In The Diagnosis Of Rare T-Cell Lymphomas

Subtle Distinctions
Vast Impact

In a landscape of complexity, many sALCL cases are misdiagnosed.1
Your role as an expert hematopathologist is critical. 2

Important clues to diagnosis such as hallmark cells, ALK expression, and importantly, CD30 expression can help differentiate sALCL from other rare lymphomas, such as PTCL-NOS. 2,3

With your help and expertise accurate diagnosis of sALCL will lead to appropriate treatment decisions for patients. 1,2

Include CD30 expression in differential diagnosis of T-cell lymphomas.3

Distinguishing sALCL from PTCL-NOS

Why is it Critical?

Systemic anaplastic large cell lymphoma (sALCL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) are both aggressive T-cell lymphomas with some morphological and/or immunophenotypic overlaps, but they are different diseases.1-4

sALCL and PTCL-NOS have distinctive clinical features that can impact patient management.1-4

sALCL is often misdiagnosed as PTCL-NOS, which comprises the largest group of PTCLs.1,3
Accurate differentiation of sALCL (ALK+), sALCL (ALK-), and PTCL-NOS is crucial for determining PROGNOSES and TREATMENT OPTIONS.1

Back to Top

PrognosesPatient Survival Differs

Patients with PTCL-NOS show a poorer prognosis than patients with sALCL. In sALCL, expression of anaplastic lymphoma kinase (ALK) is associated with a better prognosis when treated with standard chemotherapy, while ALK-negative sALCL patients show poorer outcomes.1-3

OverallsurvivalPTCL_og_image.jpg

Back to Top

Distinguishing sALCL From PTCL-NOS

sALCL and PTCL-NOS share some pathologic features, but are different diseases.1,3 ALK(-) sALCL is often misdiagnosed as PTCL-NOS, which comprises the largest group of PTCLs.1,3 The presence of hallmark cells, CD30 expression, and ALK expression can help differentiate sALCL from PTCL-NOS.1



sALCL
PTCL-NOS:
small/medium
cell variant
PTCL-NOS:
large cell variant
Morphology
sALCLPolymorphic, very large
atypical lymphoid cells

Irregular nuclear shapes
and abundant cytoplasm

Presence of hallmark
cells with horseshoe- or
kidney-shaped nuclei


Image from: webpathology.com.
PTCL Small CellSmall-to-medium sized
atypical lymphoid cells

Irregular nuclear shapes
and abundant cytoplasm

Hallmark cells are not seen



Image from: Nicolae A, et al. Am J Surg
Pathol
. 2013;37(6):816-826.
PTCL Large CellMonomorphic, large
atypical lymphoid cells

Irregular nuclear shapes and small
amounts of cytoplasm

Hallmark cells are not seen



Image from: Geissinger E, et al.,
J Mol Diagn. 2005;7:455-464 .
CD30 expression
All sALCL cases
are CD30-positive7,8


CD30 expression by
immunohistochemistry in >80% of
the cells is required for diagnosis

Large malignant cells
strongly express CD30 on
the cell membrane7
32% of PTCL-NOS cases have
some CD30-positive cells 1

Expression of CD30 is usually
focal and/or weak9,10
Cases with strong diuse
CD30 expression are
occasionally encountered1
ALK expression
ALK protein expression is
a defining feature of
ALK(+) sALCL11,12
ALK protein is not
expressed in PTCL-NOS11,12
ALK protein is not
expressed in PTCL-NOS11,12
Other immunophenotypic
characteristics


Immunohistochemical evaluation for T-cell antigens, cytotoxic markers, and other antigens may be warranted
Loss of T-cell antigens occurs more frequently in sALCL than in PTCL-NOS, with CD5 the most frequently lost antigen9,13,14

Epithelial membrane
antigen (EMA) is expressed
in most ALK(+) sALCL and
43% of ALK(-) sALCL 1,13,15

sALCL will almost always express
at least one cytotoxic marker—
including TIA1, granzyme B, and
perforin—but this phenotype is less
commonly seen in PTCL-NOS 13,15

sALCL cells show
positive for perforin in
immunohistochemical stains
Loss of T-cell antigens occurs more frequently in sALCL
than in PTCL-NOS 9,13,14

Epithelial membrane antigen
(EMA) is only expressed in a
minority of PTCL-NOS cases 1,13,15

Expression of at least one
cytotoxic marker—including
TIA1, granzyme B, and
perforin—is less common
in PTCL-NOS 13,15
Loss of T-cell antigens occurs more
frequently in sALCL
than in PTCL-NOS 9,13,14

Epithelial membrane antigen (EMA)
is only expressed in a
minority of PTCL-NOS cases 1,13,15

Expression of at least one cytotoxic
marker—including
TIA1, granzyme B, and
perforin—is less common
in PTCL-NOS 13,15
Back to Top

Differential Diagnosis of Mature B-cell and NK/T-cell Neoplasms2*

Differential diagnosis requires adequate immunophenotyping plus molecular and cytogenetic analysis.2

Antigenic markers used to differentiate between ALCL subgroups and other PTCL subtypes include the ALK protein and the paired boxed gene 5 (PAX5) transcription factor; the absence of nuclear PAX5 is one of the most important diagnostic criteria favoring a diagnosis of ALCL (ALK-).2

DifferentialDiagnosis_og_image.jpg

  • *These are meant to be general guidelines. Interpretation of results should be based on individual circumstances and may vary. Not all tests will be required in every case.
  • Rare T-cell lymphomas may be CD20+ or PAX5+. Assessment of other pan-T and –B markers is essential. The expression of multiple markers of 1 lineage and only 1 of the other lineages supports lineage assignment. PCR analysis may be required to determine lineage in such cases.

    ALCL=anaplastic large cell lymphoma; ALK=anaplastic lymphoma kinase; ATLL=adult T-cell leukemia/lymphoma; CHL=classical Hodgkin lymphoma; CTCL=cutaneous T-cell lymphomas; DLBCL=diffuse large B-cell lymphoma; EATL=enteropathy-associated T-cell lymphoma; EBV-EBER=Epstein-Barr virus-encoded small RNAs; HTLV1=human T-cell lymphotropic virus type 1; LPD=lymphoproliferative disorders; LyP=lymphomatoid papulosis; MF=mycosis fungoides; PC-ALCL=primary cutaneous anaplastic large cell lymphoma; PTCL-NOS=peripheral T-cell lymphoma, not otherwise specified.

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Hodgkin’s Lymphomas V.4.2014. © 2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Anaplastic morphology

  • Anaplastic large cell lymphoma (ALCL), ALK(+)
  • Anaplastic large cell lymphoma (ALCL), ALK(-)
  • Adult T-cell leukemia/lymphoma (ATLL), anaplastic large cell type
  • Enteropathy-associated T-cell lymphoma (EATL)
  • Primary cutaneous CD30-positive T-cell lymphoproliferative disorders
    • Lymphomatoid papulosis (LyP)
    • Primary cutaneous anaplastic large cell lymphoma (PC-ALCL)
Back to Top

Treatment Options for sALCL and PTCL-NOS Differ

An accurate diagnosis is essential to effective treatment, and remains a significant predictor of outcome.1 In the frontline settings, ALK(+) sALCL has a different recommended therapy, while in other lines, sALCL and PTCL-NOS are treated the same way.2,5,6


Frontline Therapy
Second-line Therapy
(transplant candidate)
Second-line Therapy
(non-transplant candidate)
Frontline therapy ± RT
Clinical trial (preferred)
or second-line therapy
Clinical trial (preferred)
or second-line therapy
ALK(+) ALCL
All histologies
All histologies
CHOP-21
Belinostat (category 2B*)
Alemtuzumab
CHOEP-21
Brentuximab vedotin for sALCL,
excluding PC-ALCL, and for
systemic CD30+ PTCL (category 2B*)
Belinostat (category 2B*)
Other histologies:
DHAP
Bortezomib
CHOEP
ESHAP
Brentuximab vedotin for sALCL,
excluding PC-ALCL, and for
systemic CD30+ PTCL (category 2B*)
CHOP-14 or CHOP-21
Dose-adjusted EPOCH
Cyclosporine for AITL only
CHOP followed by ICE
GDP
Dose-adjusted EPOCH
CHOP followed by IVE
GemOx
Gemcitabine
Dose-adjusted EPOCH
ICE
Pralatrexate
Hyper-CVAD alternating with
high-dose methotrexate and cytarabine
MINE
RT
Consider consolidation with
HDT and SC rescue
Pralatrexate
Romidepsin
Romidepsin
  • *Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
  • Indicated for r/r sALCL.


  • Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Hodgkin’s Lymphomas V.4.2014. © 2014 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

    BSCH Guidelines for the Management of Mature T-cell and NK-cell Neoplasms (Excluding Cutaneous T-cell Lymphoma).

    Dreyling M, Thieblemont C, Gallamini A, et al. ESMO Consensus Conferences: Guidelines on Malignant Lymphoma. Part 2.

    AITL=angioimmunoblastic T-cell lymphoma; ALK=anaplastic lymphoma kinase; ALCL=anaplastic large cell lymphoma; CHOP=cyclophosphamide, doxorubicin, vincristine, prednisone; CHOEP=cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone; DHAP=dexamethasone, cytarabine, cisplatin; EPOCH=etoposide, doxorubicin, vincristine, prednisone, cyclophosphamide; ESHAP=etoposide, methylprednisolone, cytarabine, cisplatin; GDP=gemcitabine, dexamethasone, cisplatin; GemOx=gemcitabine, oxaliplatin; HDT=high-dose therapy; hyper-CVAD=cyclophosphamide, vincristine, doxorubicin, dexamethasone; ICE=ifosfamide, carboplatin, etoposide; IVE=ifosamide, vinorelbine, etoposide; MINE=mitoguazone, ifosfamide, vinorelbine, etoposide; PC=primary cutaneous; PTCL=peripheral T-cell lymphoma; RT=radiotherapy; SC=stem cell.
Back to Top

sALCL and PTCL-NOS are different diseases,
with different prognoses and treatment options

Several characteristics can help differentiate sALCL from PTCL-NOS. The most prominent include1,7,11,12:

  • Hallmark cells — always present in sALCL, but never found in PTCL-NOS
  • CD30 expression — always seen in sALCL, but not always in PTCL-NOS
  • ALK expression — always present in ALK(+) sALCL, but never found in PTCL-NOS
After evaluation of pathological hallmarks, if ambiguity still exists, a second
opinion may be helpful in obtaining an accurate diagnosis
Back to Top

Header References:

References: 1. Herrera AF, Crosby-Thompson A, Friedberg JW, et al. Comparison of referring and final pathology for patients with T-cell lymphoma in the National Comprehensive Cancer Network.
Cancer. 2014;120:1993-1999. 2. Bossard C, Dobay MP, Parrens M, et al. Immunohistochemistry as a valuable tool to assess CD30 expression in peripheral T-cell lymphomas: high correlation with mRNA levels.
Blood. 2014;124:2983 2986. 3. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Non-Hodgkin’s Lymphoma Version 2.2015. National Comprehensive Cancer Network; March 3, 2015.

Content References:

  • 1. Savage KJ, Harris NL, Vose JM, et al. ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood. 2008;111(12):5496-5504.
  • 2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Hodgkin’s Lymphomas V.4.2014 © National Comprehensive Cancer Network, Inc 2014. Referenced with permission. All rights reserved. Accessed August 25, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.
  • 3. Vose JM, Armitage J, Weisenburger D; International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes.
    J Clin Oncol. 2008;26(25):4124-4130.
  • 4. Weisenburger DD, Savage KJ, Harris NL, et al; International Peripheral T-cell Lymphoma Project. Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project. Blood. 2011;117(12):3402-3408.
  • 5. Dearden C, Johnson R, Pettengell R, et al; British Committee for Standards in Haematology. Guidelines for the management of mature T-cell and NK-cell neoplasms (excluding cutaneous T-cell lymphoma). August 2013. http://www.bcshguidelines.com/documents/T_NHL_ guideline_3_8_13_updated_with_changes_accepted_v1_rg.pdf. Accessed August 12, 2014.
  • 6. Dreyling M, Thieblemont C, Gallamini A, et al. ESMO consensus conferences: guidelines on malignant lymphoma. part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma.
    Ann Oncol. 2013;24(4):857-877.
  • 7. Fornari A, Piva R, Chiarle R, Novero D, Inghirami G. Anaplastic large cell lymphoma: one or more entities among T-cell lymphoma? Hematol Oncol. 2009;27(4):161-170.
  • 8. Piccaluga PP, Gazzola A, Mannu C, et al. Pathobiology of anaplastic large cell lymphoma. Adv Hematol. 2010:345053. doi:10.1155/2010/345053.
  • 9. Ferreri AJM, Govi S, Pileri SA, Savage KJ. Anaplastic large cell lymphoma, ALK-negative. Crit Rev Oncol Hematol. 2013;85(2):206-215.
  • 10. Zettl A, Rüdiger T, Konrad M-A, et al. Genomic profiling of peripheral T-cell lymphoma, unspecified, and anaplastic large T-cell lymphoma delineates novel recurrent chromosomal alterations. Am J Pathol. 2004;164(5):1837-1848.
  • 11. Pileri SA, Weisenberger DD, Sng I, et al. Peripheral T-cell lymphoma, not otherwise specified. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008:306-308.
  • 12. Delsol G, Falini B, Müller-Hermelink HK, et al. Anaplastic large cell lymphoma (ALCL), ALK-positive. In: Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008:312-316.
  • 13. Jaffe ES, Harris NL, Stein H, Campo E, Pileri SA, Swerdlow SH, et al. Introduction and overview of the classification of the lymphoid neoplasms. In: Swerdlow SH, Campo E, Harris NL, et al, eds.
    WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008:158-166.
  • 14. Juco J, Holden JT, Mann KP, Kelley LG, Li S. Immunophenotypic analysis of anaplastic large cell lymphoma by flow cytometry. Am J Clin Pathol. 2003;119(2):205-212.
  • 15. Piccaluga PP, Agostinelli C, Tripodo C, et al; European T-cell Lymphoma Study Group. Peripheral T-cell lymphoma classification: the matter of cellular derivation.
    Expert Rev Hematol. 2011;4(4):415-425.

Image References:

http://webpathology.com/image.asp?n=8&case=390.

Nicolae A, Pittaluga S, Venkataraman G, et al. Peripheral T-cell lymphomas of follicular T-helper cell derivation with Hodgkin/Reed-Sternberg cells of B-cell lineage: both EBV-positive and EBV-negative variants exist. Am J Surg Pathol. 2013;37(6):816-826.

Geissinger E, Bonzheim I, Krenacs L, et al. Identification of the tumor cells in peripheral T-cell lymphomas by combined polymerase chain reaction-based T-cell receptor beta spectrotyping and immunohistological detection with T-cell receptor beta chain variable region segment-specific antibodies. J Mol Diagn. 2005;7(4):455-464.

Back to Top