Lymphoma & related disorders
Mature T/NK cell disorders
Anaplastic large cell lymphoma
Anaplastic large cell lymphoma, ALK negative


Minor changes: 30 July 2020

Copyright: 2003-2020, PathologyOutlines.com, Inc.

PubMed search: Anaplastic large cell lymphoma[TI] ALK negative[TI]

Jayalakshmi Balakrishna, M.D.
Elaine S. Jaffe, M.D.
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Cite this page: Balakrishna J, Jaffe ES. Anaplastic large cell lymphoma, ALK negative. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/lymphomanonBanaplasticneg.html. Accessed August 15th, 2020.
Definition / general
Essential features
  • T cell lymphoma
  • Characteristic hallmark cells
  • Morphologically indistinguishable from ALCL, ALK positive
  • CD30 diffusely and strongly positive
  • ALK expression negative
  • ALK gene rearrangement negative
Terminology
  • ALK- ALCL
ICD coding
  • ICD-10:
    • C84 - mature T / NK cell lymphomas
    • C84.7 - anaplastic large cell lymphoma, ALK negative
    • C84.70 - unspecified site
    • C84.71 - lymph nodes of head, face and neck
    • C84.72 - intrathoracic lymph nodes
    • C84.73 - intra-abdominal lymph nodes
    • C84.74 - lymph nodes of axilla and upper limb
    • C84.75 - lymph nodes of inguinal region and lower limb
    • C84.76 - intrapelvic lymph nodes
    • C84.77 - spleen
    • C84.78 - lymph nodes of multiple sites
    • C84.79 - extranodal and solid organ sites
Epidemiology
Sites
  • Both lymph nodes and extranodal sites (bone, soft tissue and skin; primary cutaneous ALCL needs to be distinguished)
Pathophysiology
Clinical features
  • Mostly presents at advanced stage (stage III - IV) and B symptoms
Diagnosis
Laboratory
Radiology description
  • Enlarged lymph nodes / mass lesions in extranodal sites
Prognostic factors
Case reports
Treatment
Gross description
  • Enlarged lymph nodes
  • Firm fleshy mass
Microscopic (histologic) description
  • Most of the time, morphologically indistinguishable from ALCL, ALK positive
  • Effaced architecture with solid, cohesive sheets of neoplastic cells
  • May show preserved lymph node architecture with neoplastic cells growing intrasinusoidally or only within the T cell areas
  • Variant patterns as described in ALCL, ALK positive (small cell variant, lymphohistiocytic) not described
  • Large cells with round to indented nuclei, deeply staining cytoplasm, with prominent Golgi zone
  • Hallmark cells (cells with eccentric, horseshoe or kidney shaped nuclei)
  • Cases with DUSP22 rearrangements show smaller, monomorphic cells with central nuclear pseudoinclusions (doughnut cells) (Haematologica 2019;104:e158)
  • Cases positive for DUSP22 rearrangements lack a cytotoxic phenotype
  • Cases with ERBB4 and COL29A1 expression show Hodgkin-like morphology (Blood 2016;127:221)
Microscopic (histologic) images

Contributed by Jayalakshmi Balakrishna, M.D., Elaine S. Jaffe, M.D.

Diffuse infiltrate

Invasion of sinus

Large atypical cells

Mitotic figures and apoptotic bodies

Large atypical cells


Large atypical cells

Hallmark cells

IHC stain, CD3

IHC stain, CD4

IHC stain, CD3

IHC stain, CD25


IHC stain, Ki67

IHC stain, CD2

IHC stain, perforin

IHC stain, CD30

IHC stain, CD43


IHC stain, CD45

IHC stain, EMA

IHC stain, granzyme



Contributed by Doan Minh Khuy, M.D.

23 year old man with a cervical lymphoid nodule, no B symptoms


CK-

EMA+

CD30+

ALK-


CD15-

CD20-

CD5+

Virtual slides

Images hosted on other servers:

ALCL, ALK-, ALK1

ALCL, ALK-, CD30

ALCL, ALK-, H&E

ALCL, ALK+, ALK1

ALCL, ALK+, CD30

ALCL, ALK+, H&E

Cytology description
  • Large atypical neoplastic cells, multinucleation / multilobated nuclei, prominent Golgi zone, basophilic cytoplasm
  • Basophilic nucleoli, generally less prominent than seen in Hodgkin Reed-Sternberg cells
Cytology images

Contributed by Jayalakshmi Balakrishna, M.D.

Lymph node biopsy touch preparation

Positive stains
  • Strong and diffuse uniform CD30 staining in all tumor cells (membrane and Golgi zone pattern, also cytoplasmic)
  • Variable expression / loss of pan-T cell antigens: CD2+ and CD3+ more often than CD5+
  • Almost always CD43+ and CD45+; can be used to distinguish from carcinoma
  • Often CD4+, rarely CD8+
  • TIA1, granzyme B, perforin, clusterin, fascin, rarely EMA
  • Cases with DUSP22 rearrangements tend to be less frequently positive for cytotoxic markers
Negative stains
Flow cytometry description
  • Flow cytometry shows the anaplastic large cell lymphoma cells with high forward and side light scatter properties (consistent with large and complex cells) and high density CD45 expression simulating monocytes
  • Tumor cells express CD30 and one or more of the T cell associated antigens (Arch Pathol Lab Med 2009;133:49)
Flow cytometry images

Contributed by Sanam Loghavi, M.D.

CD45 and side light scatter

CD3 and CD4

CD4 and CD8

CD5 and CD2


TCR A / B

CD3 and CD30

CD4 and CD30

Molecular / cytogenetics description
  • T cell receptor (TCR) gene rearrangement in most cases, irrespective of T cell antigen expression
  • DUSP22-IRF4 locus on 6p25.3 (referred to as DUSP22 rearrangements); (6;7)(p25.3;q32.3) (Blood 2011;117:915)
  • Recurrent rearrangement involving the TP63 gene (Blood 2012;120:2280)
  • Gains of the 1q41-qter and 6p21 are common cytogenetic aberrations (Br J Haematol 2008;140:516)
  • ERBB4 and COL29A1 are expressed in 24% of ALK- ALCL, mutually exclusive with TP63 rearrangement (Blood 2016;127:221)
  • STAT3 activation (Cancer Cell 2015;27:516)
Molecular / cytogenetics images

Contributed by Andrew Feldman, M.D.

Break apart probe FISH for chromosome region 6p25.3

Sample pathology report
  • Mass, left breast, excision:
    • Anaplastic large cell lymphoma, ALK negative (see synoptic report)
Differential diagnosis
  • ALCL, ALK positive:
    • ALK+, younger age, less aggressive
  • Classical Hodgkin lymphoma:
    • Characteristic Hodgkin Reed-Sternberg cells, CD30 and CD15 positive
    • Can be EBV positive, cytotoxic markers and T cell markers negative
  • Peripheral T cell lymphoma, NOS:
    • Difficult differential, WHO recommends conservative approach (diagnose ALCL, ALK- only if very similar to ALCL, ALK+, except for ALK expression)
  • Primary cutaneous ALCL:
    • Gene expression profiling shows that ALCL, ALK negative is closely related to primary cutaneous ALCL
    • Much better prognosis, clinical correlation with staging necessary
Board review style question #1
What is the morphologic characteristic of anaplastic large cell lymphoma, ALK negative with DUSP22-IRF4 rearrangement?

  1. Eosinophilia
  2. Hodgkin-like cells
  3. Prominent nucleoli and intranuclear inclusions (doughnut cells)
  4. Small cell morphology
Board review answer #1
C. Prominent nucleoli and intranuclear inclusions (doughnut cells)

Comment Here

Reference: Anaplastic large cell lymphoma, ALK negative
Board review style question #2
What is a prognostic factor in anaplastic large cell lymphoma, ALK negative?

  1. Age of the patient
  2. Gender of the patient
  3. Mitotic count
  4. Tumor necrosis
Board review answer #2
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