102 Cutaneous T-Cell Lymphoma (Mycosis Fungoides and Sezary Syndrome)

Question 1

The skin manifestations of MF are divided into:

Answer 1

• 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)

Question 2

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.

Answer 2

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.

Question 3

Stopping skin-directed therapies (SDTs) for ___________ weeks before biopsy can be helpful in aiding diagnosis and is strongly recommended.

Answer 3

2 to 3 weeks

Question 4

Characteristic lymphpocyte description of MF

Answer 4

Small to large, with characteristic convoluted (cerebriform) nuclei

• Classically, MF lesions show a superficial bandlike (lichenoid) lymphocytic infiltrate

Question 5

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

Answer 5

Pautrier microabscesses

Superficial dermal collagen may be thickened, so-called ropey collagen.

Question 6

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.

Answer 6

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.

Question 7

Immunophenotype of CTCL

Answer 7

CD3+CD4+CD45RO+ CD8–

A phenotype associated with mature helper-inducer T lymphocytes

Question 8

Are important markers for malignant T lymphocytes

Answer 8

Loss of maturation markers, such as CD7, and CD26 expression on CD4+ cells

Question 9

Clonal rearrangement of the _____________________ gene can be identified in approximately 90% of advanced cases of MF but in only 50% of early-stage cases.

Answer 9

T-cell receptor (TCR) Vβ gene

Question 10

MF is classified according to the widely accepted modified

Answer 10

Tumor, node, metastasis, blood (TNMB) classification

Question 11

Cutaneous lesions are classified using the T staging system

Answer 11

• 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.

Question 12

TRUE OR FALSE

Lymphadenopathy is present in more than half of patients as disease advances and increases with progressive cutaneous involvement.

Answer 12

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

Question 13

Imaging used to assess involvement of lymph nodes

Answer 13

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.

Question 14

TRUE OR FALSE

The number of circulating Sézary cells increases with advancing disease, and the cells are particularly prominent in patients with generalized erythroderma.

Answer 14

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.

Question 15

Blood involvement is rated as the B category

Answer 15

• 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%

Question 16

TRUE OR FALSE

Patients with blood involvement have a lower likelihood of lymphadenopathy and visceral involvement.

Answer 16

FALSE

Patients with blood involvement have a higher likelihood of lymphadenopathy and visceral involvement.

Question 17

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.

Answer 17

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.

Question 18

Classification of Erythrodermic Cutaneous T-Cell Lymphoma (T4)

Answer 18

• Sézary syndrome
• Erythrodermic MF
• Erythrodermic cutaneous T-cell lymphoma, not otherwise specified

Question 19

The triad that make SS have the worst prognosis among the other forms of erythrodermic CTCL.

Answer 19

• Exfoliative erythroderma
• Generalized lymphadenopathy
• Leukemia

Question 20

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

Answer 20

Folliculotropic MF

Question 21

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.

Answer 21

Pagetoid reticulosis (Woringer-Kolopp disease)

Question 22

Was previously considered the disseminated form of pagetoid reticulosis

Predominantly epidermal involvement of malignant cells and a poor prognosis

Answer 22

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

Question 23

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

Answer 23

Granulomatous slack skin

Question 24

Skin-directed therapy

Answer 24

• Topical therapy
• Light therapy
• Radiation therapy

Question 25

Systemic therapy

Answer 25

* Retinoids * Histone deacetylase inhibitors * Immunomodulators * Monoclonal antibodies and conjugates * Proteasome inhibitors * Chemotherapy * Allogeneic stem cell transplant

Question 26

# TRUE OR FALSE Ultrapotent topical glucocorticoids can be used on the face, neck, and intertriginous areas.

Answer 26

FALSE Ultrapotent topical glucocorticoids should not be used on the face, neck, and intertriginous areas. ## Footnote Topical steroids are **rarely used as monotherapy** but may be effective as an additional modality for symptomatic relief of pruritus.

Question 27

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**.

Answer 27

Topical Calcineurin Inhibitors Topical tacrolimus and pimecrolimus ## Footnote Associated with an *increased risk of lymphoma,* and their use in patients with CTCL is controversial. Should be limited to small areas

Question 28

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

Answer 28

Topical Nitrogen Mustard (Mechlorethamine Hydrochloride) ## Footnote * 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

Question 29

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**

Answer 29

Bis-chloroethylnitrosourea (BCNU) ## Footnote **Carmustine** causes **irreversible skin thinning, telangiectasias, and hyperpigmentation.**

Question 30

A **topical retinoid (rexinoid)** approved by the FDA for treatment of MF patients who are **refractory to at least one other topical therapy**.

Answer 30

Bexarotene ## Footnote * 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**

Question 31

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)

Answer 31

Phototherapy

Question 32

Hypothesized that the mechanism of action of phototherapy

Answer 32

Depletion of Langerhans cells from the epidermis

Question 33

Peak of therapeutic effectiveness of: UVB: UVA:

Answer 33

UVB: 295–313 nm UVA: 320 to 400 nm ## Footnote **NBUVB** is most appropriate for **patch-stage disease** **UVA** penetrates deeper than UVB into the **dermis**, allowing treatment of **thicker plaques.**

Question 34

A phototoxic furocoumarin activated by UVA light

Answer 34

Psoralen ## Footnote 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

Question 35

Adverse effects of PUVA therapy

Answer 35

Nausea, pruritus, and sunburn-like changes, with atrophy and dry skin Long-term side effects: **increased incidence of skin cancers and melanoma** ## Footnote 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**.

Question 36

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

Answer 36

Photodynamic Therapy ## Footnote 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

Question 37

A natural porphyrin precursor and upon irradiation is converted in the tumor to the highly photoactive endogenous protoporphyrin IX

Answer 37

5-Aminolevulinic acid

Question 38

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

Answer 38

Hypericin

Question 39

One of the oldest and the most effective forms of treatment of MF, appropriate for patients who have failed the aforementioned SDTs

Answer 39

Electron-Beam Therapy

Question 40

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

Answer 40

Imiquimod

Question 41

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)

Answer 41

Oral bexarotene ## Footnote 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)

Question 42

FDA-approved dose for Oral bexarotene

Answer 42

300 mg/m2 per day

Question 43

All patients on bexarotene rapidly develop

Answer 43

Central hypothyroidism and hyperlipidemia (most significantly hypertriglyceridemia) ## Footnote 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**.

Question 44

Examples of Histone Deacetylase Inhibitors

Answer 44

Vorinostat and romidepsin

Question 45

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**

Answer 45

Vorinostat (suberoylanilide hydroxamic acid)

Question 46

The most common drug-related adverse event with Vorinostat

Answer 46

Diarrhea, fatigue, nausea, and anorexia

Question 47

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

Answer 47

Romidepsin (depsipeptide)

Question 48

Are **immunomodulatory** polypeptides that both stimulate a Th1 immune response Adverse effects include **major depressive disorder, acute flulike symptoms and fatigue, and marrow suppression**.

Answer 48

IFN-α and -γ

Question 49

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

Answer 49

Extracorporeal Photopheresis ## Footnote Administered every 2–4 weeks until clearance of disease

Question 50

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**

Answer 50

Alemtuzumab ## Footnote It has a high rate of adverse events, including profound lymphopenia

Question 51

A humanized immunoglobulin (Ig) G1 monoclonal antibody that targets **CC chemokine receptor 4 (CCR4)** on CTCL tumor cells

Answer 51

Mogamulizumab

Question 52

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**

Answer 52

Brentuximab vedotin

Question 53

Significant adverse event with Brentuximab vedotin

Answer 53

Peripheral sensory neuropathy

Question 54

An IL-2 diphtheria toxin fusion protein targeted to malignant cells that express the CD25 component of the IL-2 receptor

Answer 54

Denileukin diftitox (DD)

Question 55

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.**

Answer 55

Bortezomib

Question 56

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**

Answer 56

Pralatrexate

Question 57

Reserved as palliation in end-stage disease or as a bridge to stem cell transplantation (SCT)

Answer 57

Multiagent chemotherapy

Question 58

# TRUE OR FALSE Autologous SCT is recommended for CTCL because of a durable response.

Answer 58

FALSE Autologous SCT is **not** recommended for CTCL because of a lack of durable response.

Question 59

Candidates for hematopoietic SCT:

Answer 59

Patients with aggressive disease such as tumor-stage MF, transformed MF, or SS refractory to multiple lines of systemic therapies

Question 60

A large outcomes study of advanced MF and SS patients identified four independent prognostic variables affecting survival:

Answer 60

* (a) stage IV disease * (b) age older than 60 years * (c) elevated serum lactate dehydrogenase, and * (d) large-cell transformation

Question 61

The second most common CTCLs after MF and represent approximately 30% of CTCL cases Indolent, carry a favorable prognosis, and tend to regress spontaneously

Answer 61

Primary cutaneous CD30+ LPDs ## Footnote 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

Question 62

Benign counterpart of PCALCL

Answer 62

Lymphomatoid Papulosis

Question 63

Three main histologic types of LyP:

Answer 63

* Type A resemble immunoblasts or Reed-Sternberg cells * Type B cells resemble MF * Type C cells resemble ALCL

Question 64

LyP is extremely responsive to

Answer 64

Low-dose methotrexate therapy ## Footnote 10–15 mg orally weekly