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Sinus Histiocytosis with Massive Lymphadenopathy a
a
a
a
Stefano Sacchi , Tullio Artusi , Umberto Torelli & Giovanni Emilia a
Second Medical Clinic, University of Modena, Modena, Italy Published online: 01 Jun 2015.
To cite this article: Stefano Sacchi, Tullio Artusi, Umberto Torelli & Giovanni Emilia (1992) Sinus Histiocytosis with Massive Lymphadenopathy, Leukemia & Lymphoma, 7:3, 189-194 To link to this article: http://dx.doi.org/10.3109/10428199209053622
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
0 1992 Harwood Academic Publishers GmbH
Leukemia and Lymphoma, Vol. 7, pp. 189-194
Printed in the United Kingdom
Reprints available directly from the publisher Photocopying permitted by license only
Sinus Histiocytosis with Massive Lymphadenopathy STEFAN0 SACCHI, TULLIO ARTUSI, UMBERTO TORELLI and GIOVANNI EMILIA Second Medical Clinic, University of Modena, Modena, Italy
Downloaded by [University of Otago] at 21:31 21 July 2015
(Received 7 November 1991)
To date, the morphological aspects of sinus histiocytosis with massive lymphadenopathy (SHML) have been fully described. The disease is characterized by an enlargement of lymph nodes in which the sinuses are dilated and infiltrated by histiocytes, often phagocytosing lymphocytes. Even if the prognosis is usually benign and not requiring therapy, several fatal cases have been reported. The etiology is still obscure and the biology is not yet completely clear. Recent immunophenotypical studies suggest that histiocytes may belong to the T-zone associated histiocyte lineage. They may be cytologically homogeneous, but can express different antigenic patterns according to their stage of differentiation. Cytogenetic and molecular aspects of the disease have only been sporadically investigated. In order to better understand the pathogenesis of SHML, which seems to be a disorder lying in between the fields of infections, immunological disease and neoplasia, it is considered very useful to systematically employ a variety of immunophenotypical, cytogenetic and molecular techniques to study the disease, particularly in cases which are clinically atypical or with a more aggressive evolution. KEY WORDS:
SHML
immunophenotype
INTRODUCTION Sinus histiocytosis with massive lymphadenopathy (SHML, Rosai-Dorfman disease) is a rare histiocytic syndrome with well defined histologic and clinical features. Rosai and Dorfman, in two reports in 1969' and 1972*, defined the main clinical and histological features of an entity recognized earlier in 1965 by Destombes3 and afterwards described under several denominations. The authors established SHML as a distinct entity. Until now, more than 150 reports have described the various characteristics of the disorder and data on 423 patients with SHML have been collected by Rosai in a Registry4. It follows that the disease is currently classified as an idiophatic Address for correspondence: Stefano Sacchi, Associate Professor, Clinica Medica 11, Policlinico, Via del Pozzo 71, 41100 Modena, Italy.
chromosomes
molecular biology
histiocytosis characterized by: (a) conspicuous enlargement of lymph nodes, but also frequent involvement of extranodal sites. (b) although the fundamental nodal architecture is preserved, the sinuses are dilated and infiltrated by histiocytes accompanied by small lymphocytes, mature plasma cells and red cells. The histiocytes often phagocytose lymphocytes. (c) the disease evolution is usually benign even if, in some cases, the extent of infiltrates or infectious complications can cause death. The diagnosis of SHML is strictly morphologic and when an extranodal site is involved, the diagnosis is generally more difficult4v5.The etiology and pathogenesis still remain obscure'. GENERAL CLINICAL CHARACTERISTICS SHML patients have been diagnosed but more than 50% of the cases were from the United
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States, Europe and Africa4. About half of the patients were black, although any racial group and socioeconomic status can be affected4. It is to be recalled that the total number of cases is probably underestimated due to misdiagnosis or an unusual referral pattern. The mean age of disease onset was 20.6 years; the youngest patient had congenital SHML, while the oldest was 74 years old. Males (58%) outnumbered females. The disease rarely occurred in several family
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member^^,^.
In a very small percentage of cases, SHML was associated with neoplasia : non-Hodgkin lymphoma, multiple myeloma, melanoma, thyroid carcinoma, ovarian and testicular teratomas, Hodgkin’s disSporadic cases were associated with other histiocytic syndromes, such as Langerhans cell granulomatosis and poorly characterized systemic histiocytic proliferative disorder. A few cases associated with diabetes mellitus or growth failure have been described4. About 13% of cases were associated or preceded by one or more immuno-mediated diseases, such as arthritis, glomerulonephritis, autoimmune hemolytic anemia, asthma and juvenile diabetes mellitus4. The presence of an immunologic disorder had an unfavorable prognostic significance. In the majority of SHML cases, the liver was normal on clinical and/or radiographic examination and the spleen was only exceptionally involved4. Fever was noted in about 25% of patients, while systemic illness such as malaise, weight loss and night sweats were occasionally seen2. To investigate the possibly infectious etiology of SHML, most patients have been studied with a variety of techniques such as serology, skin tests, special histology stains, routine or special culture of oropharynx or excised tissues. Various viral serologic tests were positive in several patients, and a significant number of cases were positive for Epstein-Barr virus (EBV). It is possible that EBV may play a role in the pathogenesis of SHML: a direct role by creating an immunologic environment favouring other factors or simply as evidence of an abnormality of immune control4. In a few cases, parasitic infestations and tuberculosis were described’*’. Involvement of lymph nodes is present in nearly all cases. About 87% of patients have cervical lymphadenopathy, usually bilateral. Other node groups are also affected, including axillary, inguinal, mediastinal and miscellaneous4. Typically, the lymphadenopathies are bulky and painless; they can increase in febrile states or partially diminish in the summer’. In a few cases, pain or tenderness were noted.
The involvement of extranodal sites is present in about 43% of cases4, either alone or in association with lymphadenopathies. The most frequent extranodal manifestations are in the head and neck regions (eyelid, nasal cavity, paranasal sinuses, orbit) and less commonly in the skin, soft tissues, bone, central nervous system, thyroid, kidney, lower respiratory tract, liver, breast, thymus and testis. The frequency of extranodal lesions is twice as high in patients with underlying immunological disease l o .
GENERAL LABORATORY DATA
A mild normochromic normocytic or hypochromic microcytic anemia is present in the majority of cases. Occasionally, patients with red cell autoantibodies were encountered, a few of whom had severe hemolytic anemia. Increase of the peripheral neutrophil cell count and lymphopenia are also frequently found. Peripheral eosinophils, monocytes and platelets are usually within normal The erythrocyte sedimentation rate is usually elevated at the time of initial clinical presentation. In the majority of the patients studied, abnormalities in serum protein level were detected. Albumin was often low and most patients showed a polyclonal elevation of IgG, while monoclonal gammopathy was raress6. Lipid studies showed normal serum cholesterol and triglycerides levels in nearly all cases4. Abnormalities of lymphocyte and histiocyte function and granulocyte phagocytic activity were only sporadically detected4. A few patients had a positive rheumatoid factor, lupus erythematosus cells and antinuclear antibody4. Eight out of ten patients studied show a reversal the circulating T4/T8 cell ratio4” I . lncreased levels of antibodies against viruses, bacteria and other parasites were occasionally found. Elevated serum levels of EBV antibodies were often d e t e ~ t e d ~ . ~
HISTOLOGY
Macroscopically the lymph nodes are enlarged and often matted together with a thickened capsule. The cut surface is often yellow-white in appearance with a nodular or diffuse architecture. Light microscopic examination shows that the fundamental nodal architecture is preserved although there is marked capsular and pericapsular fibrosis. The characteristic pattern of nodal involvement is the
SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY
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distention of the subcapsular and interfollicular sinusoids by pale staining histiocytes with eosinophilic cytoplasm and round or oval, vescicular nuclei (Figure 1). Most of these nuclei contain a single small nucleolus. The histiocytes are loosely aggregated, and
mixed with small lymphocytes, mature plasma cells and red cells. Mitotic figures in hystiocytes are generally infrequent, but may be easily identified in some cases. The cytoplasm of histiocytes contain intact lymphocytes, a phenomenon known as emperipolesis (Figure 2a,b). The histiocytes, sometimes of giant size, also often phagocytose plasma cells, neutrophils or red blood cells, and sometimes show an atypical m ~ r p h o l o g y ~ * ~Electron .' microscopy shows that the histiocytes often have complex cytoplasmic filopodia4 and show subcellular characteristics of macrophages. The cytoplasm is devoid of Birbeck granules". Hyperplasia of the germinal centers is infrequent4 and microabscesses are present in some cases4. The capsular fibrosis sometimes extends into the perinodal soft tissues, but is usually minimal in hematoxylin-eosin-stained sections4. The microscopic features of SHML in extranodal Figure 1 Representative overview of a SHML lymph node section: sites are similar to those seen in lymph nodes, but the distended sinuses, with diffuse intralurninal proliferation of sinus diagnosis is generally more difficult. In general, histiocytes are seen. H.E. x 100. extranodal SHML exhibits more prominent fibrosis, fewer typical histiocytes and a lesser degree of hemophagocytosis. A definitive diagnosis requires the presence of a large number of histiocytes containing lymphocytes and plasma cells characteristically distributed around and along the vessels of the fibrous st roma4*''.
BIOLOGY
(b)
Figure 2n,b Details of a sinus lumen showing histiocytes phagocytozing well preserved lymphocytes. H.E. A x 250; B x 400.
In recent years several studies have been performed using immunophenotyping techniques on sections of lymph nodes in order to better identify the sinus histiocytes (SH) of SHML. The SHs, in all cases studied, were found to be positive for S-100 protein, but generally with less intense positivity than in Langerhans cell histiocytosis (HX)' '*14-16 . The SHs were also positive for monoclonal antibodies O K M l (CDllb) and LeuM3 (CD14)1'.'6, KP1 (CD68) and DRC-1". Several author^'^.'^ found the SHs to be unreactive with OKM5 (CD15), OKT6 (CDla) and OKT4 (CD4), while others showed positivity for some SHs". Miettinen et al.14, on the basis of immunophenotypical analysis, suggested a relationship between the SHML cells and Langerhans cells and/or interdigitating reticulum cells. Bonetti et af.I5,showed that lymphophagocytic histiocytes were strongly positive for S-100 protein and unreactive with the monoclonal antibodies OKT6 (CDla) and OKM5 (CD15). They
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concluded that the peculiar S-100+/CDla-phenotype suggests that RD histiocytes belong to the T-zone associated histiocyte lineage. C D l a negativity distinguishes RDHs from Langerhans cells. Sacchi et al.", by immunophenotypical analysis in one case of SHML, showed that the majority of lymphophagocytic histiocytes were strongly positive for LeuM3, LeuM5, S-100 protein, KP1 and DRC-1; a proportion of these histiocytes were also positive for OKT6 (CDla) and Leu3A (CD4) (Table 1, Figure 3). KP1 recognizes the CD68 antigen on a wide variety of cells including macrophages, mast cells, granulocyte precursor^'^-'^ and melanoma cellsz0. The antigen detected by the KP1 monoclonal antibody is also present in LCH cells, although it is not expressed by all epidermal and lymph node Langerhans DRC- 1 recognizes dendritic reticulum cells forming a network within B cell follicles, but cal also label veiled cells' Thus, the immunophenotypical findings of Sacchi's case suggest a relationship between the SHML cells and veiled cells: the latter represent an intermediate step in the pathway from the Langerhans cells to interdigitating reticulum cellszz. It can be speculated that histiocytes present in SHML may be cytologically homogeneous, but may express different
Table 1 Immunohistological analysis in histiocytes of a SHML lymph-node' ' Monoclonal polyclonal antibodies
Cluster designation
Histiocytea reactivity
B4 IgG IgA IgM IgD Kappa Lambda Leu4 Leu3A Leu2A OKT6 LeuM3 OKM5 Ki-1 Ki-67 anti-5BrdU s-loo KPl DRC-1
CD19
---
+-+-+-CD3 CD4 CD8 CDla CD14 CD15 CD30
CD68
The immunostaining results are described as follows: _ _ _ = negative; + + + = >80% of histocytes positive; + + - = 40%-80% positive; + - - = lo%-% positive; f - - = 1%-10% positive.
a
+--
** -- ---f---f--
Figure 3 SH cells strongly expressing CD14 antigen. One cell (arrowed) displays obvious lymphophagocytosis. Cryostat section, APAAP. x 400. (See Colour Plate V at the back of this publication.)
antigenic patterns according to the stage of differentiation. Moreover, some histiocytes were stained by the Ki-1 antibody which recognizes the CD30 molecule, a marker for Hodgkin's or Reed-Sternberg cells and activated T and B cells. However, this finding is not surprising, because it has recently been suggested that activated human macrophages can also express the Ki-1 antigen23. Molecular studies were performed in only two cases: the first showed a germ line configuration for the immunoglobulin gene and the beta-chain T receptor". The latter", showed neither amplification nor rearrangement for the gene c-fms that is sometimes deleted in disorders affecting the monocyte-macrophage lineage, some of which evolve into acute leukemiaz4. Only two cases of SHML have been investigated by cytogenetic analysis of lymph node sinus histiocytes. In the first case, a normal karyotpe was detected2' while in the second, besides a predominant normal clone, a minor hypodiploid clone with loss of one chromosome 20, and random numerical and structural alterations were evident'
+++
+++
*_ ----
f--
+++ +++
+++
DIFFERENTIAL DIAGNOSIS The differential diagnosis includes a variety of diseases which have a microscopic resemblance to SHML, but, in practice, the most important problem is to distinguish true SHML from so-called sinus hyperplasia, Langerhans cell histiocytosis and some hemophagocytic (non Langerhans) syndromes. Until now, the diagnosis has been favoured by the pathologists who are familiar with the features of SHML and, lately, by
SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY
the use of ultrastructural microscopic techniques and immunophenotyping methods applied to lymph node or extranodal tissue sections.
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EVOLUTION
The evolution of the disease is usually prolonged and benign. Although determining complete remission is difficult owing to the lack of biopsy confirmation, about one third of the patients reach clinical r e ~ o v e r yafter ~ . ~ a few months or years. Many patients have persistent disease which is sometimes stable and, only rarely, progressive. Several fatal cases have been described. The exact role of SHML in the cause of death is often difficult to determine. Some patients died “of disease” and had disseminated nodal involvement with a larger number of extranodal systems affected. Involvement of kidney, lower respiratory tract, liver and nervous system carry a particularly poor prognosis. Some patients died “with disease” due to an association of multisystem involvement and the occurrence of immunologic abnormalities4. Unfortunately, there are no proven factors which aid in discriminating between favorable and unfavorable outcomes.
TREATMENT
As stated above, SHML is often a self-limited disease sometimes subject to spontaneous regression. Consequently, treatment does not seem to be necessary in the majority of patients, particularly when life or organ functions are not threatened. However, when the manifestations of the disease are severe or progressive, treatment appears to be timely in order to prevent loss of function or even of life. Since to date, there has been no systematic treatment study and only a few patients have been prospectively evaluated for the specific purpose of reporting response to therapy, correct interpretation of therapeutic results is difficult. Nevertheless the review of data currently available suggest that most SHML patients do not require therapy and can expect spontaneous remission. For those with extensive or progressive disease, the most effective regimen appears to be a combination of a vinca alkaloid, and alkylating agents (vinblastine, chlorambucil, cyclophosphamide) together with corticosteroids. However, these treatments do not seem to produce dramatic
193
DISCUSSION
The SHML is a rare disease mostly affecting young people, who develop painless bilateral cervical lymphoadenopathy associated with an elevated erythrocyte sedimentation rate and polyclonal hypergammaglobulinemia. Frequently, there is a reversal of the T4/T8 ratio. In a large percentage of cases, extranodal disease is present and almost all organs may be involved. There is “growing awareness that extranodal involvement is a common feature of SHML, and it is probably just a matter of time before involvement of every organ has been d o c ~ m e n t e d ” ~ . The lymph nodes or organs affected display characteristic morphologic features and the differential diagnosis with other histiocytosis, namely the prototypic idiopathic histiocytosis, (Langerhans cell histiocytosis) is not difficult today. No infectious agents are usually detected. In some patients, immunologic abnormalities can be identified and frequently, an elevated titer of Epstein-Barr virus antibodies is observed. The evolution of the disease is commonly chronic, benign and spontaneous remission is not infrequent. Nevertheless, in a small proportion of patients, aggressive and sometimes lethal disease can occur. Immunologic disorders contribute to a poor prognosis, as does involvement of certain extranodal sites such as the kidney, respiratory tract, and the liver. Treatment is often not necessary; however for the cases with progressive or extensive disease, a treatment regimen similar to that shown to be effective for other hematopoietic malignancies can be used. The etiology and pathogenesis of SHML still remain obscure. Based on recent immunophenotypical studies, it can be speculated that the histiocytes present in SHML may be cytologically homogeneous, but express different antigenic patterns according to their stage of differentiation. Thus, the histiocytic cells can appear as Langerhans or interdigitating reticulum cells, T-zone associated histiocyte lineage or veiled cells. Since the findings in SHML remain non specific and a causative agent or specific marker has yet to be discovered, it seems necessary to employ a variety of immunophenotypical, ultrastructural, cytogenetic, and molecular techniques, particularly in cases which are clinically atypical or which show a more aggressive evolution. Although SHML is a relatively rare disease, understanding of its etiology and pathogenesis may be important, since the disorder seems to fall in between the fields of infection, immunological disease
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and neoplasia. The systematic cytogenetic analysis of SHML lymph node or extranodal cells seems to be a useful tool for the detection of possible abnormal clones or consistent chromosomal anomalies. Cytogenetic findings can contribute to define the benign or malignant nature of the disease. If structural and/or numerical chromosome alterations are detected, a variety of cellular genes involved in the control of proliferation and/or differentiation may be activated which may play an important role in the processes leading to this disorder. In this context molecular biology techniques should be applied in every case of SHML in order to gain a better understanding of the pathogenesis of this unusual disorder. Acknowledgements We thank Dr. S. Pileri, University of Bologna, for the help in the critical discussion of the immunohistochemical sections.
REFERENCES I . Rosai, J. and Dorfman, R. F. (1969) Sinus histiocytosis with massive lymphadenopathy: A newly recognized benign clinicopathological entity. Arch. Pathol. 87, 63-70. 2. Rosai, J. and Dorfman, R. F. (1972) Sinus histiocytosis with massive lymphadenopathy: A pseudolymphomatous benign disorder. Analysis of 34 cases. Cancer 30, 11741 188. 3. Destombes, P. (1965) Adenites avec surcharge lipidique, de I'enfant ou de I'adulte jeune, observees aux Antilles et au Mali (quatre observations). Bull. Soc. Pathol. Exot. 58, 1169-1 175. 4. Foucar. E., Rosai, J. and Dorfman, R. F. (1990) Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman Disease): review of the entity. Seminars in Diagnostic Pathology 7, 19-73. 5. Foucar, E., Rosai, J. and Dorfman, R. F. (1988) Sinus histiocytosis with massive lymphadenopathy: current status and future directions. Arch. Dermatol. 124, 121 1-1214. 6. Boman-Ferrand, F. and Floquet, J. (1990) Histiocytose sinusale avec lymphadenophatie massive. Syndrome de DestombesRosai-Dorfman. Ann. Pathol. 10, 152-160. 7. Begue, P., Assimadi, K., Kpodzro, K., Lasfargues, G., Bensman, A., Berger, J. and Diebold, J. (1977) Deux observations de lymphadenopatie avec histiocytose sinusale chez des enfants togolais. Nouu. Presse Med. 6, 1240. 8. Riyat, M. S., Kasili, E. G. and Kyambi, J. M. (1984) Experience in the management of sinus histiocytosis with massive lymphadenopathy. East. Afr. Med. J. 61, 288-294. 9. Lampert, F. and Lennert, K. (1976) Sinus histiocytosis with massive lymphadenopathy. Fifteen new cases. Cancer 37, 783-789. 10. Foucar, E., Rosai, J., Dorfman, R. F. and Eyman, J. M. (1984) lmmunologic abnormalities and their significance in sinus
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histiocytosis with massive lymphadenopathy. Am. J. Clin. Pathol. 82, 515-525. Sacchi, S., Artusi, T., Selleri, L., Temperani, P., Zucchini, P., Vecchi, A., Emilia, G. and Torelli, U. (1990) Sinus histiocytosis with massive lymphadenopathy. Immunological, cytogenetic and molecular studies. Blut 60,339-344. Sanchez, R., Sibley, R. K., Rosai, J. and Dorfman, R. F. (1981) The electron microscopic features of sinus histiocytosis with massive lymphadenopathy. A study of I 1 cases. Ultrastruct. Pathol. 2, 101-119. Dehner, L. P. (1991) Morphologic findings in the histiocytic syndromes. Seminars in Oncology 18, 8-17. Miettinen, M., Paljakka, P., Haveri, P., and Saxen, E. (1987) Sinus histiocytosis with massive lymphadenopathy. A nodal and extranodal proliferation of S-100 protein positive histiocytes. Am. J. Clin. Pathol. 88, 27&277. Bonetti, F., Chilosi, M., Menestrina, F., Scarpa, A., Pellicci, P. G., Amorosi, E., Fiore Donati, L. and Knowles, D. M. I I (1987) Immunohistological analysis of Rosai-Dorfman histiocytosis. A disease of S-100 + CDI-histiocytes. Virchows Arch. A 411, 129-135. Esterly, N. B. and Gonzales-Crussi, F. (1989) Sinus histiocytosis. J. Am. Acad. Dermatol. 21, 155. Pulford, K. A. F., Rigney, E. M., Micklem, K. J., Jones, M. and Stross, W. P..(1989) KPI: a new monoclonal antibody that detects a monocyte/macrophage associated antigen in routinely processed tissue sections. J. Clin. Pathol. 42, 414421. Micklem, K., Rigney, E., Simmons, D., Cordell, J., Simmons, D., Stross, P., Turley, H., Seed, B. and Mason, D. (1989) A human macrophage-associated antigen (CD68) detected by six different monoclonal antibodies. Br. J. Haematol. 73, 6 - 1 1. Horny, H. P., Schaumburg-Lever, G., Bolz, S., Geerts, M. L. and Kaiserling, E. (1990) Use of monoclonal antibody KPI for identifying normal and neoplastic human mast cells. J. C/in. Pathol. 43, 719-722. Facchetti, F., Bertalot, G. and Grigolato, P. G. (1991) KPI (CD68) staining of malignant melanomas. Histopathology 19, 141-145. Ruco, L., Karen, A. F., Pulford, D., Mason, D. Y.,Ceccamea, A,, Uccini, S., Pileri, S., Baglioni, P. and Baroni, C. D. (1989) Expression of macrophage-associated antigens in tissues involved by Langerhans' cell histiocytosis (Histiocytosis X). Am. J. Pathol. 92, 273-279. Fossum, S. and Ford, W. L. (1985) The organization of cell populations within lymph nodes: their origin, life history and functional relationship. Histopathology 9, 469476. Andreesen, R., Brugger, W., Lohr, G. W. and Bross, K. J. (1989) Human macrophages can express the Hodgkin's cell-related antigen Ki-1 (CD30). Am. J. Pafhol. 134, 187-192. Le Beau, M. M., Westbrook, C. A,, Diaz, M. O., Larson, R. A., Rowley, J. D., Gasson, J. C., Golde, D. W. and Sherr, C. J. (1986) Evidence for the involvement of GM-CSF and FMS in the deletion (5q) in myeloid disorders. Science 231, 984987. Carpentier, R. J., Banks, P. M., McDonald, T. J. and Sanderson, D. R. (1978) Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): report of a case with respiratory tract involvement. Laryngoscope 88, 1963-1969. Komp, D. M. (1990) The treatment of sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). Seminars in Diagnostic Pathology 71, 83-86.
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Colour Plate V (see page 192 Figure 3) SH cells strongly expressing CD14 antigen. One cell (arrowed) displays obvious lymphophagocytosis. Cryostat section, APAAP. x 400.
Colour Plate V1 (see page 257 Figure I ) Patient with massive hepatosplenomegaly.
Colour Plate VIII (see page 258 Figure 3) Bone marrow aspirate showing numerous Leishman- Donovani bodies. M.G.G. stain.
Colour Plate VII (see page 257 Figure 2) Peripheral blood film showing abnormal lymphoid cell, rouleaux, tear drop poikilocytes and smear cell. M.G.G. stain.
Colour Plate IX (see page 258 Figure 4) Bone marrow trephine biopsy showing numerous Leishman-Donovani bodies. M.G.G.
Leukemia & Lymphoma Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ilal20
Sinus Histiocytosis with Massive Lymphadenopathy a
a
a
a
Stefano Sacchi , Tullio Artusi , Umberto Torelli & Giovanni Emilia a
Second Medical Clinic, University of Modena, Modena, Italy Published online: 01 Jun 2015.
To cite this article: Stefano Sacchi, Tullio Artusi, Umberto Torelli & Giovanni Emilia (1992) Sinus Histiocytosis with Massive Lymphadenopathy, Leukemia & Lymphoma, 7:3, 189-194 To link to this article: http://dx.doi.org/10.3109/10428199209053622
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
0 1992 Harwood Academic Publishers GmbH
Leukemia and Lymphoma, Vol. 7, pp. 189-194
Printed in the United Kingdom
Reprints available directly from the publisher Photocopying permitted by license only
Sinus Histiocytosis with Massive Lymphadenopathy STEFAN0 SACCHI, TULLIO ARTUSI, UMBERTO TORELLI and GIOVANNI EMILIA Second Medical Clinic, University of Modena, Modena, Italy
Downloaded by [University of Otago] at 21:31 21 July 2015
(Received 7 November 1991)
To date, the morphological aspects of sinus histiocytosis with massive lymphadenopathy (SHML) have been fully described. The disease is characterized by an enlargement of lymph nodes in which the sinuses are dilated and infiltrated by histiocytes, often phagocytosing lymphocytes. Even if the prognosis is usually benign and not requiring therapy, several fatal cases have been reported. The etiology is still obscure and the biology is not yet completely clear. Recent immunophenotypical studies suggest that histiocytes may belong to the T-zone associated histiocyte lineage. They may be cytologically homogeneous, but can express different antigenic patterns according to their stage of differentiation. Cytogenetic and molecular aspects of the disease have only been sporadically investigated. In order to better understand the pathogenesis of SHML, which seems to be a disorder lying in between the fields of infections, immunological disease and neoplasia, it is considered very useful to systematically employ a variety of immunophenotypical, cytogenetic and molecular techniques to study the disease, particularly in cases which are clinically atypical or with a more aggressive evolution. KEY WORDS:
SHML
immunophenotype
INTRODUCTION Sinus histiocytosis with massive lymphadenopathy (SHML, Rosai-Dorfman disease) is a rare histiocytic syndrome with well defined histologic and clinical features. Rosai and Dorfman, in two reports in 1969' and 1972*, defined the main clinical and histological features of an entity recognized earlier in 1965 by Destombes3 and afterwards described under several denominations. The authors established SHML as a distinct entity. Until now, more than 150 reports have described the various characteristics of the disorder and data on 423 patients with SHML have been collected by Rosai in a Registry4. It follows that the disease is currently classified as an idiophatic Address for correspondence: Stefano Sacchi, Associate Professor, Clinica Medica 11, Policlinico, Via del Pozzo 71, 41100 Modena, Italy.
chromosomes
molecular biology
histiocytosis characterized by: (a) conspicuous enlargement of lymph nodes, but also frequent involvement of extranodal sites. (b) although the fundamental nodal architecture is preserved, the sinuses are dilated and infiltrated by histiocytes accompanied by small lymphocytes, mature plasma cells and red cells. The histiocytes often phagocytose lymphocytes. (c) the disease evolution is usually benign even if, in some cases, the extent of infiltrates or infectious complications can cause death. The diagnosis of SHML is strictly morphologic and when an extranodal site is involved, the diagnosis is generally more difficult4v5.The etiology and pathogenesis still remain obscure'. GENERAL CLINICAL CHARACTERISTICS SHML patients have been diagnosed but more than 50% of the cases were from the United
189
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S. SACCHI e t a / .
States, Europe and Africa4. About half of the patients were black, although any racial group and socioeconomic status can be affected4. It is to be recalled that the total number of cases is probably underestimated due to misdiagnosis or an unusual referral pattern. The mean age of disease onset was 20.6 years; the youngest patient had congenital SHML, while the oldest was 74 years old. Males (58%) outnumbered females. The disease rarely occurred in several family
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member^^,^.
In a very small percentage of cases, SHML was associated with neoplasia : non-Hodgkin lymphoma, multiple myeloma, melanoma, thyroid carcinoma, ovarian and testicular teratomas, Hodgkin’s disSporadic cases were associated with other histiocytic syndromes, such as Langerhans cell granulomatosis and poorly characterized systemic histiocytic proliferative disorder. A few cases associated with diabetes mellitus or growth failure have been described4. About 13% of cases were associated or preceded by one or more immuno-mediated diseases, such as arthritis, glomerulonephritis, autoimmune hemolytic anemia, asthma and juvenile diabetes mellitus4. The presence of an immunologic disorder had an unfavorable prognostic significance. In the majority of SHML cases, the liver was normal on clinical and/or radiographic examination and the spleen was only exceptionally involved4. Fever was noted in about 25% of patients, while systemic illness such as malaise, weight loss and night sweats were occasionally seen2. To investigate the possibly infectious etiology of SHML, most patients have been studied with a variety of techniques such as serology, skin tests, special histology stains, routine or special culture of oropharynx or excised tissues. Various viral serologic tests were positive in several patients, and a significant number of cases were positive for Epstein-Barr virus (EBV). It is possible that EBV may play a role in the pathogenesis of SHML: a direct role by creating an immunologic environment favouring other factors or simply as evidence of an abnormality of immune control4. In a few cases, parasitic infestations and tuberculosis were described’*’. Involvement of lymph nodes is present in nearly all cases. About 87% of patients have cervical lymphadenopathy, usually bilateral. Other node groups are also affected, including axillary, inguinal, mediastinal and miscellaneous4. Typically, the lymphadenopathies are bulky and painless; they can increase in febrile states or partially diminish in the summer’. In a few cases, pain or tenderness were noted.
The involvement of extranodal sites is present in about 43% of cases4, either alone or in association with lymphadenopathies. The most frequent extranodal manifestations are in the head and neck regions (eyelid, nasal cavity, paranasal sinuses, orbit) and less commonly in the skin, soft tissues, bone, central nervous system, thyroid, kidney, lower respiratory tract, liver, breast, thymus and testis. The frequency of extranodal lesions is twice as high in patients with underlying immunological disease l o .
GENERAL LABORATORY DATA
A mild normochromic normocytic or hypochromic microcytic anemia is present in the majority of cases. Occasionally, patients with red cell autoantibodies were encountered, a few of whom had severe hemolytic anemia. Increase of the peripheral neutrophil cell count and lymphopenia are also frequently found. Peripheral eosinophils, monocytes and platelets are usually within normal The erythrocyte sedimentation rate is usually elevated at the time of initial clinical presentation. In the majority of the patients studied, abnormalities in serum protein level were detected. Albumin was often low and most patients showed a polyclonal elevation of IgG, while monoclonal gammopathy was raress6. Lipid studies showed normal serum cholesterol and triglycerides levels in nearly all cases4. Abnormalities of lymphocyte and histiocyte function and granulocyte phagocytic activity were only sporadically detected4. A few patients had a positive rheumatoid factor, lupus erythematosus cells and antinuclear antibody4. Eight out of ten patients studied show a reversal the circulating T4/T8 cell ratio4” I . lncreased levels of antibodies against viruses, bacteria and other parasites were occasionally found. Elevated serum levels of EBV antibodies were often d e t e ~ t e d ~ . ~
HISTOLOGY
Macroscopically the lymph nodes are enlarged and often matted together with a thickened capsule. The cut surface is often yellow-white in appearance with a nodular or diffuse architecture. Light microscopic examination shows that the fundamental nodal architecture is preserved although there is marked capsular and pericapsular fibrosis. The characteristic pattern of nodal involvement is the
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distention of the subcapsular and interfollicular sinusoids by pale staining histiocytes with eosinophilic cytoplasm and round or oval, vescicular nuclei (Figure 1). Most of these nuclei contain a single small nucleolus. The histiocytes are loosely aggregated, and
mixed with small lymphocytes, mature plasma cells and red cells. Mitotic figures in hystiocytes are generally infrequent, but may be easily identified in some cases. The cytoplasm of histiocytes contain intact lymphocytes, a phenomenon known as emperipolesis (Figure 2a,b). The histiocytes, sometimes of giant size, also often phagocytose plasma cells, neutrophils or red blood cells, and sometimes show an atypical m ~ r p h o l o g y ~ * ~Electron .' microscopy shows that the histiocytes often have complex cytoplasmic filopodia4 and show subcellular characteristics of macrophages. The cytoplasm is devoid of Birbeck granules". Hyperplasia of the germinal centers is infrequent4 and microabscesses are present in some cases4. The capsular fibrosis sometimes extends into the perinodal soft tissues, but is usually minimal in hematoxylin-eosin-stained sections4. The microscopic features of SHML in extranodal Figure 1 Representative overview of a SHML lymph node section: sites are similar to those seen in lymph nodes, but the distended sinuses, with diffuse intralurninal proliferation of sinus diagnosis is generally more difficult. In general, histiocytes are seen. H.E. x 100. extranodal SHML exhibits more prominent fibrosis, fewer typical histiocytes and a lesser degree of hemophagocytosis. A definitive diagnosis requires the presence of a large number of histiocytes containing lymphocytes and plasma cells characteristically distributed around and along the vessels of the fibrous st roma4*''.
BIOLOGY
(b)
Figure 2n,b Details of a sinus lumen showing histiocytes phagocytozing well preserved lymphocytes. H.E. A x 250; B x 400.
In recent years several studies have been performed using immunophenotyping techniques on sections of lymph nodes in order to better identify the sinus histiocytes (SH) of SHML. The SHs, in all cases studied, were found to be positive for S-100 protein, but generally with less intense positivity than in Langerhans cell histiocytosis (HX)' '*14-16 . The SHs were also positive for monoclonal antibodies O K M l (CDllb) and LeuM3 (CD14)1'.'6, KP1 (CD68) and DRC-1". Several author^'^.'^ found the SHs to be unreactive with OKM5 (CD15), OKT6 (CDla) and OKT4 (CD4), while others showed positivity for some SHs". Miettinen et al.14, on the basis of immunophenotypical analysis, suggested a relationship between the SHML cells and Langerhans cells and/or interdigitating reticulum cells. Bonetti et af.I5,showed that lymphophagocytic histiocytes were strongly positive for S-100 protein and unreactive with the monoclonal antibodies OKT6 (CDla) and OKM5 (CD15). They
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concluded that the peculiar S-100+/CDla-phenotype suggests that RD histiocytes belong to the T-zone associated histiocyte lineage. C D l a negativity distinguishes RDHs from Langerhans cells. Sacchi et al.", by immunophenotypical analysis in one case of SHML, showed that the majority of lymphophagocytic histiocytes were strongly positive for LeuM3, LeuM5, S-100 protein, KP1 and DRC-1; a proportion of these histiocytes were also positive for OKT6 (CDla) and Leu3A (CD4) (Table 1, Figure 3). KP1 recognizes the CD68 antigen on a wide variety of cells including macrophages, mast cells, granulocyte precursor^'^-'^ and melanoma cellsz0. The antigen detected by the KP1 monoclonal antibody is also present in LCH cells, although it is not expressed by all epidermal and lymph node Langerhans DRC- 1 recognizes dendritic reticulum cells forming a network within B cell follicles, but cal also label veiled cells' Thus, the immunophenotypical findings of Sacchi's case suggest a relationship between the SHML cells and veiled cells: the latter represent an intermediate step in the pathway from the Langerhans cells to interdigitating reticulum cellszz. It can be speculated that histiocytes present in SHML may be cytologically homogeneous, but may express different
Table 1 Immunohistological analysis in histiocytes of a SHML lymph-node' ' Monoclonal polyclonal antibodies
Cluster designation
Histiocytea reactivity
B4 IgG IgA IgM IgD Kappa Lambda Leu4 Leu3A Leu2A OKT6 LeuM3 OKM5 Ki-1 Ki-67 anti-5BrdU s-loo KPl DRC-1
CD19
---
+-+-+-CD3 CD4 CD8 CDla CD14 CD15 CD30
CD68
The immunostaining results are described as follows: _ _ _ = negative; + + + = >80% of histocytes positive; + + - = 40%-80% positive; + - - = lo%-% positive; f - - = 1%-10% positive.
a
+--
** -- ---f---f--
Figure 3 SH cells strongly expressing CD14 antigen. One cell (arrowed) displays obvious lymphophagocytosis. Cryostat section, APAAP. x 400. (See Colour Plate V at the back of this publication.)
antigenic patterns according to the stage of differentiation. Moreover, some histiocytes were stained by the Ki-1 antibody which recognizes the CD30 molecule, a marker for Hodgkin's or Reed-Sternberg cells and activated T and B cells. However, this finding is not surprising, because it has recently been suggested that activated human macrophages can also express the Ki-1 antigen23. Molecular studies were performed in only two cases: the first showed a germ line configuration for the immunoglobulin gene and the beta-chain T receptor". The latter", showed neither amplification nor rearrangement for the gene c-fms that is sometimes deleted in disorders affecting the monocyte-macrophage lineage, some of which evolve into acute leukemiaz4. Only two cases of SHML have been investigated by cytogenetic analysis of lymph node sinus histiocytes. In the first case, a normal karyotpe was detected2' while in the second, besides a predominant normal clone, a minor hypodiploid clone with loss of one chromosome 20, and random numerical and structural alterations were evident'
+++
+++
*_ ----
f--
+++ +++
+++
DIFFERENTIAL DIAGNOSIS The differential diagnosis includes a variety of diseases which have a microscopic resemblance to SHML, but, in practice, the most important problem is to distinguish true SHML from so-called sinus hyperplasia, Langerhans cell histiocytosis and some hemophagocytic (non Langerhans) syndromes. Until now, the diagnosis has been favoured by the pathologists who are familiar with the features of SHML and, lately, by
SINUS HISTIOCYTOSIS WITH MASSIVE LYMPHADENOPATHY
the use of ultrastructural microscopic techniques and immunophenotyping methods applied to lymph node or extranodal tissue sections.
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EVOLUTION
The evolution of the disease is usually prolonged and benign. Although determining complete remission is difficult owing to the lack of biopsy confirmation, about one third of the patients reach clinical r e ~ o v e r yafter ~ . ~ a few months or years. Many patients have persistent disease which is sometimes stable and, only rarely, progressive. Several fatal cases have been described. The exact role of SHML in the cause of death is often difficult to determine. Some patients died “of disease” and had disseminated nodal involvement with a larger number of extranodal systems affected. Involvement of kidney, lower respiratory tract, liver and nervous system carry a particularly poor prognosis. Some patients died “with disease” due to an association of multisystem involvement and the occurrence of immunologic abnormalities4. Unfortunately, there are no proven factors which aid in discriminating between favorable and unfavorable outcomes.
TREATMENT
As stated above, SHML is often a self-limited disease sometimes subject to spontaneous regression. Consequently, treatment does not seem to be necessary in the majority of patients, particularly when life or organ functions are not threatened. However, when the manifestations of the disease are severe or progressive, treatment appears to be timely in order to prevent loss of function or even of life. Since to date, there has been no systematic treatment study and only a few patients have been prospectively evaluated for the specific purpose of reporting response to therapy, correct interpretation of therapeutic results is difficult. Nevertheless the review of data currently available suggest that most SHML patients do not require therapy and can expect spontaneous remission. For those with extensive or progressive disease, the most effective regimen appears to be a combination of a vinca alkaloid, and alkylating agents (vinblastine, chlorambucil, cyclophosphamide) together with corticosteroids. However, these treatments do not seem to produce dramatic
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DISCUSSION
The SHML is a rare disease mostly affecting young people, who develop painless bilateral cervical lymphoadenopathy associated with an elevated erythrocyte sedimentation rate and polyclonal hypergammaglobulinemia. Frequently, there is a reversal of the T4/T8 ratio. In a large percentage of cases, extranodal disease is present and almost all organs may be involved. There is “growing awareness that extranodal involvement is a common feature of SHML, and it is probably just a matter of time before involvement of every organ has been d o c ~ m e n t e d ” ~ . The lymph nodes or organs affected display characteristic morphologic features and the differential diagnosis with other histiocytosis, namely the prototypic idiopathic histiocytosis, (Langerhans cell histiocytosis) is not difficult today. No infectious agents are usually detected. In some patients, immunologic abnormalities can be identified and frequently, an elevated titer of Epstein-Barr virus antibodies is observed. The evolution of the disease is commonly chronic, benign and spontaneous remission is not infrequent. Nevertheless, in a small proportion of patients, aggressive and sometimes lethal disease can occur. Immunologic disorders contribute to a poor prognosis, as does involvement of certain extranodal sites such as the kidney, respiratory tract, and the liver. Treatment is often not necessary; however for the cases with progressive or extensive disease, a treatment regimen similar to that shown to be effective for other hematopoietic malignancies can be used. The etiology and pathogenesis of SHML still remain obscure. Based on recent immunophenotypical studies, it can be speculated that the histiocytes present in SHML may be cytologically homogeneous, but express different antigenic patterns according to their stage of differentiation. Thus, the histiocytic cells can appear as Langerhans or interdigitating reticulum cells, T-zone associated histiocyte lineage or veiled cells. Since the findings in SHML remain non specific and a causative agent or specific marker has yet to be discovered, it seems necessary to employ a variety of immunophenotypical, ultrastructural, cytogenetic, and molecular techniques, particularly in cases which are clinically atypical or which show a more aggressive evolution. Although SHML is a relatively rare disease, understanding of its etiology and pathogenesis may be important, since the disorder seems to fall in between the fields of infection, immunological disease
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and neoplasia. The systematic cytogenetic analysis of SHML lymph node or extranodal cells seems to be a useful tool for the detection of possible abnormal clones or consistent chromosomal anomalies. Cytogenetic findings can contribute to define the benign or malignant nature of the disease. If structural and/or numerical chromosome alterations are detected, a variety of cellular genes involved in the control of proliferation and/or differentiation may be activated which may play an important role in the processes leading to this disorder. In this context molecular biology techniques should be applied in every case of SHML in order to gain a better understanding of the pathogenesis of this unusual disorder. Acknowledgements We thank Dr. S. Pileri, University of Bologna, for the help in the critical discussion of the immunohistochemical sections.
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Colour Plate V (see page 192 Figure 3) SH cells strongly expressing CD14 antigen. One cell (arrowed) displays obvious lymphophagocytosis. Cryostat section, APAAP. x 400.
Colour Plate V1 (see page 257 Figure I ) Patient with massive hepatosplenomegaly.
Colour Plate VIII (see page 258 Figure 3) Bone marrow aspirate showing numerous Leishman- Donovani bodies. M.G.G. stain.
Colour Plate VII (see page 257 Figure 2) Peripheral blood film showing abnormal lymphoid cell, rouleaux, tear drop poikilocytes and smear cell. M.G.G. stain.
Colour Plate IX (see page 258 Figure 4) Bone marrow trephine biopsy showing numerous Leishman-Donovani bodies. M.G.G.
