ALK-positive histiocytosis: a new clinicopathologic spectrum highlighting neurologic involvement and responses to ALK inhibition

Abstract

ALK-positive histiocytosis is a rare subtype of histiocytic neoplasm first described in 2008 in 3 infants with multisystemic disease involving the liver and hematopoietic system. This entity has subsequently been documented in case reports and series to occupy a wider clinicopathologic spectrum with recurrent KIF5B-ALK fusions. The full clinicopathologic and molecular spectra of ALK-positive histiocytosis remain, however, poorly characterized. Here, we describe the largest study of ALK-positive histiocytosis to date, with detailed clinicopathologic data of 39 cases, including 37 cases with confirmed ALK rearrangements. The clinical spectrum comprised distinct clinical phenotypic groups: infants with multisystemic disease with liver and hematopoietic involvement, as originally described (Group 1A: 6/39), other patients with multisystemic disease (Group 1B: 10/39), and patients with single-system disease (Group 2: 23/39). Nineteen patients of the entire cohort (49%) had neurologic involvement (7 and 12 from Groups 1B and 2, respectively). Histology included classic xanthogranuloma features in almost one-third of cases, whereas the majority displayed a more densely cellular, monomorphic appearance without lipidized histiocytes but sometimes more spindled or epithelioid morphology. Neoplastic histiocytes were positive for macrophage markers and often conferred strong expression of phosphorylated extracellular signal-regulated kinase, confirming MAPK pathway activation. KIF5B-ALK fusions were detected in 27 patients, whereas CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK fusions were identified in single cases. Robust and durable responses were observed in 11/11 patients treated with ALK inhibition, 10 with neurologic involvement. This study presents the existing clinicopathologic and molecular landscape of ALK-positive histiocytosis and provides guidance for the clinical management of this emerging histiocytic entity.

Graphical abstract

Figure 1.

Schematic overview of downstream ALK signaling through MAPK and PI3K/AKT/mTOR signaling pathways. ALK is a classical receptor tyrosine kinase consisting of an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. In ALK fusions such as KIF5B-ALK, the amino-terminal fusion partner is fused to the intracellular tyrosine kinase domain of ALK, leading to constitutive activation of downstream signaling, including RAS-RAF-MEK-ERK (MAPK) and PI3K/AKT/mTOR signaling pathways. MAPK pathway activation ultimately leads to phosphorylation of downstream ERK, which can enter the nucleus and increase the transcription of various effector genes, including the gene encoding for Cyclin D1 (CCND1). Translation of CCND1 messenger RNA to the Cyclin D1 protein is mTOR-dependent. Figure adapted from Emile et al, with permission from the authors.

Figure 2.

Focal liver lesions in an infant with multisystemic disease with liver and hematopoietic involvement (Group 1A). (A) Ultrasound image showing 3 hypoechoic lesions in liver segment 3. (B-C) Coronal T2-weighted fat-suppressed MRI images showing multiple hyperintense lesions in the liver, including a large rounded lesion in liver segment 3 (C). (D) Coronal T2-weighted contrast-enhanced MRI image showing late contrast accumulation in the large rounded lesion in liver segment 3.

Figure 3.

Nonneurologic disease manifestations in ALK-positive histiocytosis patients from Group 1B. (A-D) Fluorodeoxyglucose PET-CT images showing bilateral hypermetabolic long bone involvement, reminiscent of ECD, with objective metabolic response in Case 11 after 12 months of crizotinib. (E) Sagittal image of the contrast-enhanced MRI scan of the spine showing multiple hyperintense lesions in the vertebral bodies. (F-G) Axial MRI image (F) and lateral conventional radiograph (G) showing skull lesions in 2 children, with an appearance reminiscent of LCH. (H-K) Axial CT images showing nodular pulmonary involvement in 3 pediatric cases. (L) Photograph of the right axilla of an adult with a brown maculopapular exanthema that coalesces into plaques and predominates in the axillae and flanks, reminiscent of xanthoma disseminatum. (M) Photograph showing 1 of multiple scalp skin lesions in a child, which can also be observed on the MRI of the head (Figure 4A). (N) Ultrasound image demonstrating round, hypoechoic lesions in both lobes of the thyroid gland. (O-P) Axial T2-weighted (O) and diffusion-weighted (P) pelvic MRI images showing a cervical tumor with restricted diffusion in a child that presented with menorrhagia and irregular vaginal bleeding. (Q-R) Axial PET-CT images showing hypermetabolic focal lesions in the liver and pancreas (Q) and in the breast (R). (S) Coronal CT image showing a focal lesion in the left kidney.

Figure 4.

Neurologic involvement in ALK-positive histiocytosis patients from Group 1B or 2. (A-E) Axial images of the T1-weighted contrast-enhanced MRI scans of the heads of 2 pediatric cases with multiple solid brain tumors before and after treatment with ALK inhibition, demonstrating robust responses in both. (F) Sagittal image of the T1-weighted contrast-enhanced MRI scan of the spine showing leptomeningeal contrast enhancement along the descending cauda equina nerve roots. (G-I) Axial images of successive fluorodeoxyglucose PET-CT scans showing partial and complete response of a neuroforaminal tumor at level L5 after 2 cycles of cladribine (H) and subsequent treatment with alectinib (I), respectively. Coronal images (not shown) demonstrated that the tumor followed the course of the exiting nerves, highly reminiscent of nerve sheath tumors such as neurofibromas. (J-N) Axial images of successive T1-weighted contrast-enhanced MRI scans of the head of a child with a left insula tumor before and after subtotal resection and successful treatment with alectinib. (O-Q) Axial images of the T1-weighted contrast-enhanced MRI scans of the head of a child with a left oculomotor nerve tumor, demonstrating slight regression but continued contrast enhancement of the tumor after treatment with vinblastine/prednisone-based chemotherapy. (R) Coronal image of the T1-weighted contrast-enhanced MRI scan of the head showing a 30 × 25 × 34 mm large tumor with contrast enhancement in the prepontine cistern that followed the course of the trigeminal nerve and caused pressure on the pons. (S) Sagittal image of the T1-weighted contrast-enhanced MRI scan of the cervical spine showing a large (18 × 24 × 45 mm) intradural extramedullary tumor at level C1-C2.

Figure 5.

Nonneurologic disease manifestations in ALK-positive histiocytosis patients with single-system disease (Group 2). (A-D) Successive fluorodeoxyglucose PET-CT images of an adult female with a large right clavicular tumor at diagnosis (A; time, 0) and after treatment with radiotherapy (B; time, 5.5 months), 6 weeks of vinblastine/prednisone-based chemotherapy (C; time, 9.5 months), and 2 months of alectinib (D; time, 14 months). (E-I) T1-weighted contrast-enhanced (E), T2-weighted (F), diffusion-weighted (G), apparent diffusion coefficient (H), and plain T1-weighted (I) MRI images of the left lower leg of a child at diagnosis showing a single soft tissue tumor that infiltrates the musculature and shows contrast enhancement and restricted diffusion. (J-K) Photographs of the retroauricular scalp lesion of an infant, with a clear change in clinical appearance after 3 months (K).

Figure 6.

Body diagram showing recurrent anatomic sites of involvement of ALK-positive histiocytosis.

Figure 7.

Swimmer plot of outcomes in patients with ALK-positive histiocytosis (n = 11) or atypical ALK-rearranged histiocyte-rich tumors (n = 2) treated with ALK inhibition. ALK inhibition was initiated at timepoint zero. Median time on ALK inhibition was 16 months in ALK-positive histiocytosis patients (range 3-43 months). Responses were measured by CT, MRI, and/or PET-CT in all patients. Dose reductions were 67% (90 mg brigatinib/d → 30 mg/d) and 50% (1200 mg alectinib/d → 900 mg/d → 600 mg/d) in Case 15 and Case 26, respectively. Case 39 developed a severe (grade 3) anaphylactic shock on the first day of crizotinib administration, requiring the patient to be resuscitated. The patient subsequently received vinblastine/prednisone-based chemotherapy with progressive disease and then switched to alectinib with objective response after 2 months. Case A1 developed a subcutaneous gluteal metastasis during treatment with alectinib (supplemental Figure 3C), which was found to harbor an ALK p.I1171N mutation, a mutation known to confer secondary resistance to alectinib. Therefore, the patient switched to lorlatinib and later to ceritinib after repeated progressive disease. Due to continuing progressive disease during treatment with ceritinib, the patient recently stopped ceritinib, received 3 weeks of bridging therapy with lorlatinib during antalgic radiotherapy of 2 metastases, and subsequently started vinblastine/prednisone-based chemotherapy. VBL/PRED, vinblastine and prednisone-based chemotherapy.

Figure 8.

Histopathologic features of ALK-positive histiocytosis. (A) Photomicrograph of the hematoxylin and eosin (HE)-stained slide of a frontal bone tumor (Case 7; original magnification ×200) with classic xanthogranuloma morphology including many Touton giant cells. (B) HE image of a spinal nerve root tumor (Case 15; original magnification ×200) showing abundant lipidized (“foamy”) histiocytes. (C) HE image (Case 31; original magnification ×400) showing a more monomorphic histiocytic infiltrate in the skin dissecting through the dermal collagen bundles. (D) HE image of a liver biopsy (Case 4; original magnification ×400) showing sinusoidal infiltration by large histiocytes (indicated by black arrows) with ALK immunoreactivity (inlet). (E) HE image of a CNS tumor (Case 18; original magnification ×400) with a monomorphic, dense infiltrate of histiocytes that demonstrate separated red and green signals on ALK break-apart FISH analysis (inlet). (F) HE image of a CNS lesion (Case 20; ×100) showing marked infiltration of the perivascular (“Virchow-Robin”) spaces by histiocytes with clear CD163 immunoreactivity (inlet). (G) CD163 immunostain of a CNS tumor (Case 18; original magnification ×200) showing diffuse strong expression by the monomorphic histiocytic infiltrate. (H) ALK immunostain (Case 7; original magnification ×200) showing strong cytoplasmic and membranous staining of lesional histiocytes and Touton giant cells. (I) ALK immunostain of a breast tumor (Case 12; original magnification ×400) showing focal, exclusive dot-like immunoreactivity that could be misinterpreted as negative. (J) S100 immunostain of a liver biopsy (Case 4; ×200) showing immunoreactivity by the large sinusoidal histiocytes. (K) P-ERK immunostain (Case 15; original magnification ×400) showing diffuse positive staining by the lesional cells, as well as clear emperipolesis (intact intracytoplasmic leukocytes). (L) Cyclin D1 immunostain of an oculomotor nerve tumor (Case 21; original magnification ×200) showing cytoplasmic and strong nuclear staining in histiocytes with frequent nuclear indentations.