Primary cutaneous lymphomas are a heterogeneous group of lymphoproliferative T-cell or B-cell neoplasms. Skin lymphomas are among the rare forms of skin cancer. Clinical inspection has an important role in establishing the diagnosis. Often, the suspected diagnosis is confirmed in the subsequent histological and immunohistochemical examinations. The treatment options depend, among other things, on the stage of the tumor disease. Especially in the field of cutaneous T-cell lymphomas, interesting new therapeutic strategies have been developed.
The assessment of clinical presentation has a high value in the diagnosis of cutaneous lymphoma [1]. In addition to inspection of the entire integument, the initial clinical examination should include palpation of all lymph node stations. If a skin manifestation does not fit the classic clinical picture, it may be secondary skin involvement of extracutaneous lymphoma. This is an important differential diagnostic distinction, explained Prof. Reinhard Dummer, M.D., Ph. Clinic Director Dermatology Clinic and Head Skin Tumor Center, University Hospital Zurich [2]. Cutaneous lymphomas belong to the group of so-called extranodal non-Hodgkin lymphomas. Primary cutaneous lymphomas initially manifest in the skin and show no other organ involvement at the time of diagnosis, whereas in secondary cutaneous lymphomas, skin symptoms represent manifestations of disseminated primary nodal lymphomas or leukemias [1]. Primary cutaneous lymphomas are divided into cutaneous B-cell lymphomas (CBCL) and T-cell lymphomas (CTCL), as well as rarer forms, according to clinical and pathohistological features [1]. The former are by far the most common [1]. Which factors cause the development of the tumor-relevant mutations has not yet been clarified.
CBCL – the trained eye of the specialist and histology are central
For experienced clinicians, it is possible to make a tentative diagnosis of which type of B-cell lymphoma is present based on the size and distribution of the lesions, explains Prof. Dummer [2]. Most primary cutaneous B-cell lymphomas (CBCL) correspond to one of the following subtypes:
Marginal zone lymphoma: Characterized by many small isolated or multiple erythematous plaques and nodules without ulceration with a maximum diameter of about 2 to 3 cm [2,3]. Extremities and trunk are most commonly affected.
Primary cutaneous germinal center lymphoma (follicular B-cell lymphoma): solitary or grouped, blue-red to red-brown, typically larger (>3 cm), nodular, sometimes plaque-like lesions [4]. Typically, the hairline or upper trunk area is affected. Lower extremity lesions are prognostically less favorable.
Diffuse large B-cell lymphoma: multiple rapidly flaring erythematous-livid plaques or tumor nodules that confluence into larger foci and ulcerate during progression [4]. Female patients over 70 years of age are most commonly affected.
Supplementary histological examination can often confirm the suspected diagnosis. A punch biopsy is recommended for this purpose. In addition to immunohistochemical examination, further clarification (e.g., lymph node ultrasonography) may be performed to ensure that it is not a secondary manifestation of extranodular lymphoma. A “single cell analysis” of B-cell lymphomas of the skin shows that especially in marginal zone lymphomas the proportion of clonal B cells is below 10%. This helps explain why molecular biology tends to be unreliable in cutaneous lymphomas and why clonality testing is negative in half of cases, he said. CBCL without other manifestations have a much more favorable prognosis than nodal B-cell lymphomas. In many cases, local therapy is sufficient. In addition, there is the possibility of surgical removal or radiotherapy. In individual cases, interferon therapy can lead to complete remission. According to the guideline, polychemotherapy is only indicated for extracutaneous manifestations [1].
CTCL – there are some innovative treatment approaches
Primary cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of lymphomas that occur in the skin and have no evidence of extracutaneous disease at the time of diagnosis. The subtypes of CTCL have a variety of clinical, histologic, and molecular features and can have an indolent or very aggressive course [5]. A main distinction is made between mycosis fungoides (Fig. 1), Sézary syndrome, CD30+ lymphomas , and rare entities. Diagnosis is based on integration of clinical and pathologic findings. The TNM classification according to Olsen is used for staging CTCL (Table 1) [8].
In the field of translational research and the development of new drug therapies, a lot has happened in the recent past, including the market approval of the antibody-based therapies mogamulizumab and brentuximab (Fig. 2) [8]. Chemokines are known to be chemotactic cytokines involved in the imprinting of naïve T cells and the function of regulatory T cells, among others [6]. As is now known, skin-homing lymphocytes express specific chemokine receptors. On cutaneous T-cell lymphoma cancer cells, the C-C chemokine receptor type 4 (CCR4) is frequently expressed. Mogamulizumab is a humanized monoclonal antibody that binds to CCR4, thereby destroying the degenerate T cells. While treatments such as methotrexate reduce both normal and tumorous lymphocytes, the antibody mogamulizumab selectively reduces clonal cells. “With this reduction in clonal cells, the healthy lymphocytes have more room again, and we can use this to help these patients’ immune systems improve,” he said. Mogamulizumab (Poteligeo®) is approved in Switzerland for the treatment of adult patients with relapsed or refractory mycosis fungoides or Sézary syndrome, in the absence of adequate efficacy of at least one prior systemic therapy [7]. “The other new drug that is now very widely used is brentuximab,” Prof. Dummer reported [2]. This is an antibody that carries a toxin that targets CD30 antigen on malignant T cells and kills this cell population. In Switzerland, brentuximab (Adcetris®) is indicated in adult patients with CD30+ cutaneous T-cell lymphoma who show progression on systemic therapy or are not suitable for other systemic therapy [7]. Patients with conventional mycosis fungoides, characterized by low expression of CD30, can also be successfully treated with it, the speaker explained.
Blastic plasmacytoid dendritic cell neoplasia (BPDCN).
BPDCN is a very rare and usually aggressive hematologic neoplasia of immature plasmacytoid dendritic cell precursors with myeloid and lymphoid imprinting [3]. Cutaneous singular or multilocular, often contusiform lesions represent the most common initial manifestation. Prof. Dummer describes the case of a patient who had a suspected clinical diagnosis confirmed by histology/punch biopsy and immunophenotyping (CD4, CD56, CD123, TCL-1) [2]. A reddish-livid aspect is very characteristic of BPDCN, he said. “It looks like a hemorrhage,” adds the speaker [2]. Depending on age, comorbidities, general condition and patient preferences, as well as the availability of an allogeneic stem cell donation, intensive induction treatment followed by potentially curative stem cell transplantation or symptom-oriented less intensive therapy is performed with non-curative intent [3]. A new drug therapy option has been approved in the EU since November 2020. Tagraxofusp can be used as monotherapy for first-line treatment of adult patients with BPDCN. It consists of a truncated diphtheria toxin (DT) fusion protein linked to recombinant human interleukin-3 (IL-3) to target CD123-expressing cells. Tagraxofusp irreversibly inhibits protein synthesis of target cells by inactivating elongation factor, leading to apoptosis [1]. This treatment option is currently not approved in Switzerland.
Congress: Continuing Education Week for Practical Dermatology and Venereology
Literature:
- Dippel E, et al: S2k-Guidelines – Cutaneous lymphomas (ICD10 C82 – C86): Update 2021. J Dtsch Dermatol Ges 2022; 20(4): 537-554.
- “Update Diagnosis and Therapy of Rare Tumors and Cutaneous Lymphomas,” Prof. Reinhard Dummer, MD, 28th Advanced Training Week for Practical Dermatology and Venereology, July 12-16, 2022.
- Onkopedia, www.onkopedia.com/de, (last accessed Sept. 16, 2022).
- Heinzerling L, et al: Cutaneous lymphomas. In: Drug-based tumor therapy in dermato-oncology. 2014; Springer: Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-24837-5_3
- Dummer R, et al: Cutaneous T cell lymphoma. Nat Rev Dis Primers 2021; 7(1): 61.
- Huck BR, Kçtzner L, Urbahns K: Small molecules, big time: small molecule immuno-oncology combination therapies. Angew Chem 2018; 130: 4499-4516.
- Drug Information, www.swissmedicinfo.ch, (last accessed Sept. 16, 2022).
- Pujol RM, Gallardo F: Cutaneous Lymphomas – Part I: Mycosis Fungoides, Sézary Syndrome, and CD30+ Cutaneous Lymphoproliferative Disorders. Actas Dermosifiliogr 2021; 112(1): 14-23.
- Olsen E, et al: Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007; 110: 1713-1722.
DERMATOLOGIE PRAXIS 2022; 32(5): 30-31
InFo ONCOLOGY & HEMATOLOGY 2022; 10(5): 32-33.
