Clinicopathological Profile of Castleman’s Disease in Indian Population: Experience From a Tertiary Care Center

Abstract

Castleman’s disease (CD), also known as angiofollicular lymph node hyperplasia, a rare, non-malignant chronic lymphoproliferative disease characterized by, uni or multicentric lymphadenopathy. There is limited information about the clinicopathological variations and associations of this entity. A total of 50 cases of CD were retrieved from the archives, between the years 2005–2017. The cases were divided into pediatric (0–18 years), young adult (age ≤ 40 years) and older adult groups (age > 40 years respectively). Detailed clinicopathological correlation was done. The age range was 6–74 years. There was a male predominance (M: F—1.6:1). The majority (72%; 36/50) of the patients were adults; 46% young adult and 28% older adult, while only 28% (14/50) were of pediatric. Majority (78%) showed features of unicentric Castleman disease (UCD) while rest 22% presented with multi centric Castleman disease (MCD). Systemic symptoms were more frequent in MCD as compared to UCD cases (p = 0.06). The majority of the cases (40/50; 80%) were of the hyaline vascular type. Two of the cases showed mixed histological feature. Out of 50 patients 29 patient’s treatment details are available. Majority unicentric cases were cases surgically excised 14/17 (82.3%). Three patients 3/17 (17.6%) were treated with chemotherapy. In multicentric Castleman’s disease group, six of the 12 cases with MCD were managed by chemotherapy. One patient died of progressive disease. Castleman disease has varied clinical presentation and is often associated with other diseases. A high degree of suspicion and careful histological examination is required in order not to miss this entity.

Introduction

Castleman’s disease (CD), also known as angiofollicular lymph node hyperplasia, is a rare, non-malignant chronic lymphoproliferative disease. CD was first described by Benjamin Castleman and was initially thought to be a non-neoplastic lymphoproliferative disorder [1, 2]. Unfortunately, research on CD has progressed much more slowly than research on other hematological malignancies, possibly due to CD’s rarity and relatively less aggressive biological behavior. Three pathological variants of CD have been recognized: hyaline-vascular (HV), plasma cell (PC), and mixed [3–6]. Depending on the extent of lymph node involvement and the clinical profile, CD has been categorized into unicentric (UCD) and multicentric (MCD) forms. UCD usually presents in young adults with localized masses (the mediastinum being the most common site) and is rarely associated with systemic symptoms. In contrast, MCD commonly affects the elderly (age 60 and older), presents with generalized lymphadenopathy and multi-organ involvement, and is usually associated with systemic features. HV morphology is significantly more common in UCD, whereas the majority of MCD cases show PC morphology. Interestingly, this disease demonstrates some variability in the clinico-pathological spectrum in different populations [4, 7]. Two different institution-based studies from Japan and Korea reported relatively higher frequencies of MCD than have been reported in the Western literature [8, 9]. Furthermore, in the Western population, the majority of MCD cases are associated with human immunodeficiency virus (HIV) and human.

herpes virus type 8 (HHV-8) infections and have relatively aggressive disease courses [8, 10]. In contrast, Japanese MCD cases usually have indolent clinical courses and are rarely associated with HHV-8. Only a single case series is available from India, which analyzed 5 cases of CD. All these cases were HV cases and presented with cervical lymphadenopathy. Additionally, one patient had a history of fever as the systemic symptom [11].

Because CD is rare and poorly understood and there is no obviously optimal therapeutic approach, the present study was conducted to analyze the clinico-pathological characteristics and responses to treatment of patients with CD from a single medical institution. To the best of our knowledge, the present series is the largest from India.

Materials and Methods

Patient Data

A total of 50 cases of CD, which occurred during the years 2005–2016, were retrieved from the archives of the Department of Pathology, All India Institute of Medical Sciences, New Delhi. Hematoxylin and eosin-stained slides of these cases were reviewed and a concordant agreement was established to confirm the diagnosis. Patient records were reviewed to obtain demographic data, including data regarding the patient’s age, sex, tumor location, treatment, and follow-up. The cases were divided into pediatric (0–18 years), young adult (age ≤ 40 years), and older adult (age > 40 years) groups.

Results

Patient Characteristics

The age range was 6–74 years (mean age of 31 years). There was a male preponderance in the study population with male to female ratio was 1.6:1. The majority (72%; 36/50) of the patients were adults (46% young adult and 28% older adult), whereas only 28% (14/50) of the patients belonged to the pediatric age group.

Clinical Spectrum

Amongst the 50 patients included in the study, the majority (78%) showed features of UCD, whereas the rest (22%) presented with MCD; both groups predominantly consisted of males. The median age of patients with UCD (24 years) was also significantly lower than that of patients with MCD (45 years; p-value: 0.001). Interestingly, none of the pediatric cases presented with MCD, whereas approximately 30.6% of the adult cases presented with MCD (p-value: 0.02). Asymptomatic, unifocal painless lymph node enlargement (mass formation) was the most commonly presented symptom of UCD (61.5% cases). Additionally, 15.4% of the UCD cases presented with compression phenomena, including pain, neuropathy, dyspnea, and diarrhea. The cervical region was the most common site for UCD (43.6%), followed by the abdominal cavity (23.1%) and mediastinum (15.4%). On the other hand, abdominal lymphadenopathy was the most common issue (36.4% of patients) observed during the initial presentation in cases of MCD. Systemic symptoms were more frequent in MCD than UCD cases (27.3% vs 5%; p value: 0.06). Two (4%) patients in the present series also had POEMS syndrome. Hematological findings were available in 12 cases, amongst which 16.7% showed anemia. Only a single patient in the present series was immunocompromised; that patient had UCD. Paraneoplastic syndrome was identified in cases with pemphigus Vulgaris being commonest.

Histopathological Features

The majority of the cases (80%) were of the HV type, showing numerous small- to medium-sized germinal follicles in the lymph nodes, hyalinized blood vessels within and between follicles, obliteration of the medullary sinuses, and a concentrically-arranged mantle zone that produced a characteristic ‘onion peel’ appearance. Some of the follicles were traversed by radial blood vessels (Fig. 1a–d). On the other hand, only 16% of the cases showed PC histology with relatively greater retention of the nodal architecture. The inter-follicular region characteristically showed sheets of mature-appearing plasma cells (Fig. 1f, g, h). Two (4%) cases showed mixed histological features. Most of the cases with HV CD, as well as PC CD, had the unicentric form of CD. However, the frequency of the PC variant was higher in cases with MCD. A summary that compares the clinical characteristics of the UCD and MCD cases is depicted in Table 1.

Fig. 1.

a Gross photograph showing well circumscribed homogenous mass. b Variable sized follicle with expanded inter follicular area. c Center of the follicle showing hyalinized vessel with onion skin appearance. Capillaries entering right angle to follicles. d Immunohistochemistry for CD34 highlighting capillaries in follicle. e Skin biopsy from pemphigus Vulgaris showing suprabasal cleft. f Homogeneous grayish white mass. g Follicle with germinal center. h Photomicrograph showing sheets of plasma cells

Table 1.

Clinical spectrum of Hyaline vascular type and plasma cell type of CD

Features	HVD (n–40)	PCD (n–8)	p value
UCD	85%	50%	0.047 (S)
MCD	15%	50%	0.047 (S)
Age at presentation Median ± SD (range) (years)	25.5 ± 11.4 (6–57)	49.5 ± 21.3 (8–74)	0.002 (S)
Male: Female	25:15	4:4	0.69 (NS)
Commonest site	Cervical (42.5%)	Abdominal (37.5%)	–
Systemic symptoms	2.5%	37.5%	0.012 (S)
Paraneopalastic syndrome	17.5%	0%	0.44 (NS)
Size of lymphnode Median (range) (cm)	5.7 ± 3.5 (1–14)	3 ± 2.9 (1–8)	0.52 (NS)

Bold values are significant values (p < 0.05)

Two of the cases with mixed histology was not included for statistical analysis

Management

Out of 50 patients, only 29 patients’ treatment details were available. The median follow-up time was 20.9 months (IQR 10–38.9 months). A summary of the nine patients that received chemotherapy is depicted in Table 2.

Table 2.

Summary of patients with Castleman’s disease treated with chemotherapy

	Age	Disease type	Histopath	Treatment	Follow up duration (days)	Status
Case 1	41/ M	MCD	HVD	CHOP (6 cycles)	1223	SD
Case 2	30/ F	MCD	HVD	CHOP (6 cycles) Palliative RT	701	CR
Case 3	34/ M	MCD	HVD	Bortezomib + Dexa followed by ASCT	1167	CR
Case 4	49 /M	MCD	HVD	Bortezomib + DexaX 60 Followed by MP; Also received RT	555	CR
Case 5	28/ M	MCD	HVD	Bortezomib + DexaX 60 Followed by maintenance Bortezomib then ASCT
Case 6	45/ F	MCD	PCD	Danazol + prednisolone	4673	Death
Case 7	27/ F	UCD	HVD	Surgery + Steroid	307	PD
Case 8	39/ M	UCD	HVD	Diagnostic bx melphalan + Dexamethasone (1 cycle) followed by RT along with Bortezomib + Dexa	819	CR
Case 9	20/ M	UCD	HVD	Exp laperotomy and clouser + RCHOP	115	SD

MCD Multicentric castlemans disease, UCD unicentric castlemans disease, HVD hyaline vascular disease variant, PCD Plasma cell type, ASCT Autologous stem cell transplant, RCHOP Rituximab cyclophosphamide, adriamycin, vincristine and prednisolone

The majority of the UCD cases were surgically excised (82.3%). Three patients (17.6%) were treated with chemotherapy, including prednisolone, cyclophosphamide, vincristine, and doxorubicin (CHOP). The maximal response achieved was defined as the stable response in those who received chemotherapy as part of their treatment.

In the MCD group, six of the 12 cases were managed with chemotherapy: CHOP (cyclophosphamide, doxorubicin, vincristine, and corticosteroid; 2/6 cases), BorDex (bortezomib and dexamethasone; 3/6 cases) or Danazol with prednisolone (1 case). Regular follow-ups were suggested for the remaining 6 MCD cases because they were asymptomatic. The responses achieved in the chemotherapy groups were: complete response in 3/6 (50%) patients, stable disease in one patient, and death from progressive disease in one patient.

Discussion

CD is a rare pathological disorder that is characterized by lymph node hyperplasia and whose precise incidence and etiology are not well established. Several immunological mechanisms have been proposed for its genesis, including overproduction of IL-6 and HHV-8 infection [12] currently, the proposed hypothesis is thought to be due to unknown antigenic driven follicular hyperplasia [10]. The majority of studies demonstrate that UCD cases are more frequent than MCD cases [13, 14]; however, in contrast, Kawabata et al. and Luo et al. reported higher incidences of MCD cases than UCD cases [8, 15]. To the best of our knowledge, the present series is the largest from India and had a significantly higher proportion of UCD cases than MCD cases. Further, the median age at presentation of UCD was significantly lower than the median age at presentation of MCD cases and the mediastinum appeared to be the most common site of involvement in UCD cases (approximately 46–70% of the cases in different series), followed by abdominal location (3–39%) and periphery (10–15%) [16]. A higher prevalence of HIV infection was also demonstrated in MCD. In contrast to the Western literature, two studies on the Japanese population reported significantly lower frequencies of HIV seropositivity and relatively indolent clinical courses in MCD cases [17, 18]. Asymptomatic lymphadenopathy was the most common presentation in our series, although the cervical region was the most common site. Only a single case in the present series was immune-compromised (HIV serology-positive) and was associated with MCD. Hence, our findings are in line with studies of Japanese populations.

Two principal histological types of CD have been described: HV and PC. UCD and MCD cases were reported to be commonly associated with HV and PC, respectively. Similar to the published literature, the frequency of PC CD was found to be significantly more frequent in MCD cases; however, HV was more common than PC in both the UCD and MCD groups. Although the pathological characteristics of CD are well established, its diagnosis is often difficult due to the variety of histological features and large number of pathological mimics, which includes both benign and neoplastic entities. Hence, diagnosing CD is often a diagnosis of exclusion. However, a definitive diagnosis can be made on the basis of a detailed clinical history and careful histological examination, along with other ancillary studies (e.g., immunohistochemistry, flow cytometry, and molecular genetics) [18].

In contrast to adult CD, very little information is available regarding the clinicopathological spectrum of CD in the pediatric age group in terms of case reports and small series. Zhang et al., in their series of 11 cases of pediatric CD from China, reported a mean age of 9.67 years with a range of 1.3–15.5 years [19]. Similar to the adult population, the majority of the cases had UCD (UCD–82%; MCD–18%) and HV morphology (HV–91%; PC–9%). Taylor et al., in their study of pediatric CD in an African population (11 cases; age range 3–11 years), reported a lower frequency of HV (1/6; 16.6%) morphology, compared to PC morphology; two of the cases with PC histology subsequently developed Kaposi's sarcoma [20]. To the best of our knowledge, the present series is the largest in terms of pediatric CD. The pediatric cases in our study group had a homogeneous clinico-pathological spectrum: all the cases presented with UCD and all but one had HV histology, and interestingly, not one of the cases was associated with paraneoplastic symptoms.

The treatment for CD is not well- established as there are no randomized trials of the therapy and hence, treatment is often based on published case reports only. In spite of the availability of various treatment regimens in modern practice, including surgery, chemotherapy, and/or radiotherapy, the best therapeutic approach remains debatable [5, 18, 21]. Further, the treatment outcomes of CD differ depending on the specific types of disease. Complete surgical excision was found to be the primary treatment for UCD and was virtually curative in all cases reported thus far; surgical excision has a five-year survival rate approaching 100%. On the other hand, MCD cases are reported to exhibit aggressive clinical courses with the potential for malignancy. There is currently no standard therapy for MCD. Many scientists believe that chemotherapy is the mainstream form of treatment for MCD; combination chemotherapy with CHOP or cyclophosphamide/ vincristine/ prednisone (CVP) without rituximab was found to be associated with durable remissions in various series [4, 21–25] A meta-analysis of 416 CD patients from the published literature highlighted that centricity, pathology type, the presence of symptoms, gender and age as prognostic factors by univariate analysis [7]. Dong et al. in their study also found that the 1- and 3-year survival rates of UCD patients were higher than those for MCD [14]. The survivals of CD patients with HV variants were also better than those of PC variant. In the present series, all the pediatric cases and majority of the cases aged less than 40 years presented with unicentric form of CD.

Castleman disease has varied clinical presentation and is often associated with other diseases. A high degree of suspicion and careful histological examination is required in order not to miss this entity.

Funding

None.