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Castleman Disease and Rosai-Dorfman Disease
Seminars in Diagnostic Pathology 35 (2018) 44–53
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Review article
Castleman Disease and Rosai-Dorfman Disease a,⁎
a
T b
Miguel A. Piris , Elena Aguirregoicoa , Santiago Montes-Moreno , Catuxa Celeiro-Muñoz a b
b
Pathology Service, Fundación Jiménez Díaz, CIBERONC, Avenida Reyes Católicos, 2, 28040 Madrid, Spain Pathology Service, Hospital Universitario Marques de Valdecilla, Santander, Spain
A B S T R A C T This chapter describes the main features of two different diseases, Castleman Disease (CD) and Rosai-Dorfman Disease (RDD). Castleman disease (CD) is a clinical and histopathologically heterogeneous lymphoproliferative disorder that encompasses at least three distinct entities with some common overlapping morphological features: Hyaline Vascular CD (HVCD), Unicentric Plasma Cell CD and Multicentric CD. The most important feature of HVCD is the presence of abnormal germinal centers with hyaline-vascular transformation, sometimes showing multiple germinal centers within a single reactive lymphoid follicle, this outlining HVCD as a disorder of follicular dendritic cells. Unicentric and multicentric CD are, in contrast, lymphoproliferative lesions. Proinflammatory hypercytokinemia is an essential feature of multicentric CD, distinguished by a florid clinical presentation. Rosai-Dorfmann Disease is a histiocytic proliferative disorder diagnosed by the presence of tissue infiltration by S100-positive CD1a-negative histiocytes and plasma cell aggregates, often with Russell bodies. A typical, though not specific, characteristic of the disease is emperipolesis. Initially considered to be an inflammatory/ reactive condition, molecular studies suggest that at least some cases of RDD could be considered as a low-grade histiocytic neoplastic process.
Castleman Disease
then be considered jointly.
Introduction
Hyaline Vascular Castleman disease Clinical features. Hyaline Vascular Castleman Disease (HVCD) mostly occurs in the form of a localized mediastinal, cervical or abdominal mass.4 While it usually involves lymph nodes, it may also appear in an extranodal localization. Cases have been reported in which the oropharyngeal region, larynx, pericardium5,6 and orbit7,8 are the affected areas. Growth is normally slow, without constitutional syndromes. With no distinction between sexes, HVCD can appear in patients of all ages, although it is more frequent in young adults.
Castleman disease (CD) is a clinical and histopathologically heterogeneous lymphoproliferative disorder1 that encompasses at least three distinct entities. The first description, a hyperplastic mediastinal mass reminiscent of a thymoma, was made by Castleman et al. in 1956,2 corresponding to the vascular hyaline form of the disease. Subsequently, Keller and Castleman3 described the plasma cell type, a disorder associated with systemic symptoms and analytic alterations, in which the architecture of the lymph node was preserved, and in which hyperplasic germinal centers and sheets of plasma cells were present. Three main subtypes of CD are now recognized (Tables 1 and 2):
• Hyaline Vascular CD • Unicentric Plasma Cell CD • Multicentric CD The main differential characteristics of the three subtypes will be separately described in detail below. Their prognosis and treatment will
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Corresponding author. E-mail address: [email protected] (M.A. Piris).
https://doi.org/10.1053/j.semdp.2017.11.014
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Histopathological findings. The most important characteristics of HVCD are abnormal germinal centers with hyaline-vascular transformation, sometimes showing multiple germinal centers within a single reactive lymphoid follicle, and a hypervascular interfollicular zone.9 Of the various follicular morphologies, the most characteristic is that displaying small germinal centers, mainly comprising follicular dendritic cells and endothelial cells that are partially depleted of lymphoid cells. One or several venules that may, or may not be hyalinized penetrate the follicles, giving rise to the characteristic
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Table 1 The spectrum of Castleman Disease includes different clinicopathological conditions. HHV8: Human Herpes Virus 8. FDC: Follicular Dendritic Cell. POEMS syndrome: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes. TAFRO syndrome: Thrombocytopenia, anasarca/ascites, reticulin fibrosis in bone marrow, renal dysfunction, organomegaly and normal immunoglobulin levels.
Table 2 Main clinical and histological findings in the different forms of Castleman disease.
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Fig. 1. Morphology of the lymph nodes in Castleman’s Disease: lymphoid follicles with multiple germinal centers, as in A and C. Onion-skin pattern as in A-C, and lymphocyte depletion of the germinal centers (A-B), hyalinized vessels in the germinal center (B) and increased vascularization of the interfollicular area (D).
“lollipop-like” appearance. Other cases correspond to follicles with multiple discrete and continuous germinal centers, a whorled germinal center, or follicles composed exclusively of small lymphoid cells, penetrated by multiple venules.2 Bizarre large-cell follicles can also be observed, and another characteristic feature (although one not always present) is a mantle zone expansion, with a concentric arrangement of the small lymphocytes, in an onion-skin-like pattern,1 a finding that reflects the underlying rich network of follicular dendritic cells (FDCs) (Figs. 1 and 2). A characteristic feature of the interfollicular region is the rich network of high endothelial venules, mixed with abundant small lymphocytes that alternate with scarce plasma cells.9 Some cases can harbor a very prominent interfollicular zone, for which the term stroma-rich variant was previously used.5 The stroma-rich cases showed a prominent interfollicular zone that, by definition, represents > 50% of the lesion. Its follicles are either inconspicuous or isolated.5 The development of vascular or follicular dendritic cells abnormalities5,10 and even neoplasms9,11,12 has been described in these cases.
Differential diagnosis. It is worth remembering that the abnormal follicles characterizing CD are not pathognomonic of the entity itself and can be observed in other entities. For example, they can be seen in non-specific reactive lymphoid hyperplasia, HIV-associated lymphadenopathy, and angioimmunoblastic T-cell lymphoma. On the other hand, the hyperplastic mantle zone may be suggestive of a mantle-cell lymphoma in some cases. Hyperplasia/dysplasia-FDC sequence tumor-FDC sarcoma in HVCD. Multiple histopathological and molecular observations concur in highlighting FDC abnormalities as being a key alteration in the pathogenesis of HVCD.9 A sequential process has been postulated, whereby mutations and other alterations in FDCs delineate the different steps: hyperplasia/dysplasia, tumor and sarcoma.4 In addition to the dysplastic changes observable after morphological examination, the interpretations of other molecular data seem to coincide in that FDCs in HVCD carry molecular alterations. Ruco et al. 13 described the abnormal expression of the ICAM-1 molecule and proposed that this was paralleled by dysplasia of follicular dendritic reticulum cells.13 Pauwels et al. 14 reported the presence of clonal cytogenetic abnormalities in the stromal cells of a case of HVCD.14 Cokelaere et al. 15 demonstrated clonal proliferation of follicular dendritic cells in the HVCD, with the presence of the HMGIC rearrangement in CD21-positive follicular dendritic cells.16 Chang et al. 17 demonstrated cytogenetic abnormalities in stromal cells in HVCD. Follicular dendritic tumors arising in the context of HVCD were initially described by Frizzera et al and identified as a stroma-rich variant.5 Of all the cases of FDC tumor/sarcoma reported in the
Immunophenotype. Immunohistochemical analysis highlights the abnormal network of follicular dendritic cells, which are positive for CD21, CD23, CD35 and podoplanin (D2-40). These appear interrupted, expanded or as multiple tight concentric collections. Kappa and lambda staining are polytypic in plasma cells, mantle B-cells and follicular center B-cells. EBV and HHV8 are negative. CD123 staining usually reveals the presence of aggregates of plasmacytoid dendritic cells, a useful finding that can also be seen with HE staining (Fig. 3).
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Fig. 2. Lymphoid follicles with multiple germinal centers are a typical finding in HVCD (A and B), highlighted after CD21 staining (B). Morphology of follicular dendritic cell can be recognized by their characteristic nuclear morphology.
Fig. 3. Plasmacytoid dendritic cells are often seen in HVCD using HE or CD123 staining.
examination reveals the cords of small lymphocytes separated by FDC processes. The CD21, CD23 and/or D240 markers reveal the FDC expansion. 2. - HVCD associated with FDC tumor. The proliferation of FDC may lead to the formation of discrete expanding masses11 that do not infiltrate beyond the lymph node capsule, or show a high mitotic index or tumoral necrosis. In those cases in which HVCD is associated with an FDC tumor, areas with a storiform pattern are observed among the follicles. The tumor cells have a clear cytoplasm with an indistinct cell border and oval or round nuclei, which are
literature, about 14% appeared either simultaneously or after a HVCD diagnosis.18 Sequential phases in this process mays be separated into the following steps (Fig. 4): 1. - HVCD with FDC hyperplasia/dysplasia. This is a very common finding in otherwise typical HVCD. FDCs show cytological atypia, with pleomorphic nuclei and infiltrate beyond the limits of the lymphoid follicle. Atypical pleomorphic nuclei can be identified in the intrafollicular and interfollicular compartments. Microscopic
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Fig. 4. FDC hyperplasia/dysplasia is a frequent finding in HVCD. There is a sequence of HVCD with FDC hyperplasia/dysplasia, HVCD with FDC tumor and FDC sarcoma associated with HVCD.
without atypia, with a storiform growth pattern, abundant hyalinized collagen, dystrophic calcifications and an inflammatory background with histiocytes, small lymphocytes and plasma cells. Residual reactive follicles can be identified in the periphery, some of which show HVCD features. Immunostaining reveals a mixture of FDC and inflammatory findings, with SMA-positive fusiform cells and at least partial expression of some FDC markers.22
occasionally vesiculous, with a tendency towards multinucleation. Cytological atypia can be seen in FDCs, but there is neither necrosis nor a high mitotic index are noted. 3. - HVCD occasionally associated with FDC sarcoma. Diagnostic criteria require the clear presence of both components. Thus, areas with typical hyaline-vascular follicles and prominent interfollicular vascularity should be associated with others showing a tumorforming proliferation of FDCs that infiltrate beyond the lymph node capsule, replace pericapsular tissues, and show increased cellularity with a high mitotic index and/or frequent necrosis.11,19 There are several excellent reviews of the morphology and immunophenotype of FDC sarcoma.11,19,20
Unicentric Plasma Cell Castleman Disease Unicentric Plasma Cell Castleman Disease (PCCD) is far less frequent than unicentric HVCD.23 The architecture of the lymph node is preserved, with prominent reactive follicular hyperplasia and partially spared sinuses. Most follicles have a normal appearance, and some others may be of the hyaline-vascular form. The interfollicular area is expanded, with increased vascularization and the presence of large conglomerates of apparently typical plasma cells that form sheet-like collections (Fig. 5). These plasma cells may be polytypical or monotypical,24 and it is also possible to find monoclonal immunoglobulin gene rearrangements.24 Mixed features of HVCD are also frequently found. There is also some overlap between PCCD and IgG4 lymphadenitis.25 Multiple Myeloma and marginal zone lymphoma with marked
Calcifying Fibrous “Pseudotumor” Calcifying Fibrous “Pseudotumor” associated with HVCD represents a form of benign FDC tumor associated with HVCD. All cases of this have been described as being of the stroma-rich variant, with a predominantly abdominal location. Overall, there is a well-defined mass with a heterogeneous cut surface with calcifications.21 Under the microscope, however, they show stromal proliferation of spindle cells
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Fig. 5. Plasma cell variant of CD. Architecture of the lymph node is basically preserved, with reactive follicular hyperplasia (A-C), spared sinuses, interfollicular expansion (D), with increased vascularization and the presence of large sheets of plasma cells (D). Some germinal centers may display hyaline-vascular changes, as in B.
plasma cell differentiation should be excluded, since lymph node infiltration may mimic the histology of PCCD.
Hypercytokinemia may also feature in cases of idiopathic MCD, where it is due to the overproduction of human IL-620 and vascular endothelial growth factor (VEGF).26 It is generally possible to distinguish several characteristic conditions in the context of MCD, depending on whether it is associated with either of the following:
Multicentric Castleman Disease Clinical features. Multicentric CD (MCD) involves lymph nodes in multiple regions, usually associated with systemic inflammatory symptoms and organ dysfunction due to the dysregulation of cytokines, interleukin-6 (IL-6) and others. MCD is associated with HHV8 in roughly half the cases,10 but is otherwise considered to be idiopathic MCD (iMCD). HIV-positive patients almost exclusively have the HHV8-associated form. Indeed, it’s been stated that all cases of CD in the setting of HIV are linked to HHV-8-infection. In comparison with unicentric CD, MCD usually occurs among older people. Patients may exhibit multiple lymphadenopathies, fever, hepatosplenomegaly, skin rash and polyneuropathy, as well as analytic alterations such as anemia, thrombocytopenia, increased erythrocyte sedimentation rate and hypergammaglobulinemia. The clinical evolution is far more aggressive than that of unicentric CD. For a detailed review of the features of MCD, see the recent review by Fajgenbaum et al.26 Proinflammatory hypercytokinemia is an essential feature of this condition, in which the increment of some cytokines (such as IL-6, IL10, IL-1 and TNF-alpha) conditions the development of a rich clinical picture. The IL-6 protein can be produced by KSHV/HHV8, the so-called vIL-6 protein, which has a homologous sequence similar to that of the human IL-614,27 and can bind to the classic IL-6 receptors and alter their regulation.28 vIL-6 blood levels are correlated with the activity of the disease in patients with MCD associated with KSHV/HHV8.27,29
• KSHV/HHV8: •
KSHV inflammatory cytokine syndrome, found in HIV-positive patients,27,30 with the eventual appearance of germinotropic lymphoproliferative disorder14 and HHV8-positive large Bcell lymphoma.31,32 iMCD, with some specific clinicopathological syndromes such as: ￮ TAFRO syndrome (thrombocytopenia, anasarca/ascites, reticulin fibrosis in bone marrow, renal dysfunction, organomegaly and normal immunoglobulin levels)26; ￮ POEMS syndrome: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes.33,34
Diagnostic criteria have recently been refined by the Scientific Advisory Board of the Castleman Disease Collaborative Network (CDCN).26 Pathology The histology of the lymph node in HHV8-associated and idiopathic cases shows characteristics intermediate between those of PCCD and HVCD.27 The HHV8-associated cases usually show regressive germinal
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Fig. 6. HHV8-associated multicentric PCCD. HHV8-LNA-positive B-cells surround reactive germinal centers and show lambda light-chain restriction.
centers with irregularly distributed FDCs. Germinal centers may be surrounded by HHV8-positive large activated B-cells (denominated as plasmablasts but lacking the typical plasmablast morphology).35 HHV8positive plasmablasts express the monotypic lambda light-chain, but show a polyclonal pattern of immunoglobulin gene rearrangement, a finding that is yet to be satisfactorily explained (Fig. 6). Cases without KSHV/HHV8 usually feature prominent plasmacytosis and vascular proliferation, with a less striking hyalinization. Sheets of polytypic plasma cells may appear in the interfollicular areas, with hyperplastic germinal centers in the context of a patient with lymphadenopathy, prominent polyclonal hypergammaglobulinemia, anemia-elevated erythrocyte sedimentation rate, elevated serum IL-6, and bone marrow plasmacytosis. In such circumstances POEMS syndrome should be ruled out.33,34 Histological diagnostic criteria are relatively unspecific for iMCD and clinical data are essential if a correct diagnosis is to be achieved.
Clinical features While it may appear at any age, RDD is more frequently observed in children and young adults, with a slight predominance in males, and particularly in males of African descent. Patients usually develop systemic symptoms such as fever, polyclonal hypergammaglobulinemia, neutrophilic leukocytosis and an increased erythrocyte sedimentation rate.37,38 Some cases show evidence of immune-mediated diseases, such as arthralgias, glomerulonephritis or recurrent infections.37,39 RDD most characteristically appears as a large and painful bilateral cervical mass, of the typical “proconsular neck” form; this dramatic clinical presentation helped recognize the disease and prompted its histological features to be identified. Although initially described as a disease of the lymph nodes, more than a quarter of cases it show initial extranodal manifestations.37 In cases with nodal disease, the cervical lymph nodes are more frequently involved (87%), followed by axillary, inguinal and mediastinal locations.38 The most frequent extranodal sites are the central nervous system, soft tissue, skin, bone, oral cavity and salivary gland,40–43 but sporadic cases have also been described in bone, brain, testicle and other places.44–46 Different clinical presentations of RDD have been systematized47 as familial, classic (nodal), extranodal, neoplasia-associated, and immune-related.47 The usual course is benign, with spontaneous regression in many cases, or a response to therapy, but a minority of patients (< 10%) suffer from progressive disease, occasionally resulting in death, usually due to local infiltration of vital structures.39,48
Rosai-Dorfman Disease Sinus Histiocytosis with Massive Lymphadenopathy (SHML), or Rosai-Dorfman disease (RDD), is a histiocyte proliferative disorder. It was first recognized as a distinctive entity in the 1960s by Rosai and Dorfman.36 A detailed review of 423 examples of SHML was published in 1990, which included very useful information on the clinical presentation and histology of the disease.37
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Fig. 7. Rosai-Dorfman diagnostic changes include presence of aggregates of histiocytes occupying lymph node sinuses and plasma cell clusters, with Russell bodies.
the emperipolesis. Other Langerhans cell markers, such as CD1a and Langerin, are absent from RDD histiocytes. Other macrophage markers are also positive, such as CD68, CD163 and others. Plasma cells are polyclonal and can exhibit increased expression of IgG4.52
Pathology Lymph node infiltration shows a mixture of sinusoidal occupation by S100-positive histiocytes and plasma cell aggregates, often with Russell bodies. A typical, though not specific, characteristic of the disease is emperipolesis,38 a phenomenon defined by Humble et al as “the active penetration of one cell by another which remains intact”.49 In these cases, the engulfed cell maintains the integrity of the normal structure within the other cell, and both of them can exist without abnormalities arising for some time. In contrast, in phagocytosis, the lysosomal enzymes destroy the engulfed cells. Although emperipolesis is the hallmark of RDD, it can appear in other conditions such as Hodgkin lymphoma, multiple myeloma, malignant melanoma, neuroblastoma and rhabdomyosarcoma.50 RDD histiocytes usually lack atypia, but may occasionally show abnormal nuclear shapes. Most cases appear in the form of clusters of large cells, with wide and pale or eosinophilic cytoplasm, as well as rounded nuclei in which the nucleoli are evident. Others have a foamy appearance or multinucleation. Emperipolesis is a frequent finding, but can be difficult to recognize solely on the basis of morphological examination, especially when it occurs at extranodal localizations. Typically, RDD histiocytes contain engulfed plasma cells, although other cells can also be found. A marked capsular fibrosis is observed36,51 (Figs. 7 and 8). RDD histiocytes express S100, and S100 staining helps to highlight
Pathogenesis Initially considered to be an inflammatory/reactive condition of unknown cause, evidence from various sources suggests that at least some cases of RDD could be considered as a low-grade histiocytic neoplastic process. Mutually exclusive KRAS and MAP2K1 mutations have been described in one-third of RDD cases, suggesting that this is a neoplastic process in which activation of the MAPK/ERK pathway plays an essential role.53 This confirms previous observations in a larger series of patients and indicates a degree of overlap with Langerhans Cell Histiocytosis and Erdheim-Chester disease. A partial overlap with IgG4 has been found and confirmed by several studies. Overall, 40% of cases demonstrated varying degrees of increased numbers of IgG4-positive cells.54 Histological features of SHML can be seen in other conditions, such as ALPS-type IA (with TNFRSF6 heterozygous germ line mutations affecting the gene encoding Fas)55 and H syndrome, an autosomal recessive genodermatosis with multisystem involvement caused by mutations in SLC29A3.56
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Fig. 8. Rosai-Dorfman histiocytes show plasma cell emperipolesis (A-D), which is more easily recognizable after S100 staining (B,D).
Acknowledgements 12.
This work was supported by grants from the Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Economy and Competence (MINECO, RTICC ISCIII and CIBERONC) (SAF2013-47416-R, RD06/ 0020/0107-RD012/0036/0060 and Plan Nacional I+D+I: PI16/01294 and PIE15/0081) and the Asociación Española Contra el Cáncer (AECC).
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lymphadenopathy affecting the subglottis and trachea. Histopathology. 1994;24(4):393–394. Kong YY, Kong JC, Shi DR, et al. Cutaneous rosai-dorfman disease: a clinical and histopathologic study of 25 cases in China. Am J Surg Pathol. 2007;31(3):341–350. Montgomery EA, Meis JM, Frizzera G. Rosai-Dorfman disease of soft tissue. Am J Surg Pathol. 1992;16(2):122–129. Brenn T, Calonje E, Granter SR, et al. Cutaneous rosai-dorfman disease is a distinct clinical entity. Am J Dermatopathol. 2002;24(5):385–391. Walker PD, Rosai J, Dorfman RF. The osseous manifestations of sinus histiocytosis with massive lymphadenopathy. Am J Clin Pathol. 1981;75(2):131–139. Wenig BM, Abbondanzo SL, Childers EL, Kapadia SB, Heffner DR. Extranodal sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) of the head and neck. Hum Pathol. 1993;24(5):483–492. Andriko JA, Morrison A, Colegial CH, Davis BJ, Jones RV. Rosai-Dorfman disease isolated to the central nervous system: a report of 11 cases. Mod Pathol. 2001;14(3):172–178. Emile JF, Abla O, Fraitag S, et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016;127(22):2672–2681. Kroft SH. Rosai-Dorfman disease: familiar yet enigmatic. Semin Diagn Pathol. 2016;33(5):244–253. Humble JG, Jayne WH, Pulvertaft RJ. Biological interaction between lymphocytes and other cells. Br J Haematol. 1956;2(3):283–294. Lee KP. Emperipolesis of hematopoietic cells within megakaryocytes in bone marrow of the rat. Vet Pathol. 1989;26(6):473–478. Jaffe ES. Histiocytoses of lymph nodes: biology and differential diagnosis. Semin Diagn Pathol. 1988;5(4):376–390. Wenig BM. Undifferentiated malignant neoplasms of the sinonasal tract. Arch Pathol Lab Med. 2009;133(5):699–712. Garces S, Medeiros LJ, Patel KP, et al. Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease. Mod Pathol. 2017. Menon MP, Evbuomwan MO, Rosai J, Jaffe ES, Pittaluga S. A subset of RosaiDorfman disease cases show increased IgG4-positive plasma cells: another red herring or a true association with IgG4-related disease? Histopathology. 2014;64(3):455–459. Maric I, Pittaluga S, Dale JK, et al. Histologic features of sinus histiocytosis with massive lymphadenopathy in patients with autoimmune lymphoproliferative syndrome. Am J Surg Pathol. 2005;29(7):903–911. Molho-Pessach V, Ramot Y, Camille F, et al. H syndrome: the first 79 patients. J Am Acad Dermatol. 2014;70(1):80–88.
Contents lists available at ScienceDirect
Seminars in Diagnostic Pathology journal homepage: www.elsevier.com/locate/semdp
Review article
Castleman Disease and Rosai-Dorfman Disease a,⁎
a
T b
Miguel A. Piris , Elena Aguirregoicoa , Santiago Montes-Moreno , Catuxa Celeiro-Muñoz a b
b
Pathology Service, Fundación Jiménez Díaz, CIBERONC, Avenida Reyes Católicos, 2, 28040 Madrid, Spain Pathology Service, Hospital Universitario Marques de Valdecilla, Santander, Spain
A B S T R A C T This chapter describes the main features of two different diseases, Castleman Disease (CD) and Rosai-Dorfman Disease (RDD). Castleman disease (CD) is a clinical and histopathologically heterogeneous lymphoproliferative disorder that encompasses at least three distinct entities with some common overlapping morphological features: Hyaline Vascular CD (HVCD), Unicentric Plasma Cell CD and Multicentric CD. The most important feature of HVCD is the presence of abnormal germinal centers with hyaline-vascular transformation, sometimes showing multiple germinal centers within a single reactive lymphoid follicle, this outlining HVCD as a disorder of follicular dendritic cells. Unicentric and multicentric CD are, in contrast, lymphoproliferative lesions. Proinflammatory hypercytokinemia is an essential feature of multicentric CD, distinguished by a florid clinical presentation. Rosai-Dorfmann Disease is a histiocytic proliferative disorder diagnosed by the presence of tissue infiltration by S100-positive CD1a-negative histiocytes and plasma cell aggregates, often with Russell bodies. A typical, though not specific, characteristic of the disease is emperipolesis. Initially considered to be an inflammatory/ reactive condition, molecular studies suggest that at least some cases of RDD could be considered as a low-grade histiocytic neoplastic process.
Castleman Disease
then be considered jointly.
Introduction
Hyaline Vascular Castleman disease Clinical features. Hyaline Vascular Castleman Disease (HVCD) mostly occurs in the form of a localized mediastinal, cervical or abdominal mass.4 While it usually involves lymph nodes, it may also appear in an extranodal localization. Cases have been reported in which the oropharyngeal region, larynx, pericardium5,6 and orbit7,8 are the affected areas. Growth is normally slow, without constitutional syndromes. With no distinction between sexes, HVCD can appear in patients of all ages, although it is more frequent in young adults.
Castleman disease (CD) is a clinical and histopathologically heterogeneous lymphoproliferative disorder1 that encompasses at least three distinct entities. The first description, a hyperplastic mediastinal mass reminiscent of a thymoma, was made by Castleman et al. in 1956,2 corresponding to the vascular hyaline form of the disease. Subsequently, Keller and Castleman3 described the plasma cell type, a disorder associated with systemic symptoms and analytic alterations, in which the architecture of the lymph node was preserved, and in which hyperplasic germinal centers and sheets of plasma cells were present. Three main subtypes of CD are now recognized (Tables 1 and 2):
• Hyaline Vascular CD • Unicentric Plasma Cell CD • Multicentric CD The main differential characteristics of the three subtypes will be separately described in detail below. Their prognosis and treatment will
⁎
Corresponding author. E-mail address: [email protected] (M.A. Piris).
https://doi.org/10.1053/j.semdp.2017.11.014
0740-2570/ © 2017 Elsevier Inc. All rights reserved.
Histopathological findings. The most important characteristics of HVCD are abnormal germinal centers with hyaline-vascular transformation, sometimes showing multiple germinal centers within a single reactive lymphoid follicle, and a hypervascular interfollicular zone.9 Of the various follicular morphologies, the most characteristic is that displaying small germinal centers, mainly comprising follicular dendritic cells and endothelial cells that are partially depleted of lymphoid cells. One or several venules that may, or may not be hyalinized penetrate the follicles, giving rise to the characteristic
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Table 1 The spectrum of Castleman Disease includes different clinicopathological conditions. HHV8: Human Herpes Virus 8. FDC: Follicular Dendritic Cell. POEMS syndrome: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes. TAFRO syndrome: Thrombocytopenia, anasarca/ascites, reticulin fibrosis in bone marrow, renal dysfunction, organomegaly and normal immunoglobulin levels.
Table 2 Main clinical and histological findings in the different forms of Castleman disease.
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Fig. 1. Morphology of the lymph nodes in Castleman’s Disease: lymphoid follicles with multiple germinal centers, as in A and C. Onion-skin pattern as in A-C, and lymphocyte depletion of the germinal centers (A-B), hyalinized vessels in the germinal center (B) and increased vascularization of the interfollicular area (D).
“lollipop-like” appearance. Other cases correspond to follicles with multiple discrete and continuous germinal centers, a whorled germinal center, or follicles composed exclusively of small lymphoid cells, penetrated by multiple venules.2 Bizarre large-cell follicles can also be observed, and another characteristic feature (although one not always present) is a mantle zone expansion, with a concentric arrangement of the small lymphocytes, in an onion-skin-like pattern,1 a finding that reflects the underlying rich network of follicular dendritic cells (FDCs) (Figs. 1 and 2). A characteristic feature of the interfollicular region is the rich network of high endothelial venules, mixed with abundant small lymphocytes that alternate with scarce plasma cells.9 Some cases can harbor a very prominent interfollicular zone, for which the term stroma-rich variant was previously used.5 The stroma-rich cases showed a prominent interfollicular zone that, by definition, represents > 50% of the lesion. Its follicles are either inconspicuous or isolated.5 The development of vascular or follicular dendritic cells abnormalities5,10 and even neoplasms9,11,12 has been described in these cases.
Differential diagnosis. It is worth remembering that the abnormal follicles characterizing CD are not pathognomonic of the entity itself and can be observed in other entities. For example, they can be seen in non-specific reactive lymphoid hyperplasia, HIV-associated lymphadenopathy, and angioimmunoblastic T-cell lymphoma. On the other hand, the hyperplastic mantle zone may be suggestive of a mantle-cell lymphoma in some cases. Hyperplasia/dysplasia-FDC sequence tumor-FDC sarcoma in HVCD. Multiple histopathological and molecular observations concur in highlighting FDC abnormalities as being a key alteration in the pathogenesis of HVCD.9 A sequential process has been postulated, whereby mutations and other alterations in FDCs delineate the different steps: hyperplasia/dysplasia, tumor and sarcoma.4 In addition to the dysplastic changes observable after morphological examination, the interpretations of other molecular data seem to coincide in that FDCs in HVCD carry molecular alterations. Ruco et al. 13 described the abnormal expression of the ICAM-1 molecule and proposed that this was paralleled by dysplasia of follicular dendritic reticulum cells.13 Pauwels et al. 14 reported the presence of clonal cytogenetic abnormalities in the stromal cells of a case of HVCD.14 Cokelaere et al. 15 demonstrated clonal proliferation of follicular dendritic cells in the HVCD, with the presence of the HMGIC rearrangement in CD21-positive follicular dendritic cells.16 Chang et al. 17 demonstrated cytogenetic abnormalities in stromal cells in HVCD. Follicular dendritic tumors arising in the context of HVCD were initially described by Frizzera et al and identified as a stroma-rich variant.5 Of all the cases of FDC tumor/sarcoma reported in the
Immunophenotype. Immunohistochemical analysis highlights the abnormal network of follicular dendritic cells, which are positive for CD21, CD23, CD35 and podoplanin (D2-40). These appear interrupted, expanded or as multiple tight concentric collections. Kappa and lambda staining are polytypic in plasma cells, mantle B-cells and follicular center B-cells. EBV and HHV8 are negative. CD123 staining usually reveals the presence of aggregates of plasmacytoid dendritic cells, a useful finding that can also be seen with HE staining (Fig. 3).
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Fig. 2. Lymphoid follicles with multiple germinal centers are a typical finding in HVCD (A and B), highlighted after CD21 staining (B). Morphology of follicular dendritic cell can be recognized by their characteristic nuclear morphology.
Fig. 3. Plasmacytoid dendritic cells are often seen in HVCD using HE or CD123 staining.
examination reveals the cords of small lymphocytes separated by FDC processes. The CD21, CD23 and/or D240 markers reveal the FDC expansion. 2. - HVCD associated with FDC tumor. The proliferation of FDC may lead to the formation of discrete expanding masses11 that do not infiltrate beyond the lymph node capsule, or show a high mitotic index or tumoral necrosis. In those cases in which HVCD is associated with an FDC tumor, areas with a storiform pattern are observed among the follicles. The tumor cells have a clear cytoplasm with an indistinct cell border and oval or round nuclei, which are
literature, about 14% appeared either simultaneously or after a HVCD diagnosis.18 Sequential phases in this process mays be separated into the following steps (Fig. 4): 1. - HVCD with FDC hyperplasia/dysplasia. This is a very common finding in otherwise typical HVCD. FDCs show cytological atypia, with pleomorphic nuclei and infiltrate beyond the limits of the lymphoid follicle. Atypical pleomorphic nuclei can be identified in the intrafollicular and interfollicular compartments. Microscopic
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Fig. 4. FDC hyperplasia/dysplasia is a frequent finding in HVCD. There is a sequence of HVCD with FDC hyperplasia/dysplasia, HVCD with FDC tumor and FDC sarcoma associated with HVCD.
without atypia, with a storiform growth pattern, abundant hyalinized collagen, dystrophic calcifications and an inflammatory background with histiocytes, small lymphocytes and plasma cells. Residual reactive follicles can be identified in the periphery, some of which show HVCD features. Immunostaining reveals a mixture of FDC and inflammatory findings, with SMA-positive fusiform cells and at least partial expression of some FDC markers.22
occasionally vesiculous, with a tendency towards multinucleation. Cytological atypia can be seen in FDCs, but there is neither necrosis nor a high mitotic index are noted. 3. - HVCD occasionally associated with FDC sarcoma. Diagnostic criteria require the clear presence of both components. Thus, areas with typical hyaline-vascular follicles and prominent interfollicular vascularity should be associated with others showing a tumorforming proliferation of FDCs that infiltrate beyond the lymph node capsule, replace pericapsular tissues, and show increased cellularity with a high mitotic index and/or frequent necrosis.11,19 There are several excellent reviews of the morphology and immunophenotype of FDC sarcoma.11,19,20
Unicentric Plasma Cell Castleman Disease Unicentric Plasma Cell Castleman Disease (PCCD) is far less frequent than unicentric HVCD.23 The architecture of the lymph node is preserved, with prominent reactive follicular hyperplasia and partially spared sinuses. Most follicles have a normal appearance, and some others may be of the hyaline-vascular form. The interfollicular area is expanded, with increased vascularization and the presence of large conglomerates of apparently typical plasma cells that form sheet-like collections (Fig. 5). These plasma cells may be polytypical or monotypical,24 and it is also possible to find monoclonal immunoglobulin gene rearrangements.24 Mixed features of HVCD are also frequently found. There is also some overlap between PCCD and IgG4 lymphadenitis.25 Multiple Myeloma and marginal zone lymphoma with marked
Calcifying Fibrous “Pseudotumor” Calcifying Fibrous “Pseudotumor” associated with HVCD represents a form of benign FDC tumor associated with HVCD. All cases of this have been described as being of the stroma-rich variant, with a predominantly abdominal location. Overall, there is a well-defined mass with a heterogeneous cut surface with calcifications.21 Under the microscope, however, they show stromal proliferation of spindle cells
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Fig. 5. Plasma cell variant of CD. Architecture of the lymph node is basically preserved, with reactive follicular hyperplasia (A-C), spared sinuses, interfollicular expansion (D), with increased vascularization and the presence of large sheets of plasma cells (D). Some germinal centers may display hyaline-vascular changes, as in B.
plasma cell differentiation should be excluded, since lymph node infiltration may mimic the histology of PCCD.
Hypercytokinemia may also feature in cases of idiopathic MCD, where it is due to the overproduction of human IL-620 and vascular endothelial growth factor (VEGF).26 It is generally possible to distinguish several characteristic conditions in the context of MCD, depending on whether it is associated with either of the following:
Multicentric Castleman Disease Clinical features. Multicentric CD (MCD) involves lymph nodes in multiple regions, usually associated with systemic inflammatory symptoms and organ dysfunction due to the dysregulation of cytokines, interleukin-6 (IL-6) and others. MCD is associated with HHV8 in roughly half the cases,10 but is otherwise considered to be idiopathic MCD (iMCD). HIV-positive patients almost exclusively have the HHV8-associated form. Indeed, it’s been stated that all cases of CD in the setting of HIV are linked to HHV-8-infection. In comparison with unicentric CD, MCD usually occurs among older people. Patients may exhibit multiple lymphadenopathies, fever, hepatosplenomegaly, skin rash and polyneuropathy, as well as analytic alterations such as anemia, thrombocytopenia, increased erythrocyte sedimentation rate and hypergammaglobulinemia. The clinical evolution is far more aggressive than that of unicentric CD. For a detailed review of the features of MCD, see the recent review by Fajgenbaum et al.26 Proinflammatory hypercytokinemia is an essential feature of this condition, in which the increment of some cytokines (such as IL-6, IL10, IL-1 and TNF-alpha) conditions the development of a rich clinical picture. The IL-6 protein can be produced by KSHV/HHV8, the so-called vIL-6 protein, which has a homologous sequence similar to that of the human IL-614,27 and can bind to the classic IL-6 receptors and alter their regulation.28 vIL-6 blood levels are correlated with the activity of the disease in patients with MCD associated with KSHV/HHV8.27,29
• KSHV/HHV8: •
KSHV inflammatory cytokine syndrome, found in HIV-positive patients,27,30 with the eventual appearance of germinotropic lymphoproliferative disorder14 and HHV8-positive large Bcell lymphoma.31,32 iMCD, with some specific clinicopathological syndromes such as: ￮ TAFRO syndrome (thrombocytopenia, anasarca/ascites, reticulin fibrosis in bone marrow, renal dysfunction, organomegaly and normal immunoglobulin levels)26; ￮ POEMS syndrome: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes.33,34
Diagnostic criteria have recently been refined by the Scientific Advisory Board of the Castleman Disease Collaborative Network (CDCN).26 Pathology The histology of the lymph node in HHV8-associated and idiopathic cases shows characteristics intermediate between those of PCCD and HVCD.27 The HHV8-associated cases usually show regressive germinal
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Fig. 6. HHV8-associated multicentric PCCD. HHV8-LNA-positive B-cells surround reactive germinal centers and show lambda light-chain restriction.
centers with irregularly distributed FDCs. Germinal centers may be surrounded by HHV8-positive large activated B-cells (denominated as plasmablasts but lacking the typical plasmablast morphology).35 HHV8positive plasmablasts express the monotypic lambda light-chain, but show a polyclonal pattern of immunoglobulin gene rearrangement, a finding that is yet to be satisfactorily explained (Fig. 6). Cases without KSHV/HHV8 usually feature prominent plasmacytosis and vascular proliferation, with a less striking hyalinization. Sheets of polytypic plasma cells may appear in the interfollicular areas, with hyperplastic germinal centers in the context of a patient with lymphadenopathy, prominent polyclonal hypergammaglobulinemia, anemia-elevated erythrocyte sedimentation rate, elevated serum IL-6, and bone marrow plasmacytosis. In such circumstances POEMS syndrome should be ruled out.33,34 Histological diagnostic criteria are relatively unspecific for iMCD and clinical data are essential if a correct diagnosis is to be achieved.
Clinical features While it may appear at any age, RDD is more frequently observed in children and young adults, with a slight predominance in males, and particularly in males of African descent. Patients usually develop systemic symptoms such as fever, polyclonal hypergammaglobulinemia, neutrophilic leukocytosis and an increased erythrocyte sedimentation rate.37,38 Some cases show evidence of immune-mediated diseases, such as arthralgias, glomerulonephritis or recurrent infections.37,39 RDD most characteristically appears as a large and painful bilateral cervical mass, of the typical “proconsular neck” form; this dramatic clinical presentation helped recognize the disease and prompted its histological features to be identified. Although initially described as a disease of the lymph nodes, more than a quarter of cases it show initial extranodal manifestations.37 In cases with nodal disease, the cervical lymph nodes are more frequently involved (87%), followed by axillary, inguinal and mediastinal locations.38 The most frequent extranodal sites are the central nervous system, soft tissue, skin, bone, oral cavity and salivary gland,40–43 but sporadic cases have also been described in bone, brain, testicle and other places.44–46 Different clinical presentations of RDD have been systematized47 as familial, classic (nodal), extranodal, neoplasia-associated, and immune-related.47 The usual course is benign, with spontaneous regression in many cases, or a response to therapy, but a minority of patients (< 10%) suffer from progressive disease, occasionally resulting in death, usually due to local infiltration of vital structures.39,48
Rosai-Dorfman Disease Sinus Histiocytosis with Massive Lymphadenopathy (SHML), or Rosai-Dorfman disease (RDD), is a histiocyte proliferative disorder. It was first recognized as a distinctive entity in the 1960s by Rosai and Dorfman.36 A detailed review of 423 examples of SHML was published in 1990, which included very useful information on the clinical presentation and histology of the disease.37
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Fig. 7. Rosai-Dorfman diagnostic changes include presence of aggregates of histiocytes occupying lymph node sinuses and plasma cell clusters, with Russell bodies.
the emperipolesis. Other Langerhans cell markers, such as CD1a and Langerin, are absent from RDD histiocytes. Other macrophage markers are also positive, such as CD68, CD163 and others. Plasma cells are polyclonal and can exhibit increased expression of IgG4.52
Pathology Lymph node infiltration shows a mixture of sinusoidal occupation by S100-positive histiocytes and plasma cell aggregates, often with Russell bodies. A typical, though not specific, characteristic of the disease is emperipolesis,38 a phenomenon defined by Humble et al as “the active penetration of one cell by another which remains intact”.49 In these cases, the engulfed cell maintains the integrity of the normal structure within the other cell, and both of them can exist without abnormalities arising for some time. In contrast, in phagocytosis, the lysosomal enzymes destroy the engulfed cells. Although emperipolesis is the hallmark of RDD, it can appear in other conditions such as Hodgkin lymphoma, multiple myeloma, malignant melanoma, neuroblastoma and rhabdomyosarcoma.50 RDD histiocytes usually lack atypia, but may occasionally show abnormal nuclear shapes. Most cases appear in the form of clusters of large cells, with wide and pale or eosinophilic cytoplasm, as well as rounded nuclei in which the nucleoli are evident. Others have a foamy appearance or multinucleation. Emperipolesis is a frequent finding, but can be difficult to recognize solely on the basis of morphological examination, especially when it occurs at extranodal localizations. Typically, RDD histiocytes contain engulfed plasma cells, although other cells can also be found. A marked capsular fibrosis is observed36,51 (Figs. 7 and 8). RDD histiocytes express S100, and S100 staining helps to highlight
Pathogenesis Initially considered to be an inflammatory/reactive condition of unknown cause, evidence from various sources suggests that at least some cases of RDD could be considered as a low-grade histiocytic neoplastic process. Mutually exclusive KRAS and MAP2K1 mutations have been described in one-third of RDD cases, suggesting that this is a neoplastic process in which activation of the MAPK/ERK pathway plays an essential role.53 This confirms previous observations in a larger series of patients and indicates a degree of overlap with Langerhans Cell Histiocytosis and Erdheim-Chester disease. A partial overlap with IgG4 has been found and confirmed by several studies. Overall, 40% of cases demonstrated varying degrees of increased numbers of IgG4-positive cells.54 Histological features of SHML can be seen in other conditions, such as ALPS-type IA (with TNFRSF6 heterozygous germ line mutations affecting the gene encoding Fas)55 and H syndrome, an autosomal recessive genodermatosis with multisystem involvement caused by mutations in SLC29A3.56
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Fig. 8. Rosai-Dorfman histiocytes show plasma cell emperipolesis (A-D), which is more easily recognizable after S100 staining (B,D).
Acknowledgements 12.
This work was supported by grants from the Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Economy and Competence (MINECO, RTICC ISCIII and CIBERONC) (SAF2013-47416-R, RD06/ 0020/0107-RD012/0036/0060 and Plan Nacional I+D+I: PI16/01294 and PIE15/0081) and the Asociación Española Contra el Cáncer (AECC).
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