MALIGNANT HISTIOCYTOSIS: Histologic, Cytochemical, Chromosomal, and Molecular Data with a Nosologic Discussion

https://doi.org/10.1016/S0889-8588(05)70522-0Get rights and content

For several years, class III histiocytosis has been a confusing disorder, but there have been recent contributions to the subject, provided by modern techniques in cellular and molecular biology, regarding the stage of differentiation and the cell lineage involved. According to the degree of differentiation pathway from the monoblastic stem cells, the blood monocyte to the peripheral histiocyte and macrophage, malignant transformations of these lineages include acute monocytic leukemia, chronic myelomonocytic leukemia, and malignant histiocytosis (MH).

Because leukemia and lymphoma are regarded as neoplasms of lymphoid cells, MH likewise is thought to represent a malignant transformation of the reticuloendothelial system (RES).5, 14, 72, 86 Because the initial concept of RES has evolved considerably from that of a web of fixed, phagocytic cells to that of a network of bone marrow–derived, highly pleomorphic, mobile and fixed cells involved in several basic immunologic functions, the understanding and identification of these malignant changes have also evolved and given birth to various interpretations and denominations such as the mononuclear phagocyte system.33

Although it has been seriously challenged on the basis of certain immunocytochemical data, the MH concept recently received strong support from accurate chromosomal and molecular data, and it can be placed among the large and heterogeneous group of the anaplastic large cell lymphomas (ALCLs).16, 60, 61, 63, 64 Although there is general agreement on the clinical features of MH, there is still much debate as to the histiocytic or lymphoid nature of the proliferative cells, which has given rise to a number of confusing terms for this malignant entity. In addition to the equivocal innate pleomorphism of the cells of the histiocyte/macrophage lineage, the controversy is mainly fueled by the fact that numerous studies have dealt with heterogeneous material, most often selected retrospectively on the basis of either some unique histochemical data (Ki-1 or CD30 positivity) or a characteristic chromosomal abnormality (the t(2;5) associated with 5q35bp).56, 63 In addition, most of these investigations have included in a haphazard way childhood and adult cases, in spite of the fact that the clinical course is definitely not the same in children and adults, and that the disease affects preferentially a young population (Table 1).

For these reasons and the fact that this issue is devoted to histiocytic disorders, the analysis of the morphologic and molecular characteristics is under the general heading of MH and deals exclusively with pediatric cases. The nosologic discussion is left to the end of the article.

Section snippets

HISTOPATHOLOGY

MH is characterized by the proliferation of large (from 10 to 20 μm), atypical, clear, “histiocyte-like” cells according to Rappaport72 and Cazal.14 Better seen on smears, these cells have a basophilic, finely or grossly vacuolated cytoplasm. The nucleus is large and irregular and exhibits prominent and dense nucleoli and a thick nuclear membrane (Fig. 1). Mitotic figures, sometimes multipolar, are frequent and provide a crucial element for distinguishing this condition from a reactive process.

CYTOCHEMISTRY

Because the neoplastic cells are extremely immature, usually necrotic, and frequently intermingled with locally activated lymphoid and histiocytic cells, the interpretation of the cytochemical data is sometimes difficult. As anticipated, the MH cells react positively with acid phosphatase, nonspecific esterase, and most lysosome-associated enzymes.13, 63 The results of the immunostaining are more characteristic, exhibiting most typically a CD30 positivity as revealed by Ki-1 or BerH2 specific

MALIGNANT HISTIOCYTOSIS PERMANENT CELL LINES

In view of certain conflicting data regarding the true nature of the proliferative cells, cell culture appeared to be a reliable method for selection of the cell in question and study of its behavior and its capacity for differentiation, as well as of the nature of the biologic products released. To date, only a few MH-derived permanent cell lines are available. Most of them have been isolated from pleural effusions in children with a disseminated disease identified as MH by their pediatricians

CHROMOSOMAL ABNORMALITIES: THE t(2;5) AND THE 5q35 BREAKPOINT

Following the first report by Morgan et al56 in 1986, chromosomal investigations performed on several MH cell lines revealed the occurrence of a constant breakpoint located on the long arm of chromosome 5 (5q35bp). Most often, this abnormality has been found associated with a second breakpoint involving the short arm of chromosome 2 and a reciprocal translocation t(2;5). Moreover, translocations involving various regions of chromosomes 1, 3, and 6 were also reported, underscoring the value of

DIFFERENTIAL DIAGNOSIS

Because MH cells express CD30 antigen, as do Reed-Sternberg cells, MH has sometimes been regarded as a disseminated variety (Stage IV) of Hodgkin's disease.35 This assumption has recently been supported by molecular studies— that is, the presence of NPM/ALK chimeric transcript in 11 of 13 patients with Hodgkin's disease.67 These results, however, have not been confirmed by most of the investigators using the NPM/ALK probe elaborated by Morris et al.11, 25, 27, 44, 50, 51, 97, 103 Of note,

NOSOLOGIC DISCUSSION

The main diagnostic problem remains the distinction between MH and lymphoma, and more precisely ALCL. As already stated, it is more a nosologic than a differential discussion. The opinion that MH belongs to the ALCL group is based on the following arguments (Table 3): (1) the CD30 positivity, considered as a reliable marker of Reed-Sternberg cells; (2) the frequent expression of lymphoid markers such as CD3, CD2, CD4, CD7, CD8, CD43, and CD45R021, 55, 97; and (3) the frequent underlying

SUMMARY

Although myelomonoblastic leukemia is thought to originate from a malignant transformation of the stem cell of the mononuclear phagocyte system, malignant histiocytosis (MH) is classically assumed to represent a malignant change of the terminal and fixed elements of this system. Indeed, MH is characterized by the proliferation of large, clear, pleomorphic, “histiocytic-like” HLADR and CD30+ cells resulting in a nodal and extranodal disseminated neoplasm affecting preferentially and severely

References (107)

  • L. Lamant et al.

    High incidence of t(2;5)(p23;q35) translocation in anaplastic large cell lymphoma and its lack of detection in Hodgkin's disease. Comparison of cytogenetic analysis, reverse transcriptase–polymerase chain reaction and p80 immunostaining

    Blood

    (1996)
  • R. Morgan et al.

    Lack of involvement of c-fms and N-myc genes by chromosomal translocation t(2;5)(p23;q35) common to malignancies with features of so-called malignant histiocytosis

    Blood

    (1989)
  • K. Ohshima et al.

    Genotypic and immunophenotypic analysis of anaplastic large cell lymphoma (Ki-1 lymphoma)

    Pathol Res Pract

    (1990)
  • U. Rovigatti et al.

    Heavy chain immunoglobulin gene rearrangement in acute nonlymphocytic leukemia

    Blood

    (1984)
  • N.H. Russell

    Biology of acute leukemia

    Lancet

    (1997)
  • J.T. Sandlund et al.

    Clinico-pathological features and outcome of children with large-cell lymphoma and t(2;5)(p23;q35)

    Blood

    (1994)
  • C.J. Sherr et al.

    The c-fms proto-oncogene product is related to the receptor for the mononuclear phagocyte growth factor, CSF-1

    Cell

    (1985)
  • M. Shiota et al.

    Anaplastic large cell lymphomas expressing the novel chimeric protein p80 NPM/ALK. A distinct clinicopathologic entity

    Blood

    (1995)
  • H. Stein et al.

    The expression of the Hodgkin's disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: Evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells

    Blood

    (1985)
  • D.D. Weisenburger et al.

    Occurrence of the t(2;5)(p23;q35) in non Hodgkin's lymphoma

    Blood

    (1996)
  • S.L. Abbondanzo et al.

    Acute infectious mononucleosis. CD30 (Ki-1) antigen expression and histologic correlations

    Am J Pathol

    (1990)
  • B.A. Agnarsson et al.

    Ki-1 positive large cell lymphoma. A morphologic and immunologic study of 19 cases

    Am J Surg Pathol

    (1988)
  • R. Andreesen et al.

    Human macrophages can express the Hodgkin's cell-associated antigen Ki-1 (CD30)

    Am J Pathol

    (1989)
  • E. Armstrong et al.

    FLT4 receptor tyrosine kinase gene mapping to chromosome band 5q35 in relation to the t(2;5) t(5;6) and t(3;5) translocations

    Genes Chromosom Cancer

    (1993)
  • L. Aschoff

    Das Reticuloendothelial System

    Ergebnisse der Inneren Medizin und Kinderheilkunde

    (1924)
  • S. Barbey et al.

    DEL cell line. A malignant histiocytosis cell CD30+, t(5;6)-q35;p21) cell line

    Int J Cancer

    (1990)
  • M.A. Bitter et al.

    Morphology in Ki-1 (CD30) positive non-Hodgkin's lymphoma is correlated with clinical features and the presence of a unique chromosomal abnormality t(5;6)(p23;q35)

    Am J Pathol

    (1990)
  • R.J. Buchsbaum et al.

    Cellular origins of hematologic neoplasms [editorial]

    N Engl J Med

    (1990)
  • F. Bullrich et al.

    Nucleophosmin (NPM) gene rearrangements in Ki-1 positive lymphomas

    Cancer Res

    (1994)
  • M. Caniglia et al.

    Activité des monokines au cours du syndrome d'activation histiocytaire [abstract]

    Arch Fr Pediatr

    (1990)
  • A. Carbone et al.

    Histopathologic, immunophenotypic and genotypic analysis of Ki-1 anaplastic large cell lymphomas that express histiocyte-associated antigens

    Cancer

    (1990)
  • P. Cazal

    Aspects cliniques et hématologiques de la réticulose maligne

    Acta Haematol

    (1952)
  • R.L. Chen et al.

    Fulminant childhood hemophagocytic syndrome mimicking histiocytic medullary reticulosis. An atypical form of Epstein-Barr virus infection

    Am J Clin Pathol

    (1991)
  • M.J. Cline

    The molecular basis of leukemia

    N Engl J Med

    (1994)
  • C. Cozzutto et al.

    Malignant monomorphic histiocytoma in children

    Cancer

    (1981)
  • R. Datta et al.

    Functional expression of the macrophage colony-stimulating factor receptor in human THP-1 monocytic leukemia cells

    Blood

    (1992)
  • M.P. Davey et al.

    Clonality and lymphoproliferative lesions [editorial]

    N Engl J Med

    (1986)
  • E. Davis et al.

    Malignant histiocytosis: A reassessment of cases previously reported in 1975 based upon paraffin section immunophenotyping studies [abstract]

    Mod Pathol

    (1990)
  • R. Dekmezian et al.

    The 2;5 translocation: Is it specific for anaplastic (Ki-1) large cell lymphomas?

    Mod Pathol

    (1990)
  • A. Delcourt et al.

    L'histiocytose maligne. Etude anatomique de 6 cas d'expression clinique atypique

    Semaine des Hôpitaux, Paris

    (1983)
  • G. Delsol et al.

    Coexpression of epithelial membrane antigen (EMA) Ki-1 and interleukin-2 receptor by anaplastic large cell lymphomas. Diagnostic value in so-called malignant histiocytosis

    Am J Pathol

    (1988)
  • W.G. Dirks et al.

    The (2;5)(p23;q35) translocation in cell lines derived from malignant lymphomas: Absence of t(2;5) in Hodgkin analogous cell lines

    Leukemia

    (1996)
  • S.A.D. Ebrahim et al.

    Immunohistochemical, molecular and cytogenetic analysis of a consecutive series of 20 peripheral T-cell lymphomas and lymphomas of uncertain lineage, including 12 Ki-1 positive lymphomas

    Genes Chromosom Cancer

    (1990)
  • A.L. Epstein et al.

    Biology of the human malignant lymphomas. I. Establishment in continuous cell culture and heterotransplantation of diffuse histiocytic lymphomas

    Cancer

    (1974)
  • A.L. Epstein et al.

    Biology of the human malignant lymphomas. IV. Functional characterization of ten histiocytic lymphoma cell lines

    Cancer

    (1978)
  • K. Foucar et al.

    The mononuclear phagocyte and immunoregulatory effector (M.PIRE) system: Evolving concepts

    Semin Diagn Pathol

    (1990)
  • M.H. Freedman et al.

    Juvenile chronic myelogenous leukemia

    Am J Pediatr Hematol Oncol

    (1988)
  • G. Frizzera

    The distinction of Hodgkin's disease from anaplastic large cell lymphoma

    Semin Diagn Pathol

    (1992)
  • J. Fujimoto et al.

    Ki-1 lymphomas in childhood: Immunohistochemical analysis and the significance of epithelial membrane antigen (EMA) as a new marker

    Virchows Arch A

    (1988)
  • J. Gogusev et al.

    Genotype markers and proto-oncogene analysis in the CD30 positive malignant histiocytosis with t(5;6)(q35;p21)

    Int J Cancer

    (1990)
  • Cited by (24)

    • Cutaneous true histiocytic malignancy: True histiocytic lymphoma

      2004, Journal of the American Academy of Dermatology
    • The bone marrow

      2012, Stocker and Dehner's Pediatric Pathology: Third Edition
    • Skin Diseases of the Dog and Cat: Clinical and Histopathologic Diagnosis

      2008, Skin Diseases of the Dog and Cat: Clinical and Histopathologic Diagnosis
    View all citing articles on Scopus

    Address reprint requests to Jean Gogusev, MD, Chargé de Recherche à l'INSERM, U 90 Hôpital Necker Enfants Malades, 149, rue de Sèvre, 75743 PARIS Cedex 15, France

    Work supported by a grant from the Histiocytosis Association of America.

    View full text