ALK-positive histiocytosis (ALK+H) is a very rare type of histiocytosis. Only five cases have been reported to date. ALK+H manifests in early infancy, most commonly in the form of anemia, thrombocytopenia, and hepatosplenomegaly. The histological examination of liver biospy specimens reveals sinusoidal infiltration by large histiocytes with distinctive morphology. These cells express histiocytic and dendritic cell markers as well as the receptor tyrosine kinase ALK. The disease follows a chronic course but may be expected to remit after months. Sequelae are rare, and the outcome may be favorably influenced by the adequate management of complications in the acute phase.
ALK+H is a disease of infancy that manifests in non-specific symptoms. Anemia, thrombocytopenia, and hepatosplenomegaly are the hallmarks of ALK+H  . These may, in turn, induce a series of secondary complaints:
The involvement of additional organ systems has been described. Cutaneous infiltrates were detected in a single patient who presented with juvenile xanthogranuloma-like lesions, i.e., with brownish to purplish papules and nodules preferentially developing on the scalp, face and trunk  . Kidney involvement associated with long-standing renal impairment was reported in another patient. Besides the non-specific symptoms described above, she presented with proteinuria and developed symmetric enlargement of both kidneys .
In sum, this condition interferes with the development of the infant and may result in failure to thrive.
Clinical and laboratory findings are non-specific. They may raise suspicion of hematological malignancies, metabolic or immune system disorders. The examination of bone marrow specimens may be required to confirm or refute these suspicions but is unlikely to yield conclusive results in ALK+H patients. Even if abnormal, ALK-positive histiocytes are present, they are easily overlooked  .
Characteristic infiltrates are rather found in hepatic tissues, which are obtained by means of liver biopsy: Single or small aggregates of histiocytes may be recognized in liver sinusoids, central veins and portal tracts. These histiocytes are large cells with irregularly folded or lobulated nuclei, fine chromatin, and prominent, eosinophilic nucleoli. They have abundant, lightly eosinophilic cytoplasm, which may be vacuolated or foamy and contain phagocytosed material. Besides infiltrates, bile plugging and fibrotic changes may be seen. Hepatocytes may be enlarged and in disarray, and they may have multiple nuclei. In case of overt bone marrow involvement, there may be hepatic foci of extramedullary hematopoiesis  .
In cutaneous lesions, histiocytic aggregates may contain multinucleated giant cells with wreathlike nuclei , whereas renal infiltrates have been described to almost exclusively consist of large histiocytes morphologically and immunophenotypically identical to those detected in the liver. They are mainly located in the peritubular and periglomerular interstitial spaces . Regardless of the organ system, histiocytic aggregates may induce an inflammatory response and may be partially surrounded by inflammatory cells.
A comprehensive antibody panel should be employed for the immunohistochemical characterization of infiltrates. As per definition, ALK+H express ALK receptor tyrosine kinase, and they usually stain positive for histiocytic markers like CD68, CD163, and lysozyme, for dendritic cell markers like fascin and factor XIIIa, and for S100 protein. ALK has been described to be expressed in a membranous and cytoplasmic pattern . Staining for Langerhans cell markers CD1a and CD207 (langerin) yields negative results  .
There are no guidelines regarding the management of ALK+H. Its causes remain elusive and no consensus has been reached on whether or not ALK+H is a monoclonal disorder requiring anti-cancer therapy. Still, the most common "specific" approach to treatment is that of combined chemotherapy. Patients have been administered dexamethasone and etoposide, or prednisone and vinblastine, and have shown gradual improvement under therapy  . There is no evidence, however, of the efficacy of chemotherapy in ALK+H. More or less the same course of the disease has been observed when cytotoxic therapy was ceased prematurely and when only symptomatic treatment was provided . Symptomatic treatment may consist in ventilatory support and the transfusion of blood products to compensate for cytopenias  .
There are tyrosine kinase inhibitors specifically targeting ALK. In 2011, ALK tyrosine kinase inhibitor crizotinib was approved for the treatment of ALK-positive non-small cell lung cancer. This compound had previously been shown to increase response rates and to prolong progression-free survival times in patients suffering from this type of neoplasm. However, crizotinib is likely to induce resistances, and drug development was continued to overcome this drawback and to augment the efficacy of treatment. In this context, compounds like ceritinib and alectinib received their approval for non-small cell lung cancer therapy . None of these drugs is approved for the treatment of other ALK-positive disorders, although promising results have been published after off-label use in patients diagnosed with anaplastic large cell lymphoma or neuroblastoma  . These data suggest a possible efficacy of ALK tyrosine kinase inhibitors in slowing down the proliferation of histiocytes in ALK+H patients. While the necessity of chemotherapy is up for debate, it should definitely be considered in severe cases with a risk of permanent organ damage. To date, no ALK+H patient has been treated with specific tyrosine kinase inhibitors.
Hematological anomalies have been shown to resolve over the course of several months, regardless of the provision of specific treatment. Hepatosplenomegaly may persist for prolonged periods of time, but liver functions eventually normalize. The majority of patients described so far did not have to face permanent disabilities; they developed normally, both physically and mentally. Still, experts point out the possibly life-threatening complications of ALK+H during the acute phase of the disease , and the single patient with renal involvement developed chronic renal insufficiency, hypertension, and hypergammaglobulinemia .
The ALK gene is located on the short arm of chromosome 2 and encodes for ALK receptor tyrosine kinase, which is also known as anaplastic lymphoma kinase or CD246. It belongs to the insulin receptor superfamily. Chromosomal rearrangements involving ALK have been described in anaplastic large cell lymphoma, neuroblastoma, and non-small cell lung cancer, among others . Such rearrangements may result in the formation of oncogenic fusion genes, and more than 30 different ALK fusion partners have been identified to date . One of them is the TPM3 gene on the long arm of chromosome 1, which encodes for member 3 of the tropomyosin family of actin-binding proteins. Translocation t(1;2)(q25;p23) results in TMP3-ALK fusion and has indeed been revealed in one patient with ALK+H . In the remainder of cases, molecular biological studies have not been carried out or did not yield conclusive results.
The creation of oncogenic fusion genes may not be the only cause of ALK+H, but alternative hypotheses have not yet been explored.
All patients described to date presented within their first three months of life. Although the majority of affected children was female, the small number of cases doesn't allow for reliable conclusions regarding a possible predisposition of gender. Case reports were published by scientists from Hong Kong and the United States, but the ethnicity of the patients has not been reported  .
Infiltrating cells have been shown to phagocytose and to express histiocytic markers, but they also exhibit features of dendritic cells. This leaves room for speculations regarding their cell of origin . Similarly, the pathophysiological events leading to the proliferation of these cells, which are most commonly referred to as histiocytes, have yet to be resolved. Translocation t(1;2)(q25;p23) may be hypothesized to serve as a trigger: The fusion of ALK receptor tyrosine kinase with the TPM3 housekeeping gene results in the synthesis of an oncogenic protein with constitutive tyrosine kinase activity. Under physiological conditions, ALK monomers associate to homodimers upon ligand binding only, but this regulatory mechanism is disabled when its C-terminal residues are replaced by tropomyosin 3. The protein-protein interaction domain of tropomyosin 3 is not dependent on the ALK kinase domain but may induce the activation of the ALK catalytic domain. Furthermore, the promoter of TPM3 enhances the expression of the fusion gene . The lack of control of the overexpressed receptor tyrosine kinase entails the permanent activation of downstream cascades including, but not limited to, PI3 kinase, AKT, and MAPK pathways and NF-κB signaling. These are involved in the regulation of cell migration, cell-cycle progression, apoptosis, and survival, which explains why the fusion of ALK and TMP3 genes provokes the transformation of affected cells .
Due to considerable knowledge gaps regarding the etiology and pathogenesis of ALK+H, no recommendations can be given to prevent the development of the disease.
Histiocytosis refers to a heterogeneous group of diseases characterized by the uncontrolled proliferation and accumulation of cells of the mononuclear phagocytic system. Histiocytoses are classified according to the cell of origin: There are Langerhans cell histiocytosis, non-Langerhans cell histiocytosis and indeterminate cell histiocytosis   . The diagnosis of histiocytoses is based on clinical, histopathological, and immunohistochemical findings, which may allow for a prediction of the patient's response to specific therapies. Immunoreactivity for ALK receptor tyrosine kinase is rarely detected. Indeed, first cases have been described in 2008, and little more have been reported until today  . The respective type of histiocytosis has been named ALK+H.
ALK-positive histiocytosis (ALK+H) is a very rare disorder of infancy. Only a handful of cases has been described to date. Both girls and boys may be affected and are likely to develop anemia, thrombocytopenia, and hepatomegaly. Anemic children are pale, possibly cyanotic. They may suffer from fatigue, weakness, and dyspnea. Thrombocytopenia refers to decreased platelet counts, which may induce a tendency to bleed. Hepatomegaly manifests in upper abdominal distension, tenderness or pain, loss of appetite, and the formation of edema. ALK+H has been reported to affect additional organ systems, such as the skin, kidneys, or bone marrow, so that the aforementioned symptoms may be accompanied by other complaints.
The histological examination of biopsy specimens obtained from the liver of affected infants reveals an infiltration by histiocytes. Histiocytes are part of the immune system; they are able to internalize debris and pathogens, and may subsequently present their antigens to elicit an immune response. They don't usually test positive for ALK expression, whereby ALK refers to a kind of insulin receptor. Presumably, chromosomal aberrations involving the ALK gene favor the proliferation of histiocytes and the expression of ALK, but otherwise, the causes of ALK+H remain elusive.
Furthermore, there is no standard treatment for this condition. Due to the cancer-like proliferation of histiocytes, chemotherapy has been administered to infants diagnosed with ALK+H, but there are doubts as to its efficacy. In general, the disease follows a chronic course and tends to remit after months. During the acute phase of the disease, affected children should nevertheless be provided symptomatic treatment to avoid life-threatening complications. Their prognosis for normal physical and mental development is good if this can be achieved. Still, permanent organ damage has been described in rare cases.