Primary Cutaneous Lymphomas

Lead: Dr Gena Piliotis
Date of last revision: August 10, 2020

Terms of use: These guidelines are a statement of consensus of the OCC Hematology site group regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. Use of this site and any information on it is at your own risk.

1. Diagnosis and pathologic classification

   Cutaneous lymphomas are a heterogeneous group of rare disorders with variable incidence presentation and prognosis. The majority are cutaneous T cell Lymphomas with Mycoses Fungoides and Sezary Syndrome being the most common subtypes. Below is the most recent WHO-EORTC classification from 2018 with relative frequency and prognosis of the various subtypes (1)

   	Frequency %	5 yr DSS %
   CTCL
   Mycoses Fungoides (MF)	39	88
   MF Variants  Folliculotropic MF  Pagetoid Reticulosis  Granulomatous Slack Skin	5 >1 >1	75 100 100
   Sezary Syndrome	2	36
   Adult T cell Leukemia/Lymphoma	<1	NDA
   Primary Cutaneous CD30+ LPD’s  Cutaneous Anaplastic Large Cell Lymphoma  Lymphomatoid Papulosis	8 12	95 99
   Subcutaneous Panniculitis-like T-cell Lymphoma	1	87
   Extranodal NK/T cell Lymphoma Nasal Type	<1	16
   Chronic Active EBV infection	<1	NDA
   Primary Cutaneous Peripheral T-cell Lymphoma rare subtypes   Primary Cutaneous g/d T cell Lymphoma   Primary Cutaneous Aggressive Epidermotropic CD8+ cytotoxic T-cell Lymphoma (provisional) Primary Cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (provisional) Primary Cutaneous acral CD8+ T-cell lymphoma (provisional)	<1 <1 6 <1	11 31 100
   Primary Cutaneous Peripheral T-cell Lymphoma NOS	2	15
   CBCL
   Primary Cutaneous Marginal Zone Lymphoma	9	99
   Primary Cutaneous Follicular Lymphoma	12	95
   Primary Cutaneous Large B Cell Lymphoma Leg Type	4	56
   EBV+ Mucocutaneous Ulcer (provisional)	<1	100
   Intravascular B-cell Lymphoma	<1	72

Cutaneous T Cell Lymphomas

Mycoses Fungoides (MF)

Diagnosis of MF can be challenging as it can present with a variety of clinical features and may require multiple biopsies to confirm the diagnosis. Classically patients present with well-defined patches or plaques and may evolve into tumours, or total body erythroderma with varying involvement of lymph nodes and peripheral blood.

Pathologic features include band-like infiltrates in the papillary dermis of atypical small to medium sized lymphocytes with occasional large mononuclear cells. The cells typically exhibit hyperchromic indented cerebreform nuclei. Atypical cells can infiltrate the lower levels of the epidermis (epidermotropism) and occasionally form Pautrier micro-abscesses surrounding Langerhan cells. The malignant cells typically express CD3, CD4, CD45RO, lacking CD8. They typically lose expression of mature T cell antigens such as CD 7 and CD26. TCR gene rearrangements are found in most cases.

Baseline investigations

• CBC differential and blood film
• Chemistry including liver profile, renal profile, calcium profile, electrolytes and LDH
• Peripheral blood flow cytometry including CD4/CD8 ratio
• mSWAT skin score https://apps.apple.com/us/app/cutaneous-lymphoma-resource-tools/id549649890
• HTLV1 serology
• TCR gene rearrangement in peripheral blood
• Skin biopsy including TCH gene rearrangement
• Staging CT scans only needed in advanced stage patients or clinically palpable nodes
• PET scan not routinely required but can be considered to investigate for aggressive transformation

Prognosis is dependent upon clinical stage which is based on the TNM staging system:

Tumour (T)

• T1 < 10% body surface area patches and plaques
• T1a patches only / T1b patches and plaques
• T2 > 10% body surface area patches and plaques
• T2a patches only / T2b patches and plaques
• T3 one or more tumours
• T4 total body erythroderma (>80% BSA)

Nodal (N)

• N0 no clinically abnormal nodes
• N1 clinically abnormal nodes; histopathology Dutch grade 1/ NCI LN0-2
• N1a TCR clone negative / N1b TCR clone positive
• N2 clinically abnormal nodes; histopathologic Dutch grade 2/ NCI LN3
• N2a TCR clone negative / N1b TCR clone positive
• N3 clinically abnormal nodes; histopathologic Dutch grade 3,4/ NCI LN4
• Nx clinically abnormal nodes; no histologic confirmation

Metastatic (M)

• M0 no visceral involvement
• M1 visceral involvement

Blood (B)

• B0 no significant blood involvement; < 5% of lymphocytes are atypical sezary cells
• B0a TCR clone negative / B0b TCR clone positive
• B1 low blood tumour burden; > 5 % sezary cells but doesn’t meet criteria for B2
• B1a TCR clone negative / B1b TCR clone positive
• B2 high blood tumour burden; atypical sezary cells >1000/ microL or CD4/CD8 ratio >10 with TCR clone positive

Treatment is based on prognostic stage. (2,3,4)

As early stage patients have an excellent long-term prognosis treatment is based on symptom relief with skin directed therapies.

For stage 1a disease, if it is asymptomatic minimal patch stage disease it is reasonable to watch and wait. If more symptomatic we recommend first line treatment topical steroids with higher potency such as lyderm or betaderm. As more body surface area becomes involved or if topical steroids are no longer affective, next line therapy is typically Narrow band UVB 311 light therapy. Alternative light therapy with PUVA (psoralen with UVA) which penetrates deeper is typically reserved for thicker lesions as it is scarcely available and also has more skin malignancy potential. For more refractory disease light therapy can be combined with systemic retinoids or immunotherapy such as Interferon alpha with reported synergistic effects.

Systemic treatment is typically reserved for patients with more advanced stage disease with either tumours, nodal or blood involvement or have intractable skin symptoms not alleviated with skin directed therapies. First line therapy is typically a systemic retinoid often in combination with light therapy. Targretin (ÒBexarotene) which is a RXR receptor agonist has the most evidence for use (single agent activity 55% RR, combination with PUVA 85% RR) (5,6) but is not available in Canada. The retinoid that has the most similar pharmacology is alitretinoin (ÒToctino) that has pan retinoid receptor activity with target dosing 30 mg per day. Attention to headaches, endocrine, lipid and vision side effects.

Patients with more resistant disease to light and retinoid therapy can be combined with immunotherapy with low dose weekly methotrexate (up to 30 mg weekly with folic acid support 5 mg 6 days per week) and or interferon alpha (target 6 MU subcutaneous three times per week) with synergistic effects.

Radiation therapy is very effective at low doses for individual thick plaques or tumours, and in some patients can effectively delay systemic therapy.

Patients who have progressed to more advanced stage disease or have thicker resistant plaques require escalation of therapy. Selection of agent is typically based on side effect profile and drug availability with many only accessible by compassionate access programs or private insurance. HiDAC inhibitors, both romidepsin (ÒIstodax) (RR 35%) and vorinostat (ÒZolinza) (RR 30%) have demonstrated efficacy with a minority of patients obtaining complete remissions with prolonged duration; attention to gastrointestinal, renal, endocrine and cytopenia side effects (7,8). Single agent gemcitabine (ÒGemzar) (RR 60%) as well as single agent alkylators can be beneficial and may be considered in refractory or frailer older patients, however multiagent aggressive chemotherapy such as CHOP should be avoided as patient are at high risk of infection and it is of limited long term activity (9) Brentuximab (ÒAdcetris) (RR 70%), an antibody directed at CD30 can have excellent activity in patients who demonstrated CD30 expression, however is of limited availability; attention to neuropathy side effects (9,10). Pralatrexate (ÒFolotyn) (RR 58%) is also an active agent with limited current availability; attention to mucositis side effects. Mogamulizumab (ÒPoteligeo) (RR 28%) an anti CCR4 antibody also has activity but is currently not available in Canada; attention to rash, infusion reactions and immune complications. (11,12)

All the above treatments are non-curative, thus younger patients with aggressive disease should be considered for allogenic stem cell transplant if durable remissions can be obtained with OS of 59 % and DFS of 36%. (13)

Of the Mycoses Fungoides variants, folliculotropic MF is the most common. Histopathology reveals atypical MF cells infiltrating the hair follicles typically sparing the epidermis and patients typically present with thick plaques verging on tumours, often predominantly on the head and neck with associated allopecia. Given the thickness of the lesions most patients need systemic therapy early on in their disease course. Many patients can respond well to combination systemic retinoid and light therapy, however a subset of patients behave more aggressively such as tumour stage MF patients and need to be treated accordingly.

Transformation of MF to aggressive large cell lymphoma can occur, and does so more commonly in tumour stage patients. Histopathology reveals >25 large cells or sheets of large cells, CD30 expression and large cells 4x the size of a small lymphocyte. It is often difficult pathologically to differentiate between tumour stage disease and true aggressive transformation. True disseminated aggressive transformation has a dismal prognosis. Multi-agent chemotherapy or Brentuximab can be considered with the goal of high dose therapy and stem cell rescue (1,2).

Sezary Syndrome (SS)

SS is a rare leukemic type of CTCL and is typically characterized by total body pruritic erythroderma, generalized lymphadenopathy and high tumour blood burden of disease with Sezary cell count > 1000/ microL, CD4/CD8 ratio >10, CD4+/CD7- cells >=30%, or CD4+/CD26- cells >40%. (1) Early stage patients may be difficult to differentiate from other erythrodermic inflammatory disorders leading to delayed diagnosis. Histopathology from skin is often similar to MF however the perivascular infiltrates, and epidermotropism may be minimal (1,2)

Staging is similar to Mycoses Fungoides.

SS prognosis can be quite variable but is considered one of the more aggressive CTCL’s with overall poor long-term survival. Patients require initial systemic therapy, typically starting with immunotherapy with extracorporeal photophoresis with or without an immune modulatory such as interferon (interferon alpha target dose 6 MU subcutaneously three times per week) (RR 60%) (4,12). Subsequent therapeutic considerations are similar to more advance stage MF including HiDAC inhibitors, single agent traditional chemotherapy, brentuximab, pralatrexate and mogamulizomab where available. In addition alemtuzumab (ÒCampath) can have significant single agent activity (RR > 50% with CR 20%) however with significant immunosuppressive toxicity and TTF 12 months, and thus consideration of lower doses and patient selection is important. (12,14). Occasionally total electron beam skin radiation (TESB) can be considered if the blood compartment has been cleared with systemic treatment but skin is still refractory. All of the above treatments are non-curative and thus young patients should be considered for allogeneic stem cell transplant if a durable remission is obtained. (13)

Adult T cell Leukemia/Lymphoma

Covered in Mature T/NK cell lymphoma policy.

Primary Cutaneous CD30 + Lymphoproliferative Disorders

The CD30 + cutaneous LPD’s are the second most common CTCL entities and include cutaneous anaplastic large cell lymphoma (C-ALCL) and lymphomatoid papulosis which can be a spectrum of disease often co-occurring in the same patient.

C-ALCL typically presents as a single non-healing tumour, occasionally multifocal, however systemic dissemination is rare. Histopathology reveals sheets of large pleomorphic or anaplastic cells that typically express CD4 and are strongly CD30+ and have lost mature T cell markers. The malignant lymphocytes do not express ALK. Patients are managed either by local excision at diagnosis or focal radiation. If patients have recurring or multifocal disease they can often be managed with weekly low dose methotrexate, however brentuximab is the preferred agent if available (RR 70%). (9,10) Aggressive multi-agent chemotherapy such as CHOP is not indicated as it typically results in very brief responses for the degree of toxicity. (1,2,3)

Lymphomatoid papulosis is characterized by recurrent self-healing nodular lesions that typically evolve over 4-8 weeks leaving a violaceous scar. There are three classically described histopathologic subtypes which are all CD4+; Type A with scattered atypical CD30+ cells with inflammatory background; Type B resembling mycoses fungoides with epidermotropism; Type C with sheets of large anaplastic cells, indistinguishable histologically from C-ALCL. There are 3 more recently described CD 8+ variants; Type D resembling primary cutaneous aggressive epidermotropic cytotoxic t-cell lymphoma; Type E an angiocentric and angiodestructive T cell lymphoma; Type DUSP22-IRF4 rearrangement also CD8+. All entities typically have a benign self-limiting course and should be treated conservatively with skin directed therapies, or potentially low dose weekly methotrexate. (1,2)

Subcutaneous Panniculitis- like T cell lymphoma (SPTCL)

SPTCL is a rare lymphoproliferative disorder that is typically CD8 + and express alpha / beta phenotype which was distinguished from the more aggressive gamma / delta T cell lymphoma in the WHO 2008 classification. SPTCL typically presents with multiple subcutaneous plaques and nodules, and may be associated with systemic lupus in up to 20 % of cases, and may also present with initial features of hemophagocytic lymphohistiocytic features, though true systemic involvement is rare. Atypical CD8+ cytotoxic t cells expressing beta F1, granzyme B, perforin and TIA1 ring and disrupt adipocyte cell membranes in a lobular panniculitic pattern. As this is a more benign entity with an excellent long term prognosis with 5 yr overall survival of 85-91 % multi-agent chemotherapy should be restricted to highly resistant patients. Most can be managed with initial steroids followed by immunosuppressive therapy such as cyclosporine, mycofenolate or methotrexate. (15)

Extranodal NK/Tcell Lymphoma nasal type

Covered in Mature T/NK cell lymphoma policy.

Chronic active EBV infection in childhood

This is a new section and includes hydroa vacciniforme-like LPD (typically CD8+ phenotype) and hypersensitivity reactions to mosquito bites (typically NK cell phenotype) which are cutaneous manifestations of chronic EBV infection and both have a risk of progression to either EBV+ T cell or NK cell lymphoma aggressive lymphoma. (1) Lesions are typically self-limiting with aid of decreased sun exposure or topical steroids, however if patients evolve to an aggressive systemic lymphoma then they should be treated as per the mature T cell NK cell policy with the aim of allogeneic stem cell transplant in eligible patients. (16)

Primary Cutaneous g/d-T cell lymphoma

This is a more aggressive disorder typically presenting in middle age adults with deep subcutaneous lesions with ulceration. Patients typically have significant systemic symptoms and hemophagocytic lymphohistiocytic syndrome can develop in 50% of patients. Histopathology reveals lobular panniculitis similar to SPLTCL with atypical lymphocytes ringing adipose cells expressing CD56, TIA1, granzyme B and perforin however cells are typically negative for CD4 and CD8 and beta F1 and express gamma/ delta phenotype. This entity is very aggressive with high rates of systemic progression and 5 year survival estimated at 10% and thus should be treated as other aggressive T cell lymphomas and eligible patients should be considered for allogeneic stem cell transplantation if a durable remissions is obtained. (1,2)

Primary Cutaneous aggressive epidermotropic CD8+ T cell Lymphoma

Patients typically present with often acute presentations of extensive annular necrotic plaques and tumours, with notable muco-cutaneous involvement. Histopathology reveals a dense monomorphic medium sized atypical lymphoid infiltrate predominantly in the epidermis in a full thickness pagetoid pattern without significant angioinvasion. Most cases present with CD8+ disease however cases that are CD8- or co-expressing CD4 have been described. Cells typically express cytotoxic markers including granzyme B and TIA1. Some cases also express CD30+ large cells. Variable expression of alpha/ beta vs gamma delta expression has been described.

Pathologically this rare CTCL can be difficult to distinguish from type D LyP, and thus clinical correlation is essential. This is a very rare and aggressive disease without standard therapy however agents typically used in aggressive CTCL can be considered, but avoiding immunosuppressive agents such as interferon which could potentially accelerate the disease. Eligible patients should be considered for allogeneic stem cell transplantation if a durable remission is obtained. (1,2,17)

Primary Cutaneous CD4+ small/medium T cell lymphoproliferative disorder

Patients typically present with a solitary plaque or tumour with a predilection to the face or trunk. Histopathology reveals dense nodular to diffuse dermal infiltrates of predominantly CD4 + small to medium sized cells with occasionally admixed large pleomorphic cells, with a background mixture of inflammatory cells including CD8+ t cells, histiocytes, plasma cells and multinucleated giant cells. Patients have a very indolent course and systemic progression is not described thus approach to staging and treatment should be very conservative including surgical excision, intralesional steroid injection or local radiation. This entity has recently been renamed a “lymphoproliferative disorder” as it is questionable if it represents a true malignancy. (1)

Primary Cutaneous acral CD8+ T cell lymphoma NOS

This is a newly described entity with typically indolent behavior of slowly progressive nodules in acral sites. Histopathology reveals diffuse proliferation of medium sized cells in the dermis without epidermal infiltration which aids in differentiating from more aggressive CD8 positive CTCL. Malignant cells are CD3+ CD4- CD8+ CD30- T1A-1 + negative for granzyme B and perforin, with variable loss of mature T cell markers. Long term prognosis is excellent and systemic progression is very rare thus treatment should be conservative with either local excision intralesional steroids or radiation. (1)

Cutaneous B Cell Lymphomas

Primary Cutaneous Marginal Zone Lymphoma (PCMZL)

PCMZL predominantly affects younger patients who present with typically multifocal plaques or nodules. Histopathology typically reveals an inflammatory infiltrate with predominantly reactive T cells, monotypic plasma cells, and small proportion of malignant B cells that express class- switched immunoglobulins. These patients have an excellent long-term prognosis with 5yr disease specific survival of nearly 100%, rarely disseminating to extracutaneous sites, and transformation is not described. Therefore, they should be treated conservatively with local treatments for symptomatic lesions including topical or intralesional steroids or focal low dose radiation. Occasionally cases can present with more nodular lesions and more diffuse malignant infiltrates that express IgM and CXCR3 and should be monitored more closely for extracutaneous spread. (1)

Primary Cutaneous Follicle Centre Lymphoma (PCFCL)

PCFCL typically present with single or clusters of nodules, often in the head or trunk with histopathology revealing a dense infiltrate of large centrocytes that can have a nodular or diffuse pattern that typically express BCL6, rarely CD10 and do not express BCL2 and usually have a reactive T cell infiltrate. Patients have an excellent long term prognosis with 5 yr disease specific survival of 95%, and while they may have recurring nodules they rarely have systemic dissemination and thus should be treated conservatively with local excision, steroid injection or radiation. Occasionally it is a challenge to differentiate PCFCL from more aggressive cutaneous B cell lymphomas such as primary cutaneous DLBCL or primary cutaneous DLBCL leg type. If malignant lesions express a high Ki67. BCL2, strong CD10, MUM1, FOXP1, or IgM alternative diagnose such as cutaneous spread of systemic follicular lymphoma, PCDLBCL, or PCDLBCL leg type should be considered. (1,18)

Primary Cutaneous Diffuse Large B cell Lymphoma Leg type

See DLBCL policy.

Intravascular Large B cell Lymphoma

See DLBCL policy.

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