Unicentric Castleman’s Disease: Case Report and Literature Review

Castleman’s disease (CD), also known as giant lymph node hyperplasia or angiofollicular lymph node dysplasia, is a rare benign immunoproliferative disorder initially described in 1954 by Benjamin Castleman et al. [1]. Castleman identified a group of thirteen patients with a solitary mediastinal mass that microscopically showed hyperplastic lymphoid follicles with thick hyalinized walls, a germinal center formation and marked capillary proliferation [1]. This histopathologic variant is known as hyaline vascular type. Subsequently, another histopathological distinction was described by Castleman in 1971, and is known as plasma-cell type [2]. Lastly, a mix type form may also be present.


Introduction/Background
Castleman's disease (CD), also known as giant lymph node hyperplasia or angiofollicular lymph node dysplasia, is a rare benign immunoproliferative disorder initially described in 1954 by Benjamin Castleman et al. [1]. Castleman identified a group of thirteen patients with a solitary mediastinal mass that microscopically showed hyperplastic lymphoid follicles with thick hyalinized walls, a germinal center formation and marked capillary proliferation [1]. This histopathologic variant is known as hyaline vascular type. Subsequently, another histopathological distinction was described by Castleman in 1971, and is known as plasma-cell type [2]. Lastly, a mix type form may also be present.
CD can be further categorized depending upon the number of lymph nodes involved. Unicentric CD describes the involvement of a single lymph node while multicentric CD involves multiple lymph nodes. In the majority of unicentric CD cases, the patient presents with an asymptomatic solitary mass in the mediastinum along the tracheobronchial pulmonary tree or hila [3]. However, there have been reports of lymph nodes found in the intrapulmonary fissures, intercostal spaces, pelvis, neck and retroperitoneum [3]. This category of CD is usually associated with the hyaline-vascular variant, which comprises ninety percent of the cases and is considered benign [3,4].
On the other hand, multicentric CD involves multiple hyperplastic lymph nodes and is usually symptomatic. This type mostly involves a plasma cell type histology, and comprises about ten percent of the cases [4,5]. Patients in this group present with generalized systemic symptoms, such as fever, hematologic abnormalities, elevated erythrocyte sedimentation rate, growth retardation, nephrotic syndrome, and the potential involvement of other organs [4].

Case Presentation
A 24-year-old female presented with nonproductive cough for four weeks. She denied other systemic symptoms. Previous medical history was unremarkable and she was a non-smoker. Family history was contributory for ovarian cancer. Physical examination was unremarkable. Her blood work results were all within normal limits and a Human Immunodeficiency Virus test was negative.
A chest x-ray revealed mild left-ward deviation of the trachea and a contrast CT scan was obtained. A solid heterogeneous enhancing mass was found of approximately 3.5 cm is largest axial diameter localized inferior to the right thyroid lobe and extending into the anterior mediastinum, causing mass effect and left-ward deviation of the trachea (Figure 1). A positron emission tomography (PET)-CT scan was performed, and showed a soft tissue mass in the right neck Level IV compartment that extended into the superior mediastinum ( Figure 2).  A subsequent core needle biopsy was performed. This showed lymph node tissue with paracortical hyperplasia, increased vascularity, focal hyalinization, reactive germinal center and groups of follicular dendritic cells. A mediastinal mass with these characteristics, based on histologic and imaging hyaline vascular type. Six months after surgery, the patient remains asymptomatic and no other lymph node enlargement has been detected. A CT follow-up was performed and there were no abnormal findings.

Discussion
The etiology of CD is still unclear. Theories such as inflammatory origin, hyperplasia of hamartomatous lymphoid tissue or inappropriate immune response have been proposed [3,6]. CD has also been associated with human immunodeficiency virus and human herpes virus [6][7][8]. The differential diagnoses of a mediastinal mass include: thymoma, lymphoma, teratoma or unicentric CD. Normally, the former three would not show enhancement in a contrast CT scan [3]. In the case of unicentric CD, post-contrast enhancement is seen due to its hypervascularity [3]. A PET scan can be used to determine if there is any other lymph nodes involved [8]. To confirm the diagnosis, a core needle or open biopsy should be performed. This will show a polyclonal nodal expansion with the histologic features of one of the variants mentioned previously.
Diverse types of management have been proposed (Tables  1 & 2). Surgical resection is considered curative in the vast majority of cases 4 (Table 1) Bowne et al. [5]. A recent systematic review of 278 cases of unicentric CD showed that the outcomes for complete resection (R0) of the tumor were significantly better than for an incomplete resection [8,9]. Chronowski et al. [10], reported that radiotherapy has the ability to achieve complete radiographic and clinical resolution on unicentric CD in a selected group of patients, but the rates of disease free survival for surgical resection were still higher Bowne et al. [5] (Table 2). For this reason, radiotherapy should be considered for a poor surgical candidate or for unresectable unicentric CD. A study by Yoshizaki et al. [7] demonstrated that, in fact, the cells present in the germinal centers of the hyperplastic lymph nodes produce IL-6 and found a correlation of this production with the serum levels of IL-67 Abdessayed et al. [13]. Thus, another treatment modality that has been proposed is the blockage of the IL-6 dysregulated overproduction [7,11], especially in patients with plasma-cell variant [11] & Ren et al. [14].  Although unicentric CD is considered a benign condition, surgical resection is highly recommended because of mass effect on adjacent structures Nordstrom et al. [15]. A secondary consideration for surgery is that it may have malignant potential [6]. This neoplastic potential is higher with the plasma-cell variant [3]. In the case of multicentric CD, surgery does not have offer curative intent and the treatment focuses on symptom relief and clinical findings of each patient [9]. A study performed by The American Society of Hematology used a humanized anti IL-6 receptor antibody to treat patients with multicentric plasma cell or mixed type CD. After the administration of this antibody Weisenburger et al. [16], a clinical response was achieved [11][12][13][14]. Also, when histopathological examination was performed, pathological response was noted with a reduction of follicular hyperplasia and vascularity [15][16][17][18].

Cancer Therapy & Oncology International Journal
CD is an uncommon and poorly understood disease that warrants more investigation Stokes et al. [4], Sethi et al. [17], Chronowski et al. [10], Neuhof et al. [19], Noh et al. [20]. Further studies are required to identify an etiology and describe the epidemiology of CD [19,20]. Due to its low incidence, there have been no randomized clinical trials, and all the available data comes from systematic reviews, case series and case reports [8].