Post-therapeutic squamous cell transformation of a metastatic prostate adenocarcinoma with comparison of molecular profiles: a case report and review of the literature.

Transformation of primary prostate adenocarcinoma to squamous cell carcinoma after initial treatment with chemotherapy and hormonal therapy is extremely rare and typically results in rapid treatment-refractory disease progression and death. Here, we present a case of a 64-year-old man who was initially diagnosed with metastatic prostate adenocarcinoma (positive PSA and NKX3.1 stains, total PSA 747.2 ng/ml) to the thoracic spine (T8) in 2019. The patient received androgen deprivation therapy and chemotherapy with good response (PSA 2.53 ng/ml). In 2022, the patient had a tumor resection from the left humerus with a consequent fracture. Pathology showed pure squamous carcinoma without any adenocarcinoma component (PSA and NKX3.1 stains negative and weak p504s stain, PSA 19.82 ng/ml). Given the patient's history of metastatic prostate adenocarcinoma and no history of any other malignancies, a diagnosis of squamous carcinoma transformed from prostate adenocarcinoma was rendered. The patient passed away in 2023. Molecular profiling identified the same TP53 mutation and two variants of uncertain significance in both specimens, suggesting the same primary. However, there was CCND3 amplification and absence of the TMPRSS2::ETV4 fusion in the 2022 specimen, which may be associated with squamous transformation and poor prognosis. A microarray might be beneficial to confirm loss of the TMPRSS2::ETV4 fusion. This case illustrates the rare occurrence of squamous transformation in prostate adenocarcinoma and the aggressive clinical course, and need for more therapy guidance and prognostic studies. It also highlights the importance of molecular profiling to provide insights into the pathogenesis of histologic transformation.

Interactive Pathology Tutorial in Neoplastic Hematology Disorders for Medical Hematology-Oncology Fellows.

Hematology-oncology (HO) fellows receive limited instruction in the process of establishing a diagnosis for hematologic neoplasms, and learning neoplastic hematology often occurs in limited encounters. In the current study, we developed a web-based interactive pathology tutorial in neoplastic hematologic disorders for HO fellows to work up simulated cases and establish the diagnosis. An online system ("Pathology Playground") was utilized to load case materials including microscopic images and ancillary studies. Twelve high-yield simulated cases of common leukemias and lymphoma were included. At the beginning of each case, trainees review the clinical history and slide images, and then, they are given the option to request additional pathology work-up. Based on the results, they can enter their diagnostic impression. If the diagnosis is correct, the user is shown a short educational presentation. If the diagnosis is not correct, the user gets notified by the message "Incorrect." The tutorial was integrated in the educational curriculum of our HO fellowship program, and bimonthly teaching sessions were held to review two cases each time. During the sessions, trainees request ancillary studies to complete the diagnostic work-up using the software and interpret the findings. As the case is being worked up by the trainee, the hematopathologists and HO fellowship program director discuss the findings, the appropriate work-up tools, and the implications on management. All of our six HO fellows attended the sessions, and a survey from the trainees showed high ease of use of the system and they viewed it as a very useful educational tool. A pre-test and post-test were administered for one of the sessions, and the result showed improvement in the average from 62 to 73%. Expanding the use of this online interactive tutorial and incorporating additional cases would enhance its value as a learning resource.

The Journey to Improve the College of American Pathologists Cancer Biomarker Reporting Protocols.

CONTEXT.­: Biomarker reporting has increasingly become a key component of pathology reporting, providing diagnostic, prognostic, and actionable therapeutic data for patient care. OBJECTIVE.­: To expand and improve the College of American Pathologists (CAP) biomarker protocols. DESIGN.­: We surveyed CAP members to better understand the limitations they experienced when reporting cancer biomarker results. A Biomarker Workgroup reviewed the survey results and developed a strategy to improve and standardize biomarker reporting. Drafts of new and revised biomarker protocols were reviewed in both print and electronic template formats during interactive webinars presented to the CAP House of Delegates. Feedback was collected, and appropriate revisions were made to finalize the protocols. RESULTS.­: The first phase of the CAP Biomarker Workgroup saw the development of (1) a new stand-alone general Immunohistochemistry Biomarker Protocol that includes reporting for ER (estrogen receptor), PR (progesterone receptor), Ki-67, HER2 (human epidermal growth factor receptor 2), PD-L1 (programmed death ligand-1), and mismatch repair; (2) a new Head and Neck Biomarker Protocol that updates the prior 2017 paper-only version into an electronic template, adding new diagnostic and theranostic markers; (3) a major revision to the Lung Biomarker Protocol to streamline it and add in pan-cancer markers; and (4) a revision to the Colon and Rectum Biomarker Protocol to add HER2 reporting. CONCLUSIONS.­: We have taken a multipronged approach to improving biomarker reporting in the CAP cancer protocols. We continue to review current biomarker reporting protocols to reduce and eliminate unnecessary methodologic details and update with new markers as needed. The biomarker templates will serve as standardized modular units that can be inserted into cancer-reporting protocols.

DHCR7 Expression Predicts Poor Outcomes and Mortality From Sepsis.

This is a study of lipid metabolic gene expression patterns to discover precision medicine for sepsis. OBJECTIVES: Sepsis patients experience poor outcomes including chronic critical illness (CCI) or early death (within 14 d). We investigated lipid metabolic gene expression differences by outcome to discover therapeutic targets. DESIGN SETTING AND PARTICITPANTS: Secondary analysis of samples from prospectively enrolled sepsis patients (first 24 hr) and a zebrafish endotoxemia model for drug discovery. Patients were enrolled from the emergency department or ICU at an urban teaching hospital. Enrollment samples from sepsis patients were analyzed. Clinical data and cholesterol levels were recorded. Leukocytes were processed for RNA sequencing and reverse transcriptase polymerase chain reaction. A lipopolysaccharide zebrafish endotoxemia model was used for confirmation of human transcriptomic findings and drug discovery. MAIN OUTCOMES AND MEASURES: The derivation cohort included 96 patients and controls (12 early death, 13 CCI, 51 rapid recovery, and 20 controls) and the validation cohort had 52 patients (6 early death, 8 CCI, and 38 rapid recovery). RESULTS: The cholesterol metabolism gene 7-dehydrocholesterol reductase (DHCR7) was significantly up-regulated in both derivation and validation cohorts in poor outcome sepsis compared with rapid recovery patients and in 90-day nonsurvivors (validation only) and validated using RT-qPCR analysis. Our zebrafish sepsis model showed up-regulation of dhcr7 and several of the same lipid genes up-regulated in poor outcome human sepsis (dhcr24, sqlea, cyp51, msmo1, and ldlra) compared with controls. We then tested six lipid-based drugs in the zebrafish endotoxemia model. Of these, only the Dhcr7 inhibitor AY9944 completely rescued zebrafish from lipopolysaccharide death in a model with 100% lethality. CONCLUSIONS: DHCR7, an important cholesterol metabolism gene, was up-regulated in poor outcome sepsis patients warranting external validation. This pathway may serve as a potential therapeutic target to improve sepsis outcomes.

The prognostic significance of duodenal wall invasion in pancreatic adenocarcinoma.

OBJECTIVE: The most recent edition of the American Joint Committee on Cancer Staging Manual (AJCC, 8th edition) relies only on tumor size for staging resectable pancreatic adenocarcinoma, and the presence of duodenal wall invasion (DWI) no longer has an impact on staging. However, very few studies have evaluated its significance. In this study, we aim to evaluate the prognostic significance of DWI in pancreatic adenocarcinoma. METHODS: We reviewed 97 consecutive internal cases of resected pancreatic head ductal adenocarcinoma, and clinicopathologic parameters were recorded. All cases were staged according to the 8th edition of AJCC, and the patients were divided into two groups based on the presence or absence of DWI. RESULTS: Out of our 97 cases, 53 patients had DWI (55%). In univariate analysis, DWI was significantly associated with lymphovascular invasion and lymph node metastasis (AJCC 8th edition pN stage). In univariate analysis of overall survival, age > 60, absence of DWI, and African American race were associated with worse overall survival. In multivariate analysis, age > 60, absence of DWI, and African American race were associated with worse progression-free survival and overall survival. CONCLUSION: Although DWI is associated with lymph node metastasis, it is not associated with inferior disease-free/overall survival.

DHCR7 Expression Predicts Poor Outcomes and Mortality from Sepsis.

Objective: Sepsis patients experience poor outcomes including chronic critical illness (CCI) or early death (within 14 days). We investigated lipid metabolic gene expression differences by outcome to discover therapeutic targets. Design: Secondary analysis of samples from prospectively enrolled sepsis patients and a zebrafish sepsis model for drug discovery. Setting: Emergency department or ICU at an urban teaching hospital. Patients: Sepsis patients presenting within 24 hours. Methods: Enrollment samples from sepsis patients were analyzed. Clinical data and cholesterol levels were recorded. Leukocytes were processed for RNA sequencing (RNA-seq) and reverse transcriptase polymerase chain reaction (RT-qPCR). A lipopolysaccharide (LPS) zebrafish sepsis model was used for confirmation of human transcriptomic findings and drug discovery. Measurements and Main Results: There were 96 samples in the derivation (76 sepsis, 20 controls) and 52 in the validation cohort (sepsis only). The cholesterol metabolism gene 7-Dehydrocholesterol Reductase ( DHCR7) was significantly upregulated in both derivation and validation cohorts in poor outcome sepsis compared to rapid recovery patients and in 90-day non-survivors (validation only) and validated using RT-qPCR analysis. Our zebrafish sepsis model showed upregulation of dhcr7 and several of the same lipid genes upregulated in poor outcome human sepsis (dhcr24, sqlea, cyp51, msmo1 , ldlra) compared to controls. We then tested six lipid-based drugs in the zebrafish sepsis model. Of these, only the Dhcr7 inhibitor AY9944 completely rescued zebrafish from LPS death in a model with 100% lethality. Conclusions: DHCR7, an important cholesterol metabolism gene, was upregulated in poor outcome sepsis patients warranting external validation. This pathway may serve as a potential therapeutic target to improve sepsis outcomes.

Impact of Medicaid Expansion on Stage at Diagnosis for US Adults with Pancreatic Cancer: a Population-Based Study.

INTRODUCTION: We evaluated whether Medicaid expansion is associated with earlier stage at diagnosis for pancreatic cancer taking into account key demographic, clinical, and geographic factors. METHODS: We obtained Surveillance, Epidemiology, and End-Results (SEER-18) data on individuals diagnosed with pancreatic cancer from 2007 to 2016 (< 65 years of age). We defined non-metastatic as either local or regional disease (vs. metastatic disease). To estimate the association of Medicaid expansion with pancreatic cancer stage at diagnosis, we used a difference-in-differences model, at the individual level, comparing those from early-adopting states in 2014 to non-early-adopting states. We utilized cluster-robust standard errors and explored the role of demographic factors (race, sex, insurance at diagnosis), clinical indicator (disease in the head of the pancreas), and county characteristics (Urban Influence Code, Social Deprivation Index). RESULTS: In the univariable setting, the probability of non-metastatic disease at diagnosis increased by 3.9 percentage points (ppt) for those from Medicaid expansion states post-expansion (n = 36,609). After adjustment for covariates, the ppt was attenuated to 2.7. Of particular note, we observed evidence of interactions with sex and race. The beneficial effect was less pronounced for men (increase in the probability of non-metastatic stage at diagnosis by 2.1ppt) than women (3.6ppt) and non-existent for blacks (- 3.1ppt) compared to whites (4.9ppt) and other races (4.8ppt). CONCLUSION: Medicaid expansion is associated with increased probability of non-metastatic stage at diagnosis for pancreatic cancer; however, this beneficial effect is not uniform across sex and race. This underscores the need to investigate the impact of policy and implementation strategies on pancreatic cancer survival disparities.

Pathology Playground: An Interactive Web-Based System for Pathology Unknowns With Immunohistochemistry and Molecular Studies.

CONTEXT.­: Anatomic pathology slide unknown conferences are usually limited to a microscopic slide, slide images, or a virtual slide that is previewed prior to a conference. The answer is provided at a conference along with the ancillary studies, such as immunohistochemical or molecular studies, that enabled the diagnosis. In this rigid system the learner never gains experience with an appropriate workup for cases that will enable the definitive diagnosis. OBJECTIVE.­: To develop an interactive system in which the user can work through a difficult case, ordering stains and other special studies, ideally leading to more involvement and retention. DESIGN.­: An online system was developed using HTML, PHP Hypertext Preprocessor, and JavaScript for ordering and result display. When the user selects a study, an image or text result is displayed. Studies include immunohistochemistry, cytogenetics, flow cytometry, molecular, and radiology. The user then selects the diagnosis and, if correct, is shown some additional didactics. RESULTS.­: Unknown conferences were held at 3 institutions using this novel teaching method that allowed residents to work up unknown cases. Conferences are available online (http://www.drdoubleb.com/unknowns/) and include general, soft tissue, and hematopathology cases. Evaluations were obtained that showed that residents enjoyed the system, considered it better than standard unknown sessions and lectures, and wanted more sessions. CONCLUSIONS.­: This system was very highly received by the residents in all programs, who enjoyed getting immediate results and being able to work through interesting cases. More widespread use of this system could make for an effective learning tool.

HPV Associated Squamous Cell Carcinoma in the Rectal Tonsil.

Mucosa-associated lymphoid tissue has been reported throughout the gastrointestinal tract including rectum. Rarely, a nodular proliferation of predominantly submucosal lymphoid tissue in the rectum has been documented as rectal tonsil. Here we report a patient with HPV-associated squamous cell carcinoma of the rectal tonsil, presenting as a polyp. Previously, rare reports of HPV-associated lymphoepithelial carcinoma have been reported in the literature. We are presenting an extremely rare occurrence and emphasizing the importance of appropriate nomenclature based on the pathogenesis of the neoplasm.

A Case Report and Brief Literature Review on Dedifferentiated Chondrosarcoma in Proximal Phalanx: A Rare Location.

Dedifferentiated chondrosarcoma (DDCS) is a rare entity, constituting only 1-2% of all primary bone tumors, and has a dismal prognosis. Nearly two-thirds of the primary tumors of DDCSs are found in the appendicular skeleton, mostly involving the femur, humerus, and pelvis. DDCS of the small bones of the hand and foot are exceedingly rare with only four cases documented in the literature so far. In this report, we present a case of a 91-year-old woman with a rapidly growing bone tumor initially thought to be a trigger finger, which, on histologic examination of the amputation, turned out to be DDCS. On a follow-up CT scan, multiple pulmonary metastases were identified. Next-generation sequencing identified isocitrate dehydrogenase 2 (IDH2) (p.R172S, c.516G>T), TERT (c.-146C>T), and TP53 (c.559+1G>A) mutations. Microsatellite instability was equivocal and tumor mutation burden was low. Due to the advanced age of the patient, she was given palliative treatment and was alive at the six-month follow-up.

Merlin immunohistochemistry is useful in diagnosis of tumours within the spectrum of biphasic hyalinizing psammomatous renal cell carcinoma.

AIMS: Biphasic hyalinizing psammomatous (BHP) renal cell carcinoma (RCC) is a newly described emerging entity within the spectrum of papillary RCC in the WHO 2022 classification. Molecular analyses have discovered that BHP RCC consistently harbour somatic mutations in the neurofibromin 2 (NF2) gene. The NF2 gene product, merlin, is known to primarily function as a tumour suppressor. Merlin protein loss correlates closely with the presence of NF2 mutations in benign and malignant tumours arising in different sites. In the present study we explored the role of merlin immunohistochemistry (IHC) in tumours within the spectrum of BHP RCC to determine the diagnostic utility of this marker. MATERIALS AND METHODS: We performed merlin IHC in 13 BHP RCC, 18 papillary RCC, 10 TFE3-translocation RCC, 15 TFEB-altered RCC (including 13 TFEB-rearranged and 2 TFEB-amplified), and 10 mucinous tubular and spindle cell carcinomas of unknown mutational status. RESULTS: Unequivocal loss of merlin expression in >90% of the tumour cells was observed in 12/13 BHP-RCC (92%), with the remaining tumour demonstrating weak focal cytoplasmic expression in ~10% of the tumour. In contrast, merlin was diffusely or multifocally expressed in all papillary RCC, TFE3-translocation RCC, and TFEB-altered RCC, as well as in 70% of mucinous tubular and spindle carcinomas. CONCLUSIONS: In this study, merlin IHC was ~92% sensitive and ~94% specific for BHP RCC. These data suggest that merlin IHC is a reliable surrogate marker for the presence of underlying NF2 gene inactivation, being diagnostically useful to identify BHP RCC. CONCLUSIONS: In this study, merlin IHC was ~92% sensitive and ~94% specific for BHP RCC. These data suggest that merlin IHC is a reliable surrogate marker for the presence of underlying NF2 gene inactivation, being diagnostically useful to identify BHP RCC.

Flow Cytometric Findings in Primary Effusion Lymphoma: A Report of Two Cases.

Primary effusion lymphoma (PEL) is a rare B-cell lymphoma that usually occurs in the setting of HIV infection, and it is associated with Human Herpesvirus-8 (HHV-8). Diagnosis of PEL is usually established in cell centrifuge, cell block, or tissue examination, and there are few reports describing flow cytometry findings in PEL. We report two male patients (a 34-year-old and a 56-year-old) with a history of HIV infection. The first patient presented with ascites and abdominal pain, and the second patient presented with chest pain and parapneumonic pleural effusion. Cavitary fluid examination showed large pleomorphic neoplastic lymphoid cells with plasmablastic morphology. Flow cytometry analysis of the neoplastic lymphocytes showed increased forward scatter and side scatter with intermediate to a high level of CD38 expression. In one patient, lymphoma cells showed bright CD45 expression with dim expression of CD19 and kappa light chain. There was no significant expression of CD20 or any T/NK cell markers in either case. Immunohistochemistry for CD30 was positive in one patient. Immunohistochemistry for HHV-8 and in situ hybridization for Epstein-Barr virus-encoded small RNAs (EBER) was positive on cell blocks in both cases, consistent with the diagnosis of primary effusion lymphoma. PEL should be considered in the differential diagnosis of CD20-negative hematopoietic neoplasms, and flow cytometry may provide helpful clues for the diagnosis of PEL as part of the workup for pleural effusion with cytologically malignant cells.

Very low-dose radiation therapy for management of inflammatory myofibroblastic tumor of the lung.

Inflammatory myofibroblastic tumor (IMT) is an uncommon chest pathology. Treatment primarily focuses on surgical resection for diagnostic and therapeutic purposes. However, there are instances in which alternative therapies with steroids, chemotherapy, or radiation are necessary. We discuss a case of recurrent IMT for which very low dose radiation proved an effective treatment.

Impact of Medicaid Expansion on Pancreatic Cancer: An Examination of Sociodemographic Disparity in 1-Year Survival.

BACKGROUND: This study examined the effect of Medicaid expansion on 1-year survival of pancreatic cancer for nonelderly adults. We further evaluated whether sociodemographic and county characteristics alter the association of Medicaid expansion and 1-year survival. STUDY DESIGN: We obtained data from the Surveillance Epidemiology and End-Results dataset on individuals diagnosed with pancreatic cancer from 2007 to 2015. A Difference-in-Differences model compared those from early-adopting states to non-early-adopting states, before and after adoption (2014), while taking into consideration sociodemographic and county characteristics to estimate the effect of Medicaid expansion on 1-year survival. RESULTS: In the univariable Difference-in-Differences model, the probability of 1-year survival for pancreatic cancer increased by 4.8 percentage points (ppt) for those from Medicaid expansion states postexpansion (n = 35,347). After adjustment for covariates, the probability of 1-year survival was reduced to 0.8 ppt. Interestingly, after multivariable adjustment the effect of living in an expansion state on 1-year survival was similar for men and women (0.6 ppt for men vs 1.2 ppt for women), was also similar for Whites (2.6 ppt), and was higher in those of other races (5.9 ppt) but decreased for Blacks (-2.0 ppt). Those who were insured (-0.1 ppt) or uninsured (-2.2 ppt) experienced a decrease in the probability of 1-year survival; however, those who were covered by Medicaid at diagnosis experienced an increase in the probability of 1-year survival (7.4 ppt). CONCLUSIONS: Medicaid expansion during or after 2014 is associated with an increase in the probability of 1-year survival for pancreatic cancer; however, this effect is attenuated after adjustment for sociodemographic characteristics. Of note, the positive association was more pronounced in certain categories of key covariates suggesting further inquiry focused on these subgroups.

Single Nucleotide Polymorphisms (SNPs) in PRKG1 & SPATA13-AS1 are associated with bronchodilator response: a pilot study during acute asthma exacerbations in African American children.

OBJECTIVE: Inhaled bronchodilators are the first-line treatment for asthma exacerbations, but individual bronchodilator response (BDR) varies by race and ethnicity. Studies have examined BDR's genetic underpinnings, but many did not include children or were not conducted during an asthma exacerbation. This pilot study tested single-nucleotide polymorphisms' (SNPs') association with pediatric African American BDR during an acute asthma exacerbation. METHODS: This was a study of pediatric asthma patients in the age group 2-18 years treated in the emergency department for an asthma exacerbation. We measured BDR before and after inhaled bronchodilator treatments using both the Pediatric Asthma Severity Score (PASS) and asthma severity score. We collected genomic DNA and examined whether 21 candidate SNPs from a review of the literature were associated with BDR using crude odds ratios (OR) and adjusted analysis. RESULTS: The final sample population was 53 children, with an average age of 7.2 years. The average initial PASS score (scale of ascending severity from 0 to 6) was 2.5. After adjusting for BMI, age category, gender and smoke exposure, rs912142 was associated with decreased odds of having low BDR (OR, 0.20; 95% confidence interval (CI), 0.02-0.92), and rs7081864 and rs7903366 were associated with decreased odds of having high BDR (OR, 0.097; 95% CI, 0.009-0.62). CONCLUSIONS: We found three SNPs significantly associated with pediatric African American BDR that provide information regarding a child's potential response to emergency asthma exacerbation treatment. Once validated in larger studies, such information could guide pharmacogenomic evidence-based emergency asthma treatment to improve patient outcomes.

Biphasic Hyalinizing Psammomatous Renal Cell Carcinoma: Another Provisional Entity Emerging From the Papillary Renal Cell Carcinoma Pandora's Box.

Papillary renal cell carcinoma (especially type 2) is a Pandora's box with many newly described renal cell carcinomas emerging from it as a result of enhanced molecular techniques. Biphasic hyalinizing psammomatous renal cell carcinoma (BHPRCC) is the latest addition, which was first described a few months ago. Here, we report a case of BHPRCC to supplement the very limited literature available about this entity, and to highlight the characteristic morphology as well as the recurring molecular alterations in the neurofibromatosis 2 gene.

Pitfalls in Morphologic Diagnosis of Pathogens: Lessons Learned From the Pseudo-Cystoisospora Epidemic.

Multiple groups have recently reported involvement of the gallbladder mucosa of immunocompetent patients by cystoisospora organisms. However, this has recently been disproved with the support of molecular and ultrastructural studies. Here we present a summary of these events, recounting how this pseudo-Cystoisospora epidemic began and ended. This review also highlights the important role played by ancillary techniques in supplementing the morphologic diagnosis of pathogens.