IRISH DERM TUTOR

Classifying cutaneous lymphomas

Mycosis fungoides

Clinical

Histopathology

Immunohistochemistry

Clonality

Follicuotrophic MF

Clinical

Histopathology

Immunohistochemistry

Prognosis

Treatment

Pagetoid reticulosis

Clinical

Histopathology

Immunohistochemistry

Treatment

Granulomatous slack skin

Clinical

Histopathology and immunohistochemistry

Treatment

Sezary syndrome

MF and Sezary syndrome: Diagnosis, Staging, Treatment

Making a diagnosis

Staging

Treatment

Skin Directed Therapy

Topical

Phototherapy

Radiation

Systemic treatment

Chemotherapy

Extracorporeal photophoresis (ECP)

Biologic and immunologic therapies

Lymphoma is cancer of the lymphocyte

Types of lymphocytes:

• T cell

• B cell

• Natural killer cells

T cells further subdivided into:

• CD8 T cell

• CD4 T cell

• Regulatory T cells

These cells can turn in to a lymphoma

T and B lymphocytes can be defined by the proteins they express on their surface

• T cell receptors

• B cell receptors (immunoglobulins)

And you can look for clones of T cell receptors or B cell receptors to help diagnose lymphoma

Can divide all lymphoma in to Hodgkin’s and Non Hodgkin’s lymphoma

If have a lymphoma on the skin you want to think is this a primary cutaneous lymphoma or is it a systemic lymphoma that has spread to the skin (secondary cutaneous lymphoma)

Systemic lymphomas:

Majority of systemic lymphomas tend to be B cell lymphomas

Primary cutaneous lymphoma:

T cell lymphomas in the skin are far more common then B cell lymphomas

Distinguishing T cell from B cell:

Think of CD markers as flags on the surface of the lymphocytes which can be identified by using immunohistochemical stains:

CD 20: B cell

CD 3: T cell

T cells and B cells both can have multiple markers on their cell surface that can help differentiate them further

Can subdivide primary cutaneous T cell lymphomas in to:

• Classic CTCL (eg Mycosis fungoides, MF variants, Sezary syndrome)

• CD30 +ve lymphoproliferative disorders

• Rare subtypes

Classic CTCL:

2 main groups:

Mycosis fungoides (commonest)

Sezary syndrome

MF sub-types:

• Folliculotrophic MF (MF affecting hair follicle)

• Granulomatous slack skin (skin looks like its hanging loser often around axilla and groin)

• Pagetoid reticulosis

CD 30+ve lymphoproliferative disorders:

Defined by CD 30+ve on their surface

This subgroup is staged and treated differently compared to MF

• Anaplastic large cell lymphoma

• Lymphomatoid papulosis

Rare subtypes:

• CD8+ve aggresssive epidermotrophic T cell lymphoma

• NK-T cell lymphoma, nasal type

• Gamma/delta T cell lymphoma

• CD4+ small to medium sized pleomorphic T cell lymphoproliferative disease

• Subcutnaeous panniculitis-like T cell lymphoma

• Adult T cell leukaemia/lymphoma

• Acral CD8+ T cell lymphoma

B cell lymphoma:

Marignal zone and follicle centre lymphoma are commoner and are indolent tumours (slower growing)

Diffuse large B cell lymphoma behaves more aggressively and is treated differently

Intravascular large B cell lymphoma is very rare

Blastic plasmayctoid dendritic cell neoplasm:

Is a different cell type altogether

There is a drug that targets this type of lymphoma

How common are different type of cutaneous lymphoma (approximately):

MF - 50%

CD30 +ve LPD - 20%

• pcALCL 8%

• LyP 12%

B cell lyphoma - 20%

• pc Follicle centre lymphoma - 11%

• Marginal zone lymphoma - 7%

• pc Diffuse large B cell lymphoma - 4%

Sezary syndrome - 3%

Remaining 7% other rare types of lymphomas

Is the most common form of CTCL and accounts for 50% of all primary cutaneous lymphomas

Typically affects older adults (median age diagnosis: 55-60)

Can occur in children

Usually has indolent course with slow progression over years or even decades

General progression is from patch like lesions to plaque like lesions and then to tumours

The initial lesions have a predilection for the buttocks and other sun-protected areas (bathing suit distribution)

In later stages of disease the lymph nodes and visceral organs may become involved

Early patch:

• Superficial bandlike infiltrates consisting of lymphocytes and histiocytes

• Can get atypical cells with small to medium sized, highly indented (cerebriform), hyperchromatic nuclei

• These atypical cells are mostly confined to epidermis (epidermotropism) and may initial be seen around basal layer

Plaques:

• Epidermotropism is more pronounced

• May occasionally see intraepidermal collections of atypical cells (pautrier microabscesses)

Tumour:

• Dermal infiltrate becomes more diffuse and epidermotropism may be lost

• Tumour cells increase in size and numbers

• Cells become more plemorphic in size, may see blast cells

• Transformation to a diffuse large cell lymphoma (CD 30 +ve or -ve) can occur and has poor prognosis

CD3+, CD4+, CD45RO +ve (CD8 -ve usually)

Rarely can be CD4- and CD8+

Can lose pan-T cell antigens such as CD2, CD3 and CD5 which can aid in diagnosis

Clonal T-cell receptor gene arrangement is detected in most cases

Dependent on stage (discussed later)

10-year survival:

Limited patch/plaque: 97-98%

Generalized patch/plaque: 83%

Tumour stage: 42%

Histologically documented LN involvement: 20%

Poor prognosis:

Effaced Lymph nodes

Visceral involvement

Transformation into a large T-cell lymphoma

Variant of MF

Get folliculotrophic infiltrate

Often have sparing of the epidermis

Often effects head and neck

Most cases (but not all) show mucinous degeneration of the hair follicles (follicular mucinosis)

As the infiltrates are associated with the follicles they are often deeper and as such skin-target therapies are not as effective

Mostly seen in adults (can affect children)

Males > Females

Can present as:

• Grouped folliculr papules

• Acneiform lesions

• Indurates plaques or tumours
  
  
  

It is often associated with alopecia and release of clear appearing mucin from affected areas (mucinorrhoea)

Can be very itchy and progressing pruritus may indicate disease progression

See perivascular and periadnexal infiltrates with variable infiltration of the follicular epithelium by small, medium and sometimes large hyperchromatic cells with cerebriorm nuclei

The epidermis tends to be spared

Alcian blue stains: may demonstrate mucinous degeneration of follicular epithelium (‘folliuclar mucinosis’)

May see eosinophils and plasma cells

(if eccrine glands are affected and prominent it is called syringotropic MF)

Most cases CD3+, CD4+, CD8-

May also see CD30+ blast cells

Disease specfiic 5-year survival: 70-80%

Similar to that of classical tumour stage

As the infiltrates are associated with the follicles they are often deeper and as such skin-target therapies are not as effective (eg PUVA, topical nitrogen mustard)

Total skin electron beam irradiation is effective but sustained complete remission is rarely achieved

Alternatives:

pUVA + Retinoids

IFNa

Local radiotherapy

Is a variant of MF

Get localised patches or plaques with striking epidrmotropism - intraepidermal proliferation of neoplastic T cells

Used to be classified in to localised (Woringer-Kolopp) and generalised (Ketron-Goodman)

However now only use pagetoid reticulosis for the localised type

(the generalised form now classified as either epidermotrophic CD8+ CTCL, gamma/delta+ T cell lymphoma or tumour stage MF)

Appearance of solitary psoriasiform or hyperkeratotic patch or plaque which is often localised on the extremities

Slowly progressive

Extracutnaaeous dissemination or disease related deaths not reported

Hyperplastic epidermis with marked infiltration by atypical pagetoid cells (singly or in nests)

Medium or large sized hyperchromatic and cerebriform nuclei with abundant, vacuolated cytoplasm

Upper dermis may show mixed lymphoctes or histiocytes but no neoplastic T-cells

CD3+, CD4+, CD8- (or CD4-, CD+)

CD30 often expressed

Responds well to radiotherapy

Surgical excision can be considered

Topical nitrogen mustard or topical steroids can be used in some instances

Very rare

Slow development of folds of lax skin the major skin folds

Cicrcumscribed areas of lax skin with predilection for the axilla and groin

1/3 of reported cases have a Hodgkin’s disease association

An association with clasical MF also reported

Most cases have indolent course

Dense granulomatous dermal infiltrates containing atypical T cells with slightly indented to cerebriform nuclei

Macrophages and multinucleated giant cells may be seen

Destruction of elastic tissue seen

Epidrmis may sow focal infiltration by small atypical T cells

CD3+, CD4+, CD8-

Radiotherapy may help but experience limited

Rapid recurrence after excision has been reported

Triad of:

1. Erythroderma

2. Generalised lymphadenopathy

3. Neoplastic T cells (Sezary cells) in skin, lymph nodes and peripheral blood

Of the aberrant loss of pan T cell markers, the loss of CD7 and/or CD26 is the commonest

Rare, exclusive to adults

Get erythroderma which may be associated with marked exfoliation, oedema, lichenificaiton and an intense pruritus

Common associated findings:

• Lymphadenopathy

• Alopecia

• Onychodystrophy

• Palmoplantar hyperkeratotis
  

Histopathology can be similar to MF

Cellular infiltrates tend to be more monomorphic and epidermotropism may be absent

In up to 1/3 of patient with otherwise classical sezary syndrome the histologic picture may be non-specific

Lymph nodes show a dense monotonous infiltrate of Sezary cells with effacement of the normal lymph node architecture

Bone marrow may be involved but infiltrates are often sparse and mainly interstitial

Immunophenotypes:

CD3+, CD4+, CD8-

When dealing with cutaneous lymphoma the approach can be:

• Make the correct diagnosis

• Staging

• Formualate treatment plan

• History and skin exam

• Skin biopsy

  • Histopathology

  • Immunohistochemistry

  • T cell gene rearrangement

History and exam:

How long has patient had it for

If have polymorphic patches or plaques over time it is suggetive of MF

Other CTCL variants do not have the characteristic patches and plaques and may present with cutaneous tumours, nodules or subcutaneous infiltration

Sezary syndrome patients will have erythroderma

Distribution (eg bathing trunk distribution)

Blood tests:

FBC -

Usually normal in early disease

May see lymphocytosis in Sezary syndrome

Blood film - To screen for Sezary cells

Flow cytometry - immunophenotyping looking at lymphocyte subsets, CD4/CD8 ratio (discussed later in staging section)

U&E/LFT - as baseline if considering commencing a systemic agent

LDH - Can be elevated in systemic disease. Strong predictor of poor prognosis in erythrodermic CTCL

HTLV-1 serology - to disintinguish between adult T-cell leuakaemia/lymphoma which can mimic CTCL

HIV serology - to distinguish those with HIV-associated malingnancy

Skin biopsy:

• Histology

• Immunohistochemistry

• Clonality (receptor gene studies)

Histology:

Can identify abnormal cells and architecture on H&E

Immunohistochemical stains:

Looking for cells that express certain proteins on their surface

Types of proteins include:

CD2, CD4, CD5, CD7, CD8, CD20 etc

Use antibodies (brown stains) that attach to these markers

The presence or absence of certain proteins helps us decide what types of cells are present and if they are normal or abnormal

Cancer cells can lose certain markers that normal lymphocytes will have (eg CD2, CD5, CD7, CD26)

T cell receptor gene rearrangement (searching for clonality)

Various different names for testing for clonality: T-cell receptor (TCR) gene rearrangement, high-throughput sequencing, PCR

All these tests are essentially looking to see if there is one cell that is multiplying itself

Normally you see a waveform with a relatively normal distribution on the report

If one cell is multiplying itself you will initially see a small peak in the waveform

If this one cell continues to multiply itself it will become a large peak and there will be less of the other types of lymphocytes present

What is the T cell receptor?

A molecule that sits of the surface of T cells that binds to parts of viruses and other abnormal cells which then activates the immune system to destroy them

T cells all have slightly different receptors so they can identify many different things

T cell clones will have exactly the same receptor

T cell gene rearrangement studies:

DNA can be remove from lymphocytes from a blood, skin or other tissues

PCR is then used to see if there is a clone of lymphocytes present

Interpreting clonality results:

All cancers are clones, but not all clones are cancer

A clone could be part of a benign process (eg reactive process to infection, drugs, eczema) so would expect this clone to decrease when process is resolved

Sometimes if have lymphoma a clone will be missed - eg it may be too early in process or the sample may be too small/degraded

When diagnosis is made, staging starts

Staging assess the extent of the lymphoma which is critical for defining prognosis and determining appropriate treatment

Staging performed by:

• History and exam of skin

• Lymph node assessment - exam, imaging +/- biopsy if indicated

• Imaging (CT +/- PET)

• +/- Bone marrow biopsy

Imaging:

Investgations should include CT neck, chest, abdomen, pelvis in all patients with CTCL and CBCL except:

• Early Mf (IA/IB)

• LyP (unless there is palpable lymphadenopathy)

PET CT should be considered for patients with PCLBCL leg type

PET CT value in MF/SS and other CTCLs remains unclear but may indicate which nodal basin to sample

Bone marrow aspirate and trephine biopsies:

Rarely indicated in MF, SS and LyP unless there is an unexplained haematological abnormality

More commmonly required for other CTCL variants and for high-grade PCLBCL leg type

Optional for low-grade PCMZL

Should be considered for PCFCL (a systemic follicle centre lymphoma with secondary cutaneous invovlement may occur)

Staging is more helpful in MF and sezary syndrome and less helpful for all the other types of cutaneous lymphomas

International Soceity for Cutaneous Lymphomas (ISCL) - EORTC revised staging system

Tumour (T):

Takes in to account body surface area and whether it is a patch, plaque or tumour (at least 1cm in size)

Erythroderma (at least 80% of skin)

Nodes (N):

Palpable:

Do physical exam feeling for enlarged lymph nodes, liver, spleen

Consider CT scans or PET scans depending on stage of disease

Biopsies may be done if abnormalities are found

Basic lymph nodes assessment:

N0: no abnormal lymph node involvement

N1: Clinically enlarged lymph nodes (> 1.5cm) but pathology doesn’t definitively show lymphoma

N2: Small clusters of abnormal cells in lymph nodes

N3: Lymph node replaced with lymphoma cells

Metastases (M):

Again picked up on exam or imaging

Do imaging if T2 and higher (CT or PET scan)

Organs that lymphoma tends to go to is liver, brain, lungs

Rarely bone marrow biopsy can be performed

Sample often taken from hip bone and some of the bone marrow is taken (aspirate or trephine which is a small core sample of it)

Blood work:

FBC identifies any increase in lymphocytes in blood

LDH can have prognostic significance

In MF and SS, morphological asssessment of peripheral blood for Sezary cells (lymphocytes with hyperconvulted nuclei) is required

Flow cytometry:

Is a way of counting and sorting lymphocytes

Can sort lymphocytes based on the CD markers they express

Normal T cells have proteins that they make that are attached to the surface

Cancer cells stop making these normal proteins (CD7, CD26)

Use flow cytometry to find these abnormal cells

Flow cytometry can help identify and sort these normal and abnormal cells through a variety of techniques which can be quite complicated

Can look at what CD markers are expressed on the surfaces of cells:

• Look for increased CD4 or CD3 cells

• Look for increased CD4:CD8 ratio of 10 or more

• Look for increased CD4 cells with abnormal phenotype (eg loss of CD7 or CD26)

• Count the abnormal cells (Sezary cell count)

TCR gene rearrangement of blood:

Can identify clonal cell in blood

Summary of staging:

IA: Patches/plaques < 10% BSA

IB: Patches/plaques > 10% BSA

(IA or IB can have small amount of blood invovlement)

IIA: Enlarged lymph nodes, no histologic involvement (rare)

IIB: Skin tumours present, no histologic LN invovlement, no mets and no significant blood invoovlement

III: Erythroderma but no hisologic invovlement

IVA1: Lots of blood involvement

IVA2: Lots of lymph node involvement

IVB: Any visceral metastasis (eg lung, liver, brain)

I found the BMJ best practice document for cutaneous T-cell lymphoma to be a useful resource regarding management options and references from this is where many of the studies I have mentioned were cited from this journal

Cutaneous lymphoma analogy for patients:

The immune system is like a car factory

The factory is the bone marrow which makes the cells (cars). Once made the cars are stamped and they go to different parts of the body

For instance some will go to the lungs to protect against things we breathe in and some will go to the skin to protect the skin

Some of the cells in the skin have started to multiply out of control

The rest of the immune system is intact and (if in Stage 1a/1b) we do not expect this to affect how long you live

There doesn’t tend to be a cure for ti but the aim is to bring it under control with treatment

Many of the initial treatments are similar to the treatments we use for eczema or psoriasis (topical therapies, phototherapy, sometimes systemic medicaiton

The aim is to:

• Improve symptoms, cosmetic appearances and health related QoL

• Reduce incidence of recurrence

Complete cure is rarely (if ever) achieved

Skin-directed thereapy is the mainstay of treatment for early disease

Systemic treatment usually reserved for more extensive or refractory disease

A pivotal clinical trial demonstrated that aggressive systemic treatment of early stage disease using systemic chemotherapy did not alter overall survival

Kaye FJ et al. A randomized trial comparing electron-beam radiation and ehmotherapy with topical therapy in the initial treatment of mycosis fungoides

Therefore, in early disease sequential skin directed therapy is often the treatment method

In middle aged patients who have advanced disease and life expectancy may be severely reduced then may consider alloegnic haematopoietic stem cell transplant but this has considerable risk of death with this treatment

Emollients for only may be appropriate in the early stages of disease, even up to years (‘expectant therapy’)

Corticosteroids:

Often used first line

Usee extra potent topical steroid (eg dermovate)

Often recurs with cessation of topical steroid and can consider giving maintenance

Complete response in 63% of patients with T1 disease and 25% in t 2 disease after median follow up 9 months

(Zackheim et al. Topical corticosteroids for mycosis fungoides: experience in 79 patients. Arch Dermatol. 1998)

Mechlorethamine:

(Aka nitrogen mustard)

A potent DNA alkylating agent

Used to be compounded ointment but new gel preparation as effective (Valchlor)

Apply once daily

Response rates 58% stage IA-IIA patients

(Lessin SR et al. Topical chemotehrapy in cutaaneous T cell lymphoma: positive results of randomized, controlled, multicenter trial testing efficacy and safety of a novel mechlorethamine 0.02% gel in mycosis fungoides. JAMA Dermatol. 2013)

Side effects:

Burning, itching, irriation

Can minimise by treating with topical steroids, slowly uptitrating dose or decreasing frequency

Small percentage in original studies developed NMSC but further long term studies don’t appear to show increase in skin cancer to date

Carmustinee (BCNU):

Is another DNA alkylating agent that can be considered

Topical retinoid:

Bexarotene gel
Can be considered in patients with early-stage CTCL who are refractory to other topical therapies or who have not tolerated other therapies
Overall response rate 63% and clinical complete response rate 21% with median duration 99 weeks in early stage CTCL in one study
(Brenean D et al. Phse 1 and 2 trial of bexarotene gel for skin-directed treatment of patients with cuatneous T-cell lymphom. Arch Dermatol. 2002 March)

Side effects:

Mild to moderate irritation at application site that often improves with use (like any other retinoid)

Narrowband UVB:

Can be used to treat patch disease

Due to limited penetration through skin not effective for plaue disease

One study reported complete response rate of 83% with median duration remission 22 months

(Ramsay et al, UVB phototherapy for early-stage cutaneous T-cell lymphoma. ARch Dermatol. 1992)

PUVA:

Used for patients with plaque disease due to increased penetration into dermis

One of the most effective therapies for patients with early disease

Few data of effects of PUVA on overall survival

Maintenance treatment may prolong the period of remission

Can be used in combination with systemic treatments (eg interferon alfa) to improve response rates and minimize UV exposure

Restrict to < 200 sessions due to skin cancer risk

Extremely radiosensitive tumours

Localised radiotherapy:

Can be used for isolated localized skin disease and in palliation of thick patches and bulky tumour nodules

Relatively low doses needed (between 4 and 40 Gy)

Total skin electron beam therapy:

This technique used most commonly for patietns with diffuse plaque involvement refractory to other skin-directed therapies

Is a radiation treatment involving electrons that treats the entire surface of skin

95% of the radiation only penetrates into the first 2cm of the body to spare vital organs from radiation

Often given 2-4 days a week for about 8-10 weeks

Complete reponse rates for early disease range from 56% to 96%

Can be repeated if necessary

Other skin directed therapy considerations (less evidence):

Topical imiquimod

PDT

Excimer laser (wavelenght of 308nm UVB light)

Systemic chemotherapy usually reserved for patients with advanced or relapsed disease or disease refractory to SDT

Palliative rather then curative

Responses seen but overall results disappointing compared with other lymphomas

Single agent chemotherapy:

Methotrexate (response rate 76%, 5-year survival 71%)

IV purine analogues:

• Pentostatin

• Cladribine

• Fludrabine

Pyrimidine antimetabolites:

• Gemcitabine

Anthracycline agent

• Doxorubicin (liposomal formulation not as cardiotoxic)

Combination chemotherapy:

Response rates of 80%

But survival rates remain unchanged and toxciity may be considerable

Reserve only for advanced lymph node and visceral disease

CHOP (cyclophosphamide, vincristine, bleomycin, prednisolone)

VICOP-B (Idrarubicine, etoposide, cyclophosphamide, prednisolone)

EPOCH (Etoposide, vincristine, doxorubicine, cyclophosphamide, predisolone)

Systemic for of PUVA

Often used in specialized centres

Useful in selected subgroups, particularly those with Sezary syndrome refractory to prior therapies

It involves the isolation of mononuclear cells by leukophoresis

These cells are exposed to a psoralen

• Orally administered (8-MOP)

• Or by direct administration in to the photophoresis machine

The cells are then exposed to UVA and reinfused into the patient

Usual course:

Administered over 2 days And repeated at 2 to 4 week intervals

The UVA is directly toxic to irradiated cells and reinfused cells also appear to stimulate selective immune response against the malignant cells

Some studies suggest it is the most effective modality for patients with erythrodermic disease

Favourable factors for responding to ECP:

• Short duration of disease, prefarably < 2 years

• Absence of bulky lymphadenopathy or major internal organ involvement

• Leuckocytosis/leukaemia < 20,000/microliter

• Presence of discrete number of Sezary cells (10-20% of mononuclear cells)

• Normal or close to normal NK cell activity

• Close to normal number of cytotoxic T lymphocytes

• No prior intensive chemotherapy

• Plaque-stage disease should not cover more than 10-15% of skin surface area

Can use ECP in comibnation with other therapies if not proving to be effective:

• IFN-alfa

• TSEBT

• PUVA

• Chemotherapy

• Agetns that target cytokines

• Retinoids

Interferon alfa:

Good response rates reported with some remissions lasting > 2 years

Can combine with other systemic therapies but studies investigating combination with ECP, pentostatin and fludarabined failed to demonstrate significant improvements in response rates

Bexarotene:

An oral retinoid that selectively binds to the retinoid x receptor (RXR) family of nuclear receptors

Can be used for persistent or refractory early and advanced disease

Side effects:

• Hyperlipideamia (83%)

• Hypothyroidism (74%)are common but reversible adverse effects

• Neutropaenia (47%)

May consider initiating lipid lowering drugs and thyroxine prior to starting

Histone deacetylase inhibitors:

Vorinostat and romidepsin

Induce histone acetylation and protein acetylation leading to down-stream cell cycle arrest and apoptosis

Can improve skin lesions and symptoms like pruritus

Alemtuzumab (anti-CD52)

Monoclonal antibody

One study showed overall response rate of 55% in patients with advanced disease (32% complete response)

Brentuximab vedotin:

Brentuximab vedotin is a chemotherapy medication that kills cells expressing CD30

Phase II trials ave shown it is highly active in CD30+ CTCL

Overall response rate of 54% in MF, irrespective of CD30 status

May see initial flare when starting and median time to response is 12 weeks

Median duration of response 32 weeks

Side effects:

• Neuropathy

• Fatigue

• Drug rash

Phase III trial:

Previously treated adult patients with CD30+ MF or primary cutaneous anaplastic large-cell lymphoma

Significant improvement in objective global response lasting at least 4 months with brentuximab vedotin (56%) bs physician’s choice of methotrexate or bexarotene (13%)

CD30 is a protein made by activated T and B lymphocytes

It is present in CD30 +ve lymphoproliferative disorders, some cases of MF and Hodgkin’s lymphoma

Commonest ‘CTCL’ in children

Technically not a lymphoma but confers and increased risk for cutaneous lymphoma

Get recurrent papules and/or nodules that frequently cruts or ulcerate and then heal often with atrophic hypopigmented scarring

They are often asymptomatic, rapidly growing skin lesions that involute over about 6-10 weeks

Often can be mistaken for acne/insect bites

Predominantly on trunk and limbs but can present anywhere including palms and soles

Can get lesions at different stages of evolution

No associated systemic symptoms

Ddx: insect bites, acne, PLEVA, molluscum

May develop an associated systemic lymphoma in 2-10% of patients so it very important that they are kept under surveillance

Atypical lymphocytes in dermis with plemorphic and hyperchromic nuclei

May see mixed infiltrate

CD30+ve in majority of cases

Depends on when biopsy taken as biopsy at any one time only shows a snapshot in time of an evolving process
4 histological subtypes have been identified (A-D)

Most common subtype is type A in which you see large, atypical CD30+ve lymphocytes in a wedge-shaped distribution throughout the dermis and ixed with inflammatory cells

Part of the spectrum of CD30+ve CTCL

Typically get a solitary tumour which may increase in size and ulcerate

Histological features of PC-ALCL can resemble those seen in anaggressive systemic lymphoma but the disease doesn’t follow an aggressive course

• Confluent sheets of large, atypical lymphocytes infiltrating dermis and subcutis

• Don’t tend to see epidermotropism

• Mitotic figures abundant

Other ddx:

Can share histological features with Lymphomatoid papulosis

MF can show large cell transformation and can be CD30+ve (if have multiple patches and plaques consider MF)

CD30+ve cellswhich can be CD4+ or CD8+ve

(may also express CD3 and CD5)

It is essential to distinguish primary cuataneous anaplastic large cell lymphoma (PC-ALCL) from systemic ALCL

The absence of staining with anaplastic lymphoma kinase (ALK) favours the primary cutaneous variant

(Think the absence of staining means it is absent elsewhere)

ALK staining is detected in > 90% of systemic ALCLs and results from a translocation involving the ALK gene causing the expression of the ALK protein

(Translocation is detectable with cytogenetic tests)

Lesions can be excised or treated with radiotherapy

Spontaneous regression may occur

Multiple cutaneous lesions or nodal spread may require systemic treatment

Brentuximab vedoin (Adcetris):

Granted FDA approval November 2017 for treatment of adult patients with:

Primary cutaneous anaplastic large cell lymphoma or CD30 +MF who have received prior systemic therapy

ALCANZA trial:

Phase 3 trial

Looked at patients with CD 30+ cutaneous T-cell lymphomas (either CD30+ MF or pc-ALCL)

A significant improvmeent in objective global response was seen with brentuximab versus physician’s choice of mehtotrexate or bexarotene

Objective global resposne: 56% vs 13%

Complete response: 16% vs 2%

Progression free survival: 16.7 months vs 3.5 months

Generally quite good

5-year survival rates above 90%

Topics to do:

Rarer sub-types of T cell lymphoma

Subcutaneous panniculitis like T cell lymphoma:

Commonest cause of panniculitis is E nodosum

What are the things that make panniculitis atypical:

Persistance vs recurrent episodes with complete clearing in between

Tend to be on lower extremities also

On pathology tends to be a lobular panniculitis (similar to lupus panniculitis)

Will have atypical cells on H&E

Can be difficult to distinguish between lupus panniculitis and subcutaneous panniculitis like T cell lymphoma

Some consider them to be two entities in a spectrum

About 20% of patients with subcutaneous panniculitis T cell lymphoma have positive ANA

Less than 1/3 of primary cutaneous lymphomas
Main types:

Primary cutaneous:

Marginal zone B-cell lymphoma

Follicle centred B-cell lymphoma

Diffuse large B-cell lymphoma

Don’t tend to have the epidermal changes with a scaly rash with ulceration that T cell lymphomas tend to have have

Patients often present with plum coloured/reddish brown dome shaped nodules

In most cases they are asymptomatic

Can be isolated lesions or a few scattered lesions

Low grade B cell lymphomas tend to be on the head or neck or upper trunk

The more aggressive B cell lymphoma (large anaplastic B cell lymphoma) tend to be on lower extremities

Site localization can be an important distinguishing feature

Borrelia burgoderfi has been implicated in the pathogenesis of all types of CBCL in endemic areas in Europe

Serology is indicated in all patients

55% of all CBCL

Firm plum coloured dermal lesions over trunk or head

Salp lesions may be associated with alopecia

Multiple lesions may occur and relapse is frequent

Systemic spread is rare

It is very important to be aware that secondary cutaneous invovlement with systemic follicle centre lymphoma can occur so full staging investigations are essential to ensure you are dealing with a primary cutaneous lymphoma

Diffuse, folliclular or mixed pattern of large centrocytes and centroblasts in the dermis without epidermotropism

CD19, CD20, CD22, CD79, BCL-6 positive

(CD10 may be positive in some lesions)

In a systemic follicular lymphoma the t(14;18) translocation often found but typically absent in primary cutaneous FCL

Usually skin directed therapy

If have multiple lesions could consider rituximab or low dose chemotherapy (chlorambucil)

Clonal IgH gene rearrangements can aid diagnosis

B cell lymphoma pathology:

Multiple other markers used to look at to see what type of cell it is (eg CD-20, bcl-2, bcl-6)

Borrelia burgoderfi serology (reported in associated with PCMZL

B cells have immunoglobulins (antibodies) instead of a T cell receptor

Can look for clones that have identical immunoglobulin heavy chains

Clonal IgH gene rearrangements can aid diagnosis in B cell lymphoma

Management:

Low grade lymhomas:

Prognosis tends to be very good

Do blood work and imaging

If it is confirmed that this is a primary cutaneous low grade B cell lymphoma

Options could include:

Monitor

Intralesional steroids

Excise if one lesion

Radiation if larger lesion

Aggresive B cell lymphoma:

Refer urgently to haematology for management

Often has poor prognosis

Staging cutaneous lymphomas other than MF/SS:

In 2007, a staging system was developed for all ohter cuatnous lymphomas that describes the extent of the lymphoma (using a TNM classification) but it does not give any useful information about prognosis

I won’t go into much more detail about that here

Issues:

Many different type of cutaneous lymphomas

Most are rare

Not useful in clinical practice

Reason for classification:

Current stating system helps classify patients

Over time may be able to better define prognosis for different types of cutnaeous lymphoma

Currently it is easier to define prognosis based on growth pattern of the lymphom

Indolent:

Grows slowly

Treatment may not be necessary unless causing symptoms

Often not curable

Aggressive:

Grow rapidly

Treatment necessary for survival

Often curable

Parapsoriasis:

Pseudolymphoma:

Term represents several clinical entitiies that probably have multiple aetiologies

• Lymphocytoma

• Spiegler-Fendt sarcoid

• Lymphadnosis benigna cutis

• Jessner’s benign lymphocytic infiltrate
  

In most cases aetiology is unknown (some cases may be related to chronic arthropod bites)

Usually present as indloent single or grouped red/purple nodules or plaques on the head, neck and upper trunk

Infiltrate may show B or T cell predominance

Some cases can be difficult to differentiate from lymphoma and patient should be follwed up prior to definitive diangosis being made

Leukaemia cutis:

CLL in adults is the most common cause of specific leukemic skin lesions in adults

They are usually multiple and may present wih papules, nodules, plaques, erythema and rarely bullae

The neoplastic proliferation of lymphocytes is usually B cell in origin