Primary cutaneous diffuse large cell b-cell lymphoma leg type C83.3

Primary cutaneous B-cell lymphoma with rapidly progressive clinical course, high recurrence rate, and frequent extracutaneous dissemination.

This B-cell lymphoma is an extranodular variant of diffuse large B-cell lymphoma (DLBCL). This is the most common neoplasm of the lymphatic system.

This variant of lymphoma is classified as an aggressive B-cell non-Hodgkin's lymphoma (B-NHL) and originates from mature B cells. Diffuse large B-cell lymphoma (DLBCL) is characterized by rapidly progressive lymph node enlargement and/or extranodal manifestations, and also variably by general symptoms (B symptoms), and is rapidly fatal without treatment.

Unknown. Connections with EBV infections have been described. In particular, the constellation of chronic EBV infection and MTX therapy appears to be associated with the development of this type of lymphoma. Connections between long-term MTX therapy and associated B-cell lymphomas are known.

At the molecular level, numerous aberrations have been identified that explain cell hyperproliferation and cell death resistance. These are mainly localized in the p21 region of chromosome 9. These include deletions of the CDKN2A gene (cyclic-dependent kinase inhibitor 2A), which lead to increased cell proliferation. The translocalization t(q24/q32) detectable in Burkitt's lymphoma is also detectable in this type of lymphoma. Furthermore, point mutations in the MYD88 gene are detectable, which could explain the cell death resistance of the malignant cell population.

Occurs in older people (> 70 years). Women are affected 3-4 times more frequently than men. Associations with rheumatoid polyarthritis and chronic lymphedema have been described.

Preferably occurring on the lower extremity: > 70% (lower leg).

One or more, red, brownish-red or blue-red, firm surface-smooth nodules or plaques with a tendency to ulceration. In some circumstances, this variant of lymphoma appears clinically as an "ulcer of the lower leg" and its dignity is then easily misjudged. The lymphoma may also occur at other sites of manifestation in 10-15% of patients.

Diagnosis requires a sufficiently large tissue sample, preferentially as a sampling of the entire lymph node, on which histological, immunohistochemical, cytogenetic, and molecular genetic studies are performed. Morphology is of particular importance for diagnosis and delineation of differential diagnoses. The following analyses must be performed:

CD20 expression and, if necessary, other B-cell markers; testing for MYC translocations to differentiate from 'high-grade B-cell lymphomas' according to the WHO classification. The prognostic relevance of MYC translocations seems to depend on the translocation partner (Rosenwald A et al. 2019).

Parallel testing for expression of MYC and BCL2: If both markers are expressed, a so-called 'double expressor' status is present. Patients with 'double expressor' lymphoma showed a worse prognosis in retrospective analyses (Johnson NA et al 2012). However, the presence of 'double expressor' status currently has no therapeutic relevance.

Determination of COO subtype, although the choice of method is optional. COO subtyping currently has no clinical relevance, but is part of the WHO classification.

Staging: The Ann Arbor classification is used for staging (Lister TA et al. (1989). This requires a history (B symptoms), physical examination (tonsils, lymph nodes, liver, spleen, effusions, visible or palpable space-occupying lesions), computed tomography (CT) scans with contrast of the neck, thorax, and abdomen, and bone marrow biopsy (unilateral; aspiration and trephination of at least 2 cm).

Imaging: The international standard for the detection of lymphoma manifestations is positron emission tomography (PET) using the tracer 18-fluorodeoxyglucose (FDG-PET).

FDG-PET is the international standard in the diagnosis of spread and evaluation of treatment outcome (Johnson NA et al 2012). Propagation diagnosis is usually performed using whole-body PET/CT, in which pathologic glucose accumulations (PET component) are matched to anatomic structures (CT component). PET/CT can provide additional information at diagnosis regarding bone marrow infiltration and staging and leads to upstaging in approximately 20% of cases.

Laboratory investigations: Laboratory investigations include a blood count with differential blood count, clinical chemistry parameters such as: bilirubin, GOT, GPT, alkaline phosphatase, gamma-GT; creatinine. Serum LDH gives information about cell proliferation, uric acid about cell decay. Before starting therapy: perform hepatitis and HIV serology.

Further examinations: electrocardiogram; echocardiography.

Sonography of the lymph nodes, CT: neck, thorax, abdomen/pelvis.

Dense, nodular or diffuse infiltrates throughout the dermis and upper subcutis. The epidermis remains predominantly free of infiltrates. The histopathological pattern shows predominantly large cells with the characteristics of immunoblasts, centrocytes and centroblasts with high proliferative activity.

Immunohistology: Tumor cells show positivity for Pan B markers(CD19, CD20, CD79a) and express BCL2 and MUM-1 in most cases (in 60% of cases). In isolated cases, CD30 reactivity may also be present. Monoclonal rearrangement of the IgH gene is usually detectable.

The negativity for Epstein-Barr virus is helpful to differentiate from EBV-associated large B-lymphoma.

Lymphomas of other aetiology, ulcus cruris of various genesis: venous leg ulcer or arterial leg ulcer. Ulcerated epithelial tumours.

There is no guideline system for this type of lymphoma, only smaller case series with different therapeutic approaches. Important for all therapy considerations is the poor prognosis in comparison to the biologically indolent primary cutaneous B-cell lymphomas.

• For solitary tumors, primary excision followed by radiation therapy is recommended .
• For multiple tumors, polychemotherapy is recommended. According to recent studies, the highest remission rate is achieved with polychemotherapy with anthracyclines in combination with the monoclonal anti-CD20 AK ( Rituximab), e.g. R-CHOP.
• In case of local recurrence, radiotherapy should be considered in addition to excision.
• Further recommendations see below diffuse large B-cell lymphoma

Intermediate malignancy. Recurrence in 50% of cases despite early therapy. 3-year survival rate about 53%, 5-year survival rate about 41%. The prognosis is more favourable for solitary lesions with centrocyte dominance (5-year survival rate of about 100%). It is worse in patients > 70 years of age, with multiple lesions (> 5) on both legs and the occurrence of centroblasts and immunoblasts (5-year survival rate at 36%).

1. Cerroni L, Kerl H (2003) Cutaneous B-cell lymphomas. In: H. Kerl et al (eds.) Histopathology of the skin. Springer, Berlin Heidelberg New York S. 911-912
2. Erös N et al (2003) Large B-cell lymphoma of the leg in a patient with multiple malignant tumors. Acta Derm Venereol 83: 354-357
3. Grange F et al (2007) Primary cutaneous diffuse large B-cell-lymphoma, leg type. Arch Dermatol 143: 1144-1150
4. Khan JA et al (2011) Diffuse large B-cell lymphoma presenting as a chronic leg ulcer: the importance of repeat tissue biopsy. Ann R Coll Surg Engl 93:e9-10
5. Kamath NV et al (2001) Primary cutaneous large B-cell lymphoma of the leg relapsing as cutaneous intravascular large B-cell lymphoma. Arch Dermatol 137: 1657-1658
6. Kempf Wet al. (2015) Paediatric cutaneous lymphomas: a review and comparison with adult counterparts. J Eur Acad Dermatol Venereol 29:1696-1709
7. 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 101: 273-278
8. Koens L et al (2014) Methotrexate-associated B-cell lymphoproliferative disorders presenting in the skin: A clinicopathologic and immunophenotypical study of 10 cases. Am J Surg Pathol 38:999-1006
9. Nicolay JP (2016) B-cell lymphomas of the skin - pathogenesis, diagnosis and therapy. J Dtsch Dermatol Ges 14:1207-1225.
10. Paulli M et al (2002) Primary cutaneous large B-cell lymphoma of the leg: histogenetic analysis of a controversial clinicopathologic entity. Hum Pathol 33: 937-943
11. Pham-Ledard A et al (2014) High frequency and clinical prognostic value of MYD88 L265P mutation in primary cutaneous diffuse large B-cell lymphoma, leg-type. JAMA Dermatol 150:1173-1179
12. Rausch T et al (2013) EBV+ cutaneous B-cell lymphoproliferation of the leg in an elderly patient with mycosis fungoides and methotrexate treatment. APMIS 121:79-84
13. Wobser M et al (2011) Therapy of primary cutaneous large cell B-cell lymphoma, leg type, with modified R-CHOP immunochemotherapy - diagnostic and therapeutic challenge. JDDG 9: 204-211