Anaplastic large cell lymphoma (CD30+), T and Null cell types, ALCL, ALK lymphoma

Definition

A neoplasm of large T-cells, often with horse-shoe shaped nuclei and showing CD30 positivity. Most are positive for cytotoxic granule associated proteins and for the anaplastic large cell lymphoma protein, ALK

Synonyms

Epidemiology

3% of adult non-Hodgkin lymphomas, 10-30% of childhood lymphomas. Mainly seen in the first three decades of life with a male predominance of 6.5:1 in the second and third decades. ALK-negative ALCL is seen in the elderly, while ALK-positive ALCL occurs in a young patient population10. ALCL may be primary or may arise by transformation of other lymphomas.

Clinical features

Frequently both nodal and extranodal, with involvement of skin (21%), bone marrow (10% on H/E, increased to 30% with immunohistochemistry), soft tissues (17%), lung (11%), liver (8%), gastrointestinal tract (rare), salivary gland8 and CNS (rare). Most patients present with advanced disease and symptoms which include a high fever.

Histopathology

The lymphoma commonly grows in a sinusoidal pattern within lymph nodes, resembling metastatic carcinoma. The cytomorphology is variable. All cases show a variable proportion of cells with eccentric horse-shoe or reniform nuclei (hallmark cells, if sectioned so as to show the invagination as an apparent nuclear inclusions, they are called doughnut cells). There is often an eosinophilic region near the nucleus.

Bone marrow involvement is often subtle and requires immunohistochemistry for recognition (CD30, EMA and ALK).

Variants; 10% of patients show more than one variant7

These LH and small cell variants commonly occur in children and young adults, usually as nodal disease4. The hallmark of the small cell variant is a perivascular distribution. ALK-1 is positive in a high proportion of cases3. The small cell variant may consist of an admix of many small and lesser numbers of large cells, both populations having aberrant T cell immunophenotypes: there may be progression to a typical ALCL5. The large cell population is CD30 positive while only rare small cells express CD305.

The following patterns may be seen, but are not recognised as distinct variants:

Immunohistochemistry

 

CD1a

 

 

CD2†

often positive

CD3

<25% of cases positive

CD4

often positive

CD5

often negative

CD7

often negative

CD8

usually negative

CD11b

 

CD15

rarely positive in a minority of cells7

CD16

 

CD25

positive

CD30

positive, especially larger cells, membrane and Golgi

CD43

positive in 2/3rds of cases

CD45

variably positive

CD45RO

variably positive

CD56

 

CD57

 

CD68

may be positive with KP-1, but are negative with PG-M1

TdT

 

TIA-1

usually positive

granzyme B

usually positive

perforin

usually positive

ALK

60-85% of cases

EMA

positive in up to 95% of cases,2,7, with similar distribution to CD30

EBER

negative

LMP-1

negative

clusterin

positive

 

†: fresh frozen tissue only

In the Hodgkin-like and giant cell ALCL, ALK-positivity is both nuclear and cytoplasmic11: small neoplastic cells may show nuclear restriction11. About 15% of cases show cytoplasmic-restriction11. Staining for ALK is nuclear, nucleolar and cytoplasmic in ALCL with t(2;5) but is only cytoplasmic or membranous in variant translocations, such as inv(2)(2p23;q35) + ider(2)(q10)inv(2): in these cases, multiple copies of a putative 2q35-ALK chimeric gene may be required for efficient tumor development9. Cells positive for ALK are usually also positive for EMA.

 

Cytogenetic abnormalities

Differential diagnosis

 

CD15

CD30

EMA

npm/alk

 

ALK-negative nodal ALCL

 

+

3/202

-

Primary cutaneous anaplastic large T cell lymphoma

 

+

0/102

-

classical HD-NS

+

+

2/142

0/142

classical HD-MC

+

+

1/62

0/62

peripheral T cell lymphoma, NOS

 

 

1/52

0/52

T lymphoblastic lymphoma

 

 

0/22

0/22

nodal diffuse large B cell lymphoma

 

2/5

1/52

0/52

 

 

Management

Systemic ALCL is treated with multiagent chemotherapy. Primary cutaneous ALCL is managed by localised treatment, particularly radiotherapy.

Prognosis

References

World Health Organization Classification of Tumours, Tumours of the haematopoietic and lymphoid tissues, IARC Press 2001.

1 Delsol G, New antibodies and new applications of old antibodies in the diagnosis of hematolymphoid neoplasms. In Immunohistochemistry Long Course, Nice 1998.

2 ten Berge, R. L., Snijdewint, F. G., von Mensdorff-Pouilly, S. MUC1 (EMA) is preferentially expressed by ALK positive anaplastic large cell lymphoma, in the normally glycosylated or only partly hypoglycosylated form. J Clin Pathol 2001;54:933-939.

3 Christie Problems in Tumour Pathology, 7.6.2002.

4 Pileri, S., Falini, B., Delsol, G. et al. Lymphohistiocytic T-cell lymphoma (anaplastic large cell lymphoma CD30+/Ki-1 + with a high content of reactive histiocytes). Histopathology 1990;16:383-91.

5 Kinney, M. C., Collins, R. D., Greer, J. P., Whitlock, J. A., Sioutos, N., Kadin, M. E. A small-cell-predominant variant of primary Ki-1 (CD30)+ T-cell lymphoma. Am J Surg Pathol 1993;17:859-68.

6 Pulford, K., Lamant, L., Morris, S. W. et al. Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1. Blood 1997;89:1394-404.

7 Benharroch, D., Meguerian-Bedoyan, Z., Lamant, L. et al. ALK-positive lymphoma: a single disease with a broad spectrum of morphology. Blood 1998;91:2076-84.

8 Yamamoto H et al. ALK-positive anaplastic large cell lymphoma of the parotid gland. Histopathology 2003;43:397-8.

9 Wlodarska, I., C. De Wolf-Peeters, et al. (1998). "The cryptic inv(2)(p23q35) defines a new molecular genetic subtype of ALK-positive anaplastic large-cell lymphoma." Blood 92(8): 2688-95.

10 Nakamura S, Shiota M, Nakagawa A, et al. Anaplastic large cell lymphoma: a distinct molecular pathologic entity: a reappraisal with special reference to p80(NPM/ALK) expression. Am J Surg Pathol 1997; 21:1420-32

11 Falini B, Bigerna B, Fizzotti M, et al. ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum. Am J Pathol 1998; 153:875-86

12 Hutchison RE, Banki K, Shuster JJ, et al. Use of an anti-ALK antibody in the characterization of anaplastic large-cell lymphoma of childhood. Ann Oncol 1997; 8 Suppl 1:37-42

 

This page last revised 5.10.2003.

©SMUHT/PW Bishop