A Rare Case of Metaplastic Thymoma Presenting With Myasthenia Gravis.

Thymomas are tumors of the mediastinum often associated with autoimmune conditions, in particular myasthenia gravis. In contrast, among the fewer than 40 reports of metaplastic thymoma, myasthenia gravis is rarely found. We describe the fourth patient, and first man, with metaplastic thymoma and myasthenia gravis. A 34-year-old had acute onset of double vision with associated dysphagia and was found to have an elevation of serum acetylcholine receptor antibodies. He underwent a transsternal thymectomy. Tissue sections showed a biphasic proliferation of keratin-positive epithelial cells with a complement of spindle cells confirming the diagnosis of metaplastic thymoma. Terminal deoxynucleotidyl transferase (TDT)-positive T lymphocytes were rare and only found in the periphery of the tumor, consistent with thymic remnant. A YAP1::MAML2 gene fusion, with an in-frame fusion between genes YAP1 Exon5 (NM_001130145) and MAML2 Exon2 (NM_032427) was found, supporting further the diagnosis of metaplastic thymoma (Anchored multiplex RNA sequencing [Archer Dx, Boulder, CO] assay). The patient's gender and relatively young age, the presence of an autoimmune condition, and the lack of lymphocytic infiltrate all contribute unusual features to this case and suggest avenues for further exploration.

Comparing postoperative outcomes using electrocautery versus cold-knife de-epithelialization of dermal fat graft in parotidectomy reconstruction.

PURPOSE: The present study was developed to evaluate the effectiveness of a simple rapid technique for de-epithelializing cutaneous flaps and grafts in parotidectomy reconstruction. MATERIALS AND METHODS: 109 patients who underwent a parotidectomy with abdominal free dermal fat graft (FDFG) reconstruction between 2018 and 2021 were evaluated based on demographic factors, past medical/surgical history, type of parotidectomy performed, operative factors, and post-operative complications. These data were then stratified based on de-epithelialization technique as well as tumor malignancy status to determine any differences in complication rates or perioperative factors between electrocautery (EC) and cold knife (CK) techniques within both benign and malignant subgroups. RESULTS: 77 of the 109 participants underwent FDFG de-epithelialization using monopolar electrocautery (EC) and the remaining 32 participants underwent de-epithelialization using traditional cold knife (CK) technique. There was no statistical difference among the two groups in overall complication rate. The EC group had a significantly shorter operation time ("EC vs. CK": 144.2 min vs. 174.7 min; p = 0.031). Additionally, histopathologic samples showed that both techniques left the underlying dermis intact and without damage. CONCLUSIONS: This study demonstrated that there is no difference in complication rate or histology of FDFGs de-epithelialized using EC compared to CK. It was also shown that when controlling for confounders by looking solely at the benign subgroup of patients, EC de-epithelialization was a faster technique than CK. These findings suggest that EC is just as effective as CK, and may actually be a more efficient surgical technique to accomplish de-epithelialization of FDFG.

A rare case of Hidradenoma of the lower lip.

Hidradenoma are rare benign tumors with eccrine or apocrine differentiation that most often presents as a small, firm, solitary dermal nodule. At times, hidradenoma shows striking cytologic and histologic similarity to other neoplasms, including its malignant counterpart, hidradenocarcinoma. We present the first reported case of benign hidradenoma of the lower lip. The case illustrates important diagnostic features of hidradenoma and discusses the current understanding of its malignant potential and the appropriate management of such lesions.

Pathologist Concordance for Ovarian Carcinoma Subtype Classification and Identification of Relevant Histologic Features Using Microscope and Whole Slide Imaging.

CONTEXT.­: Despite several studies focusing on the validation of whole slide imaging (WSI) across organ systems or subspecialties, the use of WSI for specific primary diagnosis tasks has been underexamined. OBJECTIVE.­: To assess pathologist performance for the histologic subtyping of individual sections of ovarian carcinomas using a light microscope and WSI. DESIGN.­: A panel of 3 experienced gynecologic pathologists provided reference subtype diagnoses for 212 histologic sections from 109 ovarian carcinomas based on optical microscopy review. Two additional attending pathologists provided diagnoses and also identified the presence of a set of 8 histologic features important for ovarian tumor subtyping. Two experienced gynecologic pathologists and 2 fellows reviewed the corresponding WSI images for subtype classification and feature identification. RESULTS.­: Across pathologists specialized in gynecologic pathology, concordance with the reference diagnosis for the 5 major ovarian carcinoma subtypes was significantly higher for a pathologist reading on a microscope than each of 2 pathologists reading on WSI. Differences were primarily due to more frequent classification of mucinous carcinomas as endometrioid with WSI. Pathologists had generally low agreement in identifying histologic features important to ovarian tumor subtype classification with either an optical microscopy or WSI. This result suggests the need for refined histologic criteria for identifying such features. Interobserver agreement was particularly low for identifying intracytoplasmic mucin with WSI. Inconsistencies in evaluating nuclear atypia and mitoses with WSI were also observed. CONCLUSIONS.­: Further research is needed to specify the reasons for these diagnostic challenges and to inform users and manufacturers of WSI technology.

Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance.

Antineoplastic platinum agents are used in first-line treatment of ovarian cancer, but treatment failure frequently results from platinum drug resistance. Emerging observations suggest a role of reactive oxygen species (ROS) in the resistance of cancer drugs including platinum drugs. However, the molecular link between ROS and cellular survival pathway is poorly understood. Using quantitative high-throughput combinational screen (qHTCS) and genomic sequencing, we show that in platinum-resistant ovarian cancer elevated ROS levels sustain high level of IL-11 by stimulating FRA1-mediated IL-11 expression and increased IL-11 causes resistance to platinum drugs by constitutively activating JAK2-STAT5 via an autocrine mechanism. Inhibition of JAK2 by LY2784544 or IL-11 by anti-IL-11 antibody overcomes the platinum resistance in vitro or in vivo. Significantly, clinic studies also confirm the activated IL-11-JAK2 pathway in platinum-resistant ovarian cancer patients, which highly correlates with poor prognosis. These findings not only identify a novel ROS-IL-11-JAK2-mediated platinum resistance mechanism but also provide a new strategy for using LY2784544- or IL-11-mediated immunotherapy to treat platinum-resistant ovarian cancer.

Urethral Solitary Fibrous Tumor: A Rare Pathologic Diagnosis of a Periurethral Mass.

Solitary fibrous tumors (SFTs) may occur at any site in the body. SFTs can only be conclusively diagnosed based on histopathologic and immunohistochemical characteristics of the tumor. The presence of SFTs in the abdomen and pelvis is extremely rare. To our knowledge no cases of urethral solitary fibrous tumor in the literature have been reported so far. We present a case of a solitary fibrous tumor arising from the urethra in a twenty-three-year-old female presenting with vaginal mass.

Can problematic fibroepithelial lesions be accurately classified on core needle biopsies?

Fibroepithelial lesions (FEL) of the breast are notoriously difficult to classify on core needle biopsies. The goal of this study was to evaluate interobserver variability and accuracy of subclassifying difficult FELs into fibroadenoma (FA) and phyllodes tumors (PTs). We identified 50 breast core needle biopsies, initially diagnosed generically as FEL, with subsequent excision and final diagnosis of either FA or benign PT. Five surgical pathologists from one institution independently reviewed these in 3 rounds. The pathologists were blinded to the final excisional diagnosis. Two diagnostic categories were allowed: FA and PT. A set of histologic criteria was provided including the presence of subepithelial condensation, stromal heterogeneity, overgrowth, pleomorphism, fragmentation, cellularity, adipose tissue entrapment, and mitotic count and asked to review the slides for the second round. A third round of interpretations was conducted after each criterion was defined. Interobserver agreement for the diagnosis and each criterion was evaluated using the κ level of agreement. Accuracy of ratings to final diagnosis was calculated using Wilcoxon signed-rank test. κ Values for interobserver agreement were fair for the first and second rounds varying from 0.20 to 0.22, respectively. This increased to 0.27 in round 3. When considering each category, the κ value varied from 0.26 to 0.29 for FA and 0.28 to 0.14 for PT. Overall, there was fair agreement between the pathologists in all categories. The rate of correctly diagnosed cases ranged from 40% in the first round, to 48% in the second round, to 67% in round 3. Overall the pathologists performed better in identifying FA than PT. The accuracy of interpretations was significantly different between the first (40%), second (48%), and third rounds (67%).

Altered PTEN, ATRX, CHGA, CHGB, and TP53 expression are associated with aggressive VHL-associated pancreatic neuroendocrine tumors.

Von Hippel-Lindau (VHL) syndrome is an inherited cancer syndrome in which 8-17 % of germline mutation carriers develop pancreatic neuroendocrine tumors (PNETs). There is limited data on prognostic markers for PNETs other than Ki-67, which is included in the World Health Organization classification system. Recently, specific genes and pathways have been identified by whole exome sequencing which may be involved in the tumorigenesis of PNETs and may be markers of disease aggressiveness. The objective of this study was to identify molecular markers of aggressive disease in VHL-associated PNETs. The protein expression of eight genes (PTEN, CHGA, CHGB, ATRX, DAXX, CC-3, VEGF, and TP53) was analyzed in PNETs by immunohistochemistry and compared to clinical data, VHL genotype, functional imaging results, and pathologic findings. Subcellular distribution of phosphatase and tensin (PTEN), chromogranin A (CHGA), and alpha thalassemia/mental retardation syndrome X-linked (ATRX) were significantly different by WHO classifications (p ≤ 0.05). There was decreased PTEN nuclear to cytoplasmic ratio (p < 0.01) and decreased CHGA nuclear expression (p = 0.03) in malignant samples as compared to benign. Lower cytoplasmic chromogranin B (CHGB) expression (p = 0.03) was associated with malignant tumors and metastasis. Higher nuclear expression of PTEN was associated with VHL mutations in exon 3 (p = 0.04). Higher PTEN and CHGB expression was associated with higher FDG-PET avidity (p < 0.05). Cytoplasmic expression of CC-3 was associated with higher serum chromogranin A levels (ρ = 0.72, p = 0.02). Lastly, greater cytoplasmic expression of p53 was associated with metastasis. Our findings suggest that altered PTEN, ATRX, CHGA, and CHGB expression are associated with aggressive PNET phenotype in VHL and may serve as useful adjunct prognostic markers to Ki-67 in PNETs.

Adrenal histologic findings show no difference in clinical presentation and outcome in primary hyperaldosteronism.

BACKGROUND: Primary hyperaldosteronism is most commonly due to a solitary cortical adenoma. Thus, some surgeons have suggested a subtotal adrenalectomy is a reasonable approach when a mass can be identified. On the other hand, adrenal vein sampling (AVS) is being used more frequently to distinguish patients with unilateral disease for adrenalectomy, even if a discrete mass is not identified on axial imaging. In these cases, surgical pathology may reveal a cortical adenoma, a cortical adenoma with hyperplasia, or cortical hyperplasia. The goal of this study was to compare the presentation and outcome among patients undergoing adrenalectomy and found to have different histologic features. METHODS: We performed a retrospective analysis of 136 patients with primary hyperaldosteronism. A total of 95 patients had an adrenalectomy for unilateral disease. The preoperative clinical and laboratory, and postoperative outcome of the three aforementioned histologic groups were compared. RESULTS: A total of 95 patients underwent an adrenalectomy. We found no significant difference in age, gender, body mass index, duration of hypertension, number of antihypertensive medications, serum aldosterone level, serum renin level, or adrenal vein sampling ratios among the three histologic categories. We also found no significant difference among the three categories in postoperative cure rate. CONCLUSION: The rate of unilateral hyperplasia in patients with primary hyperaldosteronism (16%) is likely higher than previously reported, which may be due to the increasing use of AVS. The clinical presentation and outcome of patients regardless of the histologic findings are similar. Our data also suggests that subtotal adrenalectomy would not be appropriate in patients with primary hyperaldosteronism.

von Hippel-Lindau disease-associated solid microcystic serous adenomas masquerading as pancreatic neuroendocrine neoplasms.

BACKGROUND: Patients with von Hippel-Lindau disease (VHL) commonly develop pancreatic cysts and neuroendocrine neoplasms (PNENs or PNETs). Solid microcystic serous adenoma (SMSA), a rare neoplasm described in VHL patients, can be mistaken for PNEN on imaging. METHODS: Clinical, pathologic, and radiologic data were reviewed on VHL patients who underwent surgery for a preoperative diagnosis of PNEN since 1994 at 1 institution. Blinded to the pathologic diagnoses, radiologists reassessed available imaging. RESULTS: For 55 patients, 79 pancreatectomies were performed for presumed PNENs. Ten (18%) patients underwent 12 (15%) resections for neoplasms diagnosed as SMSA on final pathology. The average size of a SMSA leading to operation was 3.6 ± 0.4 cm. Four out of 11 SMSAs were still mistaken for PNENs when imaging was reassessed. The mean FDG-positron emission tomography (PET) standardized uptake value was greater for 17 PNENs (12.1 ± 1.2) compared with 6 SMSAs (4.2 ± 0.5; P = .002). The mean doubling time of SMSAs and PNENs was similar. Seven (15%) patients with pathologically proven PNENs had malignant disease. CONCLUSION: SMSAs can mimic PNENs on nonfunctional imaging; FDG-PET may help to differentiate them. A high index of suspicion is needed to minimize operations performed for SMSA and to counsel VHL patients of their risks of undergoing operation for a lesion with no known malignant potential.

Immunoreactivity for calretinin and keratins in desmoid fibromatosis and other myofibroblastic tumors: a diagnostic pitfall.

Calretinin is an intracellular calcium-binding EF-hand protein of the calmodulin superfamily. It plays a role in diverse cellular functions, including message targeting and intracellular calcium signaling. It is expressed in the mesothelium, mast cells, some neural cells, and fat cells, among others. Because of its relative specificity for mesothelial neoplasms, calretinin is widely used as one of the primary immunohistochemical markers for malignant mesothelioma and in differentiating it from adenocarcinoma. On the basis of our sporadic observation on calretinin immunoreactivity in desmoid fibromatosis, we systematically evaluated calretinin, keratin cocktail (AE1/AE3), and WT1 immunoreactivity in 268 fibroblastic/myofibroblastic neoplasms. Calretinin was observed in 75% (44/58) of desmoid fibromatosis, 50% (21/42) of proliferative fasciitis, 23% (8/35) of nodular fasciitis, 33% (13/40) of benign fibrous histiocytoma, 35% (22/62) of malignant fibrous histiocytoma, and 13% (4/31) of solitary fibrous tumors but not in normal connective tissue fibroblasts at various sites. Keratin AE1/AE3 immunoreactivity was also commonly (6/13) present in the large ganglion-like cells of proliferative fasciitis and sometimes in nodular fasciitis (3/35), solitary fibrous tumor (3/27), and malignant fibrous histiocytoma (9/62). Nuclear immunoreactivity for WT1 or keratin 5 positivity was not detected in myofibroblastic tumors. On the basis of these observations, it can be concluded that calretinin and focal keratin immunoreactivity is fairly common in benign and malignant fibroblastic and myofibroblastic lesions. Calretinin-positive and keratin-positive spindle cells in desmoid and nodular fasciitis or calretinin-positive ganglion-like cells in proliferative fasciitis should not be confused with elements of epithelioid or sarcomatoid mesothelioma. These diagnostic pitfalls can be avoided with careful observation of morphology, quantitative differences in keratin expression, and use of additional immunohistochemical markers such keratin 5 and WT1 to verify true epithelial and mesothelial differentiation typical of mesothelioma.

Prostatic abscess in a pediatric patient with chronic granulomatous disease: report of a unique case and review of the literature.

Chronic granulomatous disease (CGD) is a rare hereditary disease in which phagocytes have difficulty forming the superoxide radical required to kill certain pathogens. Individuals with CGD are susceptible to a specific set of infections and granulomatous lesions. We present the case of a 15-year-old boy with X-linked CGD who presented with unremitting cough and fevers. He had a left-sided pneumonia that persisted despite home intravenous antibiotics. He was admitted to an outside facility for bronchoalveolar lavage to obtain cultures and polymerase chain reaction. Computed tomography of chest, abdomen, and pelvis was done for baseline evaluation of extent of disease. Computed tomography revealed a fluid collection in the prostatic fossa, later determined to be a prostatic abscess. To our knowledge, this is the first reported case of a prostatic abscess in a pediatric patient with CGD.

Spinal cord glioneuronal tumor with neuropil-like islands with 1p/19q deletion in an adult with low-grade cerebral oligodendroglioma.

Glioneuronal tumor with neuropil-like islands (GTNI) is considered a rare variant of astrocytoma, characterized by discrete aggregates of cells expressing neuronal markers that punctuate a GFAP-positive glial background. Of the 24 published GTNI cases, only two occurred in adult spinal cords; none occurred concurrent with another CNS tumor; and none of those tested exhibited the 1p/19q deletion typical of oligodendroglioma. A 48-year-old man without significant past medical history was diagnosed with a WHO grade II oligodendroglioma by stereotactic biopsy of a lesion discovered after the patient suffered a generalized tonic-clonic seizure. By FISH analysis, this tumor exhibited the 1p/19q deletion present in up to 80% of oligodendrogliomas. The patient received 14 monthly cycles of temozolomide, and his cerebral tumor had a minor response. When the patient subsequently reported progressive paresthesias of his lower extremities, an MRI revealed an enhancing, cystic tumor of the thoracic spinal cord that was diagnosed as GTNI by histological analysis. By FISH analysis, this lesion exhibited the same 1p/19q deletion present in the concurrent cerebral oligodendroglioma. This case of a spinal cord GTNI with 1p/19q deletions constitutes the third report of a spinal cord GTNI in an adult patient; the first report of a GTNI in an individual with a separate CNS neoplasm; and the first report of a GTNI with 1p/19q deletions. This case establishes a potential genetic kinship between GTNI and oligodendroglioma that warrants further investigation.