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(first three decades of life) 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

• common variant; 70% of cases. There is abundant cytoplasm, which may be basophilic, eosinophilic or clear. Some cells may resemble Reed-Sternberg cells. Rarely, erythrophagocytosis by malignant cells may be seen. 60-80% are positive for ALK3.
  

• lymphohistiocytic variant; 10% of cases4
  • The LH variant contains many plasmacytoid histiocytes, which may hide the relatively small neoplastic cells. The neoplastic cells often cluster around vessels The histiocytes may occasionally show erythrophagocytosis.
• small cell variant; 5-10% of cases. Hallmark cells are always present, often around blood vessels. May be mistaken for PTL, unspecified. Peripheral blood involvement may include flower-like cells in smears.

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:

• sarcomatoid variant; rarely positive for ALK3.

• giant cell rich variant; rarely positive for ALK3.

• signet ring cell variant

• neutrophil-rich variant

• ALK-negative primary nodal ALCL: it is not clear if this is a distinct entity. It often occurs in older patients and has a poor prognosis. The cells are generally more pleomorphic.

• Primary cutaneous anaplastic large T cell lymphoma; negative for ALK3.

• Anaplastic large cell lymphoma, Hodgkin-like

Immunohistochemistry

†: 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)(this inversion involves the ALK and the PAX 3 loci) + 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

• t(2;5)(p23;q35); 70-80%, fusing part of the nucleophosmin (NPM) gene to the a portion of the ALK receptor gene6.

• less common variants, t(1;2), t(2;3), Inv 29, t(2;17) and t(2;19) variously fuse ALK with tropomyosin 3, PAX3, TRK fusion gene, Clathrin heavy chain etc3.

Differential diagnosis

• Metastatic carcinoma; ALCL may be cohesive with a sinusoidal growth pattern. ALCL may be positive for EMA and even for cytokeratin; conversely embryonal carcinoma may be positive for CD30.

• Hodgkin's disease, particularly the syncytial variant of nodular sclerosing Hodgkin's disease. Hodgkin's disease lacks the t(2:5) translocation and hence does not express NPM/ALK. Reed Sternberg cells in classical Hodgkin's disease are also negative for CD45, CD45RO, CD43 and CD20; unlike ALCL, they are commonly positive for CD15.

• True histiocytic neoplasia: some ALCL stain for CD68 using KP-1 but not with the more specific PG-M1.

• ALK+ DLBCL

Management

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

Prognosis

• The prognosis of ALK-negative ALCL(5 year survival 40%) is worse than ALK-positive ALCL(5 year survival 80%) 3,10. In a study of paediatric cases, ALK expression did not predict 2 year survival12. No difference is seen between the ALK-NPM translocation and the variant translocations.

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