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: Lymphoma, cutaneous B-cell lymphoma.

Histological differential: Benign lymphoproliferative processes.

B-cell lymphoma of other origin:

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

The therapy suggestions are based on the S2K guideline- Cutaneous Lymphoma, Update 2016.

Solitary lesion: Patients with solitary or few lesions can be treated either surgically and/or with involved field irradiation. The radiation dose ranges from 20-36Gy. The rate of full remissions is comparably high in both procedures, >95%.

Multiple lesions: In patients with multiple lesions, good results were obtained with systemically or intralesionally applied anti-CD20-Ak ( rituximab). Alternative anti-CD-20 antibodies such as Ofatunumab and Obinutuzumab have been proven 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 intralesinal application of the anti-CD20 antibody(rituximab) showed clear clinical success up to complete remission. However, they are clearly to be regarded as therapy of the 2nd choice.

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

Alternative: Doxorubicin or Gemcitabine, possibly in combination with Rituximab

As last resort, chemotherapy with doxorubicin or gemcitabine is recommended for multiple nodes.

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.

1. Akhtari M et al (2015) Primary Cutaneous B-cell Lymphoma (Non-Leg Type) Has Excellent Outcomes Even After Very Low Dose Radiation as Single-Modality Therapy. Leuk Lymphoma 10:1-13
2. Cerroni L, Kerl H (2003) Cutaneous B-cell lymphoma. In: H. Kerl et al (eds) Histopathology of the skin. Springer Berlin, Heidelberg, New York, pp. 906-908.
3. Cozzio A et al. (2006) Intra-lesional low-dose interferon alpha2a therapy for primary cutaneous marginal zone B-cell lymphoma. Leuk Lymphoma 47:865-869
4. Defrancesco I et al (2017) Overview on the management of non-gastric MALT lymphomas. Best Pract Res Clin Haematol 31:57-64.
5. Fühler M et al (2010) Cutaneous marginal zone lymphoma (SALT) in chronic Borrelia burgdorferi infection. Dermatologist 61:145-147
6. Kim MJ et al. (2015) Clinical features and treatment outcomes of primary cutaneous B-cell lymphoma: a single-center analysis in South Korea. Int J Hematol. 2015: 101: 273-278
7. Kiyohara T (2003) Cutaneous marginal zone B-cell lymphoma: a case accompanied by massive plasmacytoid cells. J Am Acad Dermatol 48: S82-85
8. Li C et al (2003) Primary cutaneous marginal zone B-cell lymphoma: a molecular and clinicopathologic study of 24 asian cases. Am J Surg Pathol 27: 1061-1069
9. Nicolay JP (2016) B-cell lymphomas of the skin - pathogenesis, diagnosis and therapy. J Dtsch Dermatol Ges 14:1207-1225.
10. Servitje O (2002) Primary cutaneous marginal zone B-cell lymphoma: a clinical, histopathological, immunophenotypic and molecular genetic study of 22 cases. Br J Dermatol 147: 1147-115
11. Soda R et al (2001) Systemic therapy of primary cutaneous B-cell-lymphoma, marginal zone type, with rituximab, a chimeric anti-CD20-monoclonal antibody. Acta Derm Venereol 81: 2007-2008
12. Taddesse-Heath L (2003) Marginal zone B-cell lymphoma in children and young adults. Am J Surg Pathol 27: 522-531
13. Teckie S (2015) Long-term outcome and patterns of relapse of early-stage extranodal marginal zone lymphoma treated with radiation therapy with curative intent. Int J Radiat Oncol Biol Phys 92: 130-137
14. Wehkamp U et al (2015) Skin involvement of mantle cell lymphoma may mimic primary cutaneous diffuse large B-cell lymphoma, leg type. Am J Surg Pathol 39:1093-1101
15. Wenzel C (2003) Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue of the head and neck area: high rate of disease recurrence following local therapy. Cancer 97: 2236-224
16. Wilcox RA (2015) Cutaneous B-cell lymphomas: 2015 update on diagnosis,
17. risk-stratification, and management. Am J Hematol 90:73-76
18. Wobser M et al (2013) E. Primary cutaneous marginal zone lymphoma with sequential development of nodalmarginal zone lymphoma in a patient with selective immunoglobulin A deficiency. J Cutan Pathol 40:1035-1041
19. Wutte N et al (2011) B. afzelii - induced cutaneous marginal zone lymphoma - A European entity? Abstract CD 46th DDG Conference.