Castleman Disease with MDM2/CDK4 Protein Expression: a Potential Mimic of Inflammatory Variant of Liposarcoma with Significant Consequences

Introduction

Castleman disease, also known as angiofollicular lymphoid hyperplasia or giant lymph node hyperplasia, is a rare lymphoproliferative disorder with a prevalence of 21–25 cases per million person-years. ¹ Approximately 70% of cases occur in lymph nodes of the mediastinum, 15% in the head & neck and 15% in the abdomen and pelvis, whereas involvement of extranodal sites such as the pancreas, lungs, larynx and meninges has also been described.^2–6 Castleman disease encompasses a spectrum of different histopathologic entities, including the hyaline vascular variant, the plasma cell variant and the multicentric HHV8-associated variant (the last mostly in HIV positive patients). Among those, the hyaline-vascular variant is the most common subtype in the US and mostly occurs in the third and fourth decade of life with a slight predilection for women. ⁷

With the exception of the HHV8-related variant, the pathogenesis of Castleman disease remains poorly understood; neoplastic, inflammatory and viral processes have all been proposed as potential pathogenetic mechanisms. According to the neoplastic hypothesis, Castleman disease might be the result of somatic mutations in monoclonal follicular dendritic cell populations, a hypothesis supported by the presence of follicular dendritic cell dysplasia in Castleman disease and the development of follicular dendritic cell sarcoma in a subset of cases.^8–11 Other studies have associated the development of Castleman disease with the presence of Epstein-Barr virus or single nucleotide polymorphisms of the IL-6 receptor.^12,13

From a clinical perspective, Castleman disease has very diverse manifestations that may range from mass effect symptomatology to constitutional symptoms and paraneoplastic pemphigus, albeit in many instances patients are asymptomatic. ¹⁴ Castleman disease is associated with a number of other disease entities such as various types of lymphoma, follicular dendritic cell sarcoma, Kaposi sarcoma and POEMS syndrome.^15,16 The clinical and histopathological heterogeneity along with the diverse sites and organs that can be involved, render the distinction of Castleman disease from its malignant and benign mimics challenging. Coexisting lymphomas or sarcomas, such as Kaposi or follicular dendritic cell sarcoma, which often arise from Castleman disease can further complicate the diagnostic process.

Herein, we describe a rare case of retroperitoneal Castleman disease which stained positively for MDM2 and CDK4, a potential pitfall when differentiating it from retroperitoneal sarcomas. To the best of our knowledge, this is the first report of Castleman disease expressing MDM2 and CDK4 in the English literature.

Case Report

A 61 year-old man presented at an outside facility with a history of fever and a syncopal episode. His past medical history was significant for chronic rhinosinusitis and asthma but was otherwise non-contributory. There was no known history of malignancy. CT imaging revealed a 3.9 cm left paraaortic retroperitoneal mass suspicious for malignancy. The subsequent core needle biopsy of the mass showed a dense lymphocytic inflammation with numerous background vessels (Figure 1A). Interspersed larger, slightly atypical cells with hyperchromatic nuclei were noted (Figure 1B). Adipose tissue without any significant atypia was focally present. Immunohistochemical stains showed that the majority of the lymphocytic component was composed of T cells, while CD20 revealed smaller areas containing B cells. The larger somewhat atypical cells within the lymphocytic component expressed MDM2 and CDK4 (Figure 1C-D). KRT-MNF116, SOX10 and STAT6 were negative. Fluorescence in situ hybridization (FISH) to assess for MDM2 amplification was attempted twice, but the quality of the biopsy material was not suitable for analysis. Based on these findings the leading differential at that time was the inflammatory variant of well-differentiated liposarcoma. A second biopsy rendered similar findings to the first one. Subsequently, the patient underwent mass resection, which was complicated by chyle leak and persistent orthostatic hypotension.

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Figure 1.

A) The core biopsy of the mass shows a heavy lymphocytic inflammation with numerous background small to medium-sized vessels (10X). B) Larger and slightly atypical cells interspersed within the lymphocytic component are noted (arrows) (200X). C) The larger, atypical cells express MDM2 and (400X) D) CDK4 (400X).

Gross examination of the resection specimen revealed a yellow-tan, firm and slightly lobulated mass with a bulging contour (Figure 2). Microscopic examination showed a lymph node with follicular hyperplasia (slight majority of sectional area) with atrophic germinal centers transversed by penetrating vessels, giving the characteristic “lollipop follicle” appearance (Figure 3A-B). The interfollicular areas (slight minority of sectional area) showed extensive vascular proliferation with perivascular hyalinization and a diffuse, dense population of polyclonal plasma cells by CD138, and kappa and lambda immunohistochemistry. No significant cytological atypia or mitotic activity was appreciated. There was no histopathological evidence of liposarcoma, lymphoma or other malignancy. Immunohistochemical staining for CD3 and CD20 revealed the presence of interfollicular T and B cells respectively, the latter predominantly within germinal centers. CD21 and CD35 highlighted normal follicular dendritic cells confined to the usual meshworks in the germinal centers, with no significant signal in interfollicular areas. There was no evidence of HHV-8 infection by immunohistochemistry, whereas MDM2 and CDK4 showed again scattered positivity (Figure 3C-D). The MDM2 and CDK4 positive cells exhibited variable cytomorphology, ranging from lymphocyte-like to dendritic shaped and were present both in the germinal centers, mantle and interfollicular areas. By flow cytometry, no monotypic B-cell population or specific pan T-cell marker aberrancies were detected. A final diagnosis of mixed hyaline-vascular/plasma cell type Castleman disease was rendered.

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Figure 2.

Gross examination of the resection specimen reveals a yellow-tan, firm and slightly lobulated mass.

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Figure 3.

A) The tumor resection reveals a lymph node demonstrating follicular hyperplasia with atrophic germinal centers. No significant cytological atypia or mitotic activity is noted (100X). B) The germinal centers are transversed by penetrating vessels giving the characteristic “lollipop follicle” appearance (200X). C) Immunohistochemistry reveals scattered positivity for MDM2 and (200X) D) CDK4 (200X).

In his last follow up evaluation, 3 months after the mass resection, the patient was doing well with no signs of recurrence.

Discussion

The term Castleman disease originated in a case report published in 1954 by Castleman and Towne, who described a large mediastinal mass consisting of hyperplastic lymphoid tissue with hyalinized germinal centers-what is currently appreciated as unicentric Castleman disease with hyaline-vascular features.^15,17 The term is now used to describe a spectrum of different lymphoproliferative disorders with distinct histopathological features and clinical presentations.

Castleman disease is divided in unicentric type when a single lymph node or region of lymph nodes is involved and multicentric type when multiple lymph node groups are involved in association with constitutional symptoms. Unicentric Castleman disease is further subdivided into two different histopathologic subtypes: the hyaline- vascular subtype, comprising 90% of unicentric Castleman disease cases, and the plasma cell subtype which is characterized by sheets of mature plasma cells in the interfollicular areas and comprises 10% of cases.^15,17 Hyaline-vascular unicentric Castleman disease can be asymptomatic or present with mass-effect symptomatology, while plasma cell unicentric Castleman disease often presents with systemic symptoms similar to multicentric Castleman disease. Interestingly, our patient presented with fever and chills, however, no evidence of multicentric disease or co-existing immunosuppression was present. Unicentric Castleman disease most commonly occurs in the mediastinum, whereas the retroperitoneal cases, such as the one presented here, are rare accounting for 7% of all cases. Multicentric Castleman disease is commonly associated with Kaposi sarcoma-associated Herpesvirus / human herpesvirus 8 (HHV8) but can also be idiopathic.^18,19 Unicentric Castleman disease is usually self-limited and carries a small risk of progressing to follicular dendritic cell sarcoma, while HHV8-associated multicentric Castleman disease is a lymphoproliferative disorder with increased risk for large B-cell, primary effusion, and plasmablastic lymphomas.^18–20

The differential diagnosis for Castleman disease is broad and includes both benign and malignant entities. The histopathological features of the hyaline-vascular and plasma cell subtypes can often overlap with those of thymoma, advanced HIV lymphadenopathy, autoimmune disorders, classic Hodgkin lymphoma or several types of non-Hodgkin lymphoma (such as mantle cell lymphoma and angioimmunoblastic T-cell lymphoma) and other malignancies including the inflammatory subtype of well-differentiated liposarcoma (WDL).^2,18 From a clinical perspective, the symptomatology of plasma cell unicentric Castleman disease or multicentric type overlaps with the non-specific constitutional symptoms commonly encountered in chronic infections, autoimmune or malignant diseases, adding another layer of difficulty in the diagnostic process.

When presented with a retroperitoneal mass, such as the one described here, soft tissue sarcomas should always be included in the differential as they encompass one third of retroperitoneal tumors. ²¹ Among retroperitoneal sarcomas, liposarcomas constitute the most common entity accounting for up to 45% of these lesions. In fact, many cases of retroperitoneal Castleman disease in the literature were labeled as sarcomas preoperatively due to their similar appearance on US and CT imaging.^22–24 Notably, the inflammatory variant of WDL – also termed “lymphocyte-rich liposarcoma” – is a rare entity, whose histopathological similarities with Castleman disease, may serve as a diagnostic pitfall for the pathologist. ²⁵ It comprises 2% of all liposarcomas and the majority of the cases have been described in the retroperitoneum with few cases also described in the thigh, pleura, scrotum and spermatic cord. ²⁶ Key histopathological features include: 1) nodular lymphoplasmacytic aggregates 2) merging of atypical adipocytic and inflammatory elements 3) intervening paucicellular stroma containing fibroblastic elements and occasionally plasma cell-rich zones 4) adjacent clearly defined zones of lipoma-like or sclerosing type liposarcoma. ²⁷ In many cases vascularity and sclerosis are present in the lymphoid nodules, while the germinal centers may demonstrate regression changes along with prominent capillaries. ²⁵ In cases where the lipomatous component is obscured by the intense inflammatory infiltrate or it is not sampled adequately during biopsy, misdiagnosis is likely to occur.^28–30

In many cases, adjunct analytical tools such as immunohistochemistry (IHC) or FISH assay have proven to be valuable when differentiating the inflammatory variant of WDL from benign/inflammatory entities. ³¹ WDL exhibits supernumerary ring or giant chromosomes with amplification of the 12q13-15 segment, which contains the MDM2 and CDK4 genes.^32,33 MDM2 is an oncogene that encodes for a nuclear-located ubiquitin ligase that degrades p53 and therefore acts as a negative regulator of the MDM2-p53 regulatory pathway while CDK4 encodes for a cyclin D kinase that promotes G1-S transition.^33,34 In our case, however, the retroperitoneal mass, which was eventually diagnosed as Castleman disease, demonstrated scattered positivity for MDM2 and CDK4 in large cells. Although MDM2 expression is highly sensitive and CDK4 is highly specific for WDL, specificity of MDM2/CDK4 immunostaining is significantly reduced when less than 30% of the neoplastic cells stain positive.^31,35 To the best of our knowledge, this is the first report in the English literature of Castleman disease staining positively for MDM2 and CDK4. It serves as an example where immunohistochemistry rather confounds the distinction of retroperitoneal Castleman disease from its malignant mimics in small biopsies, highlighting the need for meticulous study of the histopathological characteristics by the pathologist.

MDM2 positivity in Castleman disease, however, may not come entirely as a surprise. Follicular dendritic cell sarcoma, which is associated with precedent or concurrent Castleman disease in 10–20% of cases (mostly of the hyaline-vascular subtype), has been found to stain positively for MDM2 as well.^15,36,37 Follicular dendritic cell sarcoma is a rare neoplasm with the phenotype of follicular dendritic cells, which is frequently misdiagnosed as other neoplasms of meningeal, mesenchymal or lymphoid origin especially when it occurs in extranodal sites.^36,38–40 Recently Agaimy et al examined the immunohistological findings in a series of 15 patients with follicular dendritic cell sarcoma and demonstrated that 36% of the cases showed moderate to strong nuclear MDM2 expression in less than 5% to 20% of the tumor cells. ³⁶ Results were confirmed with FISH, which showed scattered amplification of MDM2 rather than the diffuse amplification pattern that is expected in liposarcoma. Out of the 15 cases, one stained weakly for CDK4 as well. Similarly, Creytens et al reported the expression of MDM2 in extranodal abdominal and retroperitoneal follicular dendritic cell sarcoma, highlighting the potential challenge when differentiating these lesions from dedifferentiated liposarcomas. ³⁷ It should be noted, however, that in our case the exact lineage of the MDM2 and CDK4 positive cells could not be identified with certainty as they showed variable cytomorphology and localization within the node, while no apparent co-expression with other immunostains was present.

Interestingly, there are reports suggesting that MDM2 dysregulation might also be implicated in the pathogenesis of Kaposi sarcoma, which is often associated with the multicentric Castleman disease in HIV + patients. ⁴¹ Lee et al demonstrated that HHV8 interacts with MDM2 ubiquitin ligase leading to the reduction of p53 and eventually dysregulation of the cell cycle. ⁴² Similarly, Chang et al identified a virally encoded protein that interacts with MDM2 favoring viral latency within the infected cells. ⁴³

Overall, our case highlights that MDM2 and CDK4 expression in retroperitoneal Castleman disease may serve as a diagnostic pitfall in small biopsies, especially in relation to the inflammatory variant of WDL. Further research is warranted in order to identify the underlying mechanism of expression and the exact nature of the MDM2 and CDK4 positive cells.