Primary cutaneous marginal zone lymphoma C85.1

Rare, indolent (low-malignant), primary cutaneous non-Hodgkin B-cell lymphoma (NHL) composed of small B cells, centrocytic cells (marginal zone cells), plasma cells, and lymphoplasmacytoid cells. This group of B-cell lymphomas is classified as extranodal marginal zone lymphomas (MALT). It includes lymphomas previously described as "primary cutaneous immunocytomas" or "cutaneous follicular lymphoid hyperplasia with monotypic plasma cells."

The rare cases of (extramedullary) primary cutaneous plasmacytomas or Waldenström's disease also belong to this group. Primary cutaneous marginal cell lymphoma (SALT = skin associated lymphoid tissue ) is considered an extranodular variant of MLZ lymphomas.

Men are affected slightly more often than women.

The MLZ originates from transformed cells of the so-called marginal zone of the lymph node. MLZ is characterized by its proliferative capacity in non-lymphoid tissues (including skin (SALT - S for skin and associated lymphoid tissue), mucosa(M ALT - M for mucosa) and bronchus (BALT- B for bronchus). The cells express on their surface markers expressed by mature B cells (they react positively for IgM and/or IgD, CD5, CD19, CD20, CD22, CD24, CD45 and CD79A).

Furthermore, they mostly express the surface antigens CD5 and CD43, but not CD10 and CD23.

The genetic "fingerprint" is a translocation t(11;14)(q13;q32 ). This translocation results in a repositioning of the cyclin D1 gene (11q13) near strong transcriptional enhancer sequences of the immunoglobulin gene encoding heavy chains (IgH) (14q32). The translocation is thought to occur upon recombination of the D and J gene segments of the heavy chains in pre-B cells. Since this translocation is a major feature of mantle cell lymphoma, its detection by FISH (= fluorescence in situ hybridization) is used for diagnostic purposes. This genomic alteration leads to an overexpression of cyclin D1.

In addition to the translocation t(11;14)(q13;q32), other recurrent genomic alterations occur in MLZ. Genomic gains frequently occur on the long arms of chromosomes 3 and 18; genomic losses are found on the short arms of chromosomes 1 and 9 and on the long arms of chromosomes 9, 6 and 11. The target genes affected by these genomic changes mainly influence the regulation of the cell cycle, DNA repair and apoptosis.

Infections: The extent to which infection with Borrelia burgdorferi is etiologically significant for primary cutaneous MLZ remains hypothetical at present.

For gastric MALT, an association with chronic infection with Helicobacter is likely. For marginal zone lymphoma of the eye, a possible association with Chlamydia psittaci is certain.

Somatic mutations: Cutaneous MLZ has characteristics of so-called aberrant somatic hypermutations. These affect genes such as PAX5 (paired box 5), the transcription factor cMYC and the protooncogene PIM1.

The translocation t(11;18)(q21;q21) is found in gastric (up to 26%), pulmonary (31% to 53%) and intestinal (12% to 56%) MALT lymphomas. Routine cytogenetic testing is currently not recommended due to lack of therapeutic consequence (see also marginal zone lymphomas extranodale).

In the group of extranodular MLZ in larger collectives, the average age of initial manifestation is 35-60 years.

In the reported cases, the lower extremity predominates, followed by the trunk and face.

Mostly disseminated, more rarely solitary, indolent, red or red-brownish papules, plaques and nodules with a smooth, non-scaly surface. Ulcer formation is rare. Spontaneous regression of the lesions is possible. An association with Borrelia burgdorferi infections has been described in European populations, but not in Asian or American populations.

Imaging procedures are necessary to differentiate primarily cutaneous marginal zone lymphoma from systemic (nodal, splenic, gastric) marginal zone lymphoma with cutaneous involvement (CT: neck, thorax, abdomen/pelvis); sonography lymph nodes.

Serum electrophoresis is recommended in addition to the routine laboratory with differential blood count. Borrelia and Chlamydia serology. A bone marrow biopsy is optional (in 5-10% focal infiltrates are expected).

Nodular or diffuse infiltrates in the area of the entire dermis. The epidermis remains free of infiltrates. The histopathological pattern shows reactive germinal centres surrounded by neoplastic marginal zone cells (centrocyte-like cells), lymphoplasmocytoid cells and plasma cells. Small to medium-sized cells with notched nuclei and a pale, broad cytoplasm predominate. Occasionally also centroblasts, immunoblasts and some eosinophils. Rarely is a transformation into a large cell B-cell lymphoma.

Immunohistology (see CD-classification): Tumor cells show positivity for CD20, CD79a and BCl2 and, in contrast to primary cutaneous germinal tumors, negativity for BCL6. Monoclonal immunoglobulin expression with expression of the heavy chains of IgG and IgA (but not IgM) could be detected in the majority of cutaneous cases. One of the two light chains kappa or lambda are expressed predominantly. A ratio of 5:1 to 10:1 is considered diagnostically conclusive. Typically, the monoclonal cells are located at the periphery of the nodular infiltrates.

Note: The actual tumor portion in the total infiltrate is often small, since numerous reactive inflammatory cells (especially reactive T cells) are added to the infiltrate. In some cases this makes it difficult to differentiate it from a pseudolymphoma.

Clinical differential diagnoses: see below lymphoma, cutaneous B-cell lymphoma.

Histologic differential diagnoses: Benign lymphoproliferative processes see remarks above.

B-cell lymphomas of other provenance:

• Primary cutaneous follicular lymphoma
• Primary cutaneous marginal zone lymphoma
• Primary cutaneous diffuse large cell lymphoma
• Primary cutaneous Burkitt's lymphoma

The treatment suggestions are based on the S2K guideline- Cutaneous lymphomas, update 2016. However, there is currently a lack of consensus on the treatment of pcMZL. In addition to watchful waiting (no evidence), various treatment modalities can be considered if the quality of life is impaired by visible skin nodules. Therapy modalities are possible:

Solitary lesion: Patients with solitary or few lesions can be treated either surgically and/or with radiotherapy (involved field radiation). The radiation dose is in the range of 20-36Gy. The rate of complete remission is comparably high for both procedures at >95%.

Multiple lesions: In patients with multiple lesions, good results have been achieved with a systemically or intralesionally applied anti-CD20-Ak ( rituximab). Alternative anti-CD-20 antibodies such as ofatunumab and obinutuzumab have so far proved successful in individual cases (Nicolay 2016).

Associated Borrelia infection: Patients with an associated Borrelia infection (see case report) should first be treated with antibiotics (multiple cycles over 21 days with ceftriaxone 2 g i.v./day).

Alternatively, (experimental) studies with intralesional low-dose interferon alfa-2a therapy (3 times/week) or intralesional application of the anti-CD20 antibody(rituximab) have shown clear clinical successes up to complete remission. However, they are clearly to be regarded as 2nd choice therapy.

Alternative: bendamustine, possibly in combination with rituximab (S2k guideline)

Alternative: doxorubicin or gemcitabine, possibly in combination with rituximab

Excellent prognosis with a 5-year survival rate of almost 100% (Wilcox 2015). The prognosis is also not impaired by repeated cutaneous recurrences.

Under the term MLZ the older designations are subsumed, some of which are still in use:

• primary cutaneous imunocytoma, which is nomenclatured as a variant of extranodal marginal zone lymphoma.
• primary cutaneous plasmocytoma

An 84-year-old female patient in good DC and AZ presented with several months old livid red, partially eroded, otherwise surface smooth nodules and plaques on the right forearm. There was marked, inguinal, painless lymphadenopathy.

Laboratory: Low thrombocytopenia; protein electrophoresis: evidence of a monoclonal IgG - band. Infections with EBV, CMV, Coxsackie virus, Toxoplasma gondii and Helicobacter pylori could be excluded. Detection of a positive Borrelia IgG AK.

Somatic examination showed no evidence of organ involvement.

Histology: Dense infiltrates of CD20 positive lymphocytes; monoclonal k-light chain restriction. PCR analysis: Detection of Borrelia burgdorferi DNA. Sequence analysis of amplified DNA identified Borrelia afzelii as the underlying genospecies.

Diagnosis: B. afzelii-induced cutaneous marginal zone lymphoma.

Therapy: Antibiotic therapy with Ceftriaxon 2g i.v. for 3 weeks resulted in a clear regression of the nodules.

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