Lymph nodes & spleen, nonlymphoma

Lymph node & spleen-nonlymphoid neoplasms

ALK+ histiocytosis



Last author update: 5 February 2024
Last staff update: 5 February 2024

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PubMed Search: ALK+ histiocytosis

Keri Janowiak, M.D., M.Ed.
Ekene Okoye, M.D.
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Cite this page: Janowiak K, Ewton A, Ravindran A, Okoye E. ALK+ histiocytosis. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphnodesalkhistiocytosis.html. Accessed February 22nd, 2024.
Definition / general
Essential features
  • Rare non-Langerhans cell histiocytic neoplasm with heterogeneous clinical features, presenting as single system disease, multisystem with systemic hematopoietic involvement (liver, spleen or marrow, skin, central nervous system [CNS]) or other multisystem disease (tumorous involvement of ≥ 2 organ systems)
  • ALK expression by immunohistochemistry, predominantly in a cytoplasmic pattern, rarely in a membranous or Golgi (dot-like) pattern and practically never in a nuclear pattern
  • Cytoplasmic ALK expression by immunohistochemistry with coexpression of histiocytic markers (CD68, CD163, CD4) is crucial to distinguish this entity from other histiocytic or spindle cell morphologic mimics
  • Characteristic ALK gene rearrangements allow for targeted therapy with ALK inhibitors
Terminology
  • ALK related histiocytosis
  • ALK rearranged histiocytosis
ICD coding
  • ICD-10: D76.3 - other histiocytosis syndromes
Epidemiology
  • Affects any age group, including children and young adults, with a female predilection (Blood 2022;139:256)
Sites
  • Multisystem with systemic hematopoietic involvement
  • Multisystem disease, others
  • Single system disease
    • Tumorous involvement of a single organ with solitary or multiple lesions
    • Most common sites include central and peripheral nervous system, skin, soft tissue and breast (Blood 2022;139:256)
Pathophysiology
  • Fusion of the receptor tyrosine kinase domain of the ALK gene, most commonly to exon 24 of KIF5B, results in constitutive activation of downstream signaling, including RAS-RAF-MEK-ERK (MAPK) and PI3K / AKT / mTOR signaling pathways
  • MAPK pathway activation leads to phosphorylation of downstream ERK, ultimately resulting in 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 (Blood 2022;139:256)
Etiology
  • Unknown at this time
Diagrams / tables

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Reported sites of involvement

Reported sites of involvement

Clinical features
  • Diverse clinical presentations depending on site(s) of involvement
  • Infants with multisystem disease involving the hematopoietic system present with hepatomegaly, anemia and thrombocytopenia, often accompanied by splenomegaly and coagulopathy
  • Other multisystem and single system disease presents with varying mass effects depending on tumor size and location (Blood 2022;139:256)
    • Neurologic involvement may present with headache, nausea / vomiting, ataxia, paresis, seizure, diplopia or trigeminal neuralgia
    • Pulmonary involvement may present with dry cough or respiratory dysfunction requiring oxygen therapy
    • Liver involvement may present with jaundice, coagulopathy or fever
    • Cutaneous lesions present as slowly growing papules or nodules
Diagnosis
  • Comprehensive patient evaluation including clinical history, physical examination and imaging studies
  • Coexpression of histiocytic markers and ALK should prompt molecular confirmation of ALK gene rearrangement either by RNA sequencing or by FISH (fluorescence in situ hybridization) analysis
  • References: Mod Pathol 2019;32:598, Blood 2022;139:256
Laboratory
  • Variable, depending on organ system(s) involved
  • Liver involvement can be associated with elevated liver enzymes, elevated bilirubin and low fibrinogen (Blood 2022;139:256)
  • Hematopoietic involvement can be associated with anemia, thrombocytopenia and prolonged prothrombin time and activated partial thromboplastin time (Blood 2022;139:256)
Radiology description
  • Mass lesions can be identified by ultrasound, Xray, magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET) CT and other imaging modalities (Blood 2022;139:256)
    • Liver, pancreas, long bone lesions appear hypermetabolic on PET CT imaging
    • Liver and thyroid lesions appear hypoechoic on ultrasound
    • Kidney tumors appear hypodense on CT imaging
    • Tumors of the vertebral bodies and liver appear hyperintense by T2 weighted MRI
  • CNS tumors rarely can mimic meningioma on MRI (Radiol Case Rep 2023;18:2259)
Radiology images

Contributed by Keri Janowiak, M.D., M.Ed.
Screening mammography

Screening mammography



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Nonneurologic disease manifestations

Nonneurologic disease manifestations

Left frontal lobe tumor

Left frontal lobe tumor

Prognostic factors
Case reports
Treatment
  • Management varies depending on extent of disease and site(s) of involvement
  • Surgical resection is often definitive treatment for single system disease (Blood 2022;139:256)
  • Systemic therapy for incompletely resected or unresectable tumors and for multisystem disease includes steroids, intravenous immune globulin (IVIG) or chemotherapy
  • Targeted therapy with ALK inhibitors has been used as first or second line treatment in a majority of cases (Blood 2022;139:256, JCO Precis Oncol 2021;5:PO.20.00383, Oncologist 2017;22:1444)
    • ALK inhibitors include alectinib, loratinib, brigatinib, crizotinib, ceritinib and entrectinib
    • Used as monotherapy or in combination with other treatment modalities
  • Rare cases have resulted in spontaneous regression (Blood 2022;139:256)
Clinical images

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scalp lesion

Scalp lesion

Gross description
  • Tumors may be well circumscribed or ill defined with a tan, white or yellow cut surface
Gross images

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Breast APH lesion

Breast APH lesion

Filum terminale

Filum terminale

Microscopic (histologic) description
Microscopic (histologic) images

Contributed by Keri Janowiak, M.D., M.Ed., Ekene Okoye, M.D. and Aishwarya Ravindran, M.D.
Storiform and fascicular growth

Storiform and fascicular growth

Infiltrative growth

Infiltrative growth

Histiocyte morphology

Histiocyte morphology

Touton giant cells

Touton giant cells

CD68

CD68


CD163

CD163

Factor XIIIa

Factor XIIIa

ALK

ALK

Cyclin D1

Cyclin D1

SMA

SMA

Peripheral smear description
  • In systemic cases with hematopoietic involvement, anemia, thrombocytopenia and leukocytosis are usually seen
Positive stains
Negative stains
Molecular / cytogenetics description
  • ALK rearrangements detected by FISH
  • ALK fusion partners identified via targeted RNA sequencing (Blood 2022;139:256)
    • Most common: KIF5B::ALK fusion (~70 - 75% of cases)
    • Other fusion partners reported: CLTC, TPM3, TFG, EML4, DCTN1, TRIM33, COL1A2
Molecular / cytogenetics images

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ALK FISH, breakapart probe

ALK FISH, breakapart probe

Sample pathology report
  • Left breast mass, lumpectomy:
    • ALK positive histiocytosis, 9 mm in greatest dimension (see comment)
    • Comment: Lesional histiocytes are characterized by cytoplasmic expression of ALK with coexpression of histiocytic markers (CD68, CD163) and cyclin D1. Molecular analysis by RNA sequencing was positive for KIF5B::ALK fusion. The overall immunophenotype in conjunction with the molecular analysis supports the above diagnosis.
Differential diagnosis
  • Reactive fibrohistiocytic proliferation:
    • Observed in infectious or inflammatory conditions as well as fat necrosis
    • Emperipolesis may be present (not pathognomonic for histiocytic neoplasms)
    • IHC negative for S100, OCT2 and ALK
    • Lacks ALK gene fusions
  • Rosai-Dorfman disease (RDD):
    • Parenchymal effacement of nodal / extranodal tissue by large histiocytes with round / oval nuclei, pale chromatin, distinct nucleoli and abundant pale cytoplasm with frequent engulfment of inflammatory cells (emperipolesis)
    • Abundant plasma cells and small lymphocytes; occasionally, neutrophils may also be present
    • By immunohistochemistry, positive for S100, OCT2; uniformly negative for ALK
    • ~10% of cases are negative for CD163 (Am J Clin Pathol 2023;160:1)
    • Lacks ALK gene fusions
  • Juvenile xanthogranuloma (JXG):
    • Usually affects pediatric population with ~33% of cases presenting within the first year of life
    • Predominantly cutaneous involvement presenting as papulonodular lesions and usually asymptomatic / self resolving over months / years
    • < 5% may be systemic JXG, including CNS that may present as seizures, hydrocephalus, diabetes insipidus; bone marrow involvement presents with cytopenias
    • Nonencapsulated circumscribed lesions composed of large xanthomatous (foamy) histiocytes with bland nuclear features and Touton giant cells; occasionally lesions may be composed of spindled, epithelioid or oncocytic histiocytes
    • Typically has an inflammatory background with a mixed population of lymphocytes, eosinophils, plasma cells, neutrophils and mast cells
    • IHC negative for ALK
    • Lacks ALK gene fusions
  • Erdheim-Chester disease:
    • Heterogeneous clinical manifestations, most commonly presenting with bone pain, secondary to bilateral symmetric osteosclerosis of metadiaphysis of femur, tibia and fibula
    • Bland appearing histiocytes characterized by abundant foamy (xanthomatous) cytoplasm with surrounding fibrosis (Mod Pathol 2018;31:581)
    • Negative for OCT2 and ALK (Am J Surg Pathol 2021;45:35, Am J Clin Pathol 2023;160:1)
    • Associated with MAPK pathway mutations, with BRAF V600E mutated in ~50 - 60% of cases
    • Lacks ALK gene fusions
  • Langerhans cell histiocytosis:
    • Langerhans cells characterized by irregular, grooved, folded or indented nuclei with fine chromatin, inconspicuous nucleoli and abundant pale eosinophilic cytoplasm
    • Positive for S100, CD1a and langerin; negative for factor XIIIa and ALK (Am J Clin Pathol 2023;160:1)
    • Lacks ALK gene fusions
  • Inflammatory myofibroblastic tumor (especially breast and soft tissue tumors):
Board review style question #1

A 41 year old woman underwent a core needle biopsy for a 3 cm breast mass discovered on her first screening mammogram. The lesional spindle cells show the CD68 immunostaining pattern seen above; they are also positive for ALK and negative for SMA and desmin. Which of the following is the most likely diagnosis?

  1. ALK positive histiocytosis
  2. Erdheim-Chester disease
  3. Extranodal Rosai-Dorfman disease
  4. Inflammatory myofibroblastic tumor
  5. Juvenile xanthogranuloma
Board review style answer #1
A. ALK positive histiocytosis (APH) can occur as a localized mass in many anatomic locations or as multisystem disease. Morphologic features vary and may include spindled, epithelioid or foamy histiocytes with or without background lymphoplasmacytic infiltrate. Lesional histiocytes show positive immunostaining for at least 1 histiocytic marker (CD68, CD163, etc.) and for ALK. Answers B, C and E are incorrect because the lesional histiocytes in each of these lesions do not show positive immunostaining for ALK. Answer D is incorrect because the neoplastic spindle cells in inflammatory myofibroblastic tumor (IMT) are myofibroblastic in origin and are therefore positive for SMA and desmin and negative for CD68.

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