Blastic NK-cell lymphoma, CD4-positive/CD56-positive lineage-negative neoplasm

Definition

Previously thought to be a neoplasm composed of NK cells of lymphoblastoid morphology, the most recent evidence is that the cells represent a precursor of a specialized dendritic cell, termed a plasmacytoid dendritic cell (pDC)¹. Plasmacytoid dendritic cells represent one of the three subsets of normal dendritic cells, the others being Langerhans' cells and myeloid dendritic cells. pDCs originate from CD34+ progenitor cells and have been identified in thymus and lymphoid tissues, including tonsil, bone marrow, peripheral blood, and spleen. Dendritic cells play a vital role in immunoregulation. The diagnosis is largely one of exclusion, there currently being a lack of established positive markers for pDC, although positivity for CD45RA and CD123 in paraffin sections has been proposed³.

Synonyms

Cutaneous agranular CD4+ CD56+ lymphoma, agranular haemotodermic neoplasm.

Epidemiology

There is a wide age range, but predominantly middle-aged to elderly: childhood cases are very rare^1,. There is a male predominance³.

Clinical features

Most patients have disseminated disease at presentation. Skin involvement is dominant^1,3, but a wide range of sites including lymph nodes, soft tissue, peripheral blood³ and bone marrow³ are commonly involved. Rarely, lung³, nasal cavity or female genital tract³ is the primary site of disease. A CD4+/CD56+ immunophenotype is associated with skin involvement².

Histopathology

The neoplastic cells are variable but generally medium to large in size and form a monotonous infiltrate with fine chromatin, resembling lymphoblastic or myeloblastic leukaemia. The cells lack azurophilic granules on a Giemsa stain. There may be cytoplasmic vacuolaton³, which may form a necklace below the cytoplasmic membrane. Cytoplasmic ‘‘pseudopod-like’’ extensions have rarely been reported. An Indian file pattern of infiltration may be seen. In the skin, there is a clear Grenz zone with sparing of the epidermis^1,4: a periadnexal pattern of tumour may be seen³. Lymph nodes show para/interfollicular infiltration⁴. In the spleen, there is massive infiltration of the red pulp³. The bone marrow shows diffuse infiltration³. Exceptionally, the tumour cells form Homer-Wright like rosettes. There is not usually karyorrhexis, coagulative necrosis or angiocentricity.

Immunohistochemistry

CD1a	0/83
CD2	usually negative, 1/83
CD3	almost always negative, 0/103
CD4	usually positive1, 10/10 (in one case staining was weak)3
CD5	0/103
CD7	usually negative, 4/8 (by flow cytometry: dim in three of the four positive cases)3
CD8	0/103
CD10	1/83
CD13	negative1, 0/93
CD16	1/73
CD19	negative1, 0/83
CD20	negative1, 0/103
CD33	negative1, 4/9 (by flow cytometry: dim in three of the four positive cases)3
CD34	may be positive, 0/103
CD35	1/83
CD38	5/53
CD43	usually positive, 10/103
CD45	positive, 10/103
CD45RA	positive, 10/103
CD56	positive1, 9/10 (one case was negative by both immunohistochemistry and flow cytometry)3
CD57	0/73
CD68	negative or focally weakly positive, 2/10 (positivity was diffuse in one case, focal and punctate in the second)3
CD79a	0/63
CD117	0/103
CD123	positive1
Lambda	0/73
Kappa	0/73
Myeloperoxidase	negative1, 0/103
Lysozyme	0/103
NSE	0/93
HLA-DR	positive3, 9/93
TdT	results inconsistent1, 2/103
BDCA-2	positive3
BDCA-4	positive3
TCL-1	positive1
TIA-1	0/93
S-100	0/8 (one case showed scattered positive cells)3
alpha-naphthyl butyrate esterase: histochemical stain	0/103
EBV	negative, 0/10 (by in situ hybridisation for EBER)3
TCR-g	0/10 (by molecular method)3

Cytogenetics and molecular genetics

There is negativity for Ig heavy chain and TCR-g gene rearrangements. Complex cytogenetic aberrations are common but abnormalities of regions 5q, 6q, chromosome 9, 12p13, 13q, and 15q may be particularly common.

Differential diagnosis

In general, T-, B- and NK-cell and myeloid neoplasms, by exclusion based on the lack of immunoreactivity for markers of these lineages lineages:

	Lineage	Clinical	Morphology	Immunoreactivity
	Dendritic	cutaneous disease	Blastic, lymphoid-like, scant cytoplasm, may show cytoplasmic vacuoles	CD4+. CD56+, HLA-DR+, Lineage negative
	Myeloid		Blastic, abundant cytoplasm	lysozyme+, MPO+
	T-LBL	mediastinal mass	dispersed chromatin, cells may look more mature	positive for T-cell markers, CD34+, TdT+, CD1a+
	B-LBL	usually young	dispersed chromatin	CD79a+, CD20 var, CD34+, CD10+, TdT+
	True NK	young adults, haemophagocytic syndrome	angio-invasive, azurophilic granules	cCD3+, CD56+, TIA1+, EBER+

• Precursor NK-cell lymphoblastic lymphoma/leukaemia may be closely related.

• CD56-positive AML; relationship requires clarification. AML is positive for myeloid markers CD13 and CD33.

Management

Treatment is with multiagent chemotherapy and/or radiation³.

Prognosis

Cases may progress to overt leukaemia⁴. The prognosis is poor (mean 9 to 17 months)³ unless limited to cutaneous disease. TdT expression is a favorable prognostic indicator¹. Anthracycline chemotherapy with stem cell transplantation have given encouraging results¹. Since the cells lack asparaginase, asparagine depletion with L-asparaginase has been used successfully in children¹.

References

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

¹ Nava VE,Jaffe ES The pathology of NK-cell lymphomas and leukemias. Adv Anat Pathol 2005; 12:27-34

² Karube K, Ohshima K, Tsuchiya T, et al. Non-B, non-T neoplasms with lymphoblast morphology: further clarification and classification. Am J Surg Pathol 2003; 27:1366-74

³ Reichard KK, Burks EJ, Foucar MK, et al. CD4(+) CD56(+) lineage-negative malignancies are rare tumors of plasmacytoid dendritic cells. Am J Surg Pathol 2005; 29:1274-83

⁴ Campo E, Chott A, Kinney MC, et al. Update on extranodal lymphomas. Conclusions of the Workshop held by the EAHP and the SH in Thessaloniki, Greece. Histopathology 2006; 48:481-504 FULL TEXT

This page last revised 28.4.2006

©SMUHT/PW Bishop