ALK‐rearranged histiocytosis: Report of two cases with involvement of the central nervous system

Abstract

Aims Histiocytoses are a heterogeneous group of localized or disseminated diseases. Clinical presentation and patients' outcome vary greatly, ranging from mild to life‐threatening disorders. Rare cases of systemic or localized histiocytosis harboring ALK rearrangement have been reported. Methods Two cases of CNS histiocytosis were thoroughly investigated by implementing multiple molecular tests, i.e. FISH, RT‐qPCR, NGS analysis. Results In a 10‐month old girl (patient #1), MRI showed two left hemispheric lesions and a right fronto‐mesial lesion histologically consisting of a moderately cellular infiltrative proliferation, composed by CD68(PGM1)+/CD163+ spindle cells. ALK 5’/3’‐imbalance and a KIF5B(exon 24)‐ALK(exon 20) fusion were documented by RT‐qPCR and NGS analysis, respectively. A subsequent CT scan showed multiple hepatic and pulmonary lesions. The patient was started on chemotherapy (vinblastine) associated to an ALK‐inhibitor (Alectinib) with remarkable response. In a 11‐year‐old girl (patient #2), MRI showed a right frontal 1.5 cm lesion. Neuropathological examination revealed a histiocytic proliferation composed by medium sized CD68(PGM1)+/HLA‐DR+ cells, showing moderate ALK1 positivity. ALK rearrangement and a KIF5B(exon 24)‐ALK(exon 20) fusion were demonstrated also in this case. Subsequent CT, 18F‐FDG‐PET and MRI scans showed the presence of a single right femoral lesion, proved to be a fibrous cortical defect. Conclusions In ALK‐histiocytoses, CNS involvement may occur as part of a systemic disease or, rarely, as its only primary disease localization, which could remain otherwise asymptomatic. The diagnosis often relies on neuropathological examination of brain biopsy, which may pose a diagnostic challenge due to the variable histopathological features. An integrated histological and molecular approach in such cases is recommended.

Failure of crizotinib based systemic treatment in ALK positive histiocytosis involving the central nervous system: a case report and literature review

“…Moreover, an accurate pathological diagnosis of ALK-positive histiocytosis can guide treatment. Due to its rarity and the overlapping morphological features with Erdheim-Chester disease (ECD), juvenile xanthogranuloma, Rosai-Dorfman disease (RDD), and Langerhans cell histiocytosis (LCH), the pathological differential diagnosis of this disease is extremely challenging [ 15 ]. The features of these entities are shown in Table 2 .…”

Case Report: ALK-Positive Histiocytosis With KIF5B-ALK Fusion in Cerebrum-Disseminated Lesions in a Child

“…The lesions of the patient were located in the left medial temporal lobe, right inferior frontal lobe and dural-based parasagittal right parietal convexity (1). Rossi et al also reported a child with the same disease whose lesions were located in frontal and parietal lobes (7). It appears that disseminated growth is a characteristic of ALK-positive histiocytosis.…”

“…Rossi et al. also reported a child with the same disease whose lesions were located in frontal and parietal lobes ( 7 ). It appears that disseminated growth is a characteristic of ALK-positive histiocytosis.…”

“…Crizotinib and alectinib is an ALK-tyrosine kinase inhibitor that has been applied in the treatment of non-small-cell lung cancer (21). Several patients with ALK-positive histiocytosis have been benefit from crizotinib and alectinib as well (3)(4)(5)7). The presence of the blood-brain barrier may affect the action of ALK-tyrosine kinase inhibitor in the CNS, but there is insufficient evidence to support the hypothesis that the efficacy of chemotherapy and anti-ALK therapy is greater for ALKpositive histiocytosis in the lung than in the cerebrum.…”

“…When invading the CNS, ALK-positive histiocytosis can cause headache, vomiting, and seizures. According to a literature review of PubMed using keyword of ALK-positive histiocytosis, 10 cases of ALK-positive histiocytosis invading the CNS have been reported, and lesions located in the frontal lobe are more commonly reported (1,(3)(4)(5)(6)(7). Once the diagnosis of ALK-positive histiocytosis has been established, chemotherapy and anti-ALK therapy are generally applied.…”