Primary cutaneous anaplastic large cell lymphoma (pcALCL)

PRIMARY CUTANEOUS ANAPLASTIC LARGE CELL LYMPHOMA (pcALCL) is an indolent CD30⁺ lymphoma usually treated with local therapy. It must be distinguished from systemic ALCL as the latter is an aggressive disease which requires multiagent systemic chemotherapy and from LyP which spontaneously regresses. The definition of "primary" cutaneous disease is somewhat controversial but generally is defined as skin disease without evidence of systemic involvement and no previous history of lymphomatoid papulosis, mycosis fungoides, or HD. Cases with cutaneous disease and nodal involvement limited to a regional draining node are problematic, and it is uncertain if they have a different prognosis or should be treated as primary cutaneous disease^ref. Unlike systemic ALCL, it is negative for epithelial membrane antigen (EMA) and it does not express ALK. Primary cutaneous ALCL is part of the spectrum of CD30⁺ cutaneous lymphoproliferative disease and clinically overlaps with lymphomatoid papulosis^ref (Kadin ME. Primary CD30+ cutaneous lymphomas (including lymphomatoid papulosis). In: Mason DY, Harrison NL, eds. Human Lymphoma: Clinical Implications of the REAL Classification. London, Springer; 1999;38:1–9)
Epidemiology : usually arises in the skin in an older patient (median age 60 years)
Symptoms & signs : isolated reddish violet tumor, which may be ulcerated^ref. Less commonly, the disease may present as multiple nodules in a circumscribed area, or rarely with widespread skin lesions.
Laboratory examinations :

The histologic features of primary cutaneous ALCL include sheets or large clusters of tumor cells in the dermis that usually extend into the subcutaneous tissue. The tumor cells in most cases are anaplastic rather than monomorphic. Vascular invasion, but not destruction, is often present^ref. Neutrophils and/or eosinophils may be prominent and one group has suggested that large numbers of eosinophils may be predictive of subsequent lymph node involvement^{ref1,
ref2,
ref3}. Cases previously called regressing atypical histiocytosis are now thought to represent ALCL^ref. The diagnosis of primary cutaneous ALCL may be difficult as there can be overlap with lymphomatoid papulosis, a regressing lymphoproliferative disorder^{ref1,
ref2,
ref3}. LyP has 3 histologic appearances^ref. Type A is composed of lymphocytes, other inflammatory cells and large, atypical cells that are CD30⁺ and oftentimes Reed-Sternberg-like. LyP type B has a band-like infiltrate with epidermotropism and atypical small to medium sized cerebriform lymphocytes simulating classical plaque stage mycosis fungoides. LyP type C has a monotonous population or large clusters of CD30⁺ T cells with few admixed inflammatory cells and a clinical history of regression. LyP types A and C can be distinguished from ALCL, in most cases by clinical and pathologic features (Kinney MC, Kadin ME. The pathologic and clinical spectrum of anaplastic large cell lymphoma and correlation with ALK gene dysregulation. Am J Clin Pathol.1999;111(Suppl.1):S56-S67) :

clinical features	LyP	ALCL
type of lesion	papules, nodules	nodules, tumors
number	multiple	single or grouped
size	usually <1 cm	> 2 cm (> 3 cm more predictive of lymphoma; borderline lesions are usually intermediate in size, 1-2 cm)
sites of disease	extremities, trunk	extremities, head and neck
regression	yes, usually with a scar	25% of cases

histology/immunophenotype	LyP	ALCL
pattern of infiltration	wedge-shaped perivascular/ periadnexal	more diffuse
subcutaneous involvement	absent or minimal	present
mixed inflammatory cells	many	few to many
CD30⁺ cells	scattered single or small clusters	large groups or sheets
epithelial membrane antigen (EMA)	present in 10-30% of cases	present in 10-30% of cases
anaplastic lymphoma kinase (ALK)	usually negative	usually negative

ALCL produces nodules or tumors that are single, but may be multiple and grouped, and are often ulcerated. LyP typically presents with multiple small papular lesions, usually < 1 cm, on the trunk or extremities that usually ulcerate and heal with a scar in 4-6 weeks. Histologically the infiltrate of LyP is wedge-shaped and perivascular and is composed of small lymphocytes and scattered single and small clusters of large atypical cells often resembling Reed-Sternberg cells. Invasion of the subcutaneous tissue is uncommon. As the lesions progress acute inflammatory cells including eosinophils become more prominent. The large atypical cells mark as T-cells and EMA may be present in up to approximately one-third of LyP. Borderline lesions (sometimes called LyP type C) typically are 1-2 cm in size and have larger clusters of CD30⁺ cells than typically seen in LyP^ref. Invasion of the subcutaneous tissue is minimal or absent. If a history of similar regressing lesions is present LyP should be favored
Treatment of localized lesions may be watchful waiting with approximately 25% of patients regressing, local excision with or without radiation, or radiation alone^ref. Patients with disseminated skin disease or localized skin disease with nodal extension may benefit from combination chemotherapy, but these patients tend to relapse^ref. Immunostaining for ALK should be performed and if positive the lesion should be considered systemic ALCL^ref. Monomorphic histology also suggests systemic disease. A recent study by Wellman et al has recently shown that all systemic ALCL expressed the adhesion molecule clusterin, and none of the primary cutaneous ALCL, but few cases were tested^ref. EMA expression is not useful as it has been reported in 54% of simultaneous cutaneous and systemic ALCL and 100% of secondary skin involvement and up to one-third of primary cutaneous ALCL^ref. Even after a diagnosis of primary cutaneous ALCL is made, careful followup is indicated as 25% later develop nodal involvement^ref.
Prognosis : the importance of ruling out systemic disease with cutaneous spread cannot be overemphasized as systemic ALCL with cutaneous spread has a 5-year survival of 29-44% as opposed to 90-100% in primary cutaneous ALCL^ref. This poor prognosis in systemic disease with skin involvement may correlate with ALK negativity but has not been studied in detail. Due to the poor prognosis, careful staging is imperative.

[lymphomatoid papulosis (LyP) is a clinically benign variant of primary cutaneous ALCL

Symptoms & signs : recurrent crops of papules/nodules up to 2 cm in diameter which undergo spontaneous regression, and rarely develop into a lymphoma
Therapy : LyP is managed by observation, ultraviolet light therapy, or low-dose weekly methotrexate can control the lesions of LyP (Vonderheid EC, Sajjadian A, Kadin ME. Methotrexate is effective therapy for lymphoimatoid papulosis and other primary cutaneous CD30-positive lymphoproliferative disorders. J Amer Acad of Dermatol. 1996;34:470–481)
Prognosis : LyP patients have a predisposition to develop malignant lymphomas, including Hodgkin's lymphoma

, mycosis fungoides, and non-Hodgkin's lymphoma, by as yet unknown mechanisms. The prognosis for patients with LyP is otherwise excellent^ref]

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