby emphasizing the need for focusing on unique features of EP-NEC/PDCs.

Exploring Real World Outcomes with Nivolumab Plus Ipilimumab in Patients with Metastatic Extra-Pulmonary Neuroendocrine Carcinoma (EP-NEC).

Simple SummaryExtrapulmonary neuroendocrine carcinomas (EP-NEC) are a group of tumors which are often metastatic and characterized by poor outcomes. Platinum-etoposide chemotherapy is the current front-line therapy for metastatic EP-NEC, and has been adapted from small cell lung cancer. There are limited treatment options for patients with platinum-resistant EP-NEC, with no current established second-line standard of care. Recently, there has been mixed evidence for the role of immunotherapy in EP-NEC, with limited existing prospective data. In this multicenter retrospective analysis, we compared outcomes between patients with refractory EP-NEC who received single, dual immune check point inhibitors (ICPIs) and cytotoxic chemotherapy in the second-line setting. This real world experience suggests that utilizing ipilimumab and nivolumab in patients with second-line pretreated EP-NEC may be more effective than other existing treatment options.Background: Dual utilization of the immune checkpoint inhibitors (ICPIs) nivolumab plus ipilimumab has demonstrated clinical promise in the treatment of patients with refractory high-grade neuroendocrine neo-plasms (NENs) in phase II clinical trials (DART SWOG 1609 and CA209), while single agent ICPIs have largely been ineffective for these types of tumors. While both trials demonstrated promising results in high grade NENs, there was no adequate description of the association between tumor differentiation (high-grade well-differentiated neuroendocrine tumor vs poorly-differentiated extra-pulmonary neuroendocrine carcinoma (EP-NEC) and ICPI outcomes in the DART SWOG 1609 trial. Our study reports on the effectiveness and toxicity profile of dual ICPIs in a real world second-line EP-NEC patient population. Methods: Data on metastatic EP-NEC patients, treated with either ICPIs (single and dual ICPIs) or chemo-therapy in the second-line setting, were retrieved from databases of three comprehensive cancer centers. Associations between treatment characteristics and outcomes, including progression-free survival (PFS) and overall survival (OS), were evaluated. Results: From 2007 to 2020, we identified 70 patients with metastatic EP-NEC (predominantly of gastro-enteropancreatic origin), of whom 42 patients (23 males, 19 females, median age 62 years old) were eligible for the final analysis. All patients were refractory to platinum etoposide doublet chemotherapy in the first-line setting. The median PFS for patients who received dual ICPIs (11 patients), single agent ICPI (8 patients), and cytotoxic chemotherapy (23 patients) was 258 days, 56.5 days, and 47 days, respectively (p = 0.0001). Median overall survival (OS) for those groups was not reached (NR), 18.7 months, and 10.5 months, respectively (p = 0.004). There were no significant differences in treatment outcomes in patients according to tumor mismatch repair (MMR) or tumor mutational burden (TMB) status. Grade 3–4 adverse events (AEs) were reported in 11.1% of the patients who received dual ICPIs; however, none of these AEs led to permanent treatment discontinuation. Conclusions: In the second-line setting, patients with EP-NECs treated with dual ICPIs (nivolumab plus ipilimumab) experienced improved PFS and OS compared to patients treated with single agent ICPI or cytotoxic chemotherapy. These results echo some of the current evidence for ICPIs in grade 3 NENs and need to be validated in future prospective studies.

Estrogen receptor expression is modulated in human and mouse prostate epithelial cells during cancer progression

Substantial data posit estrogen receptors (ERs) as promising targets for prostate cancer (PCa) therapeutics. However, the trials on assessing the chemo-preventive or therapeutic potential of ER targeting drugs or selective estrogen receptor modulators (SERMs) have not yet established their clinical benefits. This could be ascribed to a possible modulation in the ER expression during PCa progression. Further it is warranted to test various ER targeting drugs in appropriate preclinical models that simulate human ER expression pattern during PCa progression. The study was undertaken to revisit the existing data on the epithelial ER expression pattern in human cancerous prostates and experimentally determine whether these patterns are replicated in TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice, a model for human PCa. Estradiol (E2) binding to the plasma membrane of the epithelial cells and its modulation during the PCa progression in TRAMP were also investigated.A reassessment of the existing data revealed a trend towards downregulation in the epithelial expression of wild-type ESR1 transcripts in high-grade PCa, compared to non-cancerous prostate in humans. Next, epithelial cell-enriched populations from TRAMP prostates (TP) displaying low-grade prostatic intraepithelial neoplasia (LGPIN), high-grade PIN (HGPIN), HGPIN with well-differentiated carcinoma (PIN + WDC), WDC (equivalent to grade 2/3 human PCa), and poorly-differentiated carcinoma (PDC-equivalent to grade 4/5 human PCa) revealed significantly higher Esr1 and Esr2 levels in HGPIN and significantly reduced levels in WDC, compared to respective age-matched control prostates. These patterns for the nuclear ERs were similar to the trend shown by E2 binding to the plasma membrane of the epithelial cells during PCa progression in TRAMP. E2 binding to epithelial cells (EpCAM+), though significantly higher in TPs displaying LGPIN, decreased significantly as the disease progressed to WDC. The study highlights a reduction in the epithelial ESR level with the PCa progression and this pattern was evident in both humans and TRAMP. These observations may have major implications in refining PCa therapeutics targeting ER.

What Is the Status of Immunotherapy in Neuroendocrine Neoplasms?

Immunotherapy has changed the treatment of patients with advanced cancer, with different phase III trials showing durable responses across different histologies. This review focuses on the preclinical and clinical evidence of potential predictive biomarkers of response and efficacy of immunotherapy in neuroendocrine neoplasms (NENs) of gastro-entero-pancreatic origin. PD-L1 staining by immunohistochemistry has shown heterogeneous results across different studies in both well-differentiated neuroendocrine tumors (NETs) and poorly-differentiated neuroendocrine carcinomas (NECs). Tumor mutational burden in NENs is low, but seems to be higher in NECs. Immune infiltrate (CD3+ lymphocytes) at the tumor microenvironment (TME) is present in NETs and NECs. However, results from clinical trials with immunotherapy as monotherapy o combinations have shown limited efficacy. Further investigation into new strategies aside from anti-CTLA-4/PD-1/PD-L1 antibodies, validation of predictive biomarkers, and better population selection for clinical trials in NENs are more than needed in the near future.

Expression of epithelial membrane protein (EMP) 1, EMP 2, and EMP 3 in thyroid cancer.

Purpose Epithelial membrane protein (EMP) 1, EMP2, and EMP3 are expressed in various types of tumors and have been reported to be involved in carcinogenesis. In this study, we aimed to investigate the expression of these proteins in primary and metastatic thyroid cancer and its clinical implication. Methods EMP1, EMP2, and EMP3 immunohistochemistry was performed using tissue microarrays of 545 primary thyroid carcinomas [338 papillary thyroid carcinoma (PTC), 111 follicular carcinoma (FC), 69 medullary carcinoma (MC), 23 poorly differentiated carcinoma (PDC), and 4 anaplastic carcinoma (AC)] and 59 recurrent or metastatic PTCs. Results EMP1 showed high expression in AC, PTC, FC (P<0.001), and EMP2 was highly expressed in AC (P<0.001). EMP1 and EMP2 were not expressed in stromal cells. Expression of EMP3 in tumor cells [EMP3 (T)] was higher in PDC, PTC, and AC (P<0.001), and expression in stromal cells [EMP3 (S)] was observed only in AC and PTC (P=0.001). The expression of EMP1 (P=0.002) and EMP3 (T) (P<0.001) was higher in conventional PTC than in follicular variant PTC. PTC with BRAF V600E mutation showed higher expression of EMP1 (P<0.001), EMP3 (T) (P<0.001), and EMP3 (S) (P=0.012) than PTC without BRAF V600E mutation. In the PTC without BRAF V600E mutation group, expression of EMP3 (S) was associated with shorter disease free survival (P=0.004). Metastatic PTC showed higher EMP2 (3.4% vs. 0%, P=0.022) and lower EMP3 (T) (44.1% vs. 66%, P=0.001) than primary PTC. Conclusions Expression of EMP1, EMP2, and EMP3 is different according to the subtypes of thyroid cancer. Further studies are needed to determine their role as prognostic markers and treatment target in thyroid cancer.

Role of CD200 in the Detection of Nonhematologic Neoplasms by Routine Flow Cytometry Analysis

Abstract Objectives While flow cytometry is routinely used in the diagnostic work-up of hematolymphoid malignancies, its role in identifying non-hematolymphoid neoplasms is controversial. While a diagnosis of “non-hematolymphoid process” may be suggested by flow cytometry, typically, CD45-negative entities are not further characterized by their immunophenotypic profile. Some markers, such as CD56, have been well documented in non-hematolymphoid malignancies, such as high-grade neuroendocrine carcinomas (Stacchini, et al, 2018; Bryson et al, 2002). Other cell surface markers that are routinely studied with flow cytometry panels, such as CD200, are less well-described in the literature with regards to their presence/absence in non-hematolymphoid processes. We examined all flow cytometry cases from our institution over a 5-year period to identify trends in the immunophenotypes of non-hematolymphoid malignancies that were known to be CD45-negative and CD56-positive by flow cytometry. Methods We examined 3634 flow cytometry cases (2015-2020) and identified non-hematolymphoid cases based upon lack of CD45 expression. After excluding multiple myeloma cases from the CD45-negative entities, we were left with 19 CD45-negative cases. Chart review of these cases confirmed them as non-hematolymphoid by concurrent surgical pathology/cytopathology studies. Of these 19 cases, 2 were excluded because CD56 was not evaluated. Results Of the 17 CD45-negative/CD56-positive cases, 16 showed CD200 positivity (94%). Of these CD200-positive cases, 10 were ultimately diagnosed as small cell carcinoma (59%), 1 was diagnosed as Merkel cell carcinoma (6%), 1 was diagnosed as melanoma (6%), 1 was diagnosed as poorly-differentiated carcinoma (6%), 1 was diagnosed as Ewing-like sarcoma (6%), and 2 were unclassified further (12%). The single CD200-negative case was diagnosed as poorly-differentiated acinar cell carcinoma (6%). All cases of small cell carcinoma that were evaluated by flow cytometry showed expression of CD200 and CD56. Conclusions Our findings suggest that in CD45-negative/CD56-positive non-hematolymphoid malignancies, particularly small cell carcinoma, CD200 is frequently positive. CD200 was also found to be positive in rare cases of other non-hematolymphoid malignancies within the differential diagnosis of small round blue cell tumors. These findings indicate that CD200 may be a useful marker in suggesting the possibility of small cell carcinoma in non-hematolymphoid specimens that are evaluated by flow cytometry.

Periostin expression and its supposed roles in benign and malignant thyroid nodules: an immunohistochemical study of 105 cases

BackgroundThyroid tumors are often difficult to histopathologically diagnose, particularly follicular adenoma (FA) and follicular carcinoma (FC). Papillary carcinoma (PAC) has several histological subtypes. Periostin (PON), which is a non-collagenous extracellular matrix molecule, has been implicated in tumor invasiveness. We herein aimed to elucidate the expression status and localization of PON in thyroid tumors.MethodWe collected 105 cases of thyroid nodules, which included cases of adenomatous goiter, FA, microcarcinoma (MIC), PAC, FC, poorly differentiated carcinoma (PDCa), and undifferentiated carcinoma (UCa), and immunohistochemically examined the PON expression patterns of these lesions.ResultsStromal PON deposition was detected in PAC and MIC, particularly in the solid/sclerosing subtype, whereas FA and FC showed weak deposition on the fibrous capsule. However, the invasive and/or extracapsular regions of microinvasive FC showed quite strong PON expression. Except for it, we could not find any significant histopathological differences between FA and FC. There were no other significant histopathological differences between FA and FC. Although PDCa showed a similar PON expression pattern to PAC, UCa exhibited stromal PON deposition in its invasive portions and cytoplasmic expression in its carcinoma cells. Although there was only one case of UCa, it showed strong PON immunopositivity. PAC and MIC showed similar patterns of stromal PON deposition, particularly at the invasive front.ConclusionsPON may play a role in the invasion of thyroid carcinomas, particularly PAC and UCa, whereas it may act as a barrier to the growth of tumor cells in FA and minimally invasive FC.

S2777 Metastatic Cervical Adenocarcinoma: A Rare Cause of Upper GI Bleeding

INTRODUCTION: Primary small bowel neoplasms are rare, accounting for 1–5% of all gastrointestinal (GI) tract malignancies. Metastatic small bowel lesions are more common than primary and typically arise from malignant melanoma and adenocarcinomas from the lung, kidney and colon. Distant metastasis from cervical adenocarcinoma is extremely rare, most often seen with advanced stages. We report the case of a young female with known cervical cancer presenting with acute abdominal pain and melena secondary to metastatic ulcerated duodenal mass. CASE DESCRIPTION/METHODS: 43-year-old female with stage IIIB cervical adenocarcinoma status post pelvic radiation, human immunodeficiency virus (HIV) on antiretroviral therapy, and right upper extremity deep vein thrombosis on Eliquis presented with mild diffuse abdominal pain and intermittent melena over four weeks. On admission, she was afebrile and hemodynamically stable. Laboratory findings were significant for acute blood loss anemia with hemoglobin 3.3 g/dL (7.6 g/dL two months prior). Computed tomography abdomen and pelvis showed a heterogenous cervical mass near the sigmoid colon without signs of obstruction or perforation. Three units of packed red blood cells were transfused, proton pump inhibitor drip was initiated, and anticoagulation was held. Esophagogastroduodenoscopy revealed a large, infiltrative, ulcerated and friable mass within the second portion of the duodenum (Figure 1), occupying 50% of the luminal circumference with stigmata of recent bleeding. Duodenal mass biopsies confirmed metastatic cervical adenocarcinoma (Figures 2 and 3). She had no further bleeding throughout her course and was discharged home with palliative oncology care. DISCUSSION: Cervical cancer is the second most common gynecologic malignancy. Up to half of stage III cervical cancer patients present with distant metastases, most often to liver, lungs and bone marrow; however, only approximately 8% have GI tract metastases, often to the rectosigmoid secondary to local extension. Isolated metastases to the small bowel are exceedingly rare. Clinical presentations include small bowel obstruction, anemia, abdominal pain and, less commonly, overt GI bleeding. Early diagnosis of such an unusual pattern of metastasis related to cervical cancer is vital for optimal therapeutic management and prediction of prognosis.Figure 1.: Ulcerated mass at second portion of the duodenum.Figure 2.: Medium-power view demonstrating reactive duodenal mucosa on the top and poorly-differentiated carcinoma growing up from the submucosa (H&E, 100x).Figure 3.: High-power view demonstrating marked pleomorphism, 'bubbly' cytoplasm, apoptotic bodies and numerous atypical mitotic figures (H&E, 400x).

Desmoplastic Small Round Cell Tumor with an Unusual Site and Age Presentation: A Case Report and Literature Review

Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive sarcoma usually arising in the abdomen or pelvis of young males under 30 years of age. We present a case of a 32-year-old male with a palpable axillary mass and multiple bilateral lung nodules. Excisional biopsy of the axillary mass showed sheets and nests of small round cells with numerous mitoses, areas of necrosis, and desmoplastic stroma. Initial immunohistochemical stains performed at an outside institution demonstrated immunoreactivity for epithelial markers and focal reactivity for breast markers. The tumor was initially diagnosed as poorly differentiated carcinoma, with consideration of a possible primary breast cancer. Additional workup demonstrated strong, diffuse positivity for desmin in tumor cells, leading to the final diagnosis of DSRCT. Subsequent molecular testing confirmed DSRCT with EWSR1 gene rearrangement. This case illustrates the importance of recognizing the morphologic features of DSRCT in the setting of uncommon location or patient age.

Digestive Neuroendocrine Neoplasms (NEN): French Intergroup clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, GTE, RENATEN, TENPATH, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR)

IntroductionThis document is a summary of the French Intergroup guidelines regarding the management of digestive neuroendocrine neoplasms (NEN) published in February 2020 (www.tncd.org). MethodsAll French medical societies involved in the management of NEN took part in this work. Recommendations were graded into four categories (A, B, C or D), according to the level of evidence found in the literature until May 2019. ResultsThe management of NEN is challenging because of their heterogeneity and the increasing complexity of diagnostic and therapeutic procedures. Pathological analysis is required for their diagnostic and prognostic characterization, which mainly relies on differentiation, grade and stage. The two main emergency situations are functioning syndromes and poorly-differentiated carcinoma. Chromogranin A is the main biochemical marker of NET, although of limited clinical interest. Initial characterization relies on morphological and isotopic imaging. The treatment of localized NET relies on watchful follow-up and local or surgical resection depending on its supposed aggressiveness. Treatment options for metastatic disease include surgery, somatostatin analogues, chemotherapy, targeted therapies, organ-driven locoregional therapies and peptide-receptor radionuclide therapy. As specific predictive factors of treatment efficacy are yet to be identified and head-to-head comparisons have not or only rarely been performed, the therapeutic strategy currently depends on prognostic factors. Cumulative toxicity and the impact of treatment on quality of life must be considered since survival is relatively long in most patients with NET. ConclusionThese guidelines are proposed to achieve the most beneficial therapeutic strategy in clinical practice as the therapeutic landscape of NEN is becoming ever more complex. These recommendations are permanently being reviewed.

2020 challenges in diagnosis and staging of lung cancer

Pathology plays an important role in diagnosis and management of patients with non-small cell lung carcinoma (NSCLC). The current (2015) WHO classification of lung tumours includes histologic and immunophenotypic (IHC) criteria. Adenocarcinomas are the primary focus of shifting nomenclature, emphasising histologic patterns with clinical and biological relevance. Minimally invasive and lepidic-predominant non-mucinous adenocarcinomas represent well-differentiated tumours, while solid and/or micropapillary growth patterns signify poorly-differentiated adenocarcinomas. Poorly-differentiated carcinomas that cannot be classified on the basis of histology alone can instead be subclassified using a limited IHC panel targeting TTF-1 and p63/p40. For adenocarcinomas with non-invasive (lepidic) components, pT staging hinges on the size and extent of only the invasive component. Multifocal tumours are staged based on a combination of gross growth characteristics and histologic findings. Pathology’s role extends beyond diagnosis and staging in response to expectations that cells and tissues will be available for expanded biomarker testing in patients with advanced stage disease. Testing strategies for predictive biomarkers frequently include a combination of immunohistochemistry and increasingly comprehensive molecular profiling as single gene assays become less common. Panels are constructed to balance the number of actionable targets over and against our ability to test extremely small amounts of viable tumour.

Outcomes after high-dose radiation in management of neuroendocrine neoplasms.

616 Background: In this study, we analyze outcomes after the use of high-dose radiation therapy (RT) in management of neuroendocrine neoplasms (NENs) at a high-volume center. Methods: We performed a retrospective review of patients who received high-dose RT (defined as biologically effective dose (BED) &gt;40, α/β = 10) for their NEN. Patients with small cell lung cancer and Merkel cell carcinoma were excluded, given their unique treatment paradigms. Results: 61 patients completed a radiation course with BED &gt;40 for their NEN (median BED 70, range 44-180). Most tumors were gastroenteropancreatic in origin (n = 20); additional primary sites included lung (n = 11), head and neck (n = 10), cervix (n = 6), other (n = 9) and unknown (n = 5). 56% (n = 34) had well-differentiated (WD) neuroendocrine tumors, and 44% (n = 27) had poorly-differentiated (PD) neuroendocrine carcinomas. Disease stage at the time of RT was localized/locally advanced (LLA, n = 27), or metastatic/recurrent (MR, n = 34). The intent of RT was definitive (n = 18), post-operative (n = 10), for oligoprogression (n = 18), or purely palliative (n = 15). 48 patients had follow-up imaging at a median follow-up of 20 months after radiation. Outcomes were grouped by differentiation and stage, with median time to progression (mTTP) in months (Table). 8% of patients had local progression, while 44% developed new metastases, including 38% of WD-LLA, 47% of PD-LLA, 37% of WD-MR, and 67% of PD-MR disease with progressively shorter median time to progression (26, 10, 8, and 3 months, respectively). Conclusions: These data suggest that focal, high-dose radiation has a role in the management of NENs. Local failure is rare in patients with both WD-LLA and PD-LLA disease. The predominant pattern of failure is development of new metastases, which appear to occur sooner and more frequently in patients with PD and MR disease. [Table: see text]

Recurrent Ischemic Stroke as a First Manifestation of Poorly Differentiated Carcinoma (PDC) of Unknown Etiology

The association between cancer and thrombosis has been known for a long time, and the majority of the thromboembolic events associated with cancer are usually diagnosed after the cancer being identified [1]. However, a thromboembolic event may precede the identification of a cancer and maybe the first manifestation of the underlying malignancy.