ALK-positive histiocytosis (APH) is characterized by clonal proliferation of histiocytes and can present as either solitary or systemic. A series of ten cases with novel types of solitary (4/10) and systemic (6/10) histiocytosis was reported by Chan et al. (1, 2). A previous immunophenotypic study revealed that histiocytes were positive for ALK and histiocytic markers (CD68 and CD163), variably for S-100, but negative for CD1a, CD207, and BRAF-V600E (2, 3). Meanwhile, KIF5B-ALK and COL1A2-ALK gene fusions were identified via next-generation sequencing-based multiplex PCR (2), especially the primary KIF5B-ALK gene fusion, which was the most frequent (1, 4). However, no correlation has been observed between gene fusion type and disease localization or dissemination (2, 5).

Here, we report a case of aggressive systemic APH with severe recurrent pancreatitis. Furthermore, previously reported cases are reviewed.

APH is a rare disease; the first publication on APH was in 2008 (1). Currently, classification systems of histiocytosis have evolved into five groups, which are defined based on the cell of origin, molecular mutations, and clinical behavior (5). However, APH has not yet been included in the WHO classification of tumors (6). Recently, only 26 cases, including this study, have been reported under the term “APH” (1–4, 7–17).

The pathogenesis of this condition is yet to be fully elucidated. The general information, histological and clinical characters of the 26 patients is shown in Tables 1, 2. The male-to-female ratio was 9:17, and systemic and solitary cases were equal. The median age of the patients was 15 years. Regarding race, 6 patients were Caucasian, 8 were Asian, including 4 Chinese patients (1, 2, 8), and the other 12 were not stated. Histologically, the tumor histiocytes were large, with irregularly folded, lobulated, or clefted nuclei, fine chromatin, and abundant eosinophilic or foamy cytoplasm, sometimes with emperipolesis (3, 10). In some cases, the tumor cells displayed a spindle appearance with a fascicular to storiform growth pattern (3). Touton-type giant cells and lymphocytic infiltrates were observed. Immunohistochemically, the histiocytes were positive for ALK and histiocytic markers (CD68 and CD163), variable for S-100 and negative for CD1a, CD207, and BRAF-V600E. The staining pattern for ALK can be cytoplasmic, membranous, and perinuclear or cytoplasmic dot-like (14). ALK rearrangement was identified in all APH cases, and KIF5B-ALK was the most frequent gene translocation, and the detailed information on the gene types of the 26 patients is shown in Table 2.

Meanwhile, APH should be differentiated from other histiocytosis types, including juvenile xanthogranuloma (JXG), Erdheim-Chester disease (ECD), Langerhans cell histiocytosis, and Rosai-Dorfman disease (RDD) (18–20). The tumor histiocytes with marked nuclear foldings, which are not found in other histiocytosis types, could be a clue for APH (10), and an immunohistochemical profile featuring positivity to both CD68 (CD163) and ALK virtually excludes all the histiocytic neoplasms as well as all the other ALK-positive neoplasms, such as ALK-positive peripheral T cell lymphoma, ALK-positive B cell lymphoma, lung adenocarcinoma, inflammatory myofibroblastic tumor, and some melanocytic tumors of the Spitz lineage (1). Notably, some cases of histiocytosis with ALK gene rearrangement are reported under the diagnosis of ECD, JXG, atypical juvenile histiocytosis, or histiocytosis not otherwise specified (11, 12, 21), some of which have detailed clinicopathologic data displaying the lack of characteristic long bone or skin involvement for ECD or JXG, respectively (12). In addition, Huang et al. reports two cases of congenital/ early-onset RDD without any molecular detection for ALK, yet displaying an identical clinical presentation and proliferation in young children (10). These reported cases reveal that whether APH is a distinct entity is unclear and controversial. However, as illustrated by Chen (1, 2) and other researchers (3, 4, 7–16), APH differs significantly from ECD, JXG, and RDD in terms of clinical, morphological, and genetic aspects.

The clinical features of the previously reported cases of APH are summarized in Table 2. Surgery is the typical treatment for localized APH. A total of 92.3% (12/13) of the localized cases underwent surgical resection and were followed up from 1 month to 3.5 years after surgery, and no recurrence was found. One patient showing involvement of the cavernous sinus was treated with the ALK inhibitor crizotinib, and a complete response (CR) was reached 3 months later. No recurrence was observed for 6 months after follow-up. On the other hand, treatment for systemic APH mainly includes chemotherapy and/or ALK inhibitors (8, 16). Thus, 8 patients received chemotherapy, of which 37.5% (3/8) received chemotherapy alone, 50.0% (4/8) received steroid therapy, and 12.5% (1/8) was treated with the PD-1 inhibitor pembrolizumab. Moreover, previous clinical studies have shown an encouraging response of the cavernous sinus, pancreas, and lung lesions to ALK inhibitor treatment (2, 8); thus, even if chemotherapy is not effective, PR and CR might be achieved by receiving anti-ALK therapy as second-line therapy. More recently, ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, was shown to be effective in and was able to achieve CR from rare APH cases with concurrent CLL/SLL.

For this systemic APH patient with severe recurrent pancreatitis, not only was the patient unable to tolerate the standard treatment; the patient's disease also had an aggressive biological behavior and progressed rapidly. The ALK inhibitor alectinib, which did not induce pancreatitis, was selected, and a 25% reduced dose was used (12, 14).

To our knowledge, this is the first report of a patient with systemic and aggressive APH with severe recurrent pancreatitis. Because of recurrent pancreatitis, the treatment strategy is different from common APH cases since the disease is more aggressive. Thus, in summary, we indicated that APH is not just an indolent disease and that those complex complications represent APH as an aggressive disease. Moreover, the original report was published 13 years ago, but APH entities were likely under-reported.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

YJ and YL contributed to the study conception and design. YL, CS, YW, and MH performed material preparation, data collection, and analysis. YL, XX, and JL wrote the first draft of the manuscript. All authors commented on previous versions of the manuscript and read and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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