The Alphabet Soup of CD30+ Lymphoproliferative Disorders

Uma Sundram, MD, PhDProfessor of Pathology

Oakland University William Beaumont School of MedicineBeaumont Health Systems, Royal Oak, MI

September 27, 2019

Disclosures

• I have nothing relevant to disclose.

10/1/2019 2

Outline

• CD30 + Lymphoproliferative Disorders• Lymphomatoid papulosis• Primary cutaneous anaplastic large cell

lymphoma• Transformed mycosis fungoides

DD of Dense Dermal Lymphoid Infiltrates

CD20, CD3

CD20+, CD3- CD20-, CD3+CD20-, CD3-

Cutaneous B-celllymphoma

CTCLNK/T- cell lymphoma

Important Antibodies to Employ

• CD30• CD56• CD4, CD8• TIA-1• Ki-67• β-F1, TCR gamma

• EBV in situ• PD-1, CXCL-13• Other pan T cell

antigens, i.e., CD5, CD2, CD7

CD30

• First known as Ki-1 antigen• Seen in reactive B- and T-cells exposed to

virus, such as EBV or HTLV• CD30 coupled with CD30 ligand can institute

both apoptotic and proliferative effects

CD30+, CD56-, CD3+CD30+ Lymphoproliferative Disorder• More than 75% of large cells CD30 positive

– Lymphomatoid papulosis-Lyp– Primary cutaneous anaplastic large cell lymphoma-PC

ALCL– Systemic anaplastic large cell lymphoma,

alk-negative– Systemic anaplastic large cell lymphoma,

alk-positive– (Transformed mycosis fungoides)

CD30+ Lymphoproliferative Disorders

• Next most common outside of MF, 30% of primary CTCL

• Lyp and pcALCL overlap A LOT• Lyp also overlaps a lot with reactive entities• Definitive diagnosis requires clinicopathologic

correlation

CD30+ Lymphoproliferative Disorders

• Other pc lymphomas express CD30• Secondary cutaneous lymphomas express

CD30 (outside of ALCL)• If TRULY pc CD30+ LPD, great prognosis

(except for MF and some rare cases) (Kempf 2017)

What is Lymphomatoid papulosis (LyP)?• Hyperplasia: benign

– Chronic stimulation may lead to “second hit” and malignancy

• Lymphoma: malignant– Low grade lymphoma, controlled by host– Indolent end of spectrum of CD30+ LPD

• Heterogeneous entity• Don’t know, yet (still true, today)

Lymphomatoid Papulosis

• Pathologists uniformly called this lesion malignant-carcinoma, melanoma, undifferentiated malignant neoplasm, reticulum cell sarcoma

“Hence, it appears that there exists a dermatologic disorder, the clinical and histologic features of which are variable within limits….Is this condition a bona fide malignancy, self healing, or an entity to stand beside keratoacanthoma, benign juvenile melanoma, and other pseudocancers?” (Macaulay1968)

Follow-up• Patient was still alive and well 25 years later• No treatment• Eruption continued but diminished (Macauley

1968)

Lyp: Clinical Features

• Peak incidence: 4th and 5th decade– All ages

• Predilection for trunk and extremities– No area spared

• Asymptomatic• Protracted course (>20 years) more common than

self-limited

Morphology• Red-brown papules and nodules

– Central hemorrhage and necrosis• Lesions < 3cm• Involute in 3-8 weeks

– Hypo- or hyperpigmented macules– Superficial scars

• Number variable (few - >100)• Lesions in different stages of evolution

Associated Neoplasia

• 10% -20% associated with lymphoma (Kempf 2011)• Most associated lymphomas occur subsequently

– Lymphoma may precede Lyp or present simultaneously• Most common: MF, Hodgkin lymphoma, CD30+ ALCL

(de la Garza Bravo 2015)• Lyp with and without associated lymphoma

indistinguishable (Cieza-Diaz 2019)

Treatment• “Watchful waiting”• No staging necessary for Lyp (Shinohara 2019)• No curative therapy available• Therapies often tried: topical

mechlorethamine, topical carmustine, topical steroids, low dose oral methotrexate, Psoralen-UV-A

Histology• Type A• Type B• Type C• Type D• Type E• Variant with DUSP22

rearrangement• Different types can

coexist in same patient

Type A Lyp (>75%)• Variable epidermal changes• Perivascular and interstitial infiltrate• Wedge shaped• May extend into SQ• Large atypical cells in mixed background composed

of neutrophils, eosinophils, histiocytes, and small lymphocytes

CD30

CD30

Type B Lyp (<10%)

• Resembles plaque stage MF• Superficial perivascular to bandlike infiltrate with

epidermotropism• Small to medium sized cerebriform cells• Few if any CD30+ large cells• Eosinophils and neutrophils infrequent compared to

type A

CD30

Type C Lyp (approx. 10%)

• Monotonous population of large CD30+ cells• Few admixed inflammatory cells• Indistinguishable from CD30+ ALCL

CD30

Type D (Rare)

• Introduced more recently (Saggini, 2010)• Examplified by epidermotropic infiltrates of CD8 and

CD30+ infiltrates of small-medium sized cells• May have deep dermal infiltrate• Mimic of PC CD8+ aggressive epidermotropic

cytotoxic TCL

Type E (Rare)

• Angiocentric and angiodestructive lesions (Kempf 2013)• Medium sized, cytologically atypical cells• Can have hemorrhagic, necrotic and ulcerative lesions• Can be clinically large lesions (up to 4 cm) with eschars• Resolve within a few weeks• Complete resolution in half of patients studied

Histology Subtypes

• Histologic subtypes clinically and prognostically irrelevant (true of newer and more rare variants as well)

• CD30+ large cells may be absent in very early lesions, resolving lesions, type B Lyp and (sometimes) type D Lyp

• Multiple biopsies will increase diagnostic yield

Other Histopathologic Variations

• Pseudoepitheliomatous hyperplasia• Follicular; Acneiform and pustular; with follicular

mucinosis• Syringotropic; with syringosquamous metaplasia• Myxoid• Granulomatous• Spindled

Immunophenotype

• Large cells– CD30+, CD25+– CD4+ (<5% of cases CD8+)– Cytotoxic protein expression (TIA-1, granzyme B, perforins)– Variable loss of CD2, CD3, or CD5– Alk-1 -– CD15 –

• CD8 expression in types D and E, and pediatric Lyp

Immunophenotype

• Majority express TCR beta on surface; rarely TCR gamma (Rodriguez-Pinilla 2013)

• CD95 (Fas) +, Fas ligand +• Jun-B+• Occasional coexpression of CD56• c-kit -• EBV-

Pathogenesis

• Comparing Lyp, c-ALCL,s-ALCL has provided attractive model for tumorigenesis

• Much research has focused on proliferation, apoptosis and definition of specific pathways

• Jun-B• Fascin• Fas/FasL(CD95/CD95L)• TGF-beta• CD30/CD30L• Bcl-2• Granzyme B

• CD44/CD44v6• CD134• p21• Stat3• CD27• CD40• CCR3

Short (and Incomplete) List of Candidate Molecules

Fascin

• Study of fascin expression in CD30+ LPD• 11/17 (64%) ALCL• 11/45 (24%) Lyp• 6/10 (60%) Lyp associated with lymphoma (Kempf

2002)

Fas (CD95) and Fas Ligand (CD95L)

• CD95L = transmembrane protein of TNF family• Expressed by activated T-cells, NK cells and various

tumors• Binding of CD95L to CD95 induces apoptosis• CD95/CD95L plays important role in modulating

immune responses and self-tolerance

Fas (CD95) and Fas Ligand (CD95L)

• Fas expressed in majority of tumor cells in primary cutaneous CD30+ LPD, but loss of expression documented in tumor stage MF and CD30- lymphomas

• FasL expression was seen in all CD30+ LPD studied

• Fas-FasL interactions important for localized disease (Zoi-Toli 2000)

CD30 and CD30L

• CD30-CD30L interaction can lead to cell death or proliferation

• CD30L found at higher level in regressing than in growing Lyp lesions by RT-PCR and Southern blot

• CD30L appears to be colocalized with CD30 in large cells

• Postulated to be one of the mechanisms leading to regression of Lyp lesions (Mori 1999)

TGF-beta/TGF-beta Receptor

• Transforming growth factor (TGF)-beta is a potent inhibitor of proliferation

• Mutations in the TGF-beta signaling pathway lead to resistance to growth inhibition

• TGF-beta is expressed in some regressing lesions of Lyp

Molecular Data

• t(2;5) and 6p25.3 rearrangements are absent or present in very small minority of Lyp

• Approx. 70% of Lyp have detectable clone (Comfere 2018)

• Same clone when anatomically or temporally distinct lesions are examined, as well as lesions of different histologies

• Clonality does not seem to have prognostic implications for Lyp

Molecular Data

• t(2;5) and 6p25.3 rearrangements are absent or present in very small minority

• 6p25.3 rearrangement reported in 1/32 cases of Lyp (Wada 2011)

• 11 patients reported by Karai to have typical clinical course of Lyp but with 6p25.3 rearrangement (involving DUSP22) (Karai 2013)

Molecular Data

• Same clone in Lyp and associated MF (Cieza-Diaz 2019; de la Garza Bravo 2015)

• Same clone in Lyp and associated HD and ALCL (Zackheim 2003; Chott 1996)

• Hodgkin lymphoma• ALCL (systemic and

primary cutaneous)• Large cell transformed

MF• CD30+ B-cell lymphoma• PLEVA• NK/T cell lymphoma

• Viral infection• Activated cells in

reactive infiltrates• Mycosis fungoides• CD8+ epidermotropic

CTCL• Pagetoid reticulosis• Gamma delta TCL

Differential Diagnosis of Lyp

CD30+ Cutaneous Lymphoid Proliferations• Arthropod bites• Tuberculosis• Molluscum contagiosum• Orf• Herpes simplex/zoster• Scabies (more likely in older than in fresh lesions)• Drug eruption

DRUG ERUPTION

DRUG ERUPTION

DRUG ERUPTION, CD30

Lyp vs PLEVA

• Both can be clonal and contain CD30+ cells• PLEVA: younger patients, more limited time

course• PLEVA: CD8+• Lyp: CD4+ (some are CD8+ and may overlap

with PLEVA)

Diagnosis/Clinical Work up-Lyp

• Based on CPC• Overlap between cases of type B Lyp and

papular MF (Saggini 2019)– Helps to biopsy more than 1 lesion

• Borderline/indeterminate cases

Diagnosis/Clinical Work up

• No need for extensive clinical staging if initial evaluation suggests Lyp (Shinohara 2019)

• If clinical suspicion of extracutaneous disease, staging should be pursued

• Prognosis=Can develop second lymphoid neoplasm• Life long surveillance

Lyp=Arguments for Benign Disease

• Excellent prognosis• Self-regressing• Sometimes self-limited

Lyp=Arguments for Malignant Disease

• Distressing with sometimes >50 lesions• May require MTX• Morphologically malignant• Clonal• Loss of pan T-cell antigens• Association/development into lymphoma• Same clone in associated lymphoma

What is Lymphomatoid papulosis (LyP)?• Hyperplasia: benign

– Chronic stimulation may lead to “second hit” and malignancy

• Lymphoma: malignant– Low grade lymphoma, controlled by host– Indolent end of spectrum of CD30+ LPD

• Heterogeneous entity• Don’t know, yet

SPRING IN MARQUETTE, UPPER PENINSULA OF MICHIGAN

Primary Cutaneous ALCL

• Presents as an asymptomatic solitary firm nodule that persists rather than regresses

• On histology, large atypical lymphocytes with expression of CD30 in more than 75% of cells

• Favorable prognosis

Primary Cutaneous ALCL

• Mainly affects adults• Can happen in HIV+ individuals• Large ulcerated lesions• Head and neck, limbs favored• Can have spontaneous regression

Primary Cutaneous ALCL

• Histology: sheets of large atypical cells with anaplastic morphology

• Can have neutrophil or eosinophil rich versions (Kong 2009)

• More common in immunodeficient patients, resembling pyoderma

Primary Cutaneous ALCL

• Angiocentric versions• Keratoacanthomatous version (Lin 2004)• Can be intralymphatic (Ferrara 2015)• CD30+, alk-, EMA variably positive• CD4+ with expression of cytotoxic markers• CD45RO+ with loss of CD5

Primary Cutaneous ALCL

• Clonal rearrangement in 90% of cases (Macgrogan 1996)

• t(2;5) found rarely (DeCouteau 1996; Oschlies 2013)

• FISH for 6p25.3 (IRF4-DUSP22 rearrangement) highly specific for pcALCL (Wada 2011) but present in a minority of cases

Primary Cutaneous ALCL

• Important DDX=Transformed MF– difficult when the lesion is CD30 rich– Favor tMF when lesion is present in a plaque– DUSP22 rearrangement has not been reported in

tMF

Primary Cutaneous ALCL

• Important DDX=Systemic ALCL– ALK+ favors systemic ALCL over pcALCL– CLA expression favors pcALCL over systemic ALCL

CD30

TULIPS ON THE CAMPUS OF THE UNIV OF MICHIGAN

Transformed Mycosis Fungoides

• Transformed MF (tMF, MF in LCT) associated with more aggressive clinical course (median time from tranformation to death 18-36 mo)

• Important to remember that plaques, tumors, and lesional skin of patients with Sézary syndrome can all fulfill histologic criteria for LCT

Definition of Large Cell Transformation• Greater than 25% of infiltrate is composed of

large cells and/or such large cells are present in microscopic nodules

• Large cells are lymphocytes more than 4x the size of ‘regular’ lymphocytes

• Histiocytes must be discounted (Vergier 2000)

CD30

• CD30 + transformed MF do better than CD30-transformed MF

• Some studies may have included Lyp/ALCL• However, extreme variability in expression of

CD30 in clinically documented lesions of tMF

CD30

CD30

Summary

• The most important aspect of CD30 + lymphoproliferative disorders=– Know your clinical diagnosis!

• Reactive entities can look malignant, and malignant entities can look reactive

• Undercall, rather than overcall, lesions; when in doubt, revert to “atypical lymphoid infiltrate”

Summary

• Time can sort out diagnoses• Look for lesions arising in patches of mycosis

fungoides; tumors in patients with MF are always tricky

• Expression of CD30 in mycosis fungoides does not equal transformation

SAULT STE. MARIE, MICHIGAN, CONNECTS L SUPERIOR AND L HURON