102 Cutaneous T-Cell Lymphoma (Mycosis Fungoides and Sezary Syndrome) Flashcards
The skin manifestations of MF are divided into:
- Patch stage (patch-only disease)
- Plaque stage (both patches and plaques), and
- Tumor stage (more than one tumor present, usually in the context of patches and plaques)
TRUE OR FALSE
Lesions usually are associated with pruritus, which may range from mild to excruciatingly severe, leading to insomnia, weight loss, depression, and suicidal ideation.
TRUE
Lesions usually are associated with pruritus, which may range from mild to excruciatingly severe, leading to insomnia, weight loss, depression, and suicidal ideation.
Pruritus is one of the most important quality-of-life issues for these patients.
Stopping skin-directed therapies (SDTs) for ___________ weeks before biopsy can be helpful in aiding diagnosis and is strongly recommended.
2 to 3 weeks
Characteristic lymphpocyte description of MF
Small to large, with characteristic convoluted (cerebriform) nuclei
- Classically, MF lesions show a superficial bandlike (lichenoid) lymphocytic infiltrate
The hallmark of the malignant infiltrate in MF is epidermotropism (presence of lymphocytes in the epidermis without spongiosis) with formation of the epidermal clusters of lymphocytes around Langerhans cells termed
Pautrier microabscesses
Superficial dermal collagen may be thickened, so-called ropey collagen.
TRUE OR FALSE
Alternatively, high expression of CD30 in the setting of MF and SS may reflect concurrent presence of type C lymphomatoid papulosis (LyP) or primary cutaneous anaplastic large cell lymphoma (PCALCL) rather than transformed disease and carries a significantly poor prognosis.
FALSE
Alternatively, high expression of CD30 in the setting of MF and SS may reflect concurrent presence of type C lymphomatoid papulosis (LyP) or primary cutaneous anaplastic large cell lymphoma (PCALCL) rather than transformed disease and carries a significantly better prognosis.
Immunophenotype of CTCL
CD3+CD4+CD45RO+ CD8–
A phenotype associated with mature helper-inducer T lymphocytes
Are important markers for malignant T lymphocytes
Loss of maturation markers, such as CD7, and CD26 expression on CD4+ cells
Clonal rearrangement of the _____________________ gene can be identified in approximately 90% of advanced cases of MF but in only 50% of early-stage cases.
T-cell receptor (TCR) Vβ gene
MF is classified according to the widely accepted modified
Tumor, node, metastasis, blood (TNMB) classification
Cutaneous lesions are classified using the T staging system
- T1: Limited patches, papules, or plaques covering < 10% of the skin surface (T1a = patch only; T1b = plaques ± patches)
- T2: Generalized patches, papules, or plaques covering 10% or more of the skin surface (T2a = patch only; T2b = plaques ± patches)
- T3: At least one tumor (≥1 cm in diameter)
- T4: Generalized erythroderma over ≥80% body surface area
The area of the skin and type of the lesions were found to correlate with patient survival and are important prognostic predictors that need to be calculated at every visit to assess disease status.
TRUE OR FALSE
Lymphadenopathy is present in more than half of patients as disease advances and increases with progressive cutaneous involvement.
TRUE
Lymphadenopathy is present in more than half of patients as disease advances and increases with progressive cutaneous involvement.
Even the presence of dermatopathic changes alone in the lymph nodes carries prognostic significance
Imaging used to assess involvement of lymph nodes
Computerized tomography (CT) and positron emission tomography (PET) scans
Excisional lymph node biopsy is usually recommended to assess the extent of the disease and nodal architecture and is preferred over fine-needle aspiration cytology (FNAC) or core biopsy.
TRUE OR FALSE
The number of circulating Sézary cells increases with advancing disease, and the cells are particularly prominent in patients with generalized erythroderma.
TRUE
The number of circulating Sézary cells increases with advancing disease, and the cells are particularly prominent in patients with generalized erythroderma.
However, a clonal T-cell population in the blood may be detected in up to half of stage I patients using a highly sensitive polymerase chain reaction (PCR) technique, suggesting that early systemic disease is common.
Blood involvement is rated as the B category
- B0: Absence of significant blood involvement: ≤ 5% of blood lymphocytes of < 0.25 × 109/L are atypical (Sézary) cells or < 15% CD4+/CD26- or CD4+CD7- cells of total lymphocytes
- B1: Atypical circulating cells present (> 5%, minimal blood involvement) or >15% CD4+CD26- or CD4+CD7- of total lymphocytes but do not meet criteria for B0 or B2
- B2: High blood tumor burden:** ≥ 1 × 109/L** Sézary cells determined by cytopathology or ≥ 1 × 109/L CD4+CD26- or CD4+CD7- cells or other abnormal subset of T lymphocytes by flow cytometry with clone in blood same as that in skin.
Other criteria for documenting high blood tumor burden in CD4+ MF and SS include CD4+/CD7- cells ≥40% and CD4+CD26- cells ≥30%
TRUE OR FALSE
Patients with blood involvement have a lower likelihood of lymphadenopathy and visceral involvement.
FALSE
Patients with blood involvement have a higher likelihood of lymphadenopathy and visceral involvement.
TRUE OR FALSE
Marrow infiltration with extracutaneous disease occurs but is infrequently detected by biopsy despite circulating malignant cells and is not a recommended procedure for staging.
TRUE
Marrow infiltration with extracutaneous disease occurs but is infrequently detected by biopsy despite circulating malignant cells and is not a recommended procedure for staging.
Classification of Erythrodermic Cutaneous T-Cell Lymphoma (T4)
- Sézary syndrome
- Erythrodermic MF
- Erythrodermic cutaneous T-cell lymphoma, not otherwise specified
The triad that make SS have the worst prognosis among the other forms of erythrodermic CTCL.
- Exfoliative erythroderma
- Generalized lymphadenopathy
- Leukemia
MYCOSIS FUNGOIDES VARIANTS
Characterized by a folliculotropic infiltrate that spares the epidermis, often with mucinosis, and principally affects the head and neck
Worse prognosis than plaque-stage classical MF
Folliculotropic MF
MYCOSIS FUNGOIDES VARIANTS
Rare variant of MF that consists of solitary or localized cutaneous plaques, usually found on the extremities, affecting young males almost exclusively
Benign, indolent course, and the prognosis is excellent
It is an epidermal process, with the majority of atypical lymphocytes found within hyperplastic epidermis.
Pagetoid reticulosis (Woringer-Kolopp disease)
Was previously considered the disseminated form of pagetoid reticulosis
Predominantly epidermal involvement of malignant cells and a poor prognosis
Ketron-Goodman disease
The WHO-EORTC classification now defines the disease as aggressive epidermotropic CD8+ CTCL, Cutaneous γ/δ-positive T-cell lymphoma, or tumor-stage MF
MYCOSIS FUNGOIDES VARIANTS
Rare but indolent variant of MF that causes slowly progressive laxity of skin folds and granulomatous clonal T-cell infiltrate on histology
Granulomatous slack skin
Skin-directed therapy
- Topical therapy
- Light therapy
- Radiation therapy
Systemic therapy
- Retinoids
- Histone deacetylase inhibitors
- Immunomodulators
- Monoclonal antibodies and conjugates
- Proteasome inhibitors
- Chemotherapy
- Allogeneic stem cell transplant
TRUE OR FALSE
Ultrapotent topical glucocorticoids can be used on the face, neck, and intertriginous areas.
FALSE
Ultrapotent topical glucocorticoids should not be used on the face, neck, and intertriginous areas.
Topical steroids are rarely used as monotherapy but may be effective as an additional modality for symptomatic relief of pruritus.
Effective as mid- to low-potency glucocorticoids for use on facial skin and intertriginous areas in patients with MF
A major advantage: they do not suppress collagen synthesis to cause skin atrophy.
Topical Calcineurin Inhibitors
Topical tacrolimus and pimecrolimus
Associated with an increased risk of lymphoma, and their use in patients with CTCL is controversial.
Should be limited to small areas
An alkylating agent approved by the FDA for stage IA and IB patients after one prior treatment
Major advantage: low toxicity
Disadvantages: inconvenience of daily application to large areas of skin, allergic reactions, the potential for development of skin cancer, and the inability to cure the disease
Topical Nitrogen Mustard (Mechlorethamine Hydrochloride)
- It is approved for use from the neck down and applied three times weekly up to daily as tolerated.
- Therapy is usually continued for up to 12 months in responders.
- The frequency then is reduced to every other day for an additional 1 to 2 years.
- Therapy is discontinued after 3 years or when cutaneous lesions disappear completely.
- Should not be used together with UVA or UVB therapy
- Contraindicated in pregnancy
Not currently widely used for treatment of MF because of its severe irritant reactions and its absorption from the skin, which results in systemic toxicity
Causes marrow suppression
Bis-chloroethylnitrosourea (BCNU)
Carmustine causes irreversible skin thinning, telangiectasias, and hyperpigmentation.
A topical retinoid (rexinoid) approved by the FDA for treatment of MF patients who are refractory to at least one other topical therapy.
Bexarotene
- It is applied twice daily in a thin layer to the patches and plaques.
- The major toxicity is irritation at the site.
- Oral administration of bexarotene is associated with severe birth defects
Not FDA approved for the treatment of patients with MF and SS because of a lack of prospective clinical trials but is considered to be one of the most effective therapies for early disease (mainly patches and thin plaques)
Phototherapy
Hypothesized that the mechanism of action of phototherapy
Depletion of Langerhans cells from the epidermis
Peak of therapeutic effectiveness of:
UVB:
UVA:
UVB: 295–313 nm
UVA: 320 to 400 nm
NBUVB is most appropriate for patch-stage disease
UVA penetrates deeper than UVB into the dermis, allowing treatment of thicker plaques.
A phototoxic furocoumarin activated by UVA light
Psoralen
UVA radiation is used with psoralen and is referred to as PUVA
Given at a dose of 0.6 mg/kg orally, 2 hours before the UVA light therapy
Adverse effects of PUVA therapy
Nausea, pruritus, and sunburn-like changes, with atrophy and dry skin
Long-term side effects: increased incidence of skin cancers and melanoma
Disadvantages of phototherapy include the necessity to visit the physician’s office frequently (from three times a week to once a month) and its expense.
A photochemotherapy that uses two properties of porphyrins: their selective accumulation in tumor sites (eg, 5-aminolevulinic acid) and their ability to generate cytotoxic oxygen species at the tumor site after red-light irradiation
Photodynamic Therapy
Useful in patients with localized plaques or tumors; however, the pain induced during irradiation limits its use for larger areas
It is used for therapy of MF off label
A natural porphyrin precursor and upon irradiation is converted in the tumor to the highly photoactive endogenous protoporphyrin IX
5-Aminolevulinic acid
One of the most photoactive compounds, and it can be activated by fluorescent light, rather than UVA or UVB, decreasing the risk of cancer risks associated with treatment
Hypericin
One of the oldest and the most effective forms of treatment of MF, appropriate for patients who have failed the aforementioned SDTs
Electron-Beam Therapy
A Toll-like receptor-7 and -8 agonist that induces proinflammatory cytokines such as tumor necrosis factor-α and interferons (INFs), resulting in activation of a Th1-type immune response and rejection of cancer or virally infected cells
Imiquimod
An FDA-approved, RXR-selective oral retinoid, or “rexinoid,” for therapy of MF
Recommended beginning with refractory or persistent stage IA disease through more advanced stages (NCCN guidelines)
Oral bexarotene
Other retinoids have been used for treatment of MF and SS, including isotretinoin, acitretin, etretinate (not available in United States), and all-trans retinoic acid (ATRA)
FDA-approved dose for Oral bexarotene
300 mg/m2 per day
All patients on bexarotene rapidly develop
Central hypothyroidism and hyperlipidemia (most significantly hypertriglyceridemia)
Requiring coadministration of thyroid supplements, lipid-lowering agents, and a high-protein, low-fat, low-carbohydrate die
Other rare adverse events include headaches, possibly a result of pseudotumor cerebri; leukopenia; hepatotoxicity; and pruritus.
Examples of Histone Deacetylase Inhibitors
Vorinostat and romidepsin
An oral pan- HDACi FDA approved for treatment of cutaneous manifestations of recurrent, refractory, or persistent MF and SS in 2008 at the dose of 400 mg daily
Vorinostat (suberoylanilide hydroxamic acid)
The most common drug-related adverse event with Vorinostat
Diarrhea, fatigue, nausea, and anorexia
Selective HDACi given as an IV infusion
Given as a weekly 4-hour infusion of 14 mg/m2 on days 1, 8, and 15 of a 28-day cycle
Romidepsin (depsipeptide)
Are immunomodulatory polypeptides that both stimulate a Th1 immune response
Adverse effects include major depressive disorder, acute flulike symptoms and fatigue, and marrow suppression.
IFN-α and -γ
Technique where white blood cells are collected by leukapheresis, exposed to a photoactivating drug, and irradiated with UVA
Was FDA approved in 1998 for the palliative treatment of patients with CTCL
Extracorporeal Photopheresis
Administered every 2–4 weeks until clearance of disease
A humanized IgG1 monoclonal antibody that targets the CD52 antigen
Used off label for CTCL as salvage therapy
Capable of inducing long-term remission in SS patients, it is not effective in MF and CTCL with large-cell transformation
Alemtuzumab
It has a high rate of adverse events, including profound lymphopenia
A humanized immunoglobulin (Ig) G1 monoclonal antibody that targets CC chemokine receptor 4 (CCR4) on CTCL tumor cells
Mogamulizumab
An anti-CD30 antibody conjugated via a protease-cleavable linker to the potent antimicrotubule agent monomethyl auristatin E (MMAE)
Approved by the FDA in 2017 for treatment of patients with CD30+ MF who had received prior systemic therapy
Brentuximab vedotin
Significant adverse event with Brentuximab vedotin
Peripheral sensory neuropathy
An IL-2 diphtheria toxin fusion protein targeted to malignant cells that express the CD25 component of the IL-2 receptor
Denileukin diftitox (DD)
Inhibits activity of the 20S unit of the proteasome to promote apoptosis in tumor cells and is approved for myeloma and mantle cell lymphoma but not approved for CTCL
Dose-limiting side effects included myelosuppression and sensory neuropathy.
Bortezomib
A novel antifolate with high affinity for reduced folate carrier-1, which has been approved by the FDA for PTCL at 30 mg/m2 intravenously per week
Pralatrexate
Reserved as palliation in end-stage disease or as a bridge to stem cell transplantation (SCT)
Multiagent chemotherapy
TRUE OR FALSE
Autologous SCT is recommended for CTCL because of a durable response.
FALSE
Autologous SCT is not recommended for CTCL because of a lack of durable response.
Candidates for hematopoietic SCT:
Patients with aggressive disease such as tumor-stage MF, transformed MF, or SS refractory to multiple lines of systemic therapies
A large outcomes study of advanced MF and SS patients identified four independent prognostic variables affecting survival:
- (a) stage IV disease
- (b) age older than 60 years
- (c) elevated serum lactate dehydrogenase, and
- (d) large-cell transformation
The second most common CTCLs after MF and represent approximately 30% of CTCL cases
Indolent, carry a favorable prognosis, and tend to regress spontaneously
Primary cutaneous CD30+ LPDs
Most cases are CD4+, with loss of pan–T-cell markers CD2, CD3, and CD5
Negative for CD15 and epithelial membrane antigen
Does not express anaplastic lymphoma kinase-1 (ALK-1) or the t(2;5) chromosomal translocation found in nodal ALCL
Benign counterpart of PCALCL
Lymphomatoid Papulosis
Three main histologic types of LyP:
- Type A resemble immunoblasts or Reed-Sternberg cells
- Type B cells resemble MF
- Type C cells resemble ALCL
LyP is extremely responsive to
Low-dose methotrexate therapy
10–15 mg orally weekly
