Distinct Clinicopathologic Features and Possible Pathogenesis of Localized ALK-positive Histiocytosis of the Breast

Abstract

Anaplastic lymphoma kinase (ALK)-positive histiocytosis is a rare emerging entity characterized by systemic or localized proliferation of histiocytes harboring ALK rearrangements. Breasts are reportedly affected by ALK-positive histiocytosis. Here, we evaluated 2 localized cases of breast ALK-positive histiocytosis through a comprehensive clinicopathologic, molecular, and genomic analysis to further delineate this entity and better understand its pathogenesis. The cases involved 2 undiagnosed ALK-positive spindle-cell breast lesions. Both cases were Asian women aged 30s to 40s who underwent excisions for asymptomatic breast masses. Macroscopically, both lesions were well-circumscribed, solid masses. Microscopically, both lesions were predominantly composed of fascicles with uniform, bland spindle cells, admixed with epithelioid histiocyte–like cells and lymphoid aggregates. Immunohistochemically, the spindle and epithelioid cells coexpressed ALK and histiocytic markers (eg, CD68, CD163). Genetically, both lesions harbored KIF5B-ALK, confirmed by fluorescence in situ hybridization and polymerase chain reaction–direct sequencing analyses. Combining these results, both cases were successfully diagnosed as ALK-positive histiocytosis. Furthermore, no common or previously annotated somatic alterations were identified by whole-exome sequencing. One case harbored clonal immunoglobulin gene rearrangements according to the polymerase chain reaction–based BIOMED-2 protocol. Therefore, ALK-positive histiocytosis can be accurately diagnosed through a combination of morphologic, immunohistochemical, and molecular analyses. In this entity, breast cases may have distinct clinicopathologic features: Asian women aged 30s to 40s, asymptomatic masses, and predominant spindled morphology. For pathogenesis, ALK rearrangements could be the driver alteration, and a subset of ALK-positive histiocytosis may harbor a lymphoid lineage. These findings can be utilized to improve the diagnosis of ALK-positive histiocytosis and better understand its pathogenesis.

A case of ALK-positive histiocytosis with multiple lesions in the unilateral breast: A case report

“… Case No. Age Site Single or multiple lesion in the breast Size (cm) Other Tumor Sites Positive IHC Negative IHC Gene Fusion Treatment Follow-Up 1 [1] 45 R, UIQ single 1.6 None CD163, CD68, CD4, CD45, ALK S100, CD30, desmin, AE1/AE3 KIF5B-ALK Surgery NED (1 mo) 2 [1] 16 R, UOQ single 2.1 Brain, lungs, pancreas, CD163, CD68, CD4, ALK S100, CD1a, langerin, desmin, AE1/AE3 KIF5B-ALK Surgery, ALK inhibitor(alectinib) NED (44 mo) 3 [1] , [14] 38 R, OQ single 1.7 None CD163, S100, ALK CD1a, langerin, desmin KIF5B-ALK Surgery NED (1 mo) 4 [14] 45 L UIQ single 1.3 None CD163, CD68, CD13, CD45RO, ALK CD1a, langerin, desmin, BRAF V600E, CD3、CD20、PAX5, cytokeratin KIF5B-ALK Surgery NED (13 mo) 5 [6] 40 Unknown Unknown Unknown None CD163, CD68, ALK CD1a, langerin, BRAF V600E KIF5B-ALK Surgery NED (3.5 y) 6 (the present case) 38 L, UQ multiple ①1.2 ②1.1 ③1.1 None CD163, ALK AE1/AE3, SMA, CD34, ER, PgR, S100, desmin, STAT6, p63 KIF5B-ALK Surgery NED (4 mo) …”

“…The number of ALK-positive histiocytosis cases reported so far is very small, and the number of primary cases in the breast is limited to six, including this case [1] , [6] , [14] ( Table 1 ). Five cases were localized and one was systemic, suggesting the presence of a KIF5B-ALK fusion gene.…”

Multisystem ALK-positive histiocytosis: a multi-case study and literature review

“…Since 2008, more than 60 cases of ALK-positive histiocytosis have been reported in the literature [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] (see detailed information in Additional file 2: Table S3-5). In 2018, Chang et al classified ALK-positive histiocytosis into two types, systemic and localized, based on clinical manifestations [2].…”

“…Histological manifestations were diverse; histiocytes are usually very large, with irregularly folded nuclei, fine chromatin, and abundant eosinophilic cytoplasm [1,2]. However, some cases display fascicular and storiform growth of uniform spindle cells admixed with lymphocytic infiltrates in the background, which might be easily misdiagnosed as inflammatory disease, or other proliferative lesions, such as inflammatory myofibroblastic tumors (IMT) [5,6].…”

Case report: ALK-positive histiocytosis presented as bilateral synchronous breast masses with long-term remission on crizotinib

“…Most of the pediatric cases involve the liver, spleen, skin, and bone marrow ( 1 , 6 , 18 ), while most of the adult cases demonstrate visceral diseases of the lung, bone, and central nervous system, among others ( 2 , 3 , 19 ). There are five cases of breast involvement with APH, which were all presented as unilateral breast lesions ( 20 – 22 ). No previously reported APH was found in Hispanic patients, excluding this study.…”