Anaplastic Large Cell Lymphoma

1
Anaplastic Large Cell Lymphoma

• Amanda F. Cashen, M.D.
• Grand Rounds 5/7/04

2
Clinical Presentation

• 19 yo woman at 26 weeks gestation presented with
  a scalp mass and right neck LAD. The mass on her
  scalp had been increasing in size for 2 mo. and
  was painful. Her PMD found the LAD 1 mo. prior
  it had not improved with antibiotics.
• Other sx included headache, weight loss of 4 lbs
  in week prior to presentation, occasional low
  grade fever

3

• PMH
• G1P0
• Allergy to penicillin
• Medications
• Darvocet prn
• FH
• Grandmother with breast cancer
• Two siblings
• SH
• Lives with her mother and siblings
• Works in a day care center
• No tobacco or alcohol use

4
Physical Exam

• T 36.1 P89 BP 83/41 R20, SaO2 99
• HEENT 8x8 cm tender, soft, non-erythematous mass
  over left parietal area and a second, smaller
  mass just anterior 6x6 cm right submandibular
  mass
• No other LAD
• Heart and lungs normal
• Abdomen uterus palpable above the umbilicus,
  fetal heart tones dopplerable
• Neuro No focal deficits

5
Laboratory Data

• WBC 6.5
• N73, L17, M9
• Hct 30.2
• Platelets 352
• LDH 218

• Na 137
• K 3.4
• Cl 103
• HCO3 26
• BUN 5
• Cr 0.4
• Glu 87
• Ca 8.1
• Pro 5.3
• Alb 3.2
• Other LFTs WNL

6
Radiology

• MRI Subcutaneous scalp mass measuring 7.2 x 2.8
  cm. The mass extends through the calvarium into
  the extradural compartment, depressing the
  frontal lobe. A mild amount of associated brain
  edema is present. No other mass lesions are
  seen.
• Neck CT Multiple enlarged lymph nodes in the
  right internal jugular chain and spinal accessory
  chain extending inferiorly to the thoracic inlet
  and right SC region. The largest node measures
  2.7 x 3.4 cm. Multiple subcentimeter lymph nodes
  in the left internal jugular, spinal accessory
  and SC chains.
• Chest/Abd/Pelvis CT No LAD

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Pathology

• Submandibular lymph node
• Small specimen with large area of necrosis
• Neoplastic cells are CD45, CD30, CD45RO, and EMA
  positive.
• CD2, CD3, CD4, CD5, CD20, CD79A, CD57, bcl2,
  bcl6, and cytokeratin are negative.
• ALK negative
• Favor diagnosis of anaplastic large cell lymphoma

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Anaplastic Large Cell Lymphoma
Secondary ALCL
Primary ALCL
Systemic ALCL CD30 ALK /-
Primary Cutaneous ALCL CD30 ALK -
T/null-cell
(B-cell)
CD30, ALK
CD30, ALK-
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Anaplastic Large Cell Lymphoma
Secondary ALCL
Primary ALCL
Systemic ALCL CD30 ALK /-
Primary Cutaneous ALCL CD30 ALK -
T/null-cell
(B-cell)
CD30, ALK
CD30, ALK-
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Primary Cutaneous ALCL

• Median age 7th decade, male predominance
• Limited to the skin at diagnosis multicentric
  skin lesions in 20
• Path? anaplastic lymphoid cells in the skin,
  CD30, ALK -
• Accounts for 25 of cutaneous T-cell lymphoma
• Favorable prognosis, with 90 survival at 5 years
  gt50 recur, usually in the skin 20 develop
  systemic lymphoma
• Treatment
• Localized disease Radiation or surgical
  excision
• Extracutaneous involvement Chemotherapy

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Anaplastic Large Cell Lymphoma
Secondary ALCL
Primary ALCL
Systemic ALCL CD30 ALK /-
Primary Cutaneous ALCL CD30 ALK -
T/null-cell
(B-cell)
CD30, ALK
CD30, ALK-
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Systemic ALCL

• ALCL was first described in 1985 as a lymphoma
  with proliferation of large pleomorphic cells
  expressing CD30 (Ki-1)
• t(25)(p23 q35) described in ALCL in 1989,
  breakpoints cloned in 1994

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t(25)

• Present in 1/3 of ALCL
• Fusion of nucleophosmin (NPM) on chromosome 5 to
  the catalytic domain of anaplastic lymphoma
  kinase (ALK) on chromosome 2
• NPM ubiquitously expressed protein that
  shuttles ribosomal components between the nucleus
  and cytoplasm
• ALK tyrosine kinase receptor with homology to
  the insulin receptor kinase subfamily
• Expressed in the CNS but not in normal lymphoid
  cells
• Transmembrane and extracellular domains are not
  included in the NPM-ALK chimeric protein

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t(25)

• Transforming capability of the fusion protein has
  been demonstrated Proc Natl Acad Sci USA 1996
  934181
• NPM-ALK localized to the nucleus and cytoplasm
• Detected by IHC with an antibody to the
  cytoplasmic domain of ALK

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Other translocations that lead to ALK expression
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Systemic ALCL

• 3 of adult NHL and 10-30 of childhood lymphoma
• Bimodal age distributionlarger peak in 2nd and
  3rd decades, smaller peak in 6th and 7th decades
• ALK ALCL has strong male predominance (6.51)
• ALK- ALCL more prevalent in adults

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Clinical Features

• Most patients present with Stage III-IV disease
• Most common presenting sign is generalized
  lymphadenopathy
• B-symptoms common, especially fever
• Extranodal involvement is common
• Skin (21) -Lung (11)
• Bone (17) -Liver (8)
• Soft tissue (17) -CNS involvement is rare
• Bone marrow involvement is reportedly rare, but
  present in 30 if sensitive methods used
  (staining for CD30 or ALK)

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Is ALK ALCL a phenotypic variant or a different
disease?

• ALK ALCL
• Median age 16-30
• Extranodal involvement less common
• 5-year OS 71-93

• ALK- ALCL
• Median age 43-61
• Involvement of 1 extranodal site more common
• 5 year OS 30-37

At the least, ALK positivity is an important
prognostic factor.
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Histology
Pleomorphic variant Monomorphic variant
CD30 ALK
20
Immunophenotype

• CD30
• ALK in 30-85 of cases
• T-cell markers
• CD3 negative in gt 75
• CD5, CD7, CD8 negative
• CD2, CD4 positive
• Variably CD45
• Presumed cell of originactivated extrafollicular
  CD30 lymphocyte

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Treatment of ALCL
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PrognosisIs it different than DLCL?
Comparison of 146 adult patients with primary
ALCL to 1,695 patients with nonanaplastic DLCL
(patients enrolled in GELA study of treatment for
newly diagnosed aggressive NHL)

• CR rate 75 in ALCL group, 61 in non-ALCL group
  (P lt .001)
• 5-yr. OS 66 in ALCL group, 48 in non-ALCL group
  (P .0004)

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(No Transcript)
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Back to our patient

• 7/18/03-9/3/03 CHOP x 3? clinical response after
  first cycle ? recurrence before 2nd cycle
• 9/17/03 Presented with seizure and right arm
  weakness. New left frontal lobe lesion on
  MRIcentered at a sulcus, suggesting
  leptomeningeal origin with extension into the
  parenchyma surrounding edema measures 3.8 x 4.7
  cm.
• 9/18/03 Delivery by C-section
• 9/20/03-12/03 M-CHOP IT MTX x 5? CR
• 1/22/04 Presented with tender, 4 x 4 cm left
  cervical LAD. New enlarged left jugular and
  post. cervical LAD on CT FNA with atypical
  lymphocytes.
• 1/27/04 ESHAP x 1 ? CR
• 2/16/04-2/20/04 Whole brain XRT
• 2/23/04 Cytoxan/TBI/allogenic PBSCT

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Stem Cell Transplant for T-cell Lymphomas
From Song et al. Br. J. Haem. 2003, 120978
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Stem Cell Transplant for T-cell Lymphomas Song et
al. Br. J. Haem. 2003, 120978

• University of Toronto experience with autologous
  SCT for relapsed or refractory PTL (all patients
  demonstrated chemosensitive disease)

No significant difference in outcome between
groups
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Primary Systemic ALCL Sequential Intensive
Treatment with F-MACHOP and Autologous BMT Fanin
et al. Blood 1996, 87 1243

• 16 patients with ALCL (8 B-cell)
• F-MACHOP x 6 (56 CR) ? RT for residual
  mediastinal mass (6 pts, 3 had CR) ? auto BMT
  (100 CR)
• OS 100 at median follow-up of 45.5 months (range
  15-66 mo.)

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Our patient now

• Transplant course was complicated by mucositis,
  bacteremia, and fungemia
• Mild GVHD of the skin
• 4/04 MRIminimal residual edema, no mass
• Neck/chest/abd/pelvis CTdecreased LAD in
  the neck, no other LAD