Charles M. Matthews and Eli Glatstein
What subtypes of disorders are encompassed in the general term cutaneous T-cell lymphoma?
Subtypes of cutaneous T-cell lymphoma:
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 cutaneous T-cell lymphoma:
1. Lymphomatoid papulosis
2. Pagetoid reticulosis
3. Follicular mucinosis
MF comprises what % of all lymphomas?
MF comprises ~2% of all lymphomas but is the most common type of primary cutaneous lymphoma.
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 gender predilection for MF?
Yes. Black race (2:1) and male gender (2.2:1) are known risk factors for having MF.
To what do MF pts have an increased susceptibility?
MF pts have an increased susceptibility to infections and other malignancies, possibly due to an impaired immune system.
What is the histo-pathologic 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. While 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 an erythematous, scaly, and pruritic lesion 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 have LN involvement of Dz?
~15% of MF pts have LN involvement of their Dz.
What is a Sézary cell?
Sézary cells are defined as malignant T cells with hyperconvoluted cerebriform nuclei.
What is Sézary syndrome?
Sézary syndrome is an aggressive T-cell lymphoma with the presence of erythroderma + a Sézary cell count ≥100 cells/μL, CD4 to CD8 ratio ≥10, chromosomal T-cell clones that are abnl, T-cell clone detected in the bloodstream with an abnl T-lymphocyte count, and abnl expression of pan T-cell markers (CD2, -3, -4, -5). It sometimes is considered a leukemic form of Dz.
What is the workup of MF?
MF workup: Hx with focus on B Sx, duration, distribution, and changes in any lesions, with presence or absence of pain or pruritis of lesions; physical exam with focus on the entire skin, including soles, perineum, nails, and auditory canals. Delineate skin involvement with photographs. Pathologic evaluation should include T-cell receptor gene analysis. Obtain a Sézary cell count and a T-cell receptor gene analysis in the peripheral blood. Obtain a CBC, CMP, LFTs, and PET/CT to assess for extracutaneous manifestations. Consider LN and BM Bx.
Describe the T classification system for MF.
1. T1: limited patch/plaque (<10% total skin surface): (a) patch only; (b) plaque +/− patch
2. T2: generalized patch/plaque (>10% total skin surface): (a) patch only; (b) plaque +/− patch
3. T3: tumor(s) ≥1 cm in diameter
4. T4: generalized erythroderma covering ≥80% of body surface area
Describe the N and M classification system for MF.
1. N0: uninvolved
2. N1: clinically abnl peripheral LN, histopathologically Dutch grade 1 or NCI LN 0-2: (a) T-cell clone negative; (b) T-cell clone positive
3. N2: clinically abnl peripheral LNs, histopathologically Dutch grade 2 or NCI LN 3: (a) T-cell clone negative; (b) T-cell clone positive
4. N3: clinically abnl peripheral LN, histopathologically Dutch grades 3–4 or NCI LN 4, clone positive or negative
5. M0: no visceral involvement
6. M1: visceral involvement
Describe the B classification of MF.
1. B0: ≤5% of peripheral blood lymphocytes are Sézary cells: (a) T-cell clone negative; (b) T-cell clone positive
2. B1: >5% of peripheral blood lymphocytes are Sézary cells, but pt not B2: (a) clone negative; (b) clone positive
3. B2: >1,000/μL Sézary cells with a positive T-cell clone
Describing the stage grouping of MF.
1. Stage IA: T1, N0, M0, B0-1
2. Stage IB: T2, N0, M0, B0-1
3. Stage IIA: T1-2, N1-2, M0, B0-1
4. Stage IIB: T3, N0-2. M0, B0-1
5. Stage IIIA: T4, N0-2, M0, B0
6. Stage IIIB: T4, N0-2, M0, B1
7. Stage IVA1: any T, N0-2, M0, B2
8. Stage IVA2: any T, N3, M0, any B
9. 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 a T4 lesion with N0-2, M0, B0-1 Dz constitutes stage III in MF.
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
3. Topical steroids
5. UVB therapy
6. Local or total skin electron beam therapy (TSEBT)
What are the response rates of patch or plaque phase MF treated with topical chemos?
Response rates are high (85% response, 60% CR) for a given lesion, though long-term DFS is poor.
How is PUVA different from UVB therapy?
PUVA stands for psoralen + long-wave ultraviolet radiation. UVA is more penetrating than UVB and can effectively treat some plaques. UVA activates 8-methoxypsoralen, which irreversibly binds to DNA.
How are PUVA and UVB administered?
PUVA and UVB are initially administered q2–3days and then this time interval is gradually increased to q1mo. 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:
3. Extracorporeal photophoresis
4. Cytotoxic chemo (methotrexate, etoposide, chlorambucil)
Describe extracorporeal photophoresis used in MF pts.
Extracorpeal 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. The Tx results in an ~20% CR rate in erythrodermic MF.
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 (Cotter et al., IJROBP 1983; Hoppe RT et al., IJROBP 1978). A commonly used RT Rx for TSEBT is 36 Gy in 1.5–2 Gy/fx. For small localized fields, 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 3/8-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/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
3. Soles of feet
4. Under breasts in women
5. Under panniculus in obese pts
Boost with 1 Gy/fx to a total of 20 Gy.
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.
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. While 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 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)
Describe the acute (during and within 6 mos of Tx) toxicities of TSEBT.
During TSEBT, MF pts experience erythema and dry desquamation. In the 2–6 mos after TSEBT, pts may experience loss of hair, fingernails, and toenails and an inability to sweat properly.
Describe the late toxicities of TSEBT.
Late toxicities of TSEBT include chronic dry skin, atrophy and premature aging of skin telangiectasias, and secondary squamous and basal cell carcinomas.