EMA-Positive Superficial ALK-Rearranged Myxoid Spindle Cell Neoplasm Masquerading as Perineurioma/Hybrid Nerve Sheath Tumor.

ABSTRACT: Superficial anaplastic lymphoma kinase (ALK)-rearranged myxoid spindle cell neoplasm (SAMS) is a recently described entity which coexpresses ALK, CD34, and commonly S100. These neoplasms are characterized morphologically by concentric spindle cell whorls and cords and are commonly set in an abundant myxoid to myxocollagenous stroma, thus mimicking perineurioma or hybrid nerve sheath tumor. EMA immunostain has been reported to be negative in SAMS which helps in excluding the latter entities. Herein, we report the first EMA-positive SAMS of the right leg in a 37-year-old female patient masquerading as perineurioma/hybrid nerve sheath tumor. The tumor morphologically was comprised of spindle cells arranged in loose whorls and short fascicles set in myxoid to collagenous stroma and coexpressed CD34 and EMA, reminiscent of perineurioma. S100 showed focal staining. ALK immunostain was subsequently performed and was positive. ALK gene rearrangement was identified by fluorescence in situ hybridization break-apart assay and was further confirmed by next-generation sequencing-based RNA sequencing demonstrating FLNA::ALK fusion, thus supporting the diagnosis of SAMS. In conclusion, EMA can be expressed in SAMS, thus posing as a diagnostic pitfall. ALK immunostain and molecular studies are essential for confirming the diagnosis of SAMS and excluding potential mimickers, particularly perineurioma or hybrid nerve sheath tumor.

Random Skin Biopsy Is a Useful Procedure in the Evaluation of Hemophagocytic Lymphohistiocytosis: A Case Report and Review of Literature.

ABSTRACT: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome, characterized by aberrant activation of T lymphocytes and macrophages leading to hypercytokinemia. HLH can be familial or a result of various secondary etiologies. We present a case of a 46-year-old woman with a past medical history of multiple sclerosis on rituximab who presented as a transfer from an outside hospital with numerous clinical abnormalities including recurrent episodes of fever of unknown origin for 3 weeks, persistent leukocytosis, hypertriglyceridemia, and steatohepatitis. Given the uncertain nature of her illness, she underwent a random skin biopsy from the abdominal region to exclude hematolymphoid malignancy. Histopathology revealed a brisk histiocytic rich dermal infiltrate accompanied by perivascular lymphocytic infiltrate. The histiocytes were enlarged and positive for muraminadase and CD68 stains exhibiting hemophagocytosis focally. As per the HLH-2004 protocol, our patient met the diagnostic criteria of HLH. Concurrent bone marrow biopsy revealed similar rare hemophagocytosis. Cytogenetics and molecular studies were negative, supporting secondary HLH.

NEMO-NDAS: A Panniculitis in the Young Representing an Autoinflammatory Disorder in Disguise.

ABSTRACT: A 15-month-old full-term boy of African descent with an asymptomatic sickle cell trait presented with episodes of transient erythematous subcutaneous nodules involving the entire body except the face, since 2 weeks of age. The skin lesions evolved to areas of lipoatrophy and hyperpigmentation. An initial skin biopsy, studied at a different department at 2 months, was initially misinterpreted as subcutaneous fat necrosis of the newborn, despite the lack of the typical radiated crystals and needle-shaped clefts characterizing that entity. At 4 months of age, he developed systemic inflammatory manifestations, including fever, a new rash, significant periorbital edema, and failure to thrive. An extensive workup showed leukocytosis, hypercalcemia, elevated inflammatory markers, hypertriglyceridemia, and transaminitis. A new skin biopsy of the eyelid was diagnosed as neutrophilic lobular panniculitis with necrotic adipocytes. An initial whole-exome sequencing did not identify any causative mutations, but a WES reanalysis focused on autoinflammatory disorders was requested based on additional clinicopathologic data and revealed a mosaic intronic mutation in IKBKG c. 671+3 G > C. This mutation encodes an mRNA missing exon 5 resulting in NF-kB essential modulator (NEMO) Δ-exon 5-autoinflammatory syndrome (NDAS). NEMO-NDAS is one of the systemic autoinflammatory diseases that may appear as an unexplained panniculitis in young children, who should be monitored for immunodeficiency and/or autoinflammatory diseases. The differential diagnosis of autoinflammatory disorders should be considered in such cases incorporating the use of the whole-genome/exome sequencing in the investigation. The inhibitor of kappa-B kinase regulatory subunit gamma (IKBKG) is located on chromosome Xq28 and encodes the NEMO, a critical molecule upstream of NF-kB activation.

DNA mismatch repair-deficient non-neoplastic endometrial glands are common in Lynch syndrome patients and are present at a higher density than in the colon.

AIMS: The hallmark of Lynch syndrome (LS) is DNA mismatch repair protein (MMR) deficiency. Recently, MMR deficiency in non-neoplastic colonic crypts has been identified as a novel indicator of LS. We aimed to determine whether MMR-deficient non-neoplastic endometrial glands can distinguish patients with and without LS, and to compare the level of MMR deficiency in the normal endometrium and colon in LS patients. METHODS AND RESULTS: We evaluated the immunohistochemical expression of MMR proteins in the normal endometrial mucosa from 64 patients, including 34 patients with confirmed LS (17 with endometrial cancer and 17 without cancer), 30 patients with endometrial cancer without LS (10 with tumours with MLH1 promoter hypermethylation and 20 with MMR-proficient tumours), and in the normal colonic mucosa from 30 LS patients. MMR-deficient non-neoplastic endometrial glands were identified in 47% of LS patients and in no patients without LS (P < 0.001). MMR-deficient non-neoplastic glands were more often identified in LS patients with endometrial cancer (65%) than in those without endometrial cancer (29%) (P = 0.04). In contrast to what was seen in the normal colon, MMR-deficient glands in the normal endometrium were seen as large, contiguous groups, ranging in number from two to 101 (87% versus 45%, P = 0.02). MMR-deficient glands were identified at a higher density in the endometrium than in the colon in LS patients (median number of MMR-deficient glands, 22 versus two, P = 0.02). CONCLUSIONS: Our findings indicate that MMR-deficient non-neoplastic endometrial glands constitute an indicator of LS, and that MMR-deficient glands in the endometrium are present in a pattern of contiguous large groups.

Cytomorphology of metastatic dedifferentiated/undifferentiated melanoma to the gallbladder: A case report and review of literature.

Dedifferentiated/undifferentiated melanoma (DM/UM) is a distinct subtype of malignant melanoma that tends to lose all melanocytic markers of differentiation. DM/UM pose major diagnostic challenges as they could be easily confused with UM sarcoma or carcinoma, thus necessitating the use of molecular studies such as Next Generation Sequencing (NGS) for detecting melanoma-compatible mutations to confirm such diagnosis. The capability of performing NGS molecular studies on small biopsy material with confirmation of adequacy via rapid on-site evaluation (ROSE) has tremendous value in diagnosing DM/UM. Herein, we present the first reported case of metastatic DM/UM to the gall bladder arising in a 60-year-old female with a prior history of right knee melanoma. We also shed light on the cytomorphology of DM/UM, review the literature on such a challenging entity, and emphasize the crucial role of molecular testing in their diagnosis.

Mutation-specific Mismatch Repair-deficient Benign Endometrial Glands in Endometrial Biopsies and Curettings Are a Biomarker of Lynch Syndrome and Associate With Endometrial Carcinoma Development.

Endometrial carcinoma is the most common extraintestinal cancer in Lynch syndrome (LS). Recent studies have demonstrated mismatch repair (MMR) deficiency can be detected in benign endometrial glands in LS. We performed MMR immunohistochemistry in benign endometrium from endometrial biopsies and curettings (EMCs) from a study group of 34 confirmed LS patients and a control group of 38 patients without LS who subsequently developed sporadic MLH1-deficient or MMR-proficient endometrial carcinoma. MMR-deficient benign glands were only identified in patients with LS (19/34, 56%) and were not identified in any control group patient (0/38, 0%) ( P < 0.001). MMR-deficient benign glands were identified as large, contiguous groups in 18 of 19 cases (95%). MMR-deficient benign glands were identified in patients with germline pathogenic variants in MLH1 (6/8, 75%), MSH6 (7/10, 70%), and MSH2 (6/11, 55%) but not in patients with variants in PMS2 (0/4). MMR-deficient benign glands were seen in all EMC samples (100%) but in only 46% of endometrial biopsy samples ( P =0.02). Patients with MMR-deficient benign glands were significantly more likely to have endometrial carcinoma (53%) compared with LS patients with only MMR-proficient glands (13%) ( P =0.03). In conclusion, we demonstrated that MMR-deficient benign endometrial glands are frequently identified in EMB/EMC in women with LS and are a specific marker for LS. Women with LS with MMR-deficient benign glands were more likely to have endometrial carcinoma suggesting that MMR-deficient benign glands may be a biomarker of increased risk of endometrial carcinoma development in LS.

Keratitis caused by Nocardia farcinica in a contact lens wearer.

Bacterial keratitis is an infection of the cornea. This kind of infection can progress quickly and if left untreated, it can eventually cause complete blindness. While Staphylococcus aureus and Pseudomonas aeruginosa are most commonly responsible for this type of infection in the United States, Nocardia spp. is rarely encountered. Here we describe an interesting case of Nocardia farcinica keratitis in a 31-year-old male patient having an extended wear of contact lenses. The patient presented at the emergency department with irritation, foreign body sensation, redness, and pain of his left eye. Nocardia farcinica was isolated from a corneal scraping specimen, and determined by sequencing a region of 16S rRNA gene. The patient had antimicrobial therapy with good improvement. We highlight the important role of Nocardia farcinica in causing keratitis, and its accurate and timely diagnosis is needed to avoid poor visual outcomes.

Detection of Enterococcus avium in a case of urinary tract infection and haematuria.

Enterococci have been recognized as major pathogens causing nosocomial and community-acquired infections. The emergence of antimicrobial-resistant enterococci is one of the major public health challenges worldwide. While many enterococcal species have been identified, Enterococcus avium is rarely detected in humans. Here we present an interesting case of urinary tract infection and haematuria involving E. avium in a 72-year-old patient. The patient underwent antibiotic therapy and surgical procedures with excellent improvement. This case report highlights the important role of E. avium in clinical settings.

Multiplex assessment of SARS-CoV-2 antibodies improves assay sensitivity and correlation with neutralizing antibodies.

OBJECTIVES: Detection of antibodies to multiple SARS-CoV-2 antigens in a single assay could increase diagnostic accuracy, differentiate vaccination from natural disease, and aid in retrospective exposure determination. Correlation of binding antibody assessment in clinical assays with neutralizing antibodies is needed to better understand the humoral response to SARS-CoV-2 infection and establish of correlates of protection. METHODS: A cohort of 752 samples was used to assess specificity, sensitivity, and comparison to 6 other Conformitè Europëenne serologic assays for the BioRad SARS-CoV-2 IgG multiplex assay which measures receptor binding domain IgG (RBD), spike-S1 IgG (S1), spike-S2 IgG (S2), and nucleocapsid IgG (N). A subset of serial specimens from 14 patients was also tested for neutralizing antibodies (n = 61). RESULTS: Specificity for RBD and S1 IgG was 99.4% (n = 170) and 100% for S2 and N IgG (n = 170) in a cohort selected for probable interference. Overall assay concordance with other assays was >93% for IgG and total antibody assays and reached 100% sensitivity for clinical concordance at >14 days as a multiplex assay. RBD and S1 binding antibody positivity demonstrated 79-95% agreement with the presence of neutralizing antibodies. CONCLUSIONS: The BioRad SARS-CoV-2 IgG assay is comparable to existing assays, and achieved 100% sensitivity when all markers were included. The ability to measure antibodies against spike and nucleocapsid proteins simultaneously may be advantageous for complex clinical presentations, epidemiologic research, and in decisions regarding infection prevention strategies. Additional independent validations are needed to further determine binding antibody and neutralizing antibody correlations.

Overexpression of Carbonic Anhydrase IX is a Dismal Prognostic Marker in Breast Carcinoma in Egyptian Patients.

Carbonic anhydrase IX (CAIX) is an enzyme whose expression is very limited in normal tissues and it is highly expressed in various cancers. Therefore, inhibition of CAIX is considered as a promising therapeutic target for the treatment of solid tumors where hypoxic environment has developed. The aim of the current work is to evaluate the immunohistochemical (IHC) expression of CAIX in breast cancer (BC) of Egyptian patients and to investigate the associations of CAIX expression with the standard clinicopathologic features, IHC subtypes of BC, and overall survival. This retrospective study was conducted on 56 archival cases of Egyptian BC patients. Fifty-one of 56 cases (91.1%) showed positive expression of CAIX with cytoplasmic localization, whereas 5 cases (8.9%) showed negative expression. CAIX IHC overexpression is significantly associated with advanced stage and presence of coagulative tumor cell necrosis (P=0.03 and 0.02, respectively). Multivariate analysis revealed Ki67 labeling index and CAIX H-score grouping (P=0.03 and 0.02, respectively) as independent prognostic factors affecting BC patients' overall survival. We concluded that CAIX could play a role in the progression of the studied BC cases. CAIX is a good candidate for target therapy.