Primary Cutaneous Anaplastic Large Cell Lymphoma

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This page from the 4th edition of Haematolymphoid Tumours is being updated. See 5th edition Table of Contents.

Primary Author(s)*

Theresa Spivey, MD, Shashirekha Shetty, PhD

Cancer Category/Type

• Mature T- and NK-cell Neoplasms

Cancer Sub-Classification / Subtype

• Primary Cutaneous CD30-positive T-cell lymphoproliferative disorders (CD30+ LPDs)

Definition / Description of Disease

• Primary cutaneous anaplastic large cell lymphoma (C-ALCL) is a form of cutaneous T-cell lymphoma with majority (>75%) of tumor cells expressing CD30.
• CD30+ LPDs are a part of a spectrum of diseases with overlapping features and are associated with an excellent prognosis. The group includes lymphomatoid papulosis (LyP) and C-ALCL, which are distinguished by clinical features and disease course.
• C-ALCL is a distinct entity from systemic anaplastic large cell lymphoma (ALCL), which can have cutaneous involvement.
• Diagnosis must exclude large cell transformation of mycosis fungoides, which can express CD30.

Synonyms / Terminology

• Primary Cutaneous CD30-positive T-cell lymphoproliferative disorder

Epidemiology / Prevalence

• Second most common type of cutaneous T-cell lymphoma
• Median age: 60 years. Cases have been reported in children.
• Male:Female 2-3:1
• Disease-specific 5-year survival rate 95%

Clinical Features

• Solitary or localized nodules or tumors, with frequent ulceration. Multifocal lesions are seen in 20% of patients.
• Lesions may regress, either partially or completely, but cutaneous relapse is common.
• Extracutaneous dissemination is seen in 10-15% of cases, most cases involving regional lymph nodes.
• Associated with excellent prognosis, even in those with regional lymph node involvement or multifocal skin lesions.
• Anaplastic morphology does not impact disease course or prognosis.
• Distinguishing from LyP is important for therapy, as surgical excision and radiotherapy are first-line treatments in patients with C-ALCL.

Sites of Involvement

• Limited to cutaneous sites, most frequently affecting the trunk, face, and extremities.

Morphologic Features

• Sheets or nodular dermal infiltrate of large pleomorphic, anaplastic, or immunoblastic cells
• Irregularly shaped nuclei
• Abundant, pale to eosinophilic, cytoplasm
• Reactive lymphocytes in the periphery
• Ulcerated lesions may resemble lymphomatoid papulosis with increased inflammatory infiltrate composed of T-cells, histiocytes, eosinophils, and neutrophils, with fewer CD30+ cells.

• In cases harboring DUSP22-IRF4 translocations, CD30+ cells commonly display biphasic morphology - small, cerebriform lymphocytes within the epidermis and large transformed cells in dermis.

Immunophenotype

Finding	Marker
Positive (activated T-cell markers)*	CD4, CD30 (diagnosis requires >75% expression of tumor cells)
Variable (pan T-cell markers)	CD2, CD3, CD5
Positive	Cytotoxic proteins†: Granzyme B, TIA1, perforin CD15 (40%), IRF4/MUM1, CLA (cutaneous lymphocyte antigen)
Negative	EMA‡, ALK‡, PAX5, EBV, CD56 (rare cases with coexpression)

*Some cases may have a T-cell phenotype of CD4-/CD8+ or CD4+/CD8+ or null-cell phenotype.

^†Cases with DUSP22-IRF4 rearrangement tend to express

^‡EMA and ALK are typically positive in systemic ALCL, however there are rare cases of ALK+ primary C-ALCL.

Chromosomal Rearrangements (Gene Fusions)

• Rearrangements of DUSP22-IRF4 locus on chromosome 6p25.3 are found in 25% of primary C-ALCL and in rare cases of LyP and transformed mycosis fungoides. The rearrangements have not found in systemic ALCL or other T-cell LPDs.
• TYK2 (19p13) rearrangements in 15% of CD30+ lymphoproliferative disorders, with recurrent NPM1-TYK2 fusions reported in primary C-ALCL and LyP.
• TP63 rearrangements on 3q28 are rare in C-ALCL.
• Rare cases of primary C-ALCL contain ALK rearrangements and associated expression of ALK.

Characteristic Chromosomal Aberrations / Patterns

• Clonal T-cell receptor gene rearrangement is detected in majority of cases.

Genomic Gain/Loss/LOH

Chromosome Number	Gain/Loss/Amp/LOH	Associated Genes
7q31	Gain	MET
6q16-6q21	Loss	PRDM1
13q34	Loss	CDC16/CUL4A

• The genomic gains and losses listed above are the most common and seen in 45% of cases.

Gene Mutations (SNV/INDEL)

N/A

Epigenomics (Methylation)

N/A

Genes and Main Pathways Involved

• DUSP22 rearrangements associated with decreased production in the enzyme, dual-specificity phosphatase-22, which regulates MAPK signaling pathway.
• NPM1-TYK2 fusion is associated with constitutive STAT signaling.

Diagnostic Testing Methods

• Requires clinical and histopathologic correlation to diagnose and separate from lymphomatoid papulosis and large cell transformation of mycosis fungoides.
• Must exclude systemic involvement by ALCL with cutaneous involvement or history of mycosis fungoides.

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

• DUSP22-IRF4 rearrangement have not been shown to impact disease behavior prognosis.
• TP63 rearrangements are associated with refractoriness to chemotherapy and poor prognosis

Familial Forms

N/A

Other Information

N/A

Links

• HAEM4:Primary Cutaneous CD30 Positive T-cell Lymphoproliferative Disorders
• HAEM5:Primary cutaneous CD30-positive T-cell lymphoproliferative disorder: Lymphomatoid papulosis
• HAEM5:ALK-negative anaplastic large cell lymphoma
• HAEM5:ALK-positive anaplastic large cell lymphoma
• HAEM5:Mycosis fungoides

Notes

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