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Guidelines

Guidelines Summary

Guidelines contributors: Priyank P Patel, MD , Hematology/Oncology Fellow, Roswell Park Cancer Institute, University at Buffalo; Francisco J Hernandez-Ilizaliturri, MD; Chief, Lymphoma and Myeloma Section; Professor of Medicine, Department of Medical Oncology; Director of The Lymphoma Translational Research Program; Associate Professor of Immunology, Roswell Park Cancer Institute

NHL Classification Schemas

The three most commonly used classification schemas for non-Hodgkin lymphoma (NHL) are as follows:

National Cancer Institute’s Working Formulation (IWF)^[128]
Revised European-American Classification of Lymphoid Neoplasms (REAL)^[129]
World Health Organization (WHO) classification^[130]

The Working Formulation, originally proposed in 1982, classified and grouped lymphomas by morphology and clinical behavior (ie, low, intermediate, or high grade) with 10 subgroups labeled A to J.^[128]In 1994, the Revised European-American Lymphoma (REAL) classification attempted to apply immunophenotypic and genetic features in identifying distinct clinicopathologic NHL entities.^[129]

The World Health Organization (WHO) classification, first introduced in 2001 and updated in 2008, further elaborates upon the REAL approach. This classification divides NHL into two groups: those of B-cell origin and those of T-cell/natural killer (NK)–cell origin.^[130]

Although considered obsolete, the National Cancer Institute’s Working Formulation (IWF) classification is still used, mainly for historical data comparisons.^[128]

The World Health Organization–European Organization for Research and Treatment of Cancer (WHO-EORTC) classification of cutaneous T-cell lymphoma (CTCL) is divided into CTCLs with indolent clinical behavior and those with aggressive subtypes. CTCLs with indolent clinical behavior include the following^{[2, 3]}:

Mycosis fungoides
Mycosis fungoides variants and subtypes (eg, folliculotropic mycosis fungoides, pagetoid reticulosis, granulomatous slack skin)
Primary cutaneous CD30+ lymphoproliferative disorder (eg, primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis)
Subcutaneous panniculitis-like T-cell lymphoma (provisional)
Primary cutaneous CD4 ⁺ small/medium T-cell lymphoproliferative disorder (provisional)

Mycosis Fungoides/Sezary Syndrome

In addition to the guidelines from the National Comprehensive Cancer Network (NCCN)^[98], the European Organization for Research and Treatment of Cancer (EORTC) released consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome (MF/SS) in 2017.^[131] In 2018, the European Society for Medical Oncology (ESMO) updated its guidelines for primary cutaneous lymphoma.^[132]

Diagnosis

The NCCN considers the following studies essential for establishing a diagnosis of MF/SS^[98]:

Biopsy of suspicious skin sites (multiple biopsies may be necessary to capture the pathologic variability of disease at diagnosis)
Dermatopathology review of slides (including evaluation for presence of transformation or areas of folliculotropism)
Immunohistochemistry (IHC) panel of skin biopsy: CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30; an additional panel of CD25, CD56, TIA1, granzyme B, ßF1, TCR-CγM1 may be useful
Molecular analysis to detect clonal T-cell antigen receptor (TCR) gene rearrangements or other assessment of clonality

Workup

The NCCN considers the following essential for the workup of MF/SS^[98]:

Complete skin examination - Assessment of percentage of body surface area affected and type of skin lesion (ie, patch/plaque, tumor, erythroderma)
Palpation of peripheral lymph node regions
Palpation for organomegaly/masses
Complete blood cell count with differential and determination of absolute lymphocyte count
Sézary flow cytometric studies to assess and quantitate an expanded T-cell population with aberrant phenotype (optional for T1 disease)
Clonal TCR gene rearrangement in peripheral blood lymphocytes if blood involvement suspected
Comprehensive metabolic panel
Lactate dehydrogenase (LDH)
Chest/abdomen/pelvis CT with contrast or integrated whole body PET/CT for T3 or T4 (arms/legs included when disease assessment of entire body needed)

Staging

In 2007, the ISCL/EORTC released a revised tumor-node-metastasis-blood (TNMB) classification of MF/SS based on particular skin findings and extracutaneous disease.^[7] See Table 4, below.

Table 4. International Society for Cutaneous Lymphoma/European Organization for Research and Treatment of Cancer tumor-node-metastasis-blood revised classification for mycosis fungoides and Sezary syndrome (Open Table in a new window)

Skin	Involvement	Node	Involvement	Viscera	Involvement
T1	Patchy or plaquelike skin disease involving ≤10% of the skin surface area	N0	No abnormal lymph nodes	M0	No visceral organ involvement
T2	Patchy or plaquelike skin disease involving ≥10% of the skin surface area	N1	Histopathology Dutch Gr 1 or NCI LN 0-2	M1	Visceral organ involvement
T3	Tumors are present ≥1 cm in diameter	N2	Histopathology Dutch Gr 2 or NCI LN 3	MX	Abnormal visceral site; no histologic confirmation
T4	Erythroderma ≥80% of body area	N3	Histopathology Dutch Gr 3-4 or NCI LN 4	Blood	Involvement
		Nx	Abnormal lymph nodes; no histologic confirmation	B0	≤5% of peripheral blood lymphocytes are Sezary cells
				B1	>5% of peripheral blood lymphocytes are Sezary cells but do met B2 criteria
				B2	≥1000/mcL Sezary cells or CD4/CD8 ≥10 or ≥40% CD4+/CD7- or ≥30% CD4+/CD26- cells

The ISCL/EORTC system was further modified to update clinical staging classifications.^[7] See Table 5, below.

Table 5. Staging classifications for mycosis fungoides and Sezary syndrome (Open Table in a new window)

Clinical Stage	5-Year Survival ^[131]	TNM (B) Stage
IA	98%	T₁N₀M₀B₀	T₁N₀M₀B₁
IB	89%	T₂N₀M₀B₀	T₂N₀M₀B₁
IIA	89%	T₁N₁M₀B₀	T₁N₁M₀B₁	T₁N₂M₀B₀	T₁N₂M₀B₁
IIA		T₂N₁M₀B₀	T₂N₁M₀B₁	T₂N₂M₀B₀	T₂N₂M₀B₁
IIB	56%	T₃N₀M₀B₀	T₃N₀M₀B₁	T₃N₁M₀B₀	T₃N₁M₀B₁
IIB		T₃N₂M₀B₀	T₃N₂M₀B₁
IIIA	54%	T₄N₀M₀B₀	T₄N₁M₀B₀	T₄N₂M₀B₀
IIIB	48%	T₄N₀M₀B₁	T₄N₁M₀B₁	T₄N₂M₀B₁
IVA1	41%	T₁N₀M₀B₂	T₂N₀M₀B₂	T₃N₀M₀B₂	T₄N₀M₀B₂
		T₁N₁M₀B₂	T₂N₁M₀B₂	T₃N₁M₀B₂	T₄N₁M₀B₂
		T₁N₂M₀B₂	T₂N₂M₀B₂	T₃N₂M₀B₂	T₄N₂M₀B₂
IVA2	23%	T₁N₃M₀B₀	T₂N₃M₀B₀	T₃N₃M₀B₀	T₄N₃M₀B₀
		T₁N₃M₀B₁	T₂N₃M₀B₁	T₃N₃M₀B₁	T₄N₃M₀B₁
		T₁N₃M₀B₂	T₂N₃M₀B₂	T₃N₃M₀B₂	T₄N₃M₀B₂
IVB	18%	T₁N₀M₁B₀	T₂N₀M₁B₀	T₃N₀M₁B₀	T₄N₀M₁B₀
		T₁N₁M₁B₁	T₂N₁M₁B₁	T₃N₁M₁B₁	T₄N₁M₁B₁
		T₁N₂M₁B₂	T₂N₂M₁B₂	T₃N₂M₁B₂	T₄N₂M₁B₂
		T₁N₃M₁B₃	T₂N₃M₁B₃	T₃N₃M₁B₃	T₄N₃M₁B₃

Treatment

The NCCN recommends that patients be treated at specialized centers with expertise in the management of MF/SS. Unlike other non-Hodgkin lymphoma subtypes, MF/SS criteria have not correlated with prognosis, and treatment decisions are made on a clinical basis.^[98]

All three guidelines recommend treatment selection based on clinical stage.^{[98, 131, 132]}

Mycosis fungoides

In general, topical skin-directed therapies (SDTs) are recommended for localized disease (stages IA, IB and IIA), with systemic or combination systemic and topical therapies beginning with stage IIB. Systemic therapies may also be considered in patients with early-stage disease that does not respond to topical treatments.^{[98, 131, 132]}

Both the ESMO and EORTC guidelines include an expectant 'watch and wait' policy as a recommended management option for patients with stage IA disease.^{[131, 132]}EORTC guidelines note that in patients with stage 1A disease, only an estimated 10% of cases progress within 10 years, and life expectancy does not appear to be affected.^[131]

Localized therapies endorsed by the guidelines include the following^{[98, 131, 132]}

Psoralens + ultraviolet A (PUVA)—For thick plaques
Narrow-band ultraviolet B (UVB)—For patch or thin plaques
Topical corticosteroids
Localized radiation therapy (12-36 Gy)
Topical mechlorethamine (nitrogen mustard)
Topical retinoids (ie, bexarotene, tazarotene)

The guidelines diverge on the use of total skin electron beam therapy (TSEBT). EORTC recommends a standard treatment course consisting of a total dose of 30–36 Gy applied over a period of 8–10 weeks, particularly in T2 and T3 disease. While acknowledging that toxicity is dose-related, the guidelines find lack of evidence that low-dose regimens (in the range of 10–12 Gy) with shorter treatment times (2–3 weeks) will be equally effective in inducing remissions.^[131]

The ESMO guidelines prefer the lower-dose TSEBT regimen (10–12 Gy) noting the shorter duration of treatment, fewer adverse effects, and the advantage of allowing multiple retreatments.^[132] NCCN recommends TSEBT (12–36 Gy) for generalized skin involvement followed by systemic therapies such as interferon or bexarotene to maintain response.^[98]

The NCCN divides recommended systemic therapies into two categories, A and B. Category A regimens are those that can often be tolerated for longer periods of time, and are often given following initial radiation therapy; they can be considered for a patient with stage IIB disease who has limited tumor lesions, or stage IIB generalized tumor-stage disease. Category B regimens, which can have more significant cumulative toxicity, are more effective for stage IIB generalized tumor disease, stage III erythrodermic disease, or stage IV disease. Preferred category A agents include the following^[98]:

Retinoids: bexarotene
Interferons: IFN alfa-2bm or IFN gamma-1b
Histone deacetylase (HDAC)-inhibitors: vorinostat, romidepsin—not approved in Europe
Extracorporeal photopheresis (ECP)
Chemotherapy: methotrexate (≤50 mg/week)
Targeted immunotherapies: brentuximab vedotin, mogamulizumab

NCCN-recommended second-line treatments for localized disease (stage I and IIA) include category A systemic therapies with or without localized therapies, or the following combination therapies^[98]:

PUVA/UVA with ECP
PUVA/UVA with interferons
PUVA/UVA with retinoid
TSEBT with ECP
ECP with interferon
ECP with retinoid
ECP with retinoid and interferon
Retinoid with interferon

The EORTC recommends retinoids, IFN-alpha, TSEBT or low-dose methotrexate for second-line treatment of localized disease.^[131] ESMO also recommends retinoids, IFN-alpha, and TSEBT along with the following combination therapies^[132]:

Localized skin-directed therapies (SDTs) with retinoids
SDTs with IFN-alpha
Retinoids and IFN-alpha

NCCN category B systemic agents include:

Targeted immunotherapies: brentuximab vedotin
Chemotherapies: gemicitabine, liposomal doxorubicin, pralatrexate

NCCN recommendations for the treatment of stage IIB disease with limited lesions include localized radiation therapy with or without other localized therapies and category A systemic therapies with or without localized radiation therapy. For stage IIB generalized lesions, the recommendation include the following^[98]:

TSEBT
Category A systemic therapy with or without localized therapies
Category B systemic therapy with or without localized therapies
Combination therapy with or without localized therapies

EORTC recommends retinoids, IFN-alpha, TSEBT, gemcitabine, pegylated liposomal doxorubinine, low-dose methotrexate and localized radiation therapy for the first-line treatment of stage IIB. For second-line treatment, EORTC recommends combination chemotherapy and allogeneic hematopoietic cell transplantation (HCT).^[131]

ESMO recommends a combination of SDT with local radiation therapy, retinoids or IFN-alpha, or TSEBT for first-line treatment of stage IIB. For second-line treatment, gemcitabine, liposomal doxorubinine, brentuximab vedotin, combination chemotherapy, and allogeneic HCT are recommended.^[132]

Sezary syndrome and erythrodermic mycosis fungoides

The NCCN's preferred regimens for treatment of low- to intermediate-burden Sézary syndrome or stage III advanced (erythrodermic) mycosis fungoides include the following^[98]:

Combination therapies (listed above)
Category A systemic therapy with or without localized therapies

Other recommended treatments include the following^[98]:

Category B systemic therapy with or without localized therapies
Alemtuzumab
Pembrolizumab

Preferred regimens for treatment of high-burden Sézary syndrome or stage III advanced (erythrodermic) mycosis fungoides include^[98]:

Combination therapies (listed above)
Mogamulizumab with or without localized therapies
Romidepsin with or without localized therapies

Other recommended treatments include the following^[98]:

Category A systemic therapies not included in preferred regimens above
Category B systemic therapy
Alemtuzumab
Pembrolizumab

EORTC and ESMO provide separate treatment recommendations for Sézary syndrome and erythrodermic mycosis fungoides (stage III) disease. The EORTC and ESMO recommendation are in agreement for Sézary syndrome and include the following first-line treatments^[131]:

Chlorambucil with prednisone
Systemic therapies (retinoids or IFN-alpha) in combination with ECP or PUVA
Low dose methotrexate

For second-line Sézary syndrome treatments, EORTC and ESMO recommend the following^{[131, 132]}:

Chemotherapy (gemcitabine, pegylated liposomal doxorubicine, CHOP and CHOP-like regimens)
Alemtuzumab
Allogeneic HCT

For erythrodermic MF (stage III) disease, the first-line EORTC recommended treatments include^[131]:

Retinoids
IFN-alpha
ECP
Low dose methatrexate
TSEB

ESMO recommends the following first-line treatments for erythrodermic mycosis fungoides (stage III) disease^[132]:

SDT with retinoids
SDT with IFN-alpha
ECT with or without IFN-alpha with or without retinoids
Low dose methatrexate

For second-line erythrodermic MF (stage III) disease treatment, EORTC recommends the following^[131]:

Gemcitabine
Pegylated liposomal doxorubicine
Allogeneic HCT

ESMO recommends TSEBT for second-line treatment of erythrodermic mycosis fungoides (stage III) disease.^[132]

NCCN recommended treatments for erythrodermic mycosis fungoides (stage IV) includes^[98]:

Category B systemic therapy
Allogeneic hematopoietic cell transplantation (HCT)

NCCN also recommends the following, with or without radiation therapy^[98]:

Brentuximab vedotin
Gemcitabine
Liposomal doxorubicin
Pralatrexate
Romidepsin

For erythrodermic mycosis fungoides (stage IV), EORTC recommends the following treatments^[131]:

Chemotherapy (gemcitabine, pegylated liposomal doxorubicine, CHOP and CHOP-like regimens)
Localized radiotherapy or TSEBT
Alemtuzumab
Allogeneic HCT

ESMO recommends gemcitabine, lipsomal doxorubicin or brentuximab vedotin for first-line treatment of erythrodermic mycosis fungoides (stage IV) and combination chemotherapy or allogeneic HCT for second-line treatment.^[132]

Participation in a clinical trial as a treatment option for all patients with disease progression or refractory Sézary syndrome or advanced-stage mycosis fungoides is recommended by both the NCCN and EOTRTC. ^{[98, 131]}

Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders

In 2011, the the European Organization for Research and Treatment of Cancer (EORTC), the International Society for Cutaneous Lymphoma (ISCL), and the US Cutaneous Lymphoma Consortium (USCLC) published joint consensus recommendations for the management of primary cutaneous CD30+ T-Cell lymphoproliferative disorders (CD30+LPDs).^[133]

Classification

Under the WHO-EORTC classification system for cutaneous lymphomas, primary CD30+LPDs represent a wide spectrum of disease, with lymphomatoid papulosis (LyP) at the benign end of the spectrum and primary cutaneous anaplastic large cell (PC-ALCL) lymphoma at the malignant end. Borderline lesions lie somewhere in between, with overlapping clinical and histopathologic features.^[2]

Diagnosis

The National Comprehensive Cancer Network (NCCN) recommendations to establish a diagnosis of CD30+LPDs include the following^[98]:

Differentiation of LyP and PC-ALCL from other forms of cutaneous T-cell lymphoma and secondary cutaneous involvement by nodal Hodgkin lymphoma or systemic ALCL requires careful clinicopathologic correlation
Mycosis fungoides can be comorbid
Clinical features include solitary or localized nodules or tumors (often ulcerated); multifocal lesions occur in about 20% of cases; extracutaneous disease occurs in about 10% of cases, usually involving regional lymph nodes
Immunohistochemistry (IHC) panel of skin biopsy specimen: CD3, CD4,CD8, CD20, CD30, CD56, βF1, ALK1
Expanded IHC: CD2, CD5, CD7, CD25,TIA1, granzyme B, perfornin, GM1, EBER-ISH
Histologically characterized by diffuse, cohesive sheets of large CD30-positive (in >75%) cells with anaplastic, pleomorphic, or immunoblastic appearance
Molecular analysis of skin biopsy: TCR gene rearrangements
Excisional or incisional biopsy of suspicious lymph nodes (in absence of definitive skin diagnosis)
Assessment of HTLV-1 serology in at-risk populations to identify CD30+ adult T-cell leukemia/lymphoma (ATLL)
Bone marrow biopsy only in cases of multifocal tumors, unexplained hematologic results, or presence of where extracutaneous disease

Staging

NCCN, ESMO and EORTC, ISCL, and USCLC guidelines recommend staging according to the 2007 tumor-node-metastasis (TNM) ISCL/EORTC staging of cutaneous lymphomas other than mycosis fungoides/Sezary syndrome.^{[26, 133, 98, 132]}

Treatment

NCCN primary treatment recommendations for PC-ALCL, are as follows^{[98, 133]}:

For solitary or grouped lesions, surgical excision or radiation therapy for first-line treatment
Relapses are equally frequent after both treatments; if confined to the skin, treatment can be repeated
For multifocal lesions, brentuximab vedotin is the preferred treatment. Other recommended regimens with or without SDT include low dose methotrexate, retinoids, pralatrexate and observation, if asymptomatic.
Interferon is an NCCN category 3 recommendation.

For PC-ALCL with regional node involvement (N1), brentuximab vedotin with or without ISRT is the preferred regimen. Other recommended treatmens include^[98]:

Brentuximab vedotin with CHP
Methotrexate with or without ISRT
Pralatrexate with or without ISRT
CHOP or CHOEP with or without ISRT, in select cases

NICE

After reviewing the clinical- and cost-effectiveness evidence for brentuximab vedotin for treating relapsed or refractory CD30-positive (CD30+) cutaneous T-cell lymphoma (CTCL), the National Institute for Health and Care Excellence (NICE) recommended brentuximab vedotin as a second-line treatment for treating CD30+ CTCL.^[134]

Medication

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Media Gallery

Patch-stage mycosis fungoides.
Plaque-stage mycosis fungoides.
A 40-year-old woman complained of a recurrent skin rash, which she described as "bug bites." Skin biopsy results demonstrated an atypical lymphoid infiltrate that was CD30 positive. The clinical picture and pathologic findings were consistent with lymphomatoid papulosis. This condition has a benign natural history, despite clonal gene rearrangement in some cases. Skin eruptions occur in self-limited crops, which do not require treatment.
Erythroderma of Sézary syndrome.
Nail changes of Sézary syndrome.
Electron micrograph of a Sézary cell.
Tumor-stage mycosis fungoides.
Tumor-stage cutaneous T-cell lymphoma.
Patch-stage cutaneous T-cell lymphoma. Courtesy of Jeffrey Meffert, MD.
Plaque-stage parapsoriasis.
Patch-stage mycosis fungoides progressing to plaque stage, with cutaneous cigarette-paper appearance evident.
Partially confluent, erythematous plaques in advancing mycosis fungoides.
Close-up view of advancing plaque-stage mycosis fungoides with partially confluent, erythematous plaques.
Early patch-stage cutaneous T-cell lymphoma.
Hypopigmented cutaneous T-cell lymphoma. Courtesy of Jeffrey Meffert, MD.
Hypopigmented cutaneous T-cell lymphoma. Courtesy of Jeffrey Meffert, MD.
Nodular mycosis fungoides.
Middle-aged woman with mycosis fungoides showing ulceration and marked depigmentation of advanced disease.
Middle-aged woman with mycosis fungoides showing ulceration and marked depigmentation of advanced disease.
Middle-aged woman with mycosis fungoides showing ulceration and marked depigmentation of advanced disease.
Middle-aged woman with mycosis fungoides showing ulceration and marked depigmentation of advanced disease.
Mycosis fungoides with large, atypical T lymphocytes in the epidermis and dermis.
Mycosis fungoides with an epidermal nest of large, atypical T cells displaying bizarre, convoluted nuclei surrounded by a clear space (Pautrier microabscess).
A 42-year-old woman who had moved to the United States from Peru several year ago presented with an ulcerative lesion on her face near her nose, and destruction of her hard palate. Tissue biopsy revealed NK/T-cell lymphoma. Image courtesy of Jason Kolfenbach, MD, and Kevin Deane, MD, Division of Rheumatology, University of Colorado Denver School of Medicine.

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Table 1. WHO-EORTC Classification of Cutaneous T-Cell Lymphoma

WHO-EORTC Classification	Frequency (%)	5-Year Survival Rate (%)
Indolent Clinical Behavior
Mycosis fungoides	39	88
Mycosis fungoides variants and subtypes
Folliculotropic mycosis fungoides	5	75
Pagetoid reticulosis	< 1	100
Granulomatous slack skin	< 1	100
Primary cutaneous CD30⁺ lymphoproliferative disorder
Primary cutaneous anaplastic large cell lymphoma	8	95
Lymphomatoid papulosis	12	100
Subcutaneous panniculitis-like T-cell lymphoma (provisional)	1	82
Primary cutaneous CD4⁺ small/medium-sized pleomorphic T-cell lymphoma (provisional)	2	75
Aggressive Clinical Behavior
Sézary syndrome	2%	36%
Adult T-cell leukemia/lymphoma	< 1	NDA
Extranodal NK/T-cell lymphoma, nasal type	< 1	16
Primary cutaneous peripheral T-cell lymphoma, unspecified	2	15
Primary cutaneous peripheral T-cell lymphoma, rare subtypes
Primary cutaneous acral CD8⁺ T-cell lymphoma (provisional)	< 1	100
Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (provisional)	< 1	31
Primary cutaneous gamma/delta-positive T-cell lymphoma	< 1	11
Source: Adapted from Willemze et al. Blood. 2019;133(16):1703-14.^[3] EORTC = European Organization of Research and Treatment of Cancer; NDA = no data available; NK = natural killer; WHO = World Health Organization.

Table 2. Cluster Designations

CD Type	Representative Cells	Also Known As
CD2	T, NK	Sheep RBC
CD3	T
CD4	T subset	Helper
CD5	T
CD7	T, NK	Prothymocyte
CD8	T subset, NK	Suppressor
CD25	Active T, B, M	IL-2R (Tac)
CD30	Active T, B	Ki-1
CD45	T subset	CLA
CD56	NK	NCAM
B = B cell; CD = cluster designation; CLA = common leukocyte antigen; IL-2R = interleukin-2 receptor; M = M cell; NCAM = neural cell adhesion molecule; NK = natural killer; RBC = red blood cell; T = T cell; Tac = Tac antigen.

Table 3. Staging of Cutaneous T-Cell Lymphoma

Stage	Skin Lesions			Lymphadenopathy	Erythroderma	Histology
Stage	Patches/ plaques (less than10%)	Plaques/ plaques (10% or more)	Tumors	Lymphadenopathy	Erythroderma	Lymph Nodes	Viscera
IA	+	-	-	-	-	-	-
IB	+ or -	+	-	-	-	-	-
IIA	+ or -	+ or -	+ or -	+	-	-	-
IIB	+ or -	+ or -	+	+ or -	-	-	-
III	+ or -	+ or -	+ or -	+ or -	+	-	-
IVA	+ or -	+ or -	+ or -	+ or -	+ or -	+	-
IVB	+ or -	+ or -	+ or -	+ or -	+ or -	+ or -	+

Table 4. TNMB Staging of Cutaneous T-Cell Lymphoma

Stage Class	Stage	Definition
T (tumor)	T₁	Patches/plaques involving less than 10% of body surface
	T₂	Patches/plaques involving 10% or more of body surface
	T₃	Tumor(s) present on skin
	T₄	Erythroderma
N (nodes)	N₀	No enlarged lymph node present
	N₁	Enlarged lymph nodes, histologically uninvolved
	N₂	No enlarged lymph node; 1 or more nodes histologically involved*
	N₃	Enlarged lymph nodes, histologically involved
M (metastasis to viscera)	M₀	No visceral lesion present
M (metastasis to viscera)	M₁	Visceral involvement
B (blood involvement)	B₀	Circulating atypical lymphocytes (Sézary cells) less than 5% of lymphocytes
B (blood involvement)	B₁	Circulating atypical lymphocytes 5% or more of lymphocytes (Sézary syndrome)
*Uncommon finding, usually not considered/investigated.

Table 5. Comparison of Staging Systems for CTCL

Clinical Stage	TNM (B) Stage
IA	T₁ N₀ M₀
IIB	T₂ N₀ M₀
IIA	T₁ N₁ M₀	T₂ N₁ M₀
IIB	T₃ N₀ M₀	T₃ N₁ M₀
III	T₄ N₀ M₀	T₄ N₁ M₀
IVA	T₁ N₂ M₀	T₂ N₂ M₀	T₃ N₂ M₀	T₄ N₂ M₀
IVA	T₁ N₃ M₀	T₂ N₃ M₀	T₃ N₃ M₀	T₄ N₃ M₀
IVB	T₁ N₀ M₁	T₂ N₀ M₁	T₃ N₀ M₁	T₄ N₀ M₁
	T₁ N₁ M₁	T₂ N₁ M₁	T₃ N₁ M₁	T₄ N₁ M₁
	T₁ N₂ M₁	T₂ N₂ M₁	T₃ N₂ M₁	T₄ N₂ M₁
	T₁ N₃ M₁	T₂ N₃ M₁	T₃ N₃ M₁	T₄ N₃ M₁

Skin	Involvement	Node	Involvement	Viscera	Involvement
T1	Patchy or plaquelike skin disease involving ≤10% of the skin surface area	N0	No abnormal lymph nodes	M0	No visceral organ involvement
T2	Patchy or plaquelike skin disease involving ≥10% of the skin surface area	N1	Histopathology Dutch Gr 1 or NCI LN 0-2	M1	Visceral organ involvement
T3	Tumors are present ≥1 cm in diameter	N2	Histopathology Dutch Gr 2 or NCI LN 3	MX	Abnormal visceral site; no histologic confirmation
T4	Erythroderma ≥80% of body area	N3	Histopathology Dutch Gr 3-4 or NCI LN 4	Blood	Involvement
		Nx	Abnormal lymph nodes; no histologic confirmation	B0	≤5% of peripheral blood lymphocytes are Sezary cells
				B1	>5% of peripheral blood lymphocytes are Sezary cells but do met B2 criteria
				B2	≥1000/mcL Sezary cells or CD4/CD8 ≥10 or ≥40% CD4+/CD7- or ≥30% CD4+/CD26- cells

Table 5. Staging classifications for mycosis fungoides and Sezary syndrome

Clinical Stage	5-Year Survival ^[131]	TNM (B) Stage
IA	98%	T₁N₀M₀B₀	T₁N₀M₀B₁
IB	89%	T₂N₀M₀B₀	T₂N₀M₀B₁
IIA	89%	T₁N₁M₀B₀	T₁N₁M₀B₁	T₁N₂M₀B₀	T₁N₂M₀B₁
IIA		T₂N₁M₀B₀	T₂N₁M₀B₁	T₂N₂M₀B₀	T₂N₂M₀B₁
IIB	56%	T₃N₀M₀B₀	T₃N₀M₀B₁	T₃N₁M₀B₀	T₃N₁M₀B₁
IIB		T₃N₂M₀B₀	T₃N₂M₀B₁
IIIA	54%	T₄N₀M₀B₀	T₄N₁M₀B₀	T₄N₂M₀B₀
IIIB	48%	T₄N₀M₀B₁	T₄N₁M₀B₁	T₄N₂M₀B₁
IVA1	41%	T₁N₀M₀B₂	T₂N₀M₀B₂	T₃N₀M₀B₂	T₄N₀M₀B₂
		T₁N₁M₀B₂	T₂N₁M₀B₂	T₃N₁M₀B₂	T₄N₁M₀B₂
		T₁N₂M₀B₂	T₂N₂M₀B₂	T₃N₂M₀B₂	T₄N₂M₀B₂
IVA2	23%	T₁N₃M₀B₀	T₂N₃M₀B₀	T₃N₃M₀B₀	T₄N₃M₀B₀
		T₁N₃M₀B₁	T₂N₃M₀B₁	T₃N₃M₀B₁	T₄N₃M₀B₁
		T₁N₃M₀B₂	T₂N₃M₀B₂	T₃N₃M₀B₂	T₄N₃M₀B₂
IVB	18%	T₁N₀M₁B₀	T₂N₀M₁B₀	T₃N₀M₁B₀	T₄N₀M₁B₀
		T₁N₁M₁B₁	T₂N₁M₁B₁	T₃N₁M₁B₁	T₄N₁M₁B₁
		T₁N₂M₁B₂	T₂N₂M₁B₂	T₃N₂M₁B₂	T₄N₂M₁B₂
		T₁N₃M₁B₃	T₂N₃M₁B₃	T₃N₃M₁B₃	T₄N₃M₁B₃

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Author

Lauren C Pinter-Brown, MD Director of Lymphoma Program, Clinical Professor of Medicine, Department of Internal Medicine, Division of Hematology and Oncology, University of California, Los Angeles, Medical Center

Lauren C Pinter-Brown, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society of Hematology, SWOG

Disclosure: Nothing to disclose.

Coauthor(s)

Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, New York Academy of Medicine, Royal College of Physicians of Edinburgh, Sigma Xi, The Scientific Research Honor Society

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Francisco J Hernandez-Ilizaliturri, MD Professor of Medicine, Department of Medical Oncology, Associate Professor of Immunology, Department of Immunology, Chief, Lymphoma and Myeloma Section, Director, The Lymphoma Translational Research Program, Roswell Park Cancer Institute, University of Buffalo State University of New York School of Medicine and Biomedical Sciences

Francisco J Hernandez-Ilizaliturri, MD is a member of the following medical societies: American Association for Cancer Research, American Society of Hematology

Disclosure: Nothing to disclose.

Priyank P Patel, MD Hematology/Oncology Fellow, Roswell Park Cancer Institute, University

Priyank P Patel, MD is a member of the following medical societies: American Society of Hematology, American Society of Clinical Oncology, European Society for Medical Oncology, American College of Physicians

Disclosure: Nothing to disclose.

Acknowledgements

Günter Burg, MD Professor and Chairman Emeritus, Department of Dermatology, University of Zürich School of Medicine; Delegate of The Foundation for Modern Teaching and Learning in Medicine Faculty of Medicine, University of Zürich, Switzerland

Günter Burg, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, International Society for Dermatologic Surgery, North American Clinical Dermatologic Society, and Pacific Dermatologic Association

Disclosure: Nothing to disclose

David F Butler, MD Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa