Primary cutaneous B-cell lymphomas C82- C83

Primary cutaneous B-cell lymphomas are neoplasms of the lymphatic system that exhibit a tissue-specific homing pattern with primary infiltration and manifestation in the skin. They exhibit a characteristic B-cell phenotype.

Clinically, cutaneous B-cell lymphomas present as solitary or multiple, asymptomatic, red or red-livid or red-brown, surface-smooth papules, plaques, or nodules. The classification is based on histological criteria according to the WHO-EORTC classification of non-Hodgkin lymphomas.

The decisive factor for therapy and prognosis is whether it is a primary cutaneous B-cell lymphoma or a secondary skin involvement in the presence of nodal B-cell lymphoma!

The 3 most common subtypes are (see classification):

• Primary cutaneous germinal zone lymphoma
• Primary cutaneousmarginal zone lymphoma (variant: cutaneous immunocytoma = Waldenström's disease)
• Primary large cell diffuse B-cell lymphoma of the leg

CBCL can be classified according to their degree of malignancy into low or intermediate malignancy. It is also important whether the cutaneous B-cell lymphoma is primary (lymphoma of the skin as the sole manifestation of the disease) or secondary (lymphoma of the skin as a secondary manifestation of extracutaneous disease). B-cell lymphomas in which the skin is usually only secondarily (metastatically) involved include mantle cell lymphoma (MZL), a diffuse centrocytic, non-follicular "germinal center lymphoma".

Depending on the dignity of primary cutaneous B-cell lymphomas, they can be differentiated as follows (032/027 S2k guideline cutaneous lymphomas):

• Indolent CBCL with good prognosis
  • Primary cutaneous marginal zone lymphoma
  • Cutaneous plasmocytoma
  • Cutaneous immunocytoma ( Waldenström's disease)
  • Primary cutaneous follicular center l ymphoma (follicular B-cell lymphoma/germinal center lymphoma)
• CBCL with moderate prognosis
  • Primary cutaneous diffuse large B-cell lymphoma leg type (PVBLT)
  • Primary cutaneous diffuse large B-cell lymphoma other (DLBCL) (see also EBV-positive DLBCL; to be separated from this is EBV-positive mucocutaneous ulcer (provisional))
• CBCL with poor prognosis
  • Primary cutaneous intravascular large B-cell lymphoma of the skin

According to histologic/immunohistologic criteria, one distinguishes:

• Primary cutaneous follicular B-cell lymphoma.
• Primary cutaneous marginal zone lymphoma
• Cutaneous plasmocytoma
• Cutaneous immunocytoma (Waldenström's disease)
• Primary cutaneous diffuse large B-cell lymphoma leg type (PVBLT)
• Primary cutaneous diffuselarge B-cell lymphoma of other localization (this includes rare subtypes such as primary cutaneous T-cell/histiocyte-rich B-cell lymphoma; plasmablastic lymphoma, CD30+ anaplastic large lymphoma)
• Primary cutaneous intravascular large B-cell lymphoma.
• EBV-positive diffuse large B-cell lymphoma not further specified (EBV-positive DLBCL)
• EBV-positive mucocutaneous ulcer (provisional)

The proportion of B-cell lymphomas in the skin is estimated at about 20-25% of primary cutaneous lymphomas. They are thus significantly less common than cutaneous T-cell lymphomas. The incidence is about 0.3 new cases/100,000 per year.

In 2/3 of the cases primarily only skin infestation without extracutaneous manifestation. In advanced stages, systemic involvement of varying extent and localization.

Specific skin changes: Mostly asymptomatic red, red-livid or reddish-brown, surface-smooth, firm papules, plaques or nodules with mostly unchanged, rather reflective surface. In late stages ulcerations are possible. The clinical features of the different entities can be found under the respective keyword.

Non-specific skin changes: erythroderma, eczema, pigmented and infiltrated foci. Amyloid deposits in the skin: papules, nodules. Alopecia. Also macroglossia, cryoglobulinemia, disseminated plane xanthomas, zoster, epidermolysis bullosa acquisita, pruritus, symptomatic purpura, ichthyosis, lichenification.

General symptoms: Enlargement of lymph nodes, splenomegaly, involvement of lung, liver, also stomach and bone marrow.

• Common clinical differential diagnoses:
• Lymphadenosis cutis benigna (pseudolymphoma of the skin; main differential diagnosis): Large nodular solitary (most frequent appearance) or small nodular multiple (rare), circumscribed, symptomless, firm, red, brown to brown-red, hemispherical bulging nodules or papules covered by thin epithelium. Reliable differential diagnostic differentiation is only possible histologically!
• Lymphoma, cutaneous T-cell lymphoma (important DD): Rather polymorphic appearance, ranging from eczematoid, ichthyosiform ( Mucinosis follicularis) or psoriasiform to erythrodermic ( Sézary syndrome) manifestations. Cutaneous T-cell lymphoma of the mycosis fungoides type can usually be ruled out on the basis of the anamnesis (parapsoriasis stage). A smooth surface structure of a lesion is also more likely to indicate a B-cell lymphoma.
• Lupus erythematodes tumidus: Occurs at light-exposed sites; mostly disseminated plaques; pronounced photosensitivity.
• Granuloma eosinophilicum faciei (rare; only to be considered for differential diagnosis in case of facial localisation): Roundish to oval, 0.5-2.0 cm in size, usually solitary, slightly raised, firm, symptom-free, brown-red, scale-free plaques with "orange peel-like" surface aspect. This is missing in cutaneous B-cell lymphomas.
• Merkel cell carcinoma (to be considered as DD in solitary infestation and localization in UV-exposed areas): Occurs in the age group 60-70 LJ. Fast growing node; mostly solitary. The surface of the nodule is smooth, rarely crusty or ulcerated. At depth there is often an iceberg-shaped widening of the knot. Safe exclusion only possible by histology.
• Dermatofibrosarcoma protuberans: Smooth, slowly growing node with iceberg phenomenon. Exceptionally rough consistency which is not present in lymphoma nodes.
• Mastocytoma: Single or multiple plaques or nodes existing since birth or occurring in the first months of life (exclusion due to age of manifestation). After rubbing of the lesions urticarial or bullous reaction (positive foci urticarial or bullous reaction (positive rubbing test).
• Rare clinical differential diagnoses:
• Sarcoidosis: Especially the large-nodular form with brown- or blue-red, rough, plum-sized nodules and plaques, especially on the nose, cheeks and earlobes must be differentiated. Sarcoidosis often occurs in scars! Diascopic lupoid infiltrate. Histologically safe to differentiate!
• Prurigo nodularis: Eminently chronic disease characterized by numerous, large, severely itchy nodules (B-cell lymphomas do not itch; pruritus is a symptom of exclusion).
• Skin metastases: Nodular metastases are of differential diagnostic importance; usually fast-growing, rough (!) smooth, red nodules. Often iceberg phenomenon. Reliable exclusion is only possible by histology.
• Extremely rare clinical differential diagnoses:
• Cutaneous infiltrates in myeloid leukaemia: pinhead to hazelnut-sized, sharply defined, hard, blue to brown-red, sometimes blue-grey to livid-red, slightly necrotic nodules.
• Reticulohistiocytosis, multicentre: Symmetrically distributed, multiple, 0.1-0.5 cm large, usually coarse, skin-coloured or copper-brown, sometimes slow-growing, sometimes eruptively exanthematic papules and nodules, possibly with atrophic, possibly excoriated, usually smooth surface. Itching is not uncommon.
• Tuberous syphilide: Grouped standing, partly confluent, reddish-brownish, coarse to pea-size, calotte-shaped raised nodules, possibly scaling. Degeneration with development of a flat, hyper- or depigmented scar. Anamnesis and serology are diagnostic.
• Cutaneous leiomyosarcoma: 2.0-5.0 cm large plaques or nodules, which can be moved against the underlying tissue, fused with the covering dermis, very firm, usually painful (!).

Due to the relative rarity of B-cell cutaneous lymphomas, there are no evaluated standard therapies.

• Monoorganic cutaneous manifestation - few lesions:
  • Local therapy. Smaller foci can be surgically removed, larger foci are radiated: soft X-ray therapy (GD 20-30 Gy, in ED of 2 Gy, 50 kV each) or fast electron irradiation (GD 40 Gy).
• Monoorganic cutaneous manifestation - multiple lesions:
  • Studies with excellent results in smaller cohorts exist on rituximab, an anti-CD20 antibody approved for cutaneous B-cell lymphomas. In the usual dosage (375 mg/m2 KO, 8 cycles) this preparation is indicated in elderly patients with disseminated, aggressive B-cell lymphoma. The mode of administration is also being discussed: intralesional treatments are well tolerated, show few side effects and use smaller amounts of medication. The clinical symptoms show significant improvements, but these do not last long. Recurrences occur frequently after intralesional therapy. Due to the small number of test persons, the data available for intravenous application are not meaningful at present.
• Monoorganic cutaneous manifestation - multiple lesions (tumor progression):
  • In case of progression: polychemotherapy, if necessary in cooperation with haemato-oncologists, e.g. CHOP-scheme. Concerning the side effects see below. Common Toxicity Criteria (CTC).
  • Experimental: Electrochemotherapy has been used in individual cases in therapy-resistant lymphomas.

• Mantle cell lymphoma typically shows the translocation t(11;14)(q13;q32) with an IgH-cycline D1 (CCND1) rearrangement. By this translocation, the BCL-1/cyclin D1/PRAD1 gene on chromosome 11 fuses with one of the 6 J regions of the immunoglobulin heavy chain (IgH) gene on chromosome 14 and thus comes under the control of the IgH enhancer (E).
• In MALT lymphomas (extranodal marginal zone lymphoma mucosa-associated tissues) a translocation t(11;18)(q21;q21) is often observed. However, the genetic changes are very different, other IgH rearrangements or 6q deletions are also possible (see also FISH analysis).
• In follicular lymphoma, a t(14;18)(q32;q21) with a BCL-2 rearrangement is found in the majority of cases; in addition, further cytogenetic aberrations are usually found.
• Diffuse large cell B-cell lymphomas (DLBCL) often show rearrangements of BCL6, MYC or BCL2. However, they do not show specificity for a certain entity, but may also occur in other lymphatic entities.
• In lymphoplasmocytic lymphoma no specific chromosomal aberrations are found.

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