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Context.--Immunoglobulin G4 (IgG4)-related disease is rare but well characterized in adults; however, the clinical and histologic manifestations in children may differ. Objective.--To review the clinical and histologic features of IgG4-rich head and neck lesions in a pediatric population. Design.--Retrospective search for cases with IgG4 immunohistochemical staining performed at our institution from 2011 to 2019. Review of clinical courses, serology profiles, histologic patterns, and immunohistochemical staining patterns. Results.--Four pediatric IgG4-rich lesions were identified and showed distinct histologic patterns from adult IgG4-related disease, including absence of pathognomonic findings associated with the latter. One case showed intralesional immunoglobulin light-chain restriction. Clinical review showed serum IgG4 elevation in 2 of 4 cases, presence of additional autoantibody positivity, and a generally benign/treatment-responsive clinical course. Conclusions.--Pediatric IgG4-related disease shows distinct clinical, serologic, and histologic features from its adult counterpart. Pediatric IgG4-related disease involving the orbit has unique clinical characteristics, including frequently normal serum IgG4 levels and female predominance. Awareness of and evaluation for these features may improve diagnosis and treatment. (Arch Pathol Lab Med. 2022;146:611-618; doi: 10.5858/arpa.2021-0041-OA), Immunoglobulin (Ig) G4-related disease is a rare disease that typically affects middle-aged adults, with an average age of onset of 50 to 60 years and male predominance. (1,2) Owing to [...]

Infantile fibrosarcoma is the most common soft-tissue sarcoma in children under the age of 1 yr and is defined molecularly by NTRK fusion proteins. This tumor is known to be locally invasive; however, although rare, metastases can occur. The NTRK fusion acts as a driver for tumor formation, which can be targeted by first- and second-generation TRK inhibitors. Although NTRK gatekeeper mutations have been well-described as mechanisms of resistance to these agents, alternative pathway mutations are rare. Here, we report the case of a patient with infantile fibrosarcoma treated with chemotherapy and TRK inhibition that developed metastatic, progressive disease with multiple acquired mutations, including TP53, SUFU, and an NTRK F617L gatekeeper mutation. Alterations in pathways of SUFU and TP53 have been widely described in the literature in other tumors; however, not yet in infantile fibrosarcoma. Although most patients have a sustained response to TRK inhibitors, a subset will go on to develop mechanisms of resistance that have implications for clinical management, such as in our patient. We hypothesize this constellation of mutations contributed to the patient's aggressive clinical course. Taken together, we report the first case of infantile fibrosarcoma with ETV6::NTRK3 and acquired SUFU, TP53, and NTRK F617L gatekeeper mutation along with detailed clinical course and management. Our report highlights the importance of genomic profiling in recurrent infantile fibrosarcoma to reveal actionable mutations, such as gatekeeper mutations, that can improve patient outcomes. [ABSTRACT FROM AUTHOR]

* Context.--Immunoglobulin G4 (IgG4)--related disease is rare but well characterized in adults; however, the clinical and histologic manifestations in children may differ. Objective.--To review the clinical and histologic features of IgG4-rich head and neck lesions in a pediatric population. Design.--Retrospective search for cases with IgG4 immunohistochemical staining performed at our institution from 2011 to 2019. Review of clinical courses, serology profiles, histologic patterns, and immunohistochemical staining patterns. Results.--Four pediatric IgG4-rich lesions were identified and showed distinct histologic patterns from adult IgG4-related disease, including absence of pathognomonic findings associated with the latter. One case showed intralesional immunoglobulin light-chain restriction. Clinical review showed serum IgG4 elevation in 2 of 4 cases, presence of additional autoantibody positivity, and a generally benign/treatment-responsive clinical course. Conclusions.--Pediatric IgG4-related disease shows distinct clinical, serologic, and histologic features from its adult counterpart. Pediatric IgG4-related disease involving the orbit has unique clinical characteristics, including frequently normal serum IgG4 levels and female predominance. Awareness of and evaluation for these features may improve diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Cerebral cavernous malformations (CCM) may present in sporadic or familial forms, with different cutaneous manifestations including deep blue nodules, capillary malformations, and hyperkeratotic cutaneous capillary venous malformations (HCCVM). We report the case of an infant with a KRIT1‐positive HCCVM associated with familial CCM. Moreover, histopathology showed positive immunohistochemical stain with GLUT1, further expanding the differential diagnosis of GLUT1‐positive vascular anomalies. [ABSTRACT FROM AUTHOR]

Introduction. Myofibromas are rare tumors of pericytic lineage, typically affecting children, and are sometimes aggressive. A subset of sporadic and familial myofibromas have activating variants in PDGFRB. The relationship of myofibroma and PDGFRB to the NOTCH pathway has not yet been described. Methods. Ten myofibroma cases were sequenced with a targeted panel of 447 genes, including copy number variation and selected fusions. Immunohistochemical analysis of total NOTCH3 and activated NOTCH3 was assessed for all 10 myofibroma cases, and a series of histologic mimics (n = 20). Results. Alterations identified by next-generation sequencing included PDGFRB sequence variants in 8/10 cases (80%), a NOTCH3 variant in 1/10 cases (10%), and a NOTCH2 variant in 1/10 cases (10%). All 10 cases also showed a pattern of low-amplitude (1.5- to 2-fold) copy number alterations including gains in PDGFRB and NOTCH3. Ten of 10 myofibromas (100%) showed cytoplasmic staining for total NOTCH3 and 9 of 10 cases (90%) showed nuclear staining for activated NOTCH3. Within the control cohort of histologic mimics, 3 of 3 nodular fasciitis cases (100%) were positive for activated and total NOTCH3, and the remaining 17 cases were negative for pan NOTCH3, while 3 of 3 desmoid-type fibromatosis cases (100%) showed patchy weak nuclear staining for activated NOTCH3. Discussion. Our findings suggest a common pathway of PDGFRB/NOTCH3 activation in myofibromas, even in cases that lack PDGFRB sequence variants. These results support the pericytic lineage of myofibroma. Identification of the characteristic genomic alterations or immunohistochemical staining pattern may facilitate a difficult pathologic diagnosis, and support the use of targeted treatments. [ABSTRACT FROM AUTHOR]

Efficient methods are developed for preparing five C-nucleoside phosphoramidite derivatives that has provided strategies for probing the potential functional role of cytosine's keto group and imino nitrogen. The phosphoramidites are incorporated into oligonucleotides by solid-phase synthesis.