Mycosis Fungoides
BACKGROUND
What subtypes of disorders are encompassed in the general term cutaneous T-cell lymphoma (CTCL)?
Subtypes of CTCL:
1. Mycosis fungoides (MF)
2. Sézary syndrome
3. Adult T-cell leukemia/lymphoma
4. Primary cutaneous CD30 anaplastic lymphoma
The following are sometimes considered under the umbrella term of CTCL:
5. Lymphomatoid papulosis
6. Pagetoid reticulosis
7. Follicular mucinosis
What is MF?
A low-grade non-Hodgkin’s lymphoma caused by skin-homing CD4+ T cells that form cutaneous lesions.
MF comprises what % of all lymphomas? What % of all CTCL?
MF comprises ~2% of all lymphomas but is the most common type of primary cutaneous lymphoma. MF comprises 50% of all CTCLs.
What is the median age at presentation in MF?
The median age at presentation of MF is 55–60 yrs.
Is there a race and sex predilection for MF?
Yes. Black race (2:1) and male gender (2.2:1) are known risk factors for having MF.
What do MF pts have an increased susceptibility to?
MF pts have an increased susceptibility to infections and other malignancies, possibly due to an impaired immune system.
What is the histopathologic hallmark of MF?
The histopathologic hallmark of MF is the Pautrier abscess (sometimes called microabscess), which refers to the clustering of CD4 T cells around an antigen-presenting dendritic cell in the epidermis. Although this is a classic MF finding, it is present in only 20% of early-stage Dz.
What molecular study can be done to Dx early MF?
PCR for the T-cell receptor has been effective at identifying a malignant T-cell clone population in those who go on to develop MF.
What is the most common presentation of early MF?
The most common presentation of early MF is the presence of erythematous, scaly, and pruritic macules on an area of skin not commonly exposed to the sun.
What are the clinical presentations/phases of MF?
Clinical presentations/phases of MF:
1. Premycotic (erythematous macule) phase
2. Patch phase
3. Plaque phase
4. Tumor phase
5. Erythroderma (>80% surface area involvement)
When MF progresses from patch to plaque, what is seen under the microscope?
When MF progresses from patch to plaque, it is apparent that the lymphoid clones begin to invade deeper into the dermis and the Pautrier abscesses are seen.
What % of MF pts present with LN involvement?
~15% of MF pts have LN involvement at the time of diagnosis, but this varies based on T stage.
What is a Sézary cell?
Sézary cells are defined as any atypical lymphocyte with moderately to highly infolded or grooved nucleus.
What is Sézary syndrome?
Sézary syndrome is an aggressive T-cell lymphoma defined as erythroderma + evidence of circulating T cells that satisfy any of the below criteria:
1. A Sézary cell count ≥1,000 cells/μL
2. CD4/CD8 ratio ≥10
3. Chromosomal abnl T-cell clone
4. Increased lymphocyte count with T-cell clone detected in the blood
5. Abnl expression of pan T-cell markers (CD2, CD3, CD4, CD5).
WORKUP/STAGING
What is the workup of MF?
Hx: focus on B Sx and skin lesions with attention to duration, distribution, changes, and associated pain or pruritus.
Physical exam: focus on entire skin (including soles, perineum, nails, and auditory canals) and LNs. Delineate skin involvement with photographs. Perform a minimum of 2 Bx of involved skin, with pathologic evaluation including T-cell receptor gene analysis.
Blood work: obtain a Sézary cell count and a T-cell receptor gene analysis, CBC, CMP, and LFTs.
Imaging: CXR for early stage, CT C/A/P or PET/CT for suspected stages IIA–IV to assess for extracutaneous manifestations. If concerning LN, excisional biopsy. Consider BM Bx in pts with blood or visceral involvement.
Describe the difference between a patch and a plaque.
A patch does not have elevation or induration. A plaque has elevation or induration.
Describe the T classification system for MF.
T1: limited patch/plaque (<10% total skin surface):
(a) patch only
(b) plaque +/– patch
T2: generalized patch/plaque (≥10% total skin surface):
(a) patch only
(b) plaque +/– patch
T3: tumor(s) ≥1 cm in diameter
T4: generalized erythroderma covering ≥80% of body surface area
Describe the N and M classification system for MF.
N0: uninvolved
N1: clinically abnl peripheral LN, histopathologically Dutch grade 1 or NCI LN 0-2:
(a) T-cell clone negative
(b) T-cell clone positive
N2: clinically abnl peripheral LNs, histopathologically Dutch grade 2 or NCI LN 3:
(a) T-cell clone negative
(b) T-cell clone positive
N3: clinically abnl peripheral LN, histopathologically Dutch grades 3–4 or NCI LN 4, clone positive or negative
M0: no visceral involvement
M1: visceral involvement
Describe the B classification of MF.
B0: absence of significant blood involvement: ≤5% of peripheral blood lymphocytes are Sézary cells:
(a) clone negative
(b) clone positive
B1: low blood tumor burden: >5% of peripheral blood lymphocytes are Sézary cells, but pt not B2:
(a) clone negative
(b) clone positive
B2: high blood tumor burden: ≥1,000/μL Sézary cells with a positive T-cell clone
Describing the stage grouping of MF.
Stage IA: T1, N0, M0, B0-1
Stage IB: T2, N0, M0, B0-1
Stage IIA: T1-2, N1-2, M0, B0-1
Stage IIB: T3, N0-2. M0, B0-1
Stage IIIA: T4, N0-2, M0, B0
Stage IIIB: T4, N0-2, M0, B1
Stage IVA1: any T, N0-2, M0, B2
Stage IVA2: any T, N3, M0, any B
Stage IVB: any T, any N, M1, any B
If MF involves <10% of the body surface area, what T stage is this?
A T1 MF lesion involves <10% of the body surface area.
How would erythroderma be staged for MF?
Erythroderma constitutes a T4 lesion for MF.
What constitutes stage I Dz in MF?
A pt with T1 or T2, N0, M0, B0-1 would be stage I in MF.
What constitutes stage III Dz in MF?
A pt with T4, N0-2, M0, B0-1 would be stage III in MF.
TREATMENT/PROGNOSIS
What are the Tx options for MF that are limited to the skin?
Tx options for MF limited to skin:
1. Topical nitrogen mustard
2. Topical carmustine (BCNU)
3. Topical steroids
4. Topical imiquimod (immunomodulator that acts on Toll-like receptor 7)
5. PUVA (psoralen + UVA)
6. UVB therapy
7. Local or total skin electron beam therapy (TSEBT)
What is the long-term DFS of pts with a single localized MF lesion treated with topical therapy?
Long-term DFS is excess of 85%.
How is PUVA different from UVB therapy?
PUVA stands for psoralen + long-wave ultraviolet radiation (UVA). UVB is less penetrating and its use is limited to thin patches, whereas UVA is more penetrating and can effectively treat some plaques. UVA activates 8-methoxypsoralen, which results in DNA cross-linking and apoptosis.
How are PUVA and UVB administered?
PUVA and UVB are initially administered q2–3days and then this time interval is gradually increased to q1mo once a CR is achieved. Pts can be continued on this therapy for several yrs.
What are the response rates of patch or plaque phase MF treated with PUVA or UVB?
Response rates are high (70%–90% CR rate), but long-term DFS remains poor.
What are systemic Tx options for MF?
Systemic Tx options for MF:
1. Interferon-alfa-2a
2. Retinoids
3. Extracorporeal photochemotherapy (photophoresis)
4. Cytotoxic chemo (methotrexate, etoposide, chlorambucil)
Describe photophoresis used in MF pts.
Photophoresis is often used to treat pts with erythrodermic MF. It involves the use of leukapheresis to collect a pt’s WBCs, which are then treated with PUVA and transfused back to the pt.
How effective is photophoresis in MF?
Overall response rates in erythrodermic MF are around 40%, with ∼20% CR rate.
What RT total dose and fractionation should be used in pts with MF?
Several studies have shown an RT dose-response relationship in MF and noted high CR rates (95%–100%) with doses >30 Gy in 1.5–2 Gy/fx. (Hoppe RT et al., IJROBP 1978; Cotter GW et al., IJROBP 1983) A commonly used RT Rx for TSEBT is 36 Gy in 1.5–2 Gy/fx. For small localized fields or palliation, consider hypofractionation (5 Gy × 3 or 3 Gy × 5).
Describe the Stanford TSEBT setup for MF.
For TSEBT, pts are treated in the standing position, 3.5 m from the electron source with a three-eighths-inch Lucite plate degrader in the beam path. Beams are angled upward and downward 18 degrees to improve homogeneity and decrease photon contamination. Pts are treated using 6 different pt positions (all standing) that result in AP, PA, RAO, LAO, RPO, and LPO fields. (Hoppe RT et al., Derm Thera 2003)
In the Stanford TSEBT technique, are all 6 fields treated daily?
No. In the Stanford TSEBT Tx, only 3 fields are treated per day. For each field, both upward and downward (18-degree) angles are treated. (Hoppe RT et al., Derm Thera 2003)
In the Stanford TSEBT technique for MF, what 5 areas of skin may be underdosed and would require boosting? How are these areas boosted?
Areas that may be underdosed using the Stanford TSEBT technique:
1. Top of scalp
2. Perineum
3. Soles of feet
4. Inframammary folds in women
5. Under panniculus in obese pts
Boost fields are with conventional electrons or low voltage x-rays at conventional SSDs
In TSEBT for MF, what areas may require shielding?
In TSEBT, shield the eyes with internal or external eye shields. Consider shielding the scalp (to avoid permanent alopecia) and hands/feet (to avoid intense acute reaction) for a portion of the Tx.
How effective is TSEBT for patients with T2 or T3 MF?
The overall response rate is 100%, with a ∼60% CR rate (T2 Dz: 75%; T3 Dz: 47%). (Navi D et al., Arch Dermatol 2011)
Describe the EORTC criteria for TSEBT.
80% isodose should be ≥4-mm deep to the skin surface and receive a minimum of 26 Gy. The 20% isodose line should be <20 mm from the skin surface. Total dose to bone marrow should be <0.7 Gy.
Is there evidence to support early aggressive Tx with TSEBT and systemic chemo over less aggressive Tx with sequential topical Tx?
No. Kay et al. randomized 103 MF pts (all stages) to TSEBT + systemic chemo vs. sequential topical Tx. Although the aggressive arm had a superior CR rate, there was no difference in long-term DFS or OS. The authors concluded that early aggressive Tx is not warranted. (NEJM 1989)
What are the Tx options for MF pts that fail 1st-line topical therapies?
Pts that recur after 1st-line therapy for MF can be re-treated with topical therapies before switching to alternative therapies (RT, UV therapy, steroids, or systemic Tx), as many will have a continued response to the same Tx.
Estimate the 5-yr OS of MF pts with stage IA and stage IV Dz.
MF pts with stage IA Dz have a 5-yr OS that is no different from matched normal controls (97%). 5-yr OS for stage IV MF is 27%. (Kim YH et al., Arch Dermatol 2003)
TOXICITY
Describe the acute (during and within 6 mos of Tx) toxicities of TSEBT.
During TSEBT, MF pts commonly experience erythema/desquamation (76%), blisters (52%), hyperpigmentation (50%), skin pain (48%), and skin infections (32%). (Lloyd S et al., J Am Acad Dermatol 2013) In the 2–6 mos after TSEBT, pts may experience alopecia, loss of fingernails and/or toenails, and hypohidrosis (inability to sweat properly).
Describe the late toxicities of TSEBT.
Late toxicities of TSEBT include chronic dry skin, atrophy, telangiectasias, and premature aging. Additionally, secondary squamous and basal cell carcinomas as well as melanomas have been described.
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