Successful Diagnosis and Treatment of Occult Prostate Cancer Despite Multiple Negative Prostate Biopsies and Negative Prostate MRIs.

Prostate-specific antigen (PSA) values above 100 ng/mL often suggest metastatic prostate cancer. We present the case of a patient with a PSA of 110 ng/mL, 4 negative prostate biopsies, and 4 negative prostate MRIs. After his fifth MRI revealed a PI-RADS 5 lesion, he underwent his fifth transrectal biopsy; this revealed Gleason 3 + 4 = 7. He was found to have organ-confined pT2 disease on subsequent radical prostatectomy pathology. This case highlights that there may be no PSA for which one can assume metastatic disease with certainty. Depending on life expectancy, patients with extremely elevated PSA may still warrant a full staging workup.

Hemolytic anemia and metastatic carcinoma: case report and literature review.

Hemolytic anemia can complicate the development of a variety of solid tumors and hematologic malignancies. Although patients may have an established diagnosis with documented metastases, microangiopathic hemolytic anemia (MAHA) can be a presenting feature of an occult malignancy. Prompt diagnosis is essential because conditions that mimic the symptoms of MAHA, including thrombotic thrombocytopenic purpura, have different prognoses and therapeutic options. Although the exact pathogenesis is not yet delineated, we present herein a case of cancer-associated MAHA and discuss the known pathways that can contribute to the initiation and propagation of hemolytic anemia in patients with cancer. The patient is a 69-year-old woman with breast carcinoma that had metastasized to her rectum, urinary bladder, and brain. She eventually developed progressive decline in her functional status, with intermittent epistaxis and melena. The results of laboratory studies revealed hemolytic anemia and thrombocytopenia; results of a bone-marrow biopsy confirmed the involvement by metastatic carcinoma. The patient received red blood cell and platelet transfusions and was discharged to hospice care after clinical stabilization. She died soon thereafter.

Pro- and antiatherogenic effects of a dominant-negative P465L mutation of peroxisome proliferator-activated receptor-γ in apolipoprotein E-Null mice.

OBJECTIVE: The dominant-negative mutation, P467L, in peroxisome proliferator-activated receptor-γ (PPARγ) affects adipose tissue distribution, insulin sensitivity, and blood pressure in heterozygous humans. We hypothesized that the equivalent mutation, PPARγ-P465L, in mice will worsen atherosclerosis. METHODS AND RESULTS: Apolipoprotein E-null mice with and without PPARγ-P465L mutation were bred in 129S6 inbred genetic background. Mild hypertension and lipodystrophy of PPARγ-P465L persisted in the apolipoprotein E-null background. Glucose homeostasis was normal, but plasma adiponectin was significantly lower and resistin was higher in PPARγ-P465L mice. Plasma cholesterol and lipoprotein distribution were not different, but plasma triglycerides tended to be reduced. Surprisingly, there were no overall changes in the atherosclerotic plaque size or composition. PPARγ-P465L macrophages had a small decrease in CD36 mRNA and a small yet significant reduction in very-low-density lipoprotein uptake in culture. In unloaded apolipoprotein E-null macrophages with PPARγ-P465L, cholesterol uptake was reduced whereas apolipoprotein AI-mediated efflux was increased. However, when cells were cholesterol loaded in the presence of acetylated low-density lipoprotein, no genotype difference in uptake or efflux was apparent. A reduction of vascular cell adhesion molecule-1 expression in aorta suggests a relatively antiatherogenic vascular environment in mice with PPARγ-P465L. CONCLUSIONS: Small, competing pro- and antiatherogenic effects of PPARγ-P465L mutation result in unchanged plaque development in apolipoprotein E-deficient mice.

Cytomorphologic observations on the sclerosing variant of well-differentiated pancreatic neuroendocrine tumors: Towards making specific diagnoses early.

BACKGROUND: The recently described sclerosing variant of pancreatic neuroendocrine tumor (spNET) shows prominent stromal fibrosis and decreased tumor cellularity in surgical pathology specimens. Although prognostic data are currently ambivalent, some studies have reported metastatic disease in small primary tumors, highlighting the need for early diagnosis. The aim of our study is to evaluate cytology specimens of spNET to determine its characteristic cytomorphologic features to expedite an early diagnosis. METHODS: Twenty-five cytology cases of spNET from 23 patients and 29 cytology cases of typical pancreatic neuroendocrine tumor (tpNET) from 29 patients diagnosed as such by surgical pathology evaluation were reviewed by two pathologists to assess adequacy of diagnostic material, cellularity and fibrosis. Radiographic findings and outcome data were collected. RESULTS: With only 13 of 25 specimens deemed as diagnostic, spNET specimens were more often non-diagnostic (p < .01) and less often hypercellular (p = .03) compared to tpNET counterparts. While at least focal fibrosis was observed in both groups, a subset of spNET cases showed small tumor cell groups entrapped in large fibrotic fragments. Importantly, spNETs tended to be metastatic at diagnosis (both regionally and distant), with a smaller average tumor size. CONCLUSION: The hypocellular nature of spNET cytology samples makes this variant difficult to diagnose. However, when adequate sample is available, a subset of spNET show characteristic cytomorphology that enables us to consider this specific diagnosis at first diagnostic sampling. It is crucial to diagnose this variant early given the propensity of small tumors with regional lymph node involvement and liver metastases.

Refractory Cytomegalovirus Colitis Followed by De Novo Inflammatory Bowel Disease Post-Orthotopic Liver Transplantation.

Cytomegalovirus (CMV) and inflammatory bowel disease (IBD) are both immune-mediated complications that affect orthotopic liver transplantation patients. In this report, we present a 60-year-old man who underwent orthotopic liver transplantation for cryptogenic cirrhosis with serologies notable for CMV-seropositive donor and seronegative recipient. His post-transplant course was initially complicated by probable refractory CMV colitis. However, his gastrointestinal symptoms persisted, eventually leading to a diagnosis of post-transplant de novo IBD. The discussion highlights theories regarding the association between CMV and IBD, a topic that has been widely debated for decades.

Comparison of clinical efficacy, subjective user experience, and safety for two different core biopsy needles, the Achieve® and Marquee®.

PURPOSE: To compare clinical efficacy, subjective radiologist preference, and complication rates for two different core biopsy needles, the Achieve® and Marquee®. METHODS: Retrospective review included consecutive patients who underwent 18 gauge non-targeted core liver biopsy, 30 with Achieve® (Merit Medical) and 30 with Marquee® (BD Bard) Pathologist (blinded to needle type) reviewed specimen total length, maximum width, and portal triad count. Sixteen radiologists subjectively rated (1 to 5(best)) each needle for cocking, firing, recoil, chamber exposure, handling, and overall. A medical records search of all (targeted and non-targeted) core liver biopsies 1/1/17-9/30/2020 compared rates of major (requiring transfusion and/or embolization) and minor (self-limited bleeding) hemorrhagic complications. Comparison between needle types was performed using t-test. RESULTS: For Achieve® and Marquee® needles, the respective mean (SD) for total length(mm) was 29.7(7.0) and 31.9(4.6), p = 0.1; max width(mm) was 0.78(0.1) and 0.85(0.1), p < 0.01; and number of portal triads was 15.3(5.3) and 17.3(5.3), p = 0.2. Radiologists subjectively preferred the Marquee® for several measures including cocking, chamber exposure, and overall (p < 0.02 for each), while the needles were rated similarly for firing, recoil, and handling. Review of 800 cases showed no difference in major (1.0% Achieve®, 1.9% Marquee®, p = 0.5) or minor (1.5% Achieve®, 0.5% Marquee®, p = 0.3) rates of hemorrhagic complications. CONCLUSION: Liver biopsy specimens were significantly wider with Marquee® compared to Achieve®. Radiologists preferred the Marquee® for multiple tactile measures, while the major complication rate was not significantly different. While both needles have a similar side-notch design, the Marquee® needle demonstrates better sample quality and higher user preference, without compromising safety.

Plasma cells are essentially absent in the luminal gastrointestinal tract of patients with "complete" 22q11.2 deletion syndrome (DiGeorge syndrome).

Gastrointestinal symptoms are commonly reported in patients with 22q11.2 deletion syndrome or DiGeorge syndrome (DGS) in addition to the dominant cardiac manifestations and immunodeficiency. But literature providing specific morphologic details of the gastrointestinal tract pathology is very limited. Here, we provide the first comprehensive morphologic description of the luminal gastrointestinal tract changes in patients with DGS. Cytogenetically confirmed DGS patients were identified, clinical and laboratory data were reviewed to determine the severity of immunodeficiency, and patients were stratified into mildly immunocompromised, that is, partial DiGeorge anomaly or severely immunosuppressed, that is, complete DiGeorge anomaly groups. Gastrointestinal tract biopsies from these patients were retrospectively reviewed and compared with those from controls without the history of DGS. Patients with immunosuppressed DGS showed a near complete absence of plasma cells in the stomach, duodenum, and colon lamina propria by hematoxylin and eosin evaluation. Immunohistochemistry for CD138 used to highlight plasma cells confirmed this finding. The notable absence of plasma cells adds to the existing knowledge of the pathophysiology underlying DGS and expands the differential diagnostic considerations for this finding, which has been previously described in common variable immunodeficiency. It also provides a useful morphologic marker observable by the readily accessible light microscopy. Second, patients with DGS showed a mild increase in epithelial cell apoptosis in their colon. This finding is significant because of its overlap with morphologic features of gastrointestinal graft versus host disease as thymus transplantation is being used as a treatment option for patients with complete DGS.

More Than Meets the Eye?

Content available: Author Audio Recording.

Weakly supervised instance learning for thyroid malignancy prediction from whole slide cytopathology images.

We consider machine-learning-based thyroid-malignancy prediction from cytopathology whole-slide images (WSI). Multiple instance learning (MIL) approaches, typically used for the analysis of WSIs, divide the image (bag) into patches (instances), which are used to predict a single bag-level label. These approaches perform poorly in cytopathology slides due to a unique bag structure: sparsely located informative instances with varying characteristics of abnormality. We address these challenges by considering multiple types of labels: bag-level malignancy and ordered diagnostic scores, as well as instance-level informativeness and abnormality labels. We study their contribution beyond the MIL setting by proposing a maximum likelihood estimation (MLE) framework, from which we derive a two-stage deep-learning-based algorithm. The algorithm identifies informative instances and assigns them local malignancy scores that are incorporated into a global malignancy prediction. We derive a lower bound of the MLE, leading to an improved training strategy based on weak supervision, that we motivate through statistical analysis. The lower bound further allows us to extend the proposed algorithm to simultaneously predict multiple bag and instance-level labels from a single output of a neural network. Experimental results demonstrate that the proposed algorithm provides competitive performance compared to several competing methods, achieves (expert) human-level performance, and allows augmentation of human decisions.

Defying Occam's Razor: Colonic Luminal Endometriosis in an Adolescent With Crohn's Disease.

Abdominal pain is a common symptom in Crohn's disease, presumably associated with mucosal inflammation and/or luminal stenosis. However, pain is not specific to Crohn's disease, and other etiologies should be considered, particularly gynecologic pathology in an adolescent female. We present an unusual case of endometrial tissue found in the colonic polyp of an adolescent with known Crohn's disease and abdominal pain. Histologic analysis differentiated endometriosis from active inflammation secondary to Crohn's disease. Endometriosis and Crohn's disease are both classified as chronic inflammatory disorders. It remains unclear whether overlapping etiological factors exist for the two disorders. There is a paucity of data on comanagement of endometriosis and inflammatory bowel disease, especially in adolescents. Given the finding of endometriosis in the colonic polyp was unanticipated, this case also reinforces the merits of endoscopic staging of disease whenever significant changes in therapy are considered.

Ultrasound-guided non-targeted liver core biopsy: comparison of the efficacy of two different core needle biopsy systems using an ex-vivo animal model and retrospective review of clinical experience.

PURPOSE: To compare the efficacy of two 18-gauge core needle biopsy systems, the Achieve® (Merit Medical) and the Marquee® (BD Bard), using an ex-vivo animal liver model and retrospective review of clinical experience. METHODS: Sixty ex-vivo liver biopsy samples were obtained using the Achieve® (n = 30) and the Marquee® (n = 30) needles. In addition, 20 liver biopsy samples from 20 patients obtained using the Achieve® (n = 10) and Marquee® (n = 10) were compared retrospectively. One pathologist, blinded to needle type, recorded total core length and the number of complete portal triads. Ex vivo measurements were compared using mixed effects linear, logistic, and ordinal regression. In vivo measurements were compared using Student's t-test. RESULTS: For the Achieve® and Marquee® needles, the mean(SD) total core length (mm) of ex vivo samples was 11.0(3.3) and 12.6(3.4), respectively (P = 0.069) and the adequacy rate was 23.3% and 50%, respectively (P = 0.04). Mean number of portal triads of ex vivo samples was 7.2(2.9) and 8.6(3.8), respectively (P = 0.13), and the adequacy rate was 73.3% and 83.3%, respectively (P = 0.32). For in vivo samples, the Achieve® and Marquee® needles demonstrates mean(SD) total core length (mm) of 24.6(7.1) and 32.0(4.6), respectively (P = 0.01), adequacy rate (P = 0.06). Mean number of portal triads was 14.9(4.8) and 19.6(4.1), respectively (P = 0.03), adequacy rate (P = 0.47). CONCLUSIONS: Slightly longer core biopsies were obtained with the Marquee® needle compared with the Achieve® needle. Early clinical experience demonstrates no significant difference in sample adequacy rates. Both needle types can be expected to provide adequate samples for pathologic assessment of liver tissue.

Increased Rate of ASCUS Diagnosis With Concomitant Request for High-Risk Human Papillomavirus Reflex Testing May Be Due to Cognitive Bias.

OBJECTIVES: To determine if concomitant high-risk human papillomavirus (HPV-HR) reflex testing may bias the cytologic interpretation of Papanicolaou (Pap) tests. METHODS: Percentage of atypical squamous cells of undetermined significance (ASCUS) and HPV-HR positivity was compared between Pap tests with HPV-HR cotesting and HPV-HR reflex testing for ASCUS, with subset analysis of cytopathologists' experience. RESULTS: ASCUS in the reflex group (41.5%) was significantly higher than the cotesting group (33.0%) (P = .02). There was no difference in HPV-HR positivity or ASCUS/squamous intraepithelial lesion (SIL) ratios between the two groups. The cytopathologists' experience inversely correlated with the proportion of ASCUS but did not explain the higher reflex group ASCUS. CONCLUSIONS: HPV-HR reflex testing may introduce bias in cytologic diagnosis, making it more likely that an ASCUS diagnosis is rendered. HPV-HR and ASCUS/SIL ratios were similar between the groups, so cytopathologist performance was not significantly affected. There was no effect of cytopathologists' experience.

Intraosseous Rosai-Dorfman disease diagnosed by touch imprint cytology evaluation: A case series.

Sinus histiocytosis with massive lymphadenopathy, also known as Rosai-Dorfman disease (RDD) is a rare benign disorder that primarily affects the lymph nodes. Localized lymphadenopathy is the most common clinical manifestation of this disorder. However, RDD has been described in several extra-nodal sites including the head and neck region, soft tissue, skin, upper respiratory tract, gastro-intestinal tract and central nervous system (CNS). Involvement of the bone is considered very rare, occurring in less than 10% patients. RDD is one of the histiocytoses and the differential diagnosis includes entities such as Langerhans cell histiocytosis and Erdheim-Chester disease. In the rare intraosseous variant, the clinical and radiologic differential diagnosis is broader and includes neoplasms such as osteosarcoma and Ewing sarcoma. In this report, we describe three cases of extra-nodal, intraosseous RDD where touch imprint cytology played a crucial role in diagnosis. Two of the cases initially presented with involvement of the head and neck region and later developed intraosseous disease; while the third patient presented with primary bone involvement. The diagnosis was established by core biopsy with touch imprints of the bone lesions. The cytologic samples showed numerous histiocytes, often with neutrophils within their cytoplasm (emperipolesis) in addition to lymphocytes and plasma cells. The diagnosis of RDD was confirmed with appropriate immunohistochemical stains. Our account of these three cases of intraosseous Rosai-Dorfman disease highlights the role of cytology in the diagnosis of this rare entity.

Low-Grade Papillary Schneiderian Carcinoma of the Sinonasal Cavity and Temporal Bone.

OBJECTIVES:: The aim of this study was to further characterize a newly described neoplasm, low-grade papillary Schneiderian carcinoma, occurring simultaneously in the sinonasal cavity and mastoid. Additionally, the authors review the only 2 similar cases within the literature and describe the common clinical features, radiographic findings, and pathologic characteristics of this exceptionally rare disease process. METHODS:: Chart review for single patient, review of literature. RESULTS:: The patient presented with bilateral nasal obstruction. Computed tomography revealed a left sinonasal mass with skull base hyperostosis, and follow-up magnetic resonance imaging showed a concomitant olfactory groove meningioma. Examination showed a bilateral, completely obstructing sinonasal mass with skip areas, and biopsy confirmed inverted papilloma (human papilloma virus strains 16 and 18 indeterminate). The patient underwent bilateral endoscopic sinus surgery, left medial maxillectomy, and left partial nasopharyngectomy. Given her multifocal disease, she was advised that she would require additional excision, but was lost to follow up. One year later she developed acute left facial paralysis. Magnetic resonance imaging demonstrated an enhancing mass in the left mastoid with enhancement along the Eustachian tube in addition to her known recurrent sinonasal disease. Simultaneous endoscopic sinus surgery and mastoidectomy were performed. Polypoid tissue was removed from the nasopharynx, mesotympanum, epitympanum, and retrofacial air cells. Immunohistochemistry showed that cells stained positive for p63 and dermCK and negative for synaptophysin. Morphologically, cells were bland, without classic stromal invasion, retaining their smooth, cystic, and papillary features, despite their increased depth within the tissue. Upon further review and consultation with an outside pathologist, a diagnosis of low-grade papillary Schneiderian carcinoma was made. The patient was referred for radiation therapy and is disease free at 3-month follow-up, with return of her facial function. CONCLUSIONS:: This case represents the first report of concurrent low-grade papillary Schneiderian carcinoma of both the nasal cavity and mastoid. It emphasizes the importance of recognizing this new entity through pathologic analysis and suspecting it when the clinical course does not follow an expected pattern.

Further evidence for the involvement of EFL1 in a Shwachman-Diamond-like syndrome and expansion of the phenotypic features.

Recent evidence has implicated EFL1 in a phenotype overlapping Shwachman-Diamond syndrome (SDS), with the functional interplay between EFL1 and the previously known causative gene SBDS accounting for the similarity in clinical features. Relatively little is known about the phenotypes associated with pathogenic variants in the EFL1 gene, but the initial indication was that phenotypes may be more severe, when compared with SDS. We report a pediatric patient who presented with a metaphyseal dysplasia and was found to have biallelic variants in EFL1 on reanalysis of trio whole-exome sequencing data. The variant had not been initially reported because of the research laboratory's focus on de novo variants. Subsequent phenotyping revealed variability in her manifestations. Although her metaphyseal abnormalities were more severe than in the original reported cohort with EFL1 variants, the bone marrow abnormalities were generally mild, and there was equivocal evidence for pancreatic insufficiency. Despite the limited number of reported patients, variants in EFL1 appear to cause a broader spectrum of symptoms that overlap with those seen in SDS. Our report adds to the evidence of EFL1 being associated with an SDS-like phenotype and provides information adding to our understanding of the phenotypic variability of this disorder. Our report also highlights the value of exome data reanalysis when a diagnosis is not initially apparent.

A noncanonical function of cGAMP in inflammasome priming and activation.

Recognition of pathogen-associated molecular patterns and danger-associated molecular patterns by host cells is an important step in innate immune activation. The DNA sensor cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) binds to DNA and produces cGAMP, which in turn binds to stimulator of interferon genes (STING) to activate IFN-I. Here we show that cGAMP has a noncanonical function in inflammasome activation in human and mouse cells. Inflammasome activation requires two signals, both of which are activated by cGAMP. cGAMP alone enhances expression of inflammasome components through IFN-I, providing the priming signal. Additionally, when combined with a priming signal, cGAMP activates the inflammasome through an AIM2, NLRP3, ASC, and caspase-1 dependent process. These two cGAMP-mediated functions, priming and activation, have differential requirements for STING. Temporally, cGAMP induction of IFN-I precedes inflammasome activation, which then occurs when IFN-I is waning. In mice, cGAS/cGAMP amplify both inflammasome and IFN-I to control murine cytomegalovirus. Thus, cGAMP activates the inflammasome in addition to IFN-I, and activation of both is needed to control infection by a DNA virus.

Fine-needle-aspiration cytology of a proximal type epithelioid sarcoma: A case report.

Epithelioid sarcoma is a rare mesenchymal neoplasm, with an as yet unidentified cell of origin. Two subtypes of epithelioid sarcoma, distal/classic and proximal/large cell type, are recognized in the literature; with the proximal-type having a lower incidence amongst the two. Here, we present a case of proximal-type epithelioid sarcoma in a previously healthy young man. Fine-needle-aspiration of a large axillary mass was performed for diagnosis. The cytologic findings included a dispersed population of large epithelioid to polyhedral cells with abundant cytoplasm. Immunohistochemical staining showed coexpression of keratin and vimentin, as well as loss of INI1 staining, consistent with an epithelioid sarcoma, proximal subtype.

Primary Invasive Squamous Cell Carcinoma of the Nipple.

Squamous cell carcinoma is one of the most common cutaneous cancers; however, primary squamous cell carcinoma of the nipple is extremely rare. Among the few reported cases, the majority have occurred in older women with rare cases seen in younger women and male patients. Our patient presented with an exophytic mass of the right nipple while pregnant. A superficial biopsy was reviewed at an outside institution and then at our institution and diagnosed as squamous papilloma and then as hyperkeratosis of the nipple, respectively. The subsequent excisional biopsy revealed multiple nests of tumor cells extending into the dermis with associated chronic inflammatory infiltrate, and the lesion was diagnosed as a primary invasive squamous cell carcinoma of the nipple. Following that, a wide local excision of the excision site and sampling of the regional lymph nodes were negative for carcinoma. Due to the rarity of this diagnosis, it is not known whether prognosis and response to therapy differ from cutaneous squamous cell carcinoma at other sites. Therefore, risk stratification and therapy have been based on those for cutaneous squamous cell carcinoma.

Apolipoprotein E4 exaggerates diabetic dyslipidemia and atherosclerosis in mice lacking the LDL receptor.

OBJECTIVE: We investigated the differential roles of apolipoprotein E (apoE) isoforms in modulating diabetic dyslipidemia-a potential cause of the increased cardiovascular disease risk of patients with diabetes. RESEARCH DESIGN AND METHODS: Diabetes was induced using streptozotocin (STZ) in human apoE3 (E3) or human apoE4 (E4) mice deficient in the LDL receptor (LDLR(-/-)). RESULTS: Diabetic E3LDLR(-/-) and E4LDLR(-/-) mice have indistinguishable levels of plasma glucose and insulin. Despite this, diabetes increased VLDL triglycerides and LDL cholesterol in E4LDLR(-/-) mice twice as much as in E3LDLR(-/-) mice. Diabetic E4LDLR(-/-) mice had similar lipoprotein fractional catabolic rates compared with diabetic E3LDLR(-/-) mice but had larger hepatic fat stores and increased VLDL secretion. Diabetic E4LDLR(-/-) mice demonstrated a decreased reliance on lipid as an energy source based on indirect calorimetry. Lower phosphorylated acetyl-CoA carboxylase content and higher gene expression of fatty acid synthase in the liver indicated reduced fatty acid oxidation and increased fatty acid synthesis. E4LDLR(-/-) primary hepatocytes cultured in high glucose accumulated more intracellular lipid than E3LDLR(-/-) hepatocytes concomitant with a 60% reduction in fatty acid oxidation. Finally, the exaggerated dyslipidemia in diabetic E4LDLR(-/-) mice was accompanied by a dramatic increase in atherosclerosis. CONCLUSIONS: ApoE4 causes severe dyslipidemia and atherosclerosis independent of its interaction with LDLR in a model of STZ-induced diabetes. ApoE4-expressing livers have reduced fatty acid oxidation, which contributes to the accumulation of tissue and plasma lipids.