Histiocytic sarcoma

Definition

A malignant neoplasm of histiocytes, positive for one or more histiocytic markers but negative for accessory/dendritic cell markers. Many cases described in the past would now be classified as diffuse large B-cell lymphoma or anaplastic large cell lymphoma.

Synonyms

"True" histiocytic lymphoma, malignant histiocytosis (of the gastrointestinal tract).

Equivalent normal cell

Phagocytic cells may be freely mobile (monocytes) or reside in tissues (e.g. Kupffer cells). Their cytoplasm contains numerous vacuoles, lysosomes, mitochondria and residual bodies. There is immunoreactivity for lysozyme, a₁-antitrypsin, CD68, CD11c, CD14 and CD163².

Epidemiology

A rare tumour showing a wide age range including children but most common in adults. A few patients have a previous history of a mediastinal germ cell tumour.

Clinical features

One third of cases are nodal, one third cutaneous or deeper soft tissues and one third present at other extranodal sites, particularly the gastrointestinal tract². Rare sites include spleen, bone marrow, nasal cavity⁵, lung⁵ and brain⁴. Patients may have fever, weight loss, a rash, or hepatosplenomegaly. Lytic bone lesions and pancytopenia are not uncommon. Some cases present as disseminated "malignant histiocytosis². There is an association with other haematological disorders². Patients may have a profound peripheral eosinophilia⁵.

Histopathology

In extranodal cases, the mass may be well circumscribed or infiltrating. Tumour cells are usually large with abundant eosinophilic cytoplasm, which may be foamy/xanthomatous. The cells may be focally spindled⁵. Nuclei are oval to irregular with vesicular chromatin and usually large eosinophilic nucleoli⁵. Nuclear atypia is variable. Multinucleate forms are common. Mitotic rates are very variable⁵. There may be haemophagocytosis². Small lymphocytes, plasma cells, benign histiocytes and eosinophils are present in variable, often large, numbers. In lymph nodes, spleen and bone marrow, there is often sinusoidal involvement². In the central nervous system, histiocytic lymphomas with a dense mixed inflammatory cell infiltrate and abscess formation have been reported; this inflammatory component may mask the underlying neoplasm¹.

Immunohistochemistry; see the immunohistochemical differentiation of histiocytic and dendritic cell neoplasms

monocyte-macrophage markers: one or more markers should be positive0	CD68	18/18 (Granular staining. KP1 and PGM1 produced identical results)2, 14/14 (Granular staining, almost always strong and diffuse, with both KP1 and PGM1)5
	lysozyme; usually granular with Golgi accentuation	17/18 (Granular with Golgi accentuation. Stains fewer cells than does CD68)2, 12/14 (granular, with variable Golgi accentuation)5
	CD11c
	CD14
markers lacking lineage specificity	CD4	may be positive0, 9/182, 13/142
	HLA-DR	usually positive0
	CD31	8/10 (membranous, variable intensity)5
	CD45	may be positive0, 14/18 (Staining often weak / limited to a minority of cells)2, 14/14 (strong and diffuse in 12 cases)5
	CD45RO	may be positive0, 14/14 (strong and diffuse in all cases)5
specific myeloid markers: should be negative0	myeloperoxidase	0/162, 0/145
	CD33	negative0
	CD34	0/132, 0/145
accessory/dendritic cell markers: should be negative0	CD1a	negative0, 0/172, 5/14 (all but one case, very limited focal staining)5
	CD21	0/182, 0/145
	CD35	3/15 (weak or rare cells only)2, 0/145
	CNA.42	1/132
lineage-specific T cell markers: should be negative0	CD3	0/172, 0/145
lineage-specific B cell markers: should be negative0	CD20	0/182, 0/145
	CD79a	0/142
CD30 is usually negative2		negative0, 0/172, 2/14 (focal weak cytoplasmic staining)5
others	CD15	0/18 (Focal positivity)2, 1/14 (weak staining)5
	CD117	0/4 (gastrointestinal cases)5
	desmin	0/4 (gastrointestinal cases)5
	S-100	may be focally weakly positive0, 9/18 (Stained >50% of cells in 6/18 cases)2, 7/14 (both nuclear and cytoplasmic, extensive in 4 cases)2
	ALK-1	0/145
	EMA	negative0, 1/14 (focal weak cytoplasmic staining)5
	HMB-45	negative0, 0/145
	cytokeratin	negative0, 0/145

Immunoglobulin T cell antigen-receptor genes should be of germline configuration.

Ultrastructure

There are lysosomes. Birbeck granules, desmosomes and interdigitating junctions are absent.

Differential diagnosis

• Other histiocytic and dendritic cell neoplasms; see the immunohistochemical differentiation of histiocytic and dendritic cell neoplasms. Since some histiocytic sarcomas are positive for CD1a and S-100, only nuclear morphology or ultrastructure reliably differentiate.

• Differentiation from interdigitating dendritic cell sarcoma, which has an overlapping immunophenotype, may require electron microscopy².

• Diffuse large B-cell lymphoma; lineage markers are necessary to distinguish.

• Anaplastic large cell lymphoma; CD30 and EMA positive. May also show a marked inflammatory cell infiltrate.

• Cutaneous involvement by monoblastic leukaemia; the immunophenotype and ultrastructure are similar but the cells are smaller and more monomorphic with intensely basophilic cytoplasm, show Indian file infiltration and have a higher mitotic count². CD34 may be positive².

• Metastatic malignant melanoma: some cases are positive for CD68, using either PG-M1 or KP1.

• Metastatic large cell carcinoma: renal cell carcinoma may look very similar and may be positive for CD68, using either PG-M1 or KP1.

Prognosis

Usually an aggressive neoplasm with a poor response to therapy and a poor prognosis²: some localised cases behave less agressively⁵. Metastases occur to lymph nodes, lung and bone⁵.

References

⁰World Health Organization Classification of Tumours, Tumours of the haematopoietic and lymphoid tissues, IARC Press 2001.

¹Cheuk, W., Walford, N., Lou, J., et al. Primary histiocytic lymphoma of the central nervous system: a neoplasm frequently overshadowed by a prominent inflammatory component. Am J Surg Pathol 2001;25:1372-1379.

²Pileri, S.A., Grogan, T.M., Harris, N.L., Banks, P., Campo, E., Chan, J.K., Favera, R.D., Delsol, G., De Wolf-Peeters, C., Falini, B., Gascoyne, R.D., Gaulard, P., Gatter, K.C., Isaacson, P.G., Jaffe, E.S., Kluin, P., Knowles, D.M., Mason, D.Y., Mori, S., Muller-Hermelink, H.K., Piris, M.A., Ralfkiaer, E., Stein, H., Su, I.J., Warnke, R.A. and Weiss, L.M. Tumours of histiocytes and accessory dendritic cells: an immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases. Histopathology 2002;41:1-29.

³Copie-Bergman, C., Wotherspoon, A.C., Norton, A.J., Diss, T.C. and Isaacson, P.G. True histiocytic lymphoma: a morphologic, immunohistochemical, and molecular genetic study of 13 cases. Am J Surg Pathol 1998;22:1386-92.

⁴Sun, W., Nordberg, M.L. and Fowler, M.R. Histiocytic sarcoma involving the central nervous system: clinical, immunohistochemical, and molecular genetic studies of a case with review of the literature. Am J Surg Pathol 2003;27:258-65.

⁵Hornick, J. L., E. S. Jaffe, et al. (2004). "Extranodal histiocytic sarcoma: clinicopathologic analysis of 14 cases of a rare epithelioid malignancy." Am J Surg Pathol 28(9): 1133-44.

This page last revised 8.10.2004.

©SMUHT/PW Bishop