Rituximab Therapy for Insulin Allergy in Type-1 Diabetes Mellitus.

Background/Objective: Allergic reactions to insulin have decreased significantly since the introduction of human insulin preparation, but up to 2.4% of insulin-treated patients can still be affected. Rituximab is a monoclonal antibody against the surface antigen CD20 on B lymphocytes, and it is largely used to treat lymphoproliferative and rheumatological conditions. In a very few published case reports, rituximab has been used as an investigational drug to treat severe insulin allergy refractory to conventional therapy. Here, we present an unusual case of a 40-year-old woman with T1DM and severe insulin allergy that was successfully treated with rituximab. Case Report: The patient was diagnosed with T1DM at age 37. Three years later, skin reactions developed at insulin administration sites. These consisted of pruritic and painful erythema and wheals that appeared within 1 to 4 h of insulin administration, followed by induration, subcutaneous nodules, and surrounding lipodystrophy that lasted several days with spontaneous resolution in 1 to 2 weeks. Extensive immunologic evaluation suggested the reaction was related to insulin allergy. Skin biopsy revealed sublobular panniculitis. After failed conventional treatment with antihistamines, glucocorticoid, and various insulins, rituximab infusion as an investigational approach was initiated. This was very successful, leading to prolonged remission of her insulin allergy. Discussion: First-line management of insulin allergy should focus on second-generation antihistamines and switching insulin preparation. In refractory cases, systemic immunotherapy with rituximab can be a viable option. Conclusion: Practitioners should be aware that in patients with insulin allergy who fail conventional treatment, immunotherapy with rituximab can be a viable option.

Comparison of PD-L1 (22C3) Expression in Paired Primary and Metastatic Breast Carcinoma.

INTRODUCTION: PD-L1 immunohistochemistry (IHC) is being used as a predictive marker of the benefit derived from immunotherapy in several cancer types, including breast cancer. However, the insight gleaned of the prognostic and predictive value of PD-L1 status and its correlation with molecular characteristics during breast cancer progression remains limited. METHODS: We performed an PD-L1 (22C3) assay in pre-treatment primary and metastatic tumor sections from 33 patients with breast carcinoma, matched for post neoadjuvant chemotherapy (p-NACT). PD-L1 expression was evaluated using 3 scoring methods: immune cell (IC) and tumor cell (TC) with a 1% as the cutoff value, and combined positive scores (CPS) with a 1 as the cutoff value. Twenty-two samples from 11 patients had successful fluorescence in situ hybridization (FISH)-based molecular data available for analysis. RESULTS: In the 33 pre-treatment primary tumors, PD-L1 IC, TC, and CPS showed positive correlation with stromal tumor infiltrate lymphocytes (sTIL), histological grade 3, and triple negative breast carcinoma (TNBC). In the matched metastatic tumors, only PD-L1 IC showed a positive correlation with sTIL. The primary tumors showed a higher PD-L1 expression than the matched metastatic tumors by IC and CPS. Negative to positive conversion by CPS was identified in the metastatic tumors from lung, pleura and liver. p-NACT tumors also showed a trend of lower PD-L1 expression compared to the pre-treatment tumors. Six patients had matched samples for molecular and PD-L1 comparison, and none of them showed consistent gene alterations or PD-L1 expression among the primary, p-NACT and metastatic tumors. CONCLUSION: Our study showed a decrease in PD-L1 expression and disconnected molecular features during breast cancer progression. Repeating PD-L1 IHC testing could be considered in some specific metastatic sites if primary tumors were negative. Further studies are needed to identify other predictive factors for immune checkpoint inhibitor (ICI) therapy in patients with breast carcinoma.

Surgical Margins in Musculoskeletal Sarcoma.

¼ Negative margin resection of musculoskeletal sarcomas is associated with reduced risk of local recurrence.¼ There is limited evidence to support an absolute margin width of soft tissue or bone that correlates with reduced risk of local recurrence.¼ Factors intrinsic to the tumor, including histologic subtype, grade, growth pattern and neurovascular involvement impact margin status and local recurrence, and should be considered when evaluating a patient's individual risk after positive margins.¼ Appropriate use of adjuvant therapy, critical analysis of preoperative advanced cross-sectional imaging, and the involvement of a multidisciplinary team are essential to obtain negative margins when resecting sarcomas.

Pigmented intraepithelial Merkel cell carcinoma mimicking melanoma in situ.

Merkel cell carcinoma (MCC) is a rare neoplasm that arises in the skin of elderly patients on sun-exposed areas such as the head, neck, and extremities. Involvement of the epidermis by tumor cells is a relatively uncommon phenomenon. However, a few cases have been reported of Merkel cell carcinoma in situ (MCCIS) in which tumor cells are confined exclusively to the epidermis without dermal involvement. Herein, we present a peculiar MCCIS lesion in a 66-year-old man composed of tumor cells in a nested and lentiginous growth pattern, exhibiting variable quantities of intracytoplasmic dusty brown pigment consistent with melanin, thus closely mimicking melanoma in situ. In addition, the lesion was associated with invasive squamous cell carcinoma, which has not been previously reported in the literature. An extensive search of the PubMed-indexed, English-language literature yielded only 17 case reports of MCCIS without documented invasion in which clinical data were available. Out of the cases with available clinical information, individuals with strict MCCIS (n = 13) showed no evidence of recurrence or metastases. The median follow-up time in the cases with available data (n = 9) was 12 months (mean 12.8 months, range 6-21). Thus, MCCIS without invasion may have a favorable clinical course in contrast to invasive MCC tumors.

A Case of Anastomosing Hemangioma of the Breast During Pregnancy.

Anastomosing hemangiomas (AH) are rare benign masses. We report an occurrence of AH in the breast during pregnancy, its pathological analysis, and clinical management. Key in the evaluation of these rare vascular lesions is differentiating AH from angiosarcoma. A low proliferative Ki-67 index and small size on imaging and final pathology will confirm AH from angiosarcoma. Clinical management of AH requires surgical resection and standard interval mammography and clinical breast examination.

Randomized Trial of Anticoagulation Strategies for Noncritically Ill Patients Hospitalized With COVID-19.

BACKGROUND: Prior studies of therapeutic-dose anticoagulation in patients with COVID-19 have reported conflicting results. OBJECTIVES: We sought to determine the safety and effectiveness of therapeutic-dose anticoagulation in noncritically ill patients with COVID-19. METHODS: Patients hospitalized with COVID-19 not requiring intensive care unit treatment were randomized to prophylactic-dose enoxaparin, therapeutic-dose enoxaparin, or therapeutic-dose apixaban. The primary outcome was the 30-day composite of all-cause mortality, requirement for intensive care unit-level of care, systemic thromboembolism, or ischemic stroke assessed in the combined therapeutic-dose groups compared with the prophylactic-dose group. RESULTS: Between August 26, 2020, and September 19, 2022, 3,398 noncritically ill patients hospitalized with COVID-19 were randomized to prophylactic-dose enoxaparin (n = 1,141), therapeutic-dose enoxaparin (n = 1,136), or therapeutic-dose apixaban (n = 1,121) at 76 centers in 10 countries. The 30-day primary outcome occurred in 13.2% of patients in the prophylactic-dose group and 11.3% of patients in the combined therapeutic-dose groups (HR: 0.85; 95% CI: 0.69-1.04; P = 0.11). All-cause mortality occurred in 7.0% of patients treated with prophylactic-dose enoxaparin and 4.9% of patients treated with therapeutic-dose anticoagulation (HR: 0.70; 95% CI: 0.52-0.93; P = 0.01), and intubation was required in 8.4% vs 6.4% of patients, respectively (HR: 0.75; 95% CI: 0.58-0.98; P = 0.03). Results were similar in the 2 therapeutic-dose groups, and major bleeding in all 3 groups was infrequent. CONCLUSIONS: Among noncritically ill patients hospitalized with COVID-19, the 30-day primary composite outcome was not significantly reduced with therapeutic-dose anticoagulation compared with prophylactic-dose anticoagulation. However, fewer patients who were treated with therapeutic-dose anticoagulation required intubation and fewer died (FREEDOM COVID [FREEDOM COVID Anticoagulation Strategy]; NCT04512079).

An Unusual Benign Uterine Stromal Spindle Cell Tumor Harboring JAZF1::BCORL1.

Uterine mesenchymal lesions demonstrate various underlying genomic alterations involving MED12 , JAZF1 , YWHAE , BCOR , and ALK genes, among others. Recent publications describe a subset of high-grade endometrial stromal sarcoma lesions harboring BCORL1 gene aberrations including JAZF1::BCORL1 . Herein, we present an unusual benign endomyometrial spindle cell lesion that defies classificatory efforts by demonstrating mixed histomorphologic and immunohistochemical features of endometrial stromal nodule, leiomyoma, and uterine inflammatory myofibroblastic tumor while harboring a JAZF1::BCORL1 . The lesion was found in a 43-yr-old woman with pelvic pain and heavy menses as a 5.5 cm well-circumscribed ulcerated mass fungating from the cervical os. Microscopic examination revealed a polypoid, well-circumscribed, moderately cellular endomyometrial tumor composed by bland spindle cells haphazardly disposed within a slightly edematous stroma enriched by a delicate network of thin-walled vessels that were occasionally encircled by the tumor cells. Unequivocal evidence of tongue-like growth pattern into the myometrium, tumor-type necrosis or increased mitotic activity was not identified after sampling the entire lesion. The lesion showed patchy immunoreactivity for both smooth muscle actin-alpha and desmin while negative for CD10, HMB45, ALK (D5F3), and BCOR. An Archer FusionPlex panel assay demonstrated a fusion involving both exons 4 from the JAZF1 and BCORL1 genes. The JAZF1::BCORL1 has not, to the best of our knowledge, been previously reported in a benign/low-grade mesenchymal uterine lesion.

Benign Neurofibroma/Schwannoma Hybrid Peripheral Nerve Sheath Tumor of the Ulnar Nerve Harboring a Metastatic Papillary Thyroid Carcinoma Deposit: A Case Report of Tumor-to-Tumor Metastasis.

A 74-year-old man with a medical history significant for papillary thyroid cancer (PTC) presented with a rapidly enlarging grape-sized mass in his right medial arm with paresthesia in the ulnar nerve distribution. Imaging was suspicious for a peripheral nerve sheath tumor (PNST), but an ultrasound-guided biopsy was equivocal. The mass was excised with final histopathology demonstrating a benign neurofibroma/schwannoma hybrid nerve sheath tumor (N/S HNST) harboring a metastatic PTC deposit, ultimately mimicking the rare glandular schwannoma subtype. Next-generation sequencing (NGS) of the lesion demonstrated somatic variants in BRAF and TERT (common in PTC) and NF2 (common in PNSTs). After excision, the patient's nerve symptoms improved. A postsurgical PET/CT scan also showed progression in the lungs/mediastinum. Due to the metastatic nature of his PTC, he was treated with 14 mg of Lenvima (lenvatinib) daily, and his PET/CT surveillance was performed at more frequent intervals. Tumor-to-tumor metastasis (TTM) is a rare occurrence. To our knowledge, this is the first case reported on PTC metastasizing into a benign (hybrid) PNST, which mimicked glandular schwannoma. Symptomatology, imaging characteristics, NGS, and histopathological characteristics that can decipher between different benign PNST subtypes (schwannoma, neurofibroma, glandular, hybrid, etc.), malignant PNSTs (MPNSTs), and TTM are described.

Breast Implant Capsule-Associated Squamous Cell Carcinoma: Report of 2 Patients.

Breast implant augmentation is a low-risk procedure with few life-threatening complications. Capsular contracture and rupture/leakage of the implant are the most common complications encountered. Malignant breast implant augmentation-associated lesions are rare, with anaplastic large cell lymphoma being the most common. Squamous cell carcinomas associated with breast implant augmentation are exceedingly rare, with only eight patients reported. Breast implant capsule-associated squamous cell carcinoma occurs in patients with long standing breast implant augmentations (>11 years). We report two additional patients with breast implant capsule-associated squamous cell carcinoma. Review of the literature reveals that invasion beyond the breast implant capsule into the adjacent tissue by the squamous cell carcinoma appears to have negative prognostic implications, and possibly warrants close clinical follow-up.

Anticoagulation in Patients With COVID-19: JACC Review Topic of the Week.

Clinical, laboratory, and autopsy findings support an association between coronavirus disease-2019 (COVID-19) and thromboembolic disease. Acute COVID-19 infection is characterized by mononuclear cell reactivity and pan-endothelialitis, contributing to a high incidence of thrombosis in large and small blood vessels, both arterial and venous. Observational studies and randomized trials have investigated whether full-dose anticoagulation may improve outcomes compared with prophylactic dose heparin. Although no benefit for therapeutic heparin has been found in patients who are critically ill hospitalized with COVID-19, some studies support a possible role for therapeutic anticoagulation in patients not yet requiring intensive care unit support. We summarize the pathology, rationale, and current evidence for use of anticoagulation in patients with COVID-19 and describe the main design elements of the ongoing FREEDOM COVID-19 Anticoagulation trial, in which 3,600 hospitalized patients with COVID-19 not requiring intensive care unit level of care are being randomized to prophylactic-dose enoxaparin vs therapeutic-dose enoxaparin vs therapeutic-dose apixaban. (FREEDOM COVID-19 Anticoagulation Strategy [FREEDOM COVID]; NCT04512079).

Pathological characterization and clinical outcome of penile intraepithelial neoplasia variants: a North American series.

Penile intraepithelial neoplasia (PeIN) is classified as human papillomavirus (HPV)- and non-HPV-related. This classification is associated with distinct morphologic subtypes. The natural history and prognosis of PeIN subtypes are not well known. This study aims to evaluate clinicopathological features, HPV status, and outcome of PeIN subtypes. Eighty-two lesions from 64 patients with isolated PeIN were retrospectively reviewed. Mean age was 59 years. Lesions were multicentric in 34% of patients and affected glans (33%), shaft (26%), and foreskin (20%). Histologically, 22% of patients had coexisting lesions, classified as hybrid and mixed. HPV-related PeIN (97%) included basaloid (59%), warty (8%), warty-basaloid (8%), hybrid (19%) and mixed (3%) types. P16 and HPV positivity occurred in 99% and 82% of lesions, respectively. HPV 16 was more common in basaloid PeIN. Multiple genotypes were detected in 35%, more commonly in hybrid PeIN (P = 0.051). Positive margins occurred in 63% of excisions. PeIN recurred in 48% of excisions and 30% of overall repeated procedures, and progression to invasive carcinoma occurred in 2%. At follow-up, 86% of patients had no evidence of disease and 12% were alive with disease. Lichen sclerosus occurred in non-HPV and HPV-related PeIN (100% and 47%).In conclusion, HPV-related and, more specifically basaloid PeIN were the predominant types and preferentially associated with HPV 16. While PeIN had a high recurrence rate, there was a slow and infrequent progression to invasive or metastatic carcinoma with multimodal treatments. Additional studies are needed to understand biology and natural history of PeIN.

Discordance Between Immunohistochemistry and In Situ Hybridization to Detect HER2 Overexpression/Gene Amplification in Breast Cancer in the Modern Age: A Single Institution Experience and Pooled Literature Review Study.

BACKGROUND: Human epidermal growth factor 2 (HER2) amplification and/or overexpression occurs in 12% to 25% of breast cancers. Accurate detection of HER2 is critical in predicting response to HER2-targeted therapy. Both immunohistochemistry (IHC) and in situ hybridization (ISH) are FDA-approved methods for detecting HER2 status because its protein overexpression is largely attributable to gene amplification. However, variable discordant results between IHC and ISH have been reported. METHODS: We determined the frequency of HER2 IHC/ISH discordance in these patients and also performed a pooled literature review analysis. RESULTS: Of the 1125 consecutive primary or metastatic breast cancers with HER2 IHC and ISH performed simultaneously between 2015 and 2020, 84.6% had an unequivocal HER2 status. Discordance was found in 30 cases from 26 patients, including 13 IHC-/ISH+ and 17 IHC+/ISH-, representing 1.6% and 11.9% of IHC- and IHC+ cases, respectively. Review of the literature between 2001 and 2020 identified 46 relevant studies, with a total of 43,468 cases with IHC and ISH performed. The IHC-/ISH+ and IHC+/ISH- discordances were seen in all antibody clones and ISH methods used. The IHC+/ISH- discordance was significantly higher than IHC-/ISH+ (13.8% vs. 3%, P < .0001). The overall discordance constituted 4% of all cases and 5.4% of those with an unequivocal IHC status. Significantly lower incongruities for both IHC-/ISH+ and IHC+/ISH- were found in those published after 2018. The discordances probably reflect altered biology of HER2 oncogene/oncoprotein. Routinely performing both IHC and ISH may uncover such cases to prevent denial of potentially beneficial targeted therapy.

Round cell tumor with a myxoid matrix harboring a PHF1-TFE3 fusion: Myoepithelial neoplasm or ossifying fibromyxoid tumor?

Myoepithelial tumors arising in soft tissue are uncommon and mostly manifest a benign clinical course, although a malignant form does exist. An EWSR1 gene rearrangement is a common event in these tumors. Ossifying fibromyxoid tumor, a rare soft tissue neoplasm of uncertain differentiation, may have overlapping histologic and immunophenotypic features with myoepithelial tumors, but frequently harbors a PHF1 gene rearrangement. Interestingly, a PHF1-TFE3 fusion has been recently reported in both entities. Here we report a case of a malignant soft tissue tumor demonstrating myoepithelial differentiation and harboring a PHF1-TFE3 fusion. Despite being slow-growing and lacking significant cytologic atypia at initial presentation, the patient deteriorated rapidly with local recurrence and distant metastases. A discussion of the potential clinicopathologic implications of a PHF1-TFE3 fusion in these entities is also developed.

Clinicopathologic features and outcome of head and neck mucosal spindle cell squamous cell carcinoma.

Spindle cell squamous cell carcinoma (SpC-SCC) is rare, accounting for 0.4-4% of head and neck (HN) SCCs. Better understanding of HN SpC-SCC clinicopathologic characteristics, especially features that predict outcome, is needed. We present a clinicopathologic review of 71 HN mucosal SpC-SCC from three tertiary centers. The patient population showed a median age of 63 years (range 20-91), slight male predominance (M:F = 1.6:1), and a preponderance of smokers/ex-smokers (45/71, 64%). Most lesions involved oral cavity (42/71, 59%), especially oral tongue (n = 18), and larynx (n = 20, 28%). Polypoid/exophytic growth and surface ulceration were seen in 60% and 86% of cases, respectively. Histologically, most tumors showed sarcoma-like pattern (65/70, 93%), the remaining exhibiting granulation tissue-like or fibromatosis-like patterns, and 5 lesions showed osteosarcomatous/chondrosarcomatous elements. Most tumors (53/71, 74%) showed a conventional SCC (C-SCC) component, keratinizing (86%) or non-keratinizing/basaloid (14%). Nodal metastases, seen in 22 (31%) of resection specimens, showed SpC-SCC and/or C-SCC histomorphology. By immunohistochemistry, 76% of lesions showed immunoreactivity for keratin and 62/60% of lesions were p40/p63 positive. Ki-67 proliferation index ranged from 5 to 70%. Follow-up was available on 69 patients, median of 1.1 years from the time of SpC-SCC diagnosis. The 3-, 5-, and 10-year disease-specific survival (DSS) was 62, 37, and 12%, respectively. AJCC pN stage was an independent prognostic factor for DSS and distant metastasis-free survival (DMFS), whereas the presence of C-SCC was independently associated with improved DMFS. HN SpC-SCC is rare and might be diagnostically challenging. AJCC pN stage and co-existing C-SCC component appear to be prognostically relevant.

Poroid adnexal skin tumors with YAP1 fusions exhibit similar histopathologic features: A series of six YAP1-rearranged adnexal skin tumors.

BACKGROUND: Adnexal skin tumors are diagnostically challenging with few known molecular signatures. Recently, however, YAP1-MAML2 and YAP1-NUTM1 fusions were identified in poroid adnexal skin tumors. METHODS: Herein, we subjected eight poroid adnexal skin tumors (three poromas and five porocarcinomas) to fusion gene analysis by whole transcriptome sequencing and next-generation DNA sequencing analysis. RESULTS: YAP1 fusions were identified in six cases. YAP1-NUTM1 fusions were identified in two poromas and three porocarcinomas. A single case of porocarcinoma harbored a YAP1-MAML2 fusion. Two cases were negative for gene fusion. All cases that harbored YAP1-NUTM1 fusions showed nuclear protein in testis (NUT) expression by immunohistochemistry, with NUT being negative in the YAP1-MAML2-positive case. In this case series, we provide a detailed histopathologic description of six YAP1-fused poroid skin tumors, which we show harbor reproducible histopathologic features, to include broad, bulbous tumor tongues with admixtures of basaloid, poroid cells punctuated by squamatized cuticles and ductules, with uniform tumor nuclei featuring frequent grooves and pseudonuclear inclusions. CONCLUSIONS: Awareness of the characteristic histopathologic features of YAP1-fused poroid adnexal skin tumor is a step toward a more reproducible classification of adnexal skin tumors as well as a step toward targeted therapy for metastatic and/or unresectable examples of this poroid group of neoplasms.

Gastric Sclerosing Epithelioid Fibrosarcoma Harboring a Rare FUS-CREM Fusion.

Sclerosing epithelioid fibrosarcoma (SEF) is a rare, aggressive soft-tissue tumor, commonly occurring in upper and lower extremities, the limb girdle, and the head and neck, which shows morphologic and molecular overlap with low-grade fibromyxoid sarcoma. For SEF in soft tissues, 100 case reports have been published. To our knowledge, the present case is the first to be reported in English literature for a primary SEF of the stomach with a rare FUS-CREM fusion. We report a case of gastric SEF in a 35-year-old female who presented with nonspecific symptoms, including night sweat, cough, and iron deficiency anemia for the past few months. Further workup showed, on computed tomography, a large, heterogeneously enhancing and centrally necrotic left upper quadrant mass, which measured approximately 8.4 cm. A laparoscopic partial gastrectomy with distal pancreatectomy and splenectomy was performed. Histological examination and immunohistochemical staining suggested the diagnosis of primary gastric SEF, which was later confirmed by sarcoma fusion panel showing FUS-CREM fusion. In this article, we report this first case of SEF in the stomach with a rare FUS-CREM fusion, which has been previously reported only once in SEFs of soft tissue.

Clear cell papillary neoplasm of the breast with MAML2 gene rearrangement: Clear cell hidradenoma or low-grade mucoepidermoid carcinoma?

Clear cell hidradenoma (CCH) is an uncommon adnexal tumor usually arising from eccrine glands and commonly seen on the face and the upper extremities. CCH occurring in the breast is extremely rare. Herein we report a case of MAML2-rearranged CCH of breast with a papillary architecture closely mimicking intraductal papilloma, adenomyoepithelioma and low-grade mucoepidermoid carcinoma, thus representing a source of diagnostic confusion. An overview of salient histologic features and immunophenotypes to distinguish CCH and low-grade mucoepidermoid carcinoma is also integrated into the report.