Background
Castleman's disease presents with marked lymph node hyperplasia. Traditionally, the disease has been subclassified on clinical grounds (solitary or multicentric presentations) and histologic appearances, including cases with a hyaline vascular pattern, plasma cell predominance, or mixed lesions. It is now increasingly clear that there are different etiologies for each of these different subtypes. The multicentric plasma cell variant is highly associated with infection by human herpesvirus 8 (HHV8), and patients have an increased risk for the development of other HHV8-associated neoplasms, including Kaposi's sarcoma and extranodal B-cell lymphoma. The solitary plasma cell/mixed variant of Castleman's disease is often seen in patients with a history of lymphoma. Overproduction of the cytokine interleukin 6, either native or virally encoded, has been hypothesized to drive plasma cell proliferation in these subtypes.
OUTLINE
DISEASE ASSOCIATIONS CHARACTERIZATION AIDS
Multicentric Castleman's disease in HIV infection: a clinical and pathological study of 20 patients.Oksenhendler E, Duarte M, Soulier J, Cacoub P, Welker Y, Cadranel J, Cazals-Hatem D, Autran B, Clauvel JP, Raphael M.
Department of Immuno-Haematology, St Louis Hospital, Paris, France.
AIDS 1996 Jan;10(1):61-7 Abstract quote OBJECTIVES: To describe, in a retrospective study, the clinical and pathological spectrum of multicentric Castleman's disease (MCD) in HIV infection.
PATIENTS: The diagnosis of MCD was established by lymph node biopsy in 20 HIV-infected patients. All patients had been HIV-infected by sexual contact. At diagnosis, HIV infection was asymptomatic in eight patients and Kaposi's sarcoma was present in 12. Mean +/- SD CD4+ cell count was 156 +/- 99 x 10(6)/l.
RESULTS: Patients were referred with a syndrome of fever and splenomegaly (100%), peripheral lymphadenopathy (90%), hepatomegaly (70%), severe weight loss (70%), respiratory symptoms (65%) and oedema (55%). Anaemia was a constant finding and seven (35%) patients presented with pancytopenia. Serum markers of inflammation were present in most patients: a high level of C reactive protein (90%), polyclonal hypergammaglobulinaemia (89%) and hypoalbuminaemia (56%). The histological pattern of the lymph nodes was characterized by small hyalinized germinal centres surrounded by concentric layers of small lymphocytes, vascular hyperplasia, hyalinized vessels and large interfollicular sheets of plasma cells. Five patients were classified as plasma cell type MCD and 15 as hyaline vascular/plasma cell (mixed) type. Immunophenotyping studies (n = 13) demonstrated a polyclonal B-cell process. No linkage with Epstein-Barr virus (EBV) could be demonstrated immunohistochemically using an anti-latent membrane protein-1 monoclonal antibody (n = 16) or by RNA in situ hybridization with an EBV-encoded RNA transcript-specific probe (n = 13). Remission was obtained with low-dose and usually single agent chemotherapy in 16 patients. During follow-up, non-Hodgkin's lymphoma developed in two patients and Kaposi's sarcoma in three. Fatal outcome occurred in 14 patients with a median survival of 14 months.
CONCLUSION: MCD associated with HIV infection is a distinct clinico-pathological entity that can be differentiated from other types of HIV-associated systemic lymphoproliferative disorders. It is very similar to MCD observed in non-HIV-infected patients, except for the high prevalence of pulmonary symptoms and for the stronger association with Kaposi's sarcoma. Single-agent chemotherapy with vinblastine is effective and may prolong survival.
FOLLICULAR DENDRITIC CELL SARCOMA
Development of follicular dendritic cell sarcoma in hyaline-vascular Castleman's disease of the nasopharynx: tracing its evolution by sequential biopsies.
Chan AC, Chan KW, Chan JK, Au WY, Ho WK, Ng WM.
Department of Pathology, Queen Elizabeth Hospital, Kowloon, Hong Kong.
Histopathology 2001 Jun;38(6):510-8
Hyaline-vascular Castleman's disease (HVCD) and follicular dendritic cell (FDC) sarcoma occurring in the nasopharynx are both extremely rare. We report the first case of transformation of the former into the latter as documented by sequential biopsies. The steps involved in the transformation were described in detail and the possible role of p53 studied.
METHODS AND RESULTS: The patient presented at the age of 23 years with nasopharyngeal HVCD. Hyaline- vascular Castleman's disease with FDC overgrowth was diagnosed in a recurrence 8 years later, and a frank FDC sarcoma developed at the same site 11 years after initial presentation. The patient remained disease-free 3 years after excision and adjuvant chemotherapy. The FDC sarcoma comprised swirling fascicles of spindly cells with indistinct cell borders. The tumour cells expressed the FDC markers CD21, CD35 and CNA.42 and in-situ hybridization for Epstein-Barr virus-encoded RNAs was negative. Over-expression of p53 protein was observed in the FDC sarcoma and an increased number of weakly p53-positive spindly cells could also be demonstrated in the HVCD specimen. This finding suggested a possible role of p53 in the evolution from HVCD to FDC sarcoma. Critical analysis of the literature shows that, among the 13 reported cases of FDC sarcoma associated with Castleman's disease, possible progression from the latter to the former is documented in only two cases.
CONCLUSIONS: The sequential changes observed in the current case provide further evidence to strengthen the role of HVCD as a possible precursor of FDC sarcoma. There is a possible role of p53 in the transformation process but confirmation by future studies is needed.
Follicular dendritic cell tumor and vascular neoplasm complicating hyaline-vascular Castleman's disease.
Chan JK, Tsang WY, Ng CS.
Am J Surg Pathol 1994;18:517–25. Abstract quote
The localized form of hyaline-vascular Castleman's disease may rarely be complicated by a vascular neoplasm, which appears to arise in a background of vascular hyperplasia.
We report a case complicated by follicular dendritic cell tumor, a hitherto undescribed occurrence that is expected from the presence of a "dysplastic" component of follicular dendritic cells in Castleman's disease. The patient had a large tumor mass in the mesocolon, associated with multiple small peritoneal deposits. The lesion showed typical histologic features of follicular dendritic cell tumor with storiform arrangement of spindly cells and admixture of small lymphocytes. The follicular dendritic cell nature of the tumor was confirmed by immunoreactivity with CD21 and CD35 antibodies and by ultrastructural demonstration of cell processes connected by desmosomes. Hyaline-vascular follicles were identified at the peripheral portion or occasionally scattered in the center of the tumor. Rarely, follicle-like structures were formed by tumor cells, possibly representing in situ malignant change. In addition, there was a small focus of vascular neoplasm comprising well-formed pericyte-rich small blood vessels devoid of cellular atypia.
This report of the development of follicular dendritic cell tumor in Castleman's disease therefore completes the picture in that tumors corresponding to each cell type that proliferates in Castleman's disease have now been documented.
HODGKIN'S DISEASE Coexistence of Hodgkin's disease and giant lymph node hyperplasia of the plasma-cell type (Castleman's disease).
Abdel-Reheim FA, Koss W, Rappaport ES, Arber DA.
Department of Pathology, Scott and White Clinic, Temple, TX 76508, USA.
Arch Pathol Lab Med 1996 Jan;120(1):91-6
Coexistence of Hodgkin's disease and giant lymph node hyperplasia (Castleman's disease) is well documented in the literature. We present a unique case in which the original lymph node biopsy revealed interfollicular Hodgkin's disease (CD15+, CD30+, CD45-, Reed-Sternberg cells) with coexistent histologic features of the plasma-cell variant of Castleman's disease. The patient experienced a long-term remission following combined chemotherapy and radiation therapy. He presented at 18 years and again at 22 years later with clinical, hematologic, and histologic features of a multicentric plasma-cell variant of Castleman's disease without evidence of Hodgkin's disease.
This unique case report further strengthens the association of Castleman's disease and Hodgkin's lymphoma. Two pathogenetic mechanisms for this association have been suggested: (1) secretion of interleukin-6 by Hodgkin's Reed-Sternberg cells and histiocytes, and (2) manifestation of an abnormal immune state associated with Hodgkin's disease. These two mechanisms may, indeed, be related.
PARANEOPLASTIC PEMPHIGUS
Arch Dermatol. 2005 Oct;141(10):1285-93. Abstract quote
BACKGROUND: Castleman tumor, a rare lymphoproliferative disorder, is one of the associated tumors in paraneoplastic pemphigus. We analyzed the characteristics of a group of patients with Castleman tumor to clearly understand and to improve the prognosis of the disease.
OBSERVATIONS: Ten cases of paraneoplastic pemphigus associated with Castleman tumor treated in the Department of Dermatology, Peking University First Hospital, Beijing, China, from May 1, 1999, to March 31, 2004, were analyzed for clinical aspects, characteristics and histologic features of the tumors, and computed tomographic findings. Literature was reviewed and data were compared with our cases. Castleman tumor was a frequently reported neoplasm in association with paraneoplastic pemphigus in China. The disease was found to be caused by an autoimmune reaction originating from the B lymphocytes in the Castleman tumor.
CONCLUSIONS: Castleman tumor in association with paraneoplastic pemphigus is a commonly reported subtype of paraneoplastic pemphigus in China. Early detection and removal of the Castleman tumor are crucial for the treatment of this tumor-associated autoimmune disease.Paraneoplastic pemphigus in association with a retroperitoneal Castleman's disease presenting with a lichen planus pemphigoides-like eruption. A case report and review of literature.
Hsiao CJ, Hsu MM, Lee JY, Chen WC, Hsieh WC.
Department of Dermatology, National Cheng-Kung University Hospital, 138 Sheng-Li Road, Tainan, Taiwan 704.
Br J Dermatol 2001 Feb;144(2):372-6 Abstract quote
A 50-year-old man presented with severe mucosal erosions of the lips, oral cavity and perianal area, a lichen planus-like eruption on the trunk and extremities and scaly plaques of the palms and soles. The clinical impression was of Stevens--Johnson syndrome, or paraneoplastic pemphigus (PNP). Histopathology revealed vacuolar interface and lichenoid dermatitis with dyskeratosis and suprabasal acantholytic vesiculation. Direct immunofluorescence showed deposition of IgG in the intercellular space and linear deposition of C3 along the basal membrane zone. Indirect immunofluorescence revealed circulating IgG with intercellular staining of the epithelium of rat urinary bladder. Western blotting demonstrated bands of 250- and 230-kDa antigens.
The clinical, histological and immunological features were consistent with the lichen planus pemphigoides variant of PNP. A retroperitoneal hyaline-vascular Castleman's disease was detected and excised. The skin lesions worsened initially after tumour resection but improved gradually, leaving extensive melanosis after cyclosporin and mycophenolate mofetil treatment.
POEMS SYNDROME Castleman disease in POEMS syndrome with elevated interleukin-6.
Emile C, Danon F, Fermand JP, Clauvel JP.
Cancer 1993 Feb 1;71(3):874
CHARACTERIZATION Laboratory Markers IL-6Present in multicentric plasma cell type High levels of human herpesvirus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric castleman disease in HIV-infected patients.
Oksenhendler E, Carcelain G, Aoki Y, Boulanger E, Maillard A, Clauvel JP, Agbalika F.
Department of Immunology and Hematology, Laboratory of Virology, Hopital Saint-Louis, Paris, France.
Blood 2000 Sep 15;96(6):2069-73 Abstract quote Multicentric Castleman disease (MCD) is a distinct type of lymphoproliferative disorder associated with inflammatory symptoms and interleukin-6 (IL-6) dysregulation. In the context of human immunodeficiency virus (HIV) infection, MCD is associated with human herpesvirus 8 (HHV8) infection.
In a prospective study of 23 HIV-infected patients with MCD, clinical symptoms of MCD were present at 45 visits, whereas patients were in chemotherapy-induced clinical remission at 50 visits. Symptoms were associated with a high level of serum C reactive protein, high HHV8 viral load in peripheral blood mononuclear cells, and high plasma human IL-6 and IL-10 levels.
Strong correlations between plasma IL-6 and plasma IL-10 with the HHV8 viral load suggest that both cytokines may be involved in the pathogenesis of this virus-associated lymphoproliferative disorder.
GROSS APPEARANCE/
CLINICAL VARIANTSCHARACTERIZATION GENERAL Multicentric Plasma cell type Hyaline vascular typeSolitary, slow-growing mass, usually in the absence of constitutional symptoms.
Most lesions are located in the mediastinum, abdomen, or neck
Less frequently associated with paraneoplastic phenomenon (for example, neuropathy) and has a benign clinical course
BONE MARROW
Bone Marrow Findings in Multicentric Castleman Disease in HIV-negative Patients.*Institut fur Pathologie daggerAbteilung fur Haematologie/Onkologie, Klinikum der Johannes Gutenberg Universitat, Langenbeckstr. 1, 55101 Mainz, Germany.
Am J Surg Pathol. 2007 Mar;31(3):398-402. Abstract quote
Because bone marrow histology in multicentric Castleman disease in human immunodeficiency virus-negative patients is not well reported, we investigated sequential bone marrow biopsies of 3 affected human immunodeficiency virus-negative patients, of which one was human herpes virus 8 (HHV8)-positive.
The histologic evaluation of the bone marrow revealed lymphoid follicles with regressed germinal centers in 1 patient. Another patient showed tumorlike but bland polyclonal plasmacytosis with large perivascular plasma cell clusters. The HHV8-positive patient revealed interstitial HHV8-positive cells accompanied by a mild plasmacytosis. The atypical lymphoid follicles could be regarded as a bone marrow manifestation of multicentric Castleman disease, whereas the plasmacytosis most likely is the result of excess interleukin 6 production.
The presence of HHV8-positive cells within the bone marrow may indicate the dissemination of the virus in a compromised immune system.PEDIATRIC
Paediatric Castleman disease: report of seven cases and review of the literature.Parez N, Bader-Meunier B, Roy CC, Dommergues JP.
Service de Pediatrie, CHU Bicetre, Le Kremlin Bicetre, France.
Eur J Pediatr 1999 Aug;158(8):631-7 Abstract quote Castleman disease is a distinct lymphoproliferative disorder of unknown origin. Seven new cases in children are reported here and 76 cases from the paediatric literature are reviewed.
The disease has been reported in 46 females and 37 males, their age ranging from 2 months to 17 years. The disease was localized in 72 cases and multicentric in 11 cases. The hyalinovascular type was more frequently encountered (54%) than the plasma cell type (24%).
Laboratory abnormalities were more often associated with the plasma cell type and were mainly represented by anaemia and hypergammaglobulinaemia. Treatment of the localized tumour consisted of surgical excision, whereas treatment of the multicentric form was medical, comprising prednisone and other immunosuppressor drugs. The disease in the paediatric population seems to have a more favourable course than in adults.
CONCLUSION: The paediatric features of the disease suggest that Castleman disease in this population could represent an earlier form of the pathology or even suggest a benign lymphoproliferative disorder.
SKIN
- Sarcoma Arising in Hyaline-Vascular Castleman Disease of Skin and Subcutis.
Kazakov DV, Morrisson C, Plaza JA, Michal M, Suster S.
From *Sikl's Department of Pathology, Charles University, Medical Faculty Hospital, Pilsen, Czech Republic; and daggerDepartment of Pathology, The Ohio State University Medical Center, Columbus, Ohio.
Am J Dermatopathol. 2005 Aug;27(4):327-332. Abstract quote
We report on a case of a sarcoma arising in the hyaline-vascular variant of Castleman disease (HVCD) of the skin and subcutis.
The patient was a 38-year-old man who clinically presented with a subcutaneous non-fixed cyst-like mass on his right shoulder with an unremarkable prior medical history.
Histologic sections showed a biphasic tumor with numerous atretic lymphoid follicles located in the deep dermis and subcutis and a spindle-cell neoplasm mainly situated in the deep subcutis and adjacent soft tissue. The atretic lymphoid component fulfilled the criteria for HVCD, whereas the spindle-cell lesion showed all the criteria for sarcoma including nuclear atypia and frequent mitotic figures.
The sarcomatous component was diffusely positive for fascin, nerve growth factor receptor, and CD34 with focal weak reactivity for CD21 and CNA.42. Stains for CD23, CD31, CD35, CD99, ALK-1, SMA, ASMA, desmin, factor XIIIa, AE1-AE3, EMA, bcl-2, S-100, Melan-A, HMB-45, Cam 5.2, and factor VIII were negative in the neoplastic spindle cells. No monoclonal population of lymphocytes was detected and we could not identify EBV or HHV-8 virus by PCR. Electron microscopy of the sarcomatous component showed spindle cells with labyrinth-like invaginations of the nucleus and numerous long, slender, interwoven cytoplasmic processes.
The sarcomatous component in this case is most consistent with a poorly differentiated follicular dendritic cell sarcoma based upon the morphologic and ultrastructural findings.
Multicentric plasma cell variant of Castleman's disease with cutaneous involvement.
Klein WM, Rencic A, Munshi NC, Nousari CH.
Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA.
J Cutan Pathol. 2004 Jul;31(6):448-52. Abstract quote
BACKGROUND: Castleman's disease (CD) is a rare low-grade B-cell lymphoproliferative disorder that can be associated with a variety of antibody-mediated paraneoplastic syndromes. The disease is classified clinically by two forms and three histologic variants.
METHODS: We describe the clinical and pathological features of a 44-year-old woman who presented with an autoimmune hemolytic anemia, thrombocytosis, polyclonal gammopathy, axillary lymphadenopathy, hepatosplenomegaly, and several erythematous and violaceous nodules and plaques without scaling involving the trunk and extremities.
RESULTS: Histologic examination of the skin lesions revealed a deep dermal and subcutaneous nodular mononuclear infiltrate composed primarily of polyclonal plasmacytoid cells without atypia and an increased vascular proliferation. Additional studies including a bone marrow and lymph node biopsy, serum and urine protein electrophoresis, and computed tomography scans supported the diagnosis of multicentric plasma cell variant of CD with an associated autoimmune paraneoplastic hemolytic anemia.
CONCLUSION: Cutaneous involvement in CD is part of the multicentric nature and should be considered in the differential diagnosis of a polyclonal plasma cell-rich lymphoproliferative disorder associated with paraneoplastic autoimmune disease.SOFT TISSUE
Castleman Disease of the Subcutis and Underlying Skeletal Muscle: Report of 6 Cases.
Kazakov DV, Fanburg-Smith JC, Suster S, Neuhauser TS, Palmedo G, Zamecnik M, Kempf W, Michal M.
*Sikl's Department of Pathology, Charles University, Medical Faculty Hospital, Pilsen, Czech Republic; daggerDepartment of Soft Tissue Pathology, Armed Forced Institute of Pathology, Washington, DC; double daggerDepartment of Pathology, Ohio State University Medical Center, Columbus, OH; section signDepartment of Pathology, Wilford Hall Medical Center, San Antonio, TX; paragraph signDermatopathologische Gemeinschaftspraxis, Friedrichshafen, Germany; and Unit of Dermatopathology, Department of Dermatology, University Hospital, Zurich, Switzerland.
Am J Surg Pathol. 2004 May;28(5):569-577. Abstract quote
Castleman disease of the subcutis and skeletal muscle is rare. We have collected a series of 6 cases of extranodal Castleman disease, located in the subcutis and skeletal muscles of the extremities and trunk. Tumors from mediastinal and retroperitoneal soft tissue and those histologically involving peripheral or truncal lymph nodes were excluded.
There were four females and two males; ages ranged from 18 to 37 years (mean, 26 years). Locations included thigh (n = 3), anterior chest (n = 2), and upper arm (n = 1). Sizes ranged from 4.0 to 6.0 cm (mean, 5.2 cm). All patients presented with localized disease. One patient had involvement of the mediastinum 1 year prior to the appearance of his soft tissue lesion. None of the patients demonstrated systemic involvement or signs of the POEMS syndrome.
Histopathologically, all cases were classified as hyaline-vascular type (HVCD). In 3 cases, follicular dendritic cell dysplasia was observed. In 1 case, the dysplasia was marked. The subcutaneous lesion of 1 patient revealed a maze of capillaries set in a lipomatous background with occasional lymphoid follicles possessing hyalinized lymphocyte-depleted centers. This lesion probably represented incipient HVCD.
Molecular biologic studies did not reveal the presence of Epstein-Barr virus or human herpesvirus-8 DNA in the lesional tissue. There also were no monoclonal rearrangements of IgH. Four patients with follow-up included 2 patients with no evidence of disease at 10 and 13 years, respectively, and 2 patients with local recurrence at 2 and 6 months, respectively.
In conclusion, soft tissue Castleman disease is a disease of young patients with a female predominance and a propensity to involve the trunk and limbs. It can be of large size and is generally solitary. There may be mild to marked follicular dendritic cell dysplasia. The HVCD predominates in this location. These lesions are usually unassociated with POEMS, Epstein-Barr virus, human herpesvirus-8, or monoclonal rearrangements of IgH.
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