Malignancy Flashcards
1
Q
Immunophenotype CTCL
A
- To immunophenotype:
- antigen retrieval techniques allow immunophenotyping on formalin-fixed tissue sections
- loss of one or more T cell associated antigens such as CD 2,3,4 and 5 by the neoplastic T cells is important criteria
- loss of CD7 can be a variation of normal
- Clonal T cell populations have been identified in CTCL but also PLEVA, LP, lichen sclerosus, pseudolymphomas
2
Q
B/G info CTCL
A
- heterogenous group of neoplasms of skin homing T cells
- represent ~ 75-80% of cutaneous lymphomas
- neoplastic T cells in most CTCLs express cutaneous lymphocyte antigenand the CC-chemokine receptors CCR4 and CCR10, indicating they are the neoplastic counterparts of normal skin-homing T cells
- To diagnose: 4-6 mm PB or excisional/incisional from untreated skin
3
Q
Approach to CTCL diagnosis
A
- Distinction is made between MF, MF variants and SS and the remainder of CTCL –> these are the 65% most common
- Consider primary cutaneous CD30 positive lymphoprolifrative disorders –> do CD30 immunostaining
- After this, 90% will be diagnosed. Then consider the rest.
4
Q
MF Epidemiology
A
- 50% of cutaneous lymphomas
- 0.4 per 100 000 per year
- Adults and men more affected
5
Q
MF Pathogenesis
A
- Genetics:
- ?overexpression of TOX
- gains of chromosomes
- Loss of 9p21.3 - harbours the CDKN2a, CDKN2B and MTAP tumour suppressor genes associated wtih shorter survival
- Whole genome sequencing has implicated NF-KB signalling
- Environmental
- Persistent antigenic stimulation
- MALT, H pylori, CBCL (Lyme disease), coeliac disease
- Immunologic
- CD8 T cells higher in dermal infiltrates, associated with better prognosis
- Neoplastic T cells are derived from CD4 T cells with a Th2 cytokine profile (IL-4, IL-5 and IL-10)
- Believed to be a gradual shift from type 1 cytokine profiles to type 2 –> increased levels of Th2 cytokines may impair the Th1 cell mediated antitumour response
6
Q
MF clinical
A
- Pre-MF: many years of non-specific lesions with no diagnostic biopsies, 4-6 years median
- Early patch MF: variably sized erythematous, finely scaling lesions which may be pruritic, +/- atrophy, poikiloderma, mottled hyper and hypopigmentation,a trophy, telangiectasia (poikiloderma vasculare atrophicans). Prediliction for sunhidden spots.
- Annular, polycyclic, typical shorse show
- <10% develop nodules or tumours
- if tumours present without preceding or co-existing patches then unlikely to be MF
- Extra-cutaneous
- lymph nodes usually always first, then any visceral
- bone marrow rarely involved
7
Q
MF histology
A
- Early patch:
- superficial band like or lichenoid infiltrate, primarily lymphocytes
- atypical cells, highly convoluted (cerebriform)
- epidermotropism
- colonize basal layer as single cells surrounded by vacuolated halos, often in a linear configuration
- Plaques:
- Epidermotropism: Pautrier microabscesses (intra-epidermal nests of atypical cells)
- Acanthosis and elongation of rete ridges
- +/_ eos and plasma cells
- Tumour:
- epidermotropism gone
- small, medium or large cells with cerebriform nuclei, blast cells with prominent nuclei
- Large cell transofrmation: presence of CD30 negative or CD30 positive large cells exceeding 25% of the infiltrate or forming microscopic nodules. Of these, CD30 positive have a better prognosis
8
Q
MF Immunophenotype
A
- Mature CD3+, CD4+, CD45RO+, CD8- memory T cell phenotype
- Minority CD3+, CD4-, CD8+
- May demonstrate partial loss of T cell antigens
9
Q
MF DDx
A
- Benign dermatoses
- Eczema
- Psoriasis
- Superficial fungal infections
- Drug reactions
- Parapsoriasis
- Benign dermatoses with histologic features of MF
- Lymphomatoid contact dermatitis
- Lymphomatoid drug reactions
- Actinic reticuloid
- Other types of epidermotropic CTCL
10
Q
MF TNMB classification
A
- T skin:
- 1 - <10% body patch/plaque
- 2 - generalised patch/plaque >10%
- 3 - tumours
- 4 - erythroderma
- N nodes
- 1 - enlarged, no histological findings
- 2 - enlarged, histo findings, nodal architecture uneffaced
- 3 - enlarged, nodal architecture partially effaced
- M - visceral
- 1 - involvement
- B - bloods
- 0 - no Sezary cells (or <5% of lymphocytes)
- 1 - low blood tumour burden (>5% of lymphocytes are Sezary)
- 2 - high blood tumour burden - >1000/mcl Sezary cells + positive clone
11
Q
MF staging
A
- 1A: T1N0M0,B0-1
- 1B: T2,N0M0, B0-1
- 2A: T1-2, N1-2, M0, B0-1
- 2B: T3, N0-1, M0, B0-1
- 3: T4, N0-2, M0, B0-1
- 4A1: T1-4, N0-2, M0, B2
- 4A2: T1-4, N3, M0, B0-2
- 4B: T1-4, N0-3, M1, B0-2
12
Q
MF Monitoring
A
- No further examinations are recommended for patients with Stage 1A-B disease except for monitoring and checking for clinical lymphadenopathy
- Do CT chest in patients in whom extracutaneous disease is suspected
13
Q
MF Treatment options
A
- Early stages - skin directed therapies:
- Topical steroids –> complete remission in up to 60%
- Topical chemotherapy - mechlorethamine –> remission in 60-80%
- Radiation treatment - total skin electronc beam irradiation with an energy of 4-6 MeV, total dose of 36 Gy over an 8-10 week period.
- Phototherapy - PUVA, NBUVB, Broadband, UVA1
- PUVA has become standard for early stages of MR, 80-90% complete response rates have been reported
- Later stage - systemic therapies
- Interferons - interferon-alpha inhibitors, can cause flu-like symptoms, hair loss, nausea, depression, BM suppression
- Retinoids - isotretinoin, acitretin, bexarotene + PUVA –> with PUVA gives similar results as just PUVA but require less treatments
- Denileukin diftitox - fusion protein, diphtheria toxin is linked to IL-2, binds to the high affinity IL-2 receptor expressed on neoplastic T cells in MF, and internalization of the toxin results in inhibition of protein synthesis and cell death
- Histone deacetylase inhibitors - vorinostat and romidepsin - inhibition of the enzyme HDAC affects the expression of many genes that are involved in cellular proliferation. ?unsure if patients benefit
- Systemic chemotherapy - only used in patients with unequivocal lymph node or visceral involvement, or in patients with progressive skin tumours. Get 6 cycles of CHOP.
- Young patients: allogeneic haematopoietic stem cell transplantation may be considered
14
Q
MF Guide to treatment
A
- Pre-mycotic –> steroids, NBUVB
- Stage 1A-2A –> PUVA, NBUVB, topical steroids or retinoids, RT, TSEB (total skin electron beam irradiation)
- Stage 2B –> PUVA or HN2 + RT, TSEB, if relapse PUVA + IFN-alpha, PUVA + retinoids, HDACi
- Stage 3 –> ECP, if not effective add INF-alpha, low dose chlorambucil + prednisone, add skin directed therapies if necessary. Second line: oral bexarotene, denileukin, HDACI, low dose alemtuzumab
- Stage 4 –> chemotherapy, biologics - denileukin, IFN-alpha, oral retinoids, skin-directed therapies, if recalcitrant allogeneic haemotopoietic stem cell transplant
15
Q
MF prognosis
A
- Stage 1A - 96% survival 10 years
- 1B - 77-83%
- 2B - 42%
- 4 - 20%
16
Q
Folliculotropic MF Epi
A
- Approximately 10% of MF patients
- M>F
17
Q
Folliculotropic MF clinical and staging
A
- Grouped follicular papules, acneiform lesions, indurated plaques and sometimes tumours
- Preferentially involve the head and neck
- Associated with alopecia, and mucinorrhoea
- Infiltrated plaques in the eyebrow region with concurrent alopecia are highligh characteristic
- Pruritis
- Secondary bacterial infections
- Is not helpful
- Peri-follicular localization makes it hard to respond to cutaneous treament
- Assume they are at tumour stage
18
Q
Folliculotropic MF Histology
A
- Peri-vascular and peri-adnexal localization of dermal infiltrates, with variable infiltration of the follicular epithelium by small, medium sized or sometimes large T cells with hyperchromatic and cerebriform nuclei
- Has folliculotropism instead of epidermotropism
- Mucinous degeneration of follicular epithelium
- Stain: Alcian blue or colloidal iron staining will show mucin
- In peri-follicularm neoplastic T cells may be blasts rather than cerebriform
- Phenotypes: CD3+, CD4+ and CD8-, may have CD30 positive blast cells
19
Q
Folliculotropic MF DDx
A
- Other epidermotropic CTCL
- Seb derm and atopic dermatitis
- Follicular mucinosis
20
Q
Folliculotropic MF Rx
A
Combination of PUVA with either IFN-alpha or retinoids, local radiotherapy or TSEB
21
Q
Pagetoid Reticulosis Clinical
A
- extremely rare, <1% of CTCL
- Solitary psoriasiform or hyperkeratotic patch or plaque, localized to extremity and slowly progressive
22
Q
Pagetoid Reticulosis Histology
A
- hyperplastic epidermis
- marked infiltration of large atypical pagetoid cells into epidermis - arranged singly or in nests or clusters
- Atypical cells have medium sized or large, sometimes hyperchromatic and cerebriform ncueli
- Superficial dermis may have small lymphocytes
- Immunophenotype:
- CD3+, CD4+, CD8- or CD3+, CD4- and CD8+
CD30 often expressed
- CD3+, CD4+, CD8- or CD3+, CD4- and CD8+
23
Q
Pagetoid Reticulosis Treatment
A
radiotherapy or surgical excision
24
Q
Granulomatous Slack Skin
A
- also very rare
- pendulous lax skin with a prediliction for axillae and groin
- association with Hodgkin lymphoma
- Indolent course
- Histology:
- dense granulomatous dermal infiltrates containing atypical T cells with cerebriform nuclei, macrophages
- Destruction of elastic tissue and elastophagocytosis
- Epidermis may be infiltrated by small atypical T cells
- CD3+, CD4+ and CD8=
- Treatment: radiotherapy
25
What is a primary cutaneous lymphoma
malignant lymphoma confined to the skin at presentation after complete staging procedures
26
WHO classification of CBCL (i.e. name them)
- Primary cutaneous follicle centre lymphoma
- Primary cutaneous diffuse large B cell, leg type
- Primary cutaneous marginal zone b cell lymphoma - Extranodal marginal zone lymphoma of MALT lymphoma
- Diffuse large B cell lymphoma, NOS
- Intravascular diffuse large B-cell lymhoma
27
CBCL epidemiology
- Varies worldwide, seem to be more in Europe
- Borrelia associated - so more in endemic regions
- M=F
- Uncommon in kids a part from B lymphoblastic lymphoma/leukaemia
28
Pathogenesis of CBCL
- Unknown
- Little data on genetics
- Possible longstanding antigenic stimulation due to chronic infection with specific microorganisms --> H pyloria, Borrelia
- Immune dysregulation: associated with immunosuppression, AIDS, transplant recipients, methotrexate
29
CBCL how to stage
comple blood exam, flow cytometry, CT chest, abdomen and pelbis, and PET
- Internationally, BM biopsy still recommended in follicle centre lymphoma, leg type and intravascular but not helpful in marginal zone
30
Primary cutaneous follicle centre lymphoma clinical
- Neoplastic proliferation of germinal centre cells confined to the skin
- Most common
- Solitary or grouped, pink-plum coloured papules, plaques or tumours
- Particularly to trunk, can be surrounded by patches of erythema
- 'Crosti's lymphoma' = peripheral patch of erythema
- Rarely - miliary or clustered small papules that are acneiform in nature
- Preferences scalp, forehead, back
- B symptoms are rare, LDH is normal and has good prognosis
- Recurrences in up to 50% of patients, but dissemination to lymph nodes and internal organs are rare
31
Primary cutaneous marginal zone B cell lymphoma (Extranodal marginal zone lymphoma of the MALT) clinical
- Previously classified as primary cutaneous immunocytoma or primary cutaneous plasmacytoma
- Recurrent asymptomatic pink-violet to red-brown papules, plaques and nodules that favour extremities (upper > lower) or trunk
- Rarely generalized, raerly ulcerate
- B symptoms are not present, LDH within normal limits, good prognosis
- Resolution - may be accompanied by secondary anetoderma due to loss of elastic fibres int he area of the tumour
- Can arise in areas affected by acrodermatitis chronica atrophicans - Europe
32
Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type clinical
- Characterised by predominance of large round cells - centroblasts, immunoblasts - that are positive for Bcl-2, MUM-1 and FOX-P1
- Exclusively in older patients and mostly women
- Solitary or clustered erythematous to red-brown nodules, located primarily on the distal aspect of one leg (therefore leg type). Small erythematous papules adjacent to larger nodules
- Lesions may arise on both lower extremities within a short time interval
- Ulceration
- In ~20% will not be on the legs
- Prognosis: not as good, 5 year survival 40-50%, loss of CDKN2A associated with a worse prognosis
- Ddx: large B cell lymphoma with leg involvement, so need complete work up prior to diagnosis of leg type
33
Intravascular diffuse large B cell lymphoma clinical
- Rare, malignant proliferation of large B lymphocytes within blood vessels
- Occasionally, skin is the only affected site but often there is systemic involvement including the CNS
- Clinically: indurated, erythematous or violaceous patches and plaques - trunks and thighs, prominent telangiectasia
- Not typical of cutaneous lymphoma, and may suggest diagnosis of panniculitis or vascular tumour
- Prognosis is bad, it is aggressive
- Several patients, was observed to be confined to cherry angioma lesions
34
Precursor B Lymphoblastic Lymphoma/Leukaemia clinical
- Malignant proliferation of precursor B lymphocytes
- rarely is the skin the primary site, if it is still treat them like it is systemic
- Children and young adults
- Solitary, large erythematous tumours - commonly located on the head and neck
- Often asymptomatic for a few weeks
- If secondary skin lesions - B symptoms present, LDH elevated
- Agressive, poor prognosis
35
Plasmablastic lymphoma clinical
arises in oral cavity of immunosuppressed, associated with EBV
36
CBCL how to diagnose
- Histology
| - PCR + FISH --> detect rearrangements in immunoglobulin genes as well as specific chromosomal translocations
37
Primary cutaneous follicle centre lymphoma histo
- Epidermis is spared
- Bottom heavy infiltrate in varying size and shape
- 25% have clear cut follicular pattern with formation of neoplastic germinal centres
- neoplastic follicles show morphologic features of malignancy: reduced or absent mantle zone, lack of tingible body macrophages, monomorphism of follicles
- Centroblasts and medium-large sized centrocytes (large, cleaved follicle centre cells)
- Keep in mind, if monotonous proliferation of centroblasts and/or immunoblasts then classify as diffuse large B cell lymphoma
- There is a variant that looks like spindle cell tumours
38
Primary cutaneous follicle centre lymphoma stains and molecular analysis
- CD10 (follicular has 10 letters)
- bcl-6
- CD20
- MIB-1
- CD79a
How to differentiate - lower degree of proliferative activity within malignant follicles by anti-Ki 67 antibody in contrast to strong Ki-67 positivity in reactive follicles
Negative for CD5, CD23, bcl-2 and MUM-1
Genetic analysis: immunoglobulin heavy chain rearrangement in 60-70% of patients
39
Primary Cutaneous Marginal Zone B cell Lymphoma histo
- Patchy, nodular or diffuse infiltrate involving the dermis and subcutaneous fat
- Epidermis is spared
- Characteristic pattern:
- nodules of reactive lymphocytes which have reactive germinal centre. These are surrounded by neoplastic marginal zone cells
- surrounded by marginal zone cells pale staining small to mediu sized cells with indented nuclei, inconspicious nucleoli and abundant pale cytoplasm
- in addition, plasma cells at the margins of the infiltrate, lymphoplasmacytoid cells, small lymphocytes, eosinophils
- Dutcher bodies: PAS positive intranuclear inclusions - eosinophilic
- Rarely, the predominant cell type is the plasma cell
40
Primary Cutaneous Marginal Zone B cell Lymphoma stains and molecular analysis
- Stains: bcl-2, CD20, CD79a
- Negative for CD5, CD10, CD23, Bcl-6
- Intracytoplasmic monotypic expression of immunoglobulin light chains - kappa or gamma - can be observed
- Monoclonal rearrangement of IGH can be detected in 60-80% of cases
- Express class switched immunoglobulins
- although the B lymphocyte changes antibody production from one class to another, the cell retains affinity for the same antigen
- Particular translocation that has been detected: IGH and MALT1
- In 50% patients no molecular abnormalities are found
- Other genetic aberrations in trisomy 3
41
Primary Cutaneous Diffuse Large B Cell Lymphoma histo
- Grenz zone
- Diffue infiltrate in dermis and subcutis
- Can involve epidermis - Pautrier microabscesses
- Immunoblasts (large round cells with abundant cytoplasm and prominent nucleoli) and centroblasts
- Cells are + large
42
Primary Cutaneous Diffuse Large B Cell Lymphoma stains and molecular analysis
- Positive for CD20, CD79a, PAX-5 and IgM (B cell markers) but there can be a partial loss of antigen expression
- Neoplastic cells mostly express Bcl-2, MUM-1, FOX-P1 and MYC
- Demonstrate monoclonal rearrangement of IGH
43
Approach to diagnosis of cutaneous large b cell lymphoma:
- if the predominant cell type is large and cleaved then it is a follicle centre diagnosis
- if large round --> check where it is
- Intra-vascular --> intravascular dx
- Dermis or subcutis --> do BcL immunophenotype
- Bcl-2 positive --> diffuse large cell, leg type
- Bcl-2 negative --> diffuse large cell, other
- So basically - marginal and diffuse large cell are positive for Bcl-2 and follicle cell isn't
44
Intravascular diffuse large b cell lymphoma histo, stains and molecular analysis
- proliferation of large atypical lymphocytes that fills dilated blood vessels within the dermis and subcutaneous tissues
- positive for B cell markers and Bcl-2 and MUM-1 and FOX-P1
- Stain with CD31 and CD34 to highlight intravascular location
- Monoclonal rearrangement of IGH or molecular analysis
45
Precursor B lymphoblastic lymphoma/leukaemia histo, stains and molecular analysis
- monomorphous proliferation of medium-sized cells with scanty cytoplasm and round or convoluted nuclei with fine chromatin
- 'Starry sky' due to tingible bodies: macrophages with inclusion bodies
- Mosaic stone pattern
- Mitoses + necrotic cells
- Positive for Tdt (present on precursor T and B cells), PAX-5, CD10, CD20, CD79 and cytoplasmic mu chain of immunoglobulins
- Monoclonal rearrangement of IGH and polyclonal for TCR
46
CBCL management
- Once you have diagnosis from histo, molecular and immunohistochemistry then you must stage
Low grade:
- watchful waiting - follow up every 6 months
- papulonodules - can use IL-kenacort
- Few lesions --> surgical excision with close margins, radiation treatment with wide margins (10-20 cm)
- Reports of antibiotics (similar to treating H pylori and MALT). Complete response in those caused by borrelia
- Subcutaneous or intralesional interferon
- IL rituximab
High grade:
- Chemotherapy + rituximab - CHOP
- IV rituximab
47
Sezary triad and diagnostic criteria
- triad: erythroderma, generalized lymphadenopathy, presence of neoplastic T cells (Sezary) in the skin, LN and blood
- Diagnostic criteria:
- demonstration of a T-cell clone in the peripheral blood
- Absolute Sezary cell count >1000 cells or immunophenotypical abnormalities
48
Sezary epi
- rare - 5% of all CTCL
| - exclusively in adults
49
Sezary clinical
- erythroderma with marked exfoliation, oedema and lichenification
- ++ pruritic
- Lymphadenopathy, alopecia, onychodystrophy, palmoplantar hyperkeratosis
- Prior - may have non-diagnostic dermaittis
- Poor prognosis - 5 year survival 25%, most die of opportunistic infections due to immunosuppression
50
Sezary histology
- Can be similar to MF
- Cellular infiltrates more monotonous, and epidermotropism may be absent
- 1/3 --> may be non-specific
- LN: dense, monotonous infiltrate of Sezary, with effacement of the normal lymph node architecture
- BM may be involved
- Phenotype: CD3+, CD4+, CD8- phenotype, lack CD7 and CD26, and express programmed death-1
51
Sezary pathogenesis
- unknown
- Neoplastic CD4+ T cells have the phenotype of a central memory T-cell subset, and are capable of circulating between skin, LN and peripheral blood, whereas MF iits derived from non-circulating skin resident effector memory T cells
- SS and MF have major genomic differences
- Deletions of chromosomes that encode PTEN, and gains of those including MYC
52
Sezary ddx
- Psoriasis
- Atopic dermatitis
- PRP
- Drug reaction
- Actinic reticuloid --> CD3+, CD4- and CD8+
53
Sezary Rx
- Skin directed therapies as an adjuvant may be helpful - PUVA and topical steroids
- Extracorporeal photopheresis - alone or in combination with others --> overall response rate ~25%
- Others: interferon alpha, and prolonged treatment with MTX or low dose chlorambucil + pred, CHOP --> higher response rates but generally short lived
- Recent studies indicated: bexarotene, denileukin, diftitox, HDACi, alemtuzumab (anti-CD52)
- Curative for advanced disease: allogenic haemotpoietic stem cell transplant
54
Adult T Cell Leukaemia-Lymphoma epi
- Endemic to areas with high HTLV-1 --> southwestern Japan, the Carribean, parts of Central Africa
- Jewish population in Mashad, Iran
- Only minority who are seropositive develop ATLL
- Occurs in adults, M>F
- Vertical transmission more common than horizontal
55
Adult T Cell Leukaemia-Lymphoma clinical
- Acute: lymphadenopathy, organomegaly, hypercalcaemia, skin lesions
- Chronic: more smoldering, patches, plaques, papular skin --> closely resemble MF --> more protrated clinical course
56
Adult T Cell Leukaemia-Lymphoma Histology
- Superficial or diffuse infiltrate of small, medium sized or large pleomorphic T cells
- Marked epidermotropism
- May be difficult to distinguish from MF
- Express: CD3+, CD4+, CD8-, CD25+, strongly expressed PD-1
57
Adult T Cell Leukaemia-Lymphoma Ddx
- MF
| - Dx of ATLL requires demonstration of clonally integrated HTLV-1
58
Adult T Cell Leukaemia-Lymphoma Rx
- Zidovudine and interferon-alpha, but mostly needs chemotherapy
- In Japan - anti-CCR4 (mogamulizumab) is approved for treating ATLL
- If chronic, can do skin-directed therapies
59
Primary Cutaneous CD30 Positive Lymphoproliferative disorders
- Second most common group, accounting for 25% of CTCL
- Includes:
- Primary cutaneous anaplastic large cell lymphoma
- Lymphomatoid papulosis
- Borderline cases --> cannot decide between ALCL and LyP
- Should be differentiated from:
- 1. Skin involvement by systemic ALCL
- 2. CD30 positive transformed MF
- 3. Other well-defined types of CTCL which may be CD30 positive
- 4. Reactive skin conditions with infiltrates containing CD30 positive blast cells - viral, arthropod, scabies, etc
60
Primary Cutaneous Anaplastic Large Cell Lymphoma Epi
- ~12% of all CTCLs
- M>F, 2:1, mostly adults
- More common in breast implants - relative risk of 421.8
61
Primary Cutaneous Anaplastic Large Cell Lymphoma clinical
- Solitary or localized nodules or tumours (occasionally papules) that often develop ulceration
- 20% --> multifocal lesions
- May show partial or complete spontaneous regression, and frequently relapse in the skin
- Extracutaneous in 10% --> mainly regional lymph nodes
- Prognosis is good --> 10 year disease related survival exceeding 85%
62
Primary Cutaneous Anaplastic Large Cell Lymphoma Histology
- Diffuse non-epidermotropic infiltrates with cohesive sheets of large CD30 positive tumour cells
- Most cases, the tumour cells have characteristic morphology of anaplastic cells, with round, oval or irregularly shaped nuclei, prominent eosinophilic nucleoli, and abundant cytoplasm
- Less commonly tumour cells have a plemorphic, immunoblastic or Reed-Steenberg cell-like appearance
- High mitotic index
- Reactive lymphocytes at the periphery of the tumour
- Ulcerating lesions may show an LyP-like histology --> abundant inflammatory infiltrate of reactive T cells, histiocytes, eosinophils, neutrophils and relatively few CD30 positive cells. Epidermal hyperplasia may be prominent. Intra-lymphatic complexes of tumour cells are common
63
Primary Cutaneous Anaplastic Large Cell Lymphoma IMmunophenotype
- CD4+, loss of CD2, CD5 and CD3
- CD30 must be expressed by the majority of neoplastic cells
- 70% of cases - expression of cytotoxic proteins - granzyme, TIA-1, perforin
- MUM1/IRF4 expressed in almost all cases
- Express cutaneous lymphocyte antigen, but do not express EMA (epithelial membrane antigen) or ALK (anapplastic lymphoma kinase)
64
Primary Cutaneous Anaplastic Large Cell Lymphoma genetics
- Systemic ALCL in kids has t(2;5) translocation
- There have been unusual cases of ALK+ C-ALCL including:
- Strong nuclear and cytoplasmic staining of the t(2;5) chromosomal translocation
- Or expression of cytoplasmic ALK protein
- C-ALCL: rearrangements of the DUSP22-IRF4 locus onf 6p25.3 almost exclusively in C-ALCL and small subset of LyP
- There are other chromosomal aberrations
- High expression of skin-homing chemokine receptor genes CCR10 and CCR8 --> may explain affinity for skin and low incidence of dissemination to extracutaneous sites
65
Primary Cutaneous Anaplastic Large Cell Lymphoma Rx
- Initial: radiation therapy or surgical excision
- If solitary lesion disappears spontaneously, no further therapy is required
- Multi-focal: radiation treatment, low dose MTX, interferon alpha
- Extra-cutaneous: doxorubicin-based multi-agent chemotherapy
- If on one or both legs then risk for more aggressive clinical course
- Brentuximab - anti-CD30 is FDA approved for relapsed systemic ALCL
- In an international open-label randomized phase 3 trial - 56.3% of patients receiving brentuximac versus 12.5% receiving methotrexate or bexarotene responded at 22.9 months
- major side effect: peripheral neuropathy in 2/3 of patients
66
Lymphomatoid papulosis pathogenesis
- Unknown
- ?viral --> no real evidence
- randomly goes away as well
- Interactions between CD30 and its ligand may contribute to apoptosis of the neoplastic T cells and subsequent regression of skin lesions
- Mutation in TGF-beta has been suggested
67
Lymphomatoid papulosis epi
- 15% of all CTCL
- Any age
- Average age 35-45 years
- Male:female - 1.5:1
68
Lymphomatoid papulosis clinical
- red-brown papules and nodules - can develop central haemorrhage, necrosis and crusting
- spontaneously dissappear 3-12 weeks later
- lesions in different stages of evolution coexist
- residual transient hypopigmented or hyperpigmented macules, and superficial atrophic varioliform scars that may disappear without ulceration or sequelae
- number of lesions varies from several to >100
- lesions may be localized, sometimes clustered within rather well-defined areas or generalized
- predominant sites: trunk and limbs
- asymptomatic
- Ranges from a few months to 40 years
- 20% --> associated with cutaneous or systemic lymphoma - generally MF< C-ALCL, Hodgkin lymphoma
- Prognosis: excellent
69
Lymphomatoid papulosis histology
- Correlates with the age of the sampled skin lesion
- Several histologic subtypes have been described, not helpful in therapeutic or prognostic implications
- Type A: classic, most common. >75%. Wedge-shaped infiltrate, with scattered or small clusters of atypical CD30 T cells. Prominent epithelial hyperplasia with focail vesiculation, and subepidermal oedema, and dense lymphoid infiltrates in the dermis
- Type B: epidermotropic, superficial perivascular to band0like and sometimes wedge-shaped infiltrate of small to medium sized, atypical CD4+, CD30+ or CD30-
- Type C: diffuse infiltrates or large clusters of large CD30 T cells
- Type D: marked epidermotropism of atypical, small to medium sized, CD8+, CD30+, pleomorphic T cells, necrotic keratinocytes
- Type E: angioinvastion and destruction by CD8, CD30
- Type F: perifollicular infiltrates with variable degree of folliculotropism of atypical CD30 T cells
70
Lymphomatoid papulosis ddx
- Folliculitis
- Arthropod bites
- PLEVA and PLC
71
Lymphomatoid papulosis Rx
- Topical or systemic steroids and antibiotics are not helpful
- Systemic chemotherapy or TSEB irradiation may help, but once you stop therapy it comes back
- If have few non-scarring lesions, can just monitor
- Cosmetically disturbing: low dose methotrexate
- Consider PUVA, topical mechlorethamine or carmustine, low dose etoposide
- If large skin tumour --> observe for 4-12 weeks, if doesn't remit then excise or radiotherapy
- Long term follow up for all patients
72
5 year survival for anogenital melanoma
25-60% for vulval
10% penile
<20% anorectal
