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Liu, W.; Wang, H.; Yeh, Y.; Wong, T. Primary Cutaneous Lymphomas. Encyclopedia. Available online: https://encyclopedia.pub/entry/43945 (accessed on 21 December 2024).
Liu W, Wang H, Yeh Y, Wong T. Primary Cutaneous Lymphomas. Encyclopedia. Available at: https://encyclopedia.pub/entry/43945. Accessed December 21, 2024.
Liu, Wei-Ting, Han-Tang Wang, Yi-Hsuan Yeh, Tak-Wah Wong. "Primary Cutaneous Lymphomas" Encyclopedia, https://encyclopedia.pub/entry/43945 (accessed December 21, 2024).
Liu, W., Wang, H., Yeh, Y., & Wong, T. (2023, May 08). Primary Cutaneous Lymphomas. In Encyclopedia. https://encyclopedia.pub/entry/43945
Liu, Wei-Ting, et al. "Primary Cutaneous Lymphomas." Encyclopedia. Web. 08 May, 2023.
Primary Cutaneous Lymphomas
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This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15051328

Primary cutaneous lymphomas (PCLs) are a heterogenous group of extranodal non-Hodgkin lymphomas of T-cell, NK-cell, or B-cell origin, which primarily affect the skin. PCLs are uncommon, accounting for only about 4% of all non-Hodgkin lymphomas. The classification and treatment guidelines of PCLs is mainly from the World Health Organization (WHO), updated in 2018, which is mainly based on the cell types (T-cells or B-cells), histopathology, and certain proteins expressed on the tumor cell.

primary cutaneous lymphoma CTCL mycosis fungoides CBCL

1. Classification of Different Subtypes of Cutaneous Lymphoma

Most of the PCLs are cutaneous T-cell lymphomas (CTCLs) (75–80%), and around 20–25% are cutaneous B-cell lymphomas (CBCLs) with different subtypes in the Western world (Table 1). Such differences are even greater in the Asian population, where up to 85.7% are CTCLs, as demonstrated in a Japanese nationwide study [1][2][3]. Epidemiological studies have shown that rare subtypes of CTCLs are more frequently found in Asian countries, whereas other types are evenly spread in other regions across the world [1].
Table 1. Subtypes of PCLs according to WHO-EORTC classification 2018 and changes according to International Consensus Classification (ICC) of Mature Lymphoid Neoplasms 2021 [4][5].
Entity Disease Changes in ICC, 2021
CTCL MF
MF variants
  Folliculotropic MF
  Pagetoid reticulosis
  Granulomatous slack skin
SS
Adult T-cell leukemia/lymphoma
Primary cutaneous CD30+ LPDs
  C-ALCL
  LyP
Subcutaneous panniculitis-like T-cell lymphoma
Extranodal NK/T-cell lymphoma, nasal type
Chronic active EBV infection
Primary cutaneous peripheral T-cell lymphoma, rare subtypes
  Primary cutaneous γ/δ T-cell lymphoma
  CD8+ AECTCL (provisional)
  Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (provisional)
  Primary cutaneous acral CD8+ T-cell lymphoma (provisional)
Primary cutaneous peripheral T-cell lymphoma, NOS		 Primary cutaneous acral CD8+ T-cell LPD
CBCL PCMZL
PCFCL
PCDLBLC, LT
EBV+ mucocutaneous ulcer (provisional)
Intravascular large B-cell lymphoma		 Primary cutaneous marginal zone LPD
MF: mycosis fungoides; SS: Sezary syndrome; LPD: lymphoproliferative disorder; C-ALCL: cutaneous anaplastic large cell lymphoma; LyP: lymphomatoid papulosis; CD8+ AECTCL: primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma; PCMZL: primary cutaneous marginal zone lymphoma; PCFDL: primary cutaneous follicle center lymphoma; PCDLBCL, LT: primary cutaneous diffuse large B-cell lymphoma, leg type.

1.1. Cutaneous T-Cell Lymphoma

Around half of all CTCLs are mycosis fungoides (MF) [6]. MF affects mostly men and is twice as frequent compared to women in their 50s or 60s. The early stage of MF can be confused with other dermatoses with itchy or asymptomatic patchy, scaly, and red lesions on the skin, which poses the need for several skin biopsies to confirm. The disease course is usually slow and can take years to develop into plaques and tumorous stages. Some MF patients may develop Sezary syndrome (SS) [7]. Rare variants of MF include folliculotropic MF, pagetoid reticulosis, and granulomatous slack skin [8]. SS typically affects all skin with redness and severe itching, so-called erythroderma [8]. The tumor cells are characterized by cerebriform nuclei found in the blood, skin, and lymph nodes. Compared to MF, SS is harder to treat and grows faster, and patients are at a higher risk of serious infection with weakened immunity [8].
Adult T-cell leukemia-lymphoma (ATLL) affects mainly other parts of the body, but can sometimes be limited to the skin. ATLL is linked to human T-cell leukemia virus Type 1 (HTLV-1) infection, which often occurs in HTLV-1-endemic areas, such as Japan, the Caribbean islands, Central and South America, Intertropical Africa, and the Middle East [9]. This type of lymphoma is usually aggressive, but may grow slowly in some cases or even resolve over time.
Primary cutaneous anaplastic large-cell lymphoma (C-ALCL) usually affects people in their 50s or 60s, but can also occur in children. It begins with one or a few tumors of various sizes with or without ulceration on the skin [10]. The prognosis of this lymphoma is very good.
Lymphomatoid papulosis (LyP) is a benign, waxing and waning, slow-growing disease, even without treatment [11]. However, it might progress to lymphoma. The histology of LyP shows features that look like primary cutaneous ALCL. LyP affects younger men more than women, with an average age of 45 years old. The disease usually begins as several large pimple-like lesions with a central ulcer. Although it is rare, some LyP patients may develop a more serious type of lymphoma [11].
Extranodal NK/T-cell lymphoma, nasal type, usually begins in the nose or sinuses, but sometimes begins in the skin [12]. It is related to Epstein–Barr virus (EBV) infection, which is more common in Asia, as well as Central and South America. The tumor grows fast and aggressively [12].
There are several rare subtypes of primary cutaneous peripheral T-cell lymphoma, which are described in the following paragraphs.
Primary cutaneous gamma/delta T-cell lymphoma usually develops as thick plaques or tumors on the skin of the arms and legs, but sometimes on the nasal mucosa or in the intestines [13]. This lymphoma grows and spreads quickly.
Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (CD8+ AECTCL) develops as widespread patches, nodules, and tumors with a central ulcer. This lymphoma may sometimes look like mycosis fungoides clinically, but tends to grow and spread quickly [14].
Primary cutaneous acral CD8+ T-cell lymphoma is very rare and typically grows on the acral skin such as the ear, nose, hand, or foot. It grows slowly and can be cured after treatments [15].
Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder often begins as a single plaque or tumor on the head and neck area or the upper trunk. This lymphoma grows slowly and can be cured with treatments [16].

1.2. Cutaneous B-Cell Lymphoma

PLCs with B-cell origin are referred to as cutaneous B-cell lymphomas (CBCLs). Different types of CBCLs are primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicle center lymphoma, and primary cutaneous diffuse large B-cell lymphoma, leg type [17][18].
Primary cutaneous marginal zone B-cell lymphoma is a very slow-growing, curable lymphoma which is sometimes caused by Borrelia infection in Europe [19]. The disease can affect people of all ages with more cases in older adults. The tumor can appear as red to purplish, with single or a few papules, plaques or nodules on the arms or upper trunk [20].
Primary cutaneous follicle center lymphoma is the most common, slow-growing B-cell lymphoma of the skin in middle-aged adults [21]. They appear as groups of red papules, nodules, or plaques on the scalp, forehead, or upper trunk, and sometimes on the legs. These tumors are sensitive to radiation and the outcome of the disease is excellent [22].
Primary cutaneous diffuse large B-cell lymphoma, leg type, is a fast-growing lymphoma that starts as large nodules on the lower legs in older people, affecting more women than men [23]. The tumor requires intensive treatment and may spread to lymph nodes and internal organs to cause serious disease. In general, a single lesion at the time of diagnosis has a better prognosis [23].

2. Management of Cutaneous T-Cell Lymphomas

Early aggressive treatments with combined chemotherapy and radiation therapy provide no overall survival benefit in patients with mycosis fungoides [24], and cures, if any, are rarely achieved [25]. The general consideration for the treatment of mycosis fungoides is aiming at achieving disease control while balancing quality of life at the same time, with treatment modalities tolerated for a longer duration and less cumulative toxicity. SDTs are suitable especially for patients with early-stage (stages IA-IIA) mycosis fungoides [26]. For patients with limited skin involvement, topical therapies including topical corticosteroids, topical mechlorethamine (nitrogen mustard), topical carmustine (BCNU), topical retinoids (bexarotene, tazarotene), and topical imiquimod are all optional local treatments [27]. The current guideline from National Comprehensive Cancer Network (NCCN) suggests no priority in choosing either one of the SDTs. Phototherapy with narrow-band UVB, PUVA, or TSEBT should be considered for patients with generalized skin involvement [28].
For primary cutaneous CD30+ T-cell lymphoproliferative disorders, which encompass primary cutaneous anaplastic large-cell lymphoma (ALCL) and lymphomatoid papulosis (LyP), involved-site radiation therapy or surgical excision are options for solitary or grouped lesions of primary cutaneous ALCL, while topical steroids or phototherapy are suitable for limited lesions of LyP. For all other rare subtypes of CTCLs, treatments depend on each subtype, and SDTs are suggested only for those with indolent behavior. Excision and/or local radiotherapy are recommended for CD4+ small/medium pleomorphic T-cell lymphoproliferative disorder and primary cutaneous CD8+ acral T-cell lymphoma by the British Association of Dermatologists and U.K. Cutaneous Lymphoma Group Guidelines [26]. For the treatment of CTCLs, photodynamic therapy is mentioned only in the British guidelines for mycosis fungoides, serving as an alternative for solitary plaques that are resistant to topical treatment.

3. Management of Cutaneous B-Cell Lymphomas

For primary cutaneous follicle center lymphoma (PCFCL) or primary cutaneous marginal zone lymphoma (PCMZL), SDTs including low-dose localized radiation therapy, topical or intralesional steroids, or even the watch-and-wait strategy are excellent treatment options for solitary/regional (T1-2) or even generalized skin-only (T3) disease [29]. Whereas for the aggressive variant primary cutaneous diffuse large B-cell lymphoma (PCDLBCL), the treatment rationale is similar to systemic diffuse large B-cell lymphoma, where localized radiation therapy is added to chemoimmunotherapy. However, none of the society guidelines recommend photodynamic therapy as a treatment option for CBCLs [30].

References

  1. Dobos, G.; Pohrt, A.; Ram-Wolff, C.; Lebbé, C.; Bouaziz, J.D.; Battistella, M.; Bagot, M.; de Masson, A. Epidemiology of Cutaneous T-Cell Lymphomas: A Systematic Review and Meta-Analysis of 16,953 Patients. Cancers 2020, 12, 2921.
  2. Willemze, R.; Hodak, E.; Zinzani, P.L.; Specht, L.; Ladetto, M. Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2018, 29, iv30–iv40.
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  7. Keto, J.; Hahtola, S.; Linna, M.; Väkevä, L. Mycosis fungoides and Sézary syndrome: A population-wide study on prevalence and health care use in Finland in 1998–2016. BMC Health Serv. Res. 2021, 21, 166.
  8. Olsen, E.A.; Whittaker, S.; Willemze, R.; Pinter-Brown, L.; Foss, F.; Geskin, L.; Schwartz, L.; Horwitz, S.; Guitart, J.; Zic, J.; et al. Primary cutaneous lymphoma: Recommendations for clinical trial design and staging update from the ISCL, USCLC, and EORTC. Blood 2022, 140, 419–437.
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  12. Takahara, M.; Kumai, T.; Kishibe, K.; Nagato, T.; Harabuchi, Y. Extranodal NK/T-Cell Lymphoma, Nasal Type: Genetic, Biologic, and Clinical Aspects with a Central Focus on Epstein–Barr Virus Relation. Microorganisms 2021, 9, 1381.
  13. David, K.A.; Pulitzer, M.; Guitart, J.; Martinez-Escala, M.E.; Geller, S.; Wang, Y.; Bennani, N.N.; Ristow, K.M.; Landsburg, D.J.; Winchell, N.; et al. Characteristics, Treatment Patterns, and Outcomes in Primary Cutaneous Gamma Delta T Cell Lymphoma (PCGDTCL): A Real World Multi-Institutional Analysis of a Rare Malignancy. Blood 2019, 134, 4028.
  14. Vutukuri, S.; Powell, F.; Haddad, P.A. Primary Cutaneous CD8+ Aggressive Epidermotropic Cytotoxic T-Cell Lymphoma (PCAECTCL) Descriptors and Clinicopathologic Determinants of Survival: Analysis of a Pooled Database. Blood 2022, 140, 6591.
  15. Kempf, W.; Petrella, T.; Willemze, R.; Jansen, P.; Berti, E.; Santucci, M.; Geissinger, E.; Cerroni, L.; Maubec, E.; Battistella, M.; et al. Clinical, histopathological and prognostic features of primary cutaneous acral CD8+ T-cell lymphoma and other dermal CD8+ cutaneous lymphoproliferations: Results of an EORTC Cutaneous Lymphoma Group workshop*. Br. J. Dermatol. 2022, 186, 887–897.
  16. Surmanowicz, P.; Doherty, S.; Sivanand, A.; Parvinnejad, N.; Deschenes, J.; Schneider, M.; Hardin, J.; Gniadecki, R. The Clinical Spectrum of Primary Cutaneous CD4+ Small/Medium-Sized Pleomorphic T-Cell Lymphoproliferative Disorder: An Updated Systematic Literature Review and Case Series. Dermatology 2021, 237, 618–628.
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  18. Lucioni, M.; Fraticelli, S.; Neri, G.; Feltri, M.; Ferrario, G.; Riboni, R.; Paulli, M. Primary Cutaneous B-Cell Lymphoma: An Update on Pathologic and Molecular Features. Hemato 2022, 3, 23.
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  20. Li, C.; Inagaki, H.; Kuo, T.T.; Hu, S.; Okabe, M.; Eimoto, T. Primary cutaneous marginal zone B-cell lymphoma: A molecular and clinicopathologic study of 24 asian cases. Am. J. Surg. Pathol. 2003, 27, 1061–1069.
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  24. Kaye, F.J.; Bunn, P.A., Jr.; Steinberg, S.M.; Stocker, J.L.; Ihde, D.C.; Fischmann, A.B.; Glatstein, E.J.; Schechter, G.P.; Phelps, R.M.; Foss, F.M.; et al. A randomized trial comparing combination electron-beam radiation and chemotherapy with topical therapy in the initial treatment of mycosis fungoides. N. Engl. J. Med. 1989, 321, 1784–1790.
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Subjects: Oncology
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Wei-Ting Liu
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Han-Tang Wang
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Tak-Wah Wong
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