Pathology and Genetics of Skin Tumours

World Health Organization Classification of Tumours

IARCPress Lyon, 2006

Primary cutaneous anaplastic large-cell lymphoma

Definition
Primary cutaneous anaplastic lymphoma (C-ALCL) is a neoplasm composed of large atypical lymphocytes of either pleomorphic, anaplastic or immunoblastic cytomorphology and expression of the CD30 antigen by the majority, i.e. more than 75% of tumour cells. Primary cutaneous and primary nodal CD30+ ALCL are distinct clinical entities that can have similar morphologic features and some overlap in immunophenotype, but differ in age of onset, genetic features, etiology and prognosis.

Synonyms
Regressing atypical histiocytosis , EORTC: Primary cutaneous large cell T cell lymphoma CD30+

Epidemiology
C-ALCL is the second most common form of cutaneous T-cell lymphoma with an incidence of 0.1-0.2 patients per 100’000. This form of lymphoma affects mainly people in their sixth decade with a male to female ratio of 2-3:1 , but it can also occur in childhood. CALCL is a common form of cutaneous Tcell lymphoma in HIV-infected individuals.

Localization
The extremities and head are predilection sites.

Clinical features
ALCL usually presents as an asymptomatic, solitary firm nodule which rapidly grows and often ulcerates. Approximately 20% of the patients have multifocal disease, i.e. two or more lesions at multiple anatomic sites. Involvement of regional lymph nodes can occur. Other extra-cutaneous spread is rare. If there is no therapeutic intervention, spontaneous regression occurs in 10-40% of the tumour lesions.

Histopathology
There is a dense nodular infiltrate extending through all levels of the dermis into the subcutis. Epidermotropism may be found. The infiltrate consists of cohesive sheets of large, cells with irregularly shaped nuclei and one or multiple nucleoli and an abundant, clear or eosinophilic cytoplasm. Mitoses are frequent. Clusters of small reactive lymphocytes are found within and around the tumour. Eosinophils, plasma cells, and accessory dendritic cells usually are not prominent in C-ALCL. Variants of C-ALCL include neutrophil-rich or pyogenic CD30+ ALCL presenting histologically with small aggregations or scattered CD30+ medium to large pleomorphic
lymphoid cells within an extensive infiltrate of neutrophils.

Immunohistochemistry
C-ALCL displays an activated T-cell phenotype with expression of T-cell associated antigens CD2, CD3, CD4 and CD45RO, activation markers such as CD25 (IL-2R), CD30, CD71 and HLA-DR, and frequent expression of cytotoxic molecules such as TIA-1, granzyme B and perforin. CD30 must be expressed by at least 75% of the large pleomorphic or anaplastic lymphoid cells. Variable loss of T cell antigens (CD2, CD3, CD5 and CD7) can be found. In contrast to systemic (nodal) ALCL, C-ALCL does not express EMA, but may express the cutaneous lymphocyte antigen (CLA, HECA-452) and homeobox gene HOXC5 {243}. C-ALCL is consistently negative for the anaplastic lymphoma related tyrosine kinase (ALK).

Genetics
Clonal rearrangement of T cell receptor genes is detected by Southern blot and PCR in most cases (over 90%) of C-ALCL. The translocation t(2;5) (p23;q35) resulting in expression of npm-alk protein (p80), which is a characteristic feature of systemic anaplastic large cell lymphomas,
is rarely if ever found in C-ALCL. Systemic ALCL may present with cutaneous disease, and the identification of ALK-expression is helpful in this distinction.

Histogenesis
Activated skin-homing T-cell. Prognosis and predictive factors C-ALCL has a favourable prognosis with 5 year-survival rates of 90%. Up to 40% of C-ALCL show spontaneous regression. Regional lymph nodes may be involved, but the survival rate is similar to patients with skin lesions only {191}. Other extracutaneous spread occurs in 10% of the patients, especially in those with multiple grouped or multifocal tumour lesions with a fatal outcome in only a minority of the patients. Spontaneous regression and age less than 60 years are associated with a better
prognosis, while extracutaneous disease and higher age tend to have a worse outcome. Cytomorphology (anaplastic or pleomorphic and immunoblastic) seems not to be a prognostic factor.

BLOOD, 15 MAY 2005 VOLUME 105, NUMBER 10

Primary cutaneous anaplastic large-cell lymphoma.

Definition

Primary cutaneous anaplastic large cell lymphoma. (CALCL) is composed of large cells with an anaplastic, pleomorphic, or immunoblastic cytomorphology and expression of the CD30 antigen by the majority (more than 75%) of tumor cells. There is no clinical evidence or history of LyP, MF, or another type of CTCL.

Clinical features

C-ALCL affects mainly adults with a male to female ratio of 2-3:1. Most patients present with solitary or localized nodules or tumors, and sometimes papules, and often show ulceration. Multifocal lesions are seen in about 20% of the patients. The skin lesions may show partial or
complete spontaneous regression, as in LyP. These lymphomas frequently relapse in the skin. Extracutaneous dissemination occurs in approximately 10% of the patients, and mainly involves the regional lymph nodes.

Histopathology

There is a diffuse, nonepidermotropic infiltrate with cohesive sheets of large CD30 tumor cells. In most cases the tumor cells have the characteristic morphology of anaplastic cells, showing round, oval, or irregularly shaped nuclei, prominent eosinophilic nucleoli, and abundant cytoplasm. Less commonly (20%-25%), they have a nonanaplastic (pleomorphic or immunoblastic) appearance. Reactive lymphocytes are often present at the periphery of the lesions. Ulcerating lesions may show a LyP-like histology with an abundant inflammatory infiltrate of reactive T cells, histiocytes, eosinophils and/or neutrophils, and relatively few CD30 cells. In such cases epidermal hyperplasia may be prominent.

Immunophenotype

The neoplastic cells generally show an activated CD4 T-cell phenotype with variable loss of CD2, CD5, and/or CD3, and frequent expression of cytotoxic proteins (granzyme B, TIA-1, perforin). Some cases (less than 5%) have a CD8 T-cell phenotype. CD30 must be expressed by the majority (more than 75%) of the neoplastic T cells. Unlike systemic CD30 lymphomas, most C-ALCLs express the cutaneous lymphocyte antigen (CLA), but do not express epithelial membrane antigen (EMA) and anaplastic lymphoma kinase (ALK), indicative of the 2;5 chromosomal translocation or its variants.2,107,108 Unlike Hodgkin and Reed-Sternberg cells in Hodgkin disease, staining for CD15 is generally negative. Coexpression of CD56 is observed in rare cases, but does not appear to be associated with an unfavorable prognosis.

Genetic features.

Most cases show clonal rearrangement of T-cell receptor genes. The (2;5)(p23;q35) translocation and its variants, which is a characteristic feature of systemic ALCL, is not or rarely found in C-ALCL.

Prognosis and predictive factors

The prognosis is usually favorable with a 10-year disease-related survival exceeding
90%. Patients presenting with multifocal skin lesions and patients with involvement of only regional lymph nodes have a similar prognosis to patients with only skin lesions. No difference in clinical presentation, clinical behavior, or prognosis is found between cases with an anaplastic morphology and cases with a nonanaplastic (pleomorphic or immunoblastic) morphology.

Treatment

Radiotherapy or surgical excision is the first choice of treatment in patients presenting with a solitary or few localized nodules or tumors. Patients presenting with multifocal skin lesions can best be treated with radiotherapy in case of only a few lesions, or with low-dose methotrexate, as in LyP. Patients presentingwith or developing extracutaneous disease or rare patients with rapidly progressive skin disease should be treated with doxorubicinbased multiagent chemotherapy.

For more details on cutaneous lymphomas, see (click) the review article below

BLOOD, 15 MAY 2005 VOLUME 105, NUMBER 10