Artificial Intelligence-Triaged 3-Dimensional Pathology to Improve Detection of Esophageal Neoplasia While Reducing Pathologist Workloads.

Early detection of esophageal neoplasia via evaluation of endoscopic surveillance biopsies is the key to maximizing survival for patients with Barrett's esophagus, but it is hampered by the sampling limitations of conventional slide-based histopathology. Comprehensive evaluation of whole biopsies with 3-dimensional (3D) pathology may improve early detection of malignancies, but large 3D pathology data sets are tedious for pathologists to analyze. Here, we present a deep learning-based method to automatically identify the most critical 2-dimensional (2D) image sections within 3D pathology data sets for pathologists to review. Our method first generates a 3D heatmap of neoplastic risk for each biopsy, then classifies all 2D image sections within the 3D data set in order of neoplastic risk. In a clinical validation study, we diagnose esophageal biopsies with artificial intelligence-triaged 3D pathology (3 images per biopsy) vs standard slide-based histopathology (16 images per biopsy) and show that our method improves detection sensitivity while reducing pathologist workloads.

Nondestructive 3D Pathology Image Atlas of Barrett Esophagus With Open-Top Light-Sheet Microscopy.

CONTEXT.­: Anatomic pathologists render diagnosis on tissue samples sectioned onto glass slides and viewed under a bright-field microscope. This approach is destructive to the sample, which can limit its use for ancillary assays that can inform patient management. Furthermore, the subjective interpretation of a relatively small number of 2D tissue sections per sample contributes to low interobserver agreement among pathologists for the assessment (diagnosis and grading) of various lesions. OBJECTIVE.­: To evaluate 3D pathology data sets of thick formalin-fixed Barrett esophagus specimens imaged nondestructively with open-top light-sheet (OTLS) microscopy. DESIGN.­: Formalin-fixed, paraffin-embedded Barrett esophagus samples (N = 15) were deparaffinized, stained with a fluorescent analog of hematoxylin-eosin, optically cleared, and imaged nondestructively with OTLS microscopy. The OTLS microscopy images were subsequently compared with archived hematoxylin-eosin histology sections from each sample. RESULTS.­: Barrett esophagus samples, both small endoscopic forceps biopsies and endoscopic mucosal resections, exhibited similar resolvable structures between OTLS microscopy and conventional light microscopy with up to a ×20 objective (×200 overall magnification). The 3D histologic images generated by OTLS microscopy can enable improved discrimination of cribriform and well-formed gland morphologies. In addition, a much larger amount of tissue is visualized with OTLS microscopy, which enables improved assessment of clinical specimens exhibiting high spatial heterogeneity. CONCLUSIONS.­: In esophageal specimens, OTLS microscopy can generate images comparable in quality to conventional light microscopy, with the advantages of providing 3D information for enhanced evaluation of glandular morphologies and enabling much more of the tissue specimen to be visualized nondestructively.

Rapidly Growing Pancreatic Adenocarcinoma Presenting as an Irreducible Umbilical Hernia.

Hernia sacs are a common anatomic pathology specimen, which rarely contain malignancy. We present a case of rapidly growing pancreatic adenocarcinoma, which initially presented as metastasis to an umbilical hernia sac. The patient was a 55-year-old male with a two-year history of umbilical hernia. Two months prior to herniorrhaphy, the hernia became painful and the patient experienced nausea and weight loss. The gross examination did not reveal distinct lesions. Microscopically, the hernia sac was diffusely infiltrated by moderately differentiated adenocarcinoma, which was positive for CK7 and pancytokeratin and negative for TTF-1, CK20, PSA, and CDX2. Clinical laboratory tests found elevated levels of CA 19-9 and CEA. Computed tomography scan with intravenous contrast showed a 5 cm ill-defined and hypoattenuating mass involving the pancreatic tail and body, as well as numerous ill-defined lesions in the liver and peritoneal carcinomatosis. The patient had an earlier noncontrast computed tomography scan four months prior to the surgery, which did not detect any lesions in the abdomen. This case highlights the importance of intravenous contrast with computed tomography for the evaluation of pancreatic lesions and also emphasizes the importance of thorough histologic evaluation of hernia sacs for the detection of occult malignancy.

Grade Assignment by Ki-67 Proliferative Index, Mitotic Count, and Phosphohistone H3 Count in Surgically Resected Gastrointestinal and Pancreatic Neuroendocrine Tumors.

OBJECTIVES: The aim of this study was to evaluate the concordance in grade assignment for gastroenteropancreatic neuroendocrine tumors using mitotic count (MC), Ki-67 proliferative index (KPI), and phosphohistone H3 count (PHH3C). METHODS: Resected gastroenteropancreatic neuroendocrine tumors were graded based on MC, KPI, and PHH3C. Concordance was determined using a weighted κ statistic. Median survival across each grade category was determined using Kaplan-Meier methods. RESULTS: Of the 110 patients, the majority had gastrointestinal primaries and grade 1 or 2 tumors. Rates of discordance in grade assignment were 29% of cases for KPI versus MC (κW = 0.26), 32% for PHH3C versus MC (κW = 0.34), and 32% for PHH3C versus KPI (κW = 0.37). There was fair agreement between grading by KPI and MC. Relative to grade by KPI and MC, PHH3C tended to upgrade tumors. The proportion alive at 3 and 5 years was not significantly different for patients with grade 1 versus grade 2 tumors. CONCLUSIONS: The concordance between KPI and MC was fair. Phosphohistone H3 count tended to upgrade tumors using the cutoffs established by MC. Grade 1 and grade 2 tumors were associated with similar survival regardless of grading method. The overall relevance of the current cutoff values used in grading neuroendocrine tumors may need to be revisited.

Acquisition of CD30 and CD15 accompanied with simultaneous loss of all pan-T-cell antigens in a case of histological transformation of mycosis fungoides with involvement of regional lymph node: an immunophenotypic alteration resembling classical Hodgkin lymphoma.

: Acquired expression of CD30 is frequently noted in histological transformation of mycosis fungoides (MF), but simultaneous gain of CD15 accompanied with loss of pan-T-cell antigens are extremely rare. We report an unusual case of transformed MF with such an immunophenotypic alteration resembling classical Hodgkin lymphoma. The patient was an 81-year-old male with MF, who was initially treated with topical steroids and phototherapy. Despite the initial response, the patient developed a tumor-like skin lesion that was confirmed to be CD30-positive large T-cell lymphoma and was subsequently found to have a regional lymph node involvement by pleomorphic large cell lymphoma. Besides CD30, pleomorphic large cells were positive for CD15 but negative for all B cell- and T cell-specific antigens. Epstein-Barr virus was negative. Polymerase chain reaction-based assays demonstrated a clonal rearrangement of T-cell receptor gamma gene but detected no B-cell clone. The mechanism and clinical significance of this phenotypic conversion remains to be elucidated.

Scleroderma and IgG4-related disease.

IgG4-related disease is a syndrome which involves lymphoplasmacytic infiltrates and soft tissue sclerosis, elevated serum IgG4 titer, and increased IgG4-positive plasma cells in a variety of tissues. Scleroderma is also characterized by fibrosis and lymphoplasmacytic infiltrates. To our knowledge, the presence of IgG4-positive cells has not been well characterized in scleroderma. A retrospective review of scleroderma and related disorders (calcinosis, raynaud's syndrome, esophageal dysmotility, sclerodactyly, telangiectasia (CREST) syndrome, progressive systemic sclerosis, morphea) was performed. Thirty-four cases of scleroderma and related disorders were identified; IgG4-positive and IgG-positive plasma cells were counted in 10 HPF and an IgG4:IgG ratio determined. A cutoff ratio of 0.3 was used to define significant elevation. Three of the scleroderma cases had IgG4:IgG greater than 0. Only 1 case had a significant elevation. Of the 3 cases with elevated ratio, IgG4-positive cells ranged from 2 to 64 (median = 14), with an IgG4:IgG ranging from 0.06 to 0.34 (median = 0.22). Similar results were produced with the other sclerosing disorders. These results suggest that scleroderma is not part of the IgG4-related disease spectrum.

Myeloid neoplasms secondary to plasma cell myeloma: an intrinsic predisposition or therapy-related phenomenon? A clinicopathologic study of 41 cases and correlation of cytogenetic features with treatment regimens.

We describe 41 cases of myeloid neoplasms (MNs) secondary to plasma cell myeloma (PCM). The types of MN included myelodysplastic syndrome (MDS) in 34 (82.9%), acute myeloid leukemia (AML) in 4 (9.8%), and myeloproliferative neoplasm (MPN) or MDS/MPN in 3 (7.3%) cases. The latency from treatment to diagnosis of MN ranged from 9 to 384 months, with a median of 60 months. Of 37 cases with cytogenetic studies, complex abnormalities were detected in 22 (59.5%), -5(q)/-7(q) in 4 (10.8%), other abnormalities in 8 (21.6%), and normal karyotype in 3 (8.1%) cases. Complex abnormalities and -5(q)/-7(q) correlated directly with multiple chemotherapeutic regimens, particularly with combined melphalan/cyclophosphamide. Moreover, the features of cytogenetic abnormalities in our series were significantly different from those with concomitant PCM/MN who had significantly lower complex abnormalities. The latency, skewed proportion of MDS, and bias toward complex cytogenetic abnormalities/unbalanced aberrations of chromosomes 5/7 suggested an alkylating mutagenic effect on pathogenesis of secondary MN. Kaplan-Meier survival analysis demonstrated a median survival of 19 months, which was better than that for therapy-related (t)-MDS/AML. In contrast to t-MDS, the survival in our patients appeared to depend on subtypes of MDS as seen in de novo diseases.

Banding pattern on polarized hair microscopic examination and unilateral polymicrogyria in a patient with steroid sulfatase deficiency.

BACKGROUND: Several forms of ichthyosis are associated with neurologic manifestations, including Sjögren-Larsson syndrome, Refsum disease, and mental retardation-enteropathy-deafness-neuropathy-ichthyosis-keratoderma (MEDNIK) syndrome. We report a case of X-linked steroid sulfatase deficiency, ichthyosis, seizures, abnormal hair banding pattern, and unilateral polymicrogyria. OBSERVATIONS: A 3-year-old Caucasian male with a history of ichthyosis since birth presented with generalized tonic seizures. Findings from a physical examination were remarkable for thin hair, retinitis pigmentosa, and poor dentition. Polarized light microscopic examination of all the hair samples demonstrated a banding pattern. Magnetic resonance imaging of the brain revealed left hemispheric polymicrogyria with decreased sulcal pattern and stable asymmetric dilation of the left lateral ventricle. Constitutional microarray revealed the typical approximately 1.5-Mb deletion of the steroid sulfatase gene. CONCLUSIONS: Steroid sulfatase deficiency is a cause of X-linked ichthyosis; however, our patient also had retinitis pigmentosa, seizures, and abnormal hair findings. The presence of abnormal hair with a banding pattern on polarized microscopy may be helpful for diagnosis; however, this pattern is not specific to this disease. In addition, to our knowledge, the presence of a malformation of cortical development has not been previously reported in patients with steroid sulfatase deficiency.