Unmasking Hodgkin’s Lymphoma and Its Mimics: Delving into the Interfollicular Zone Beyond Castleman’s Disease

Introduction

Castleman’s disease (CD) is an infrequent lymphoproliferative disease with a complex pathophysiology. In the recent 5th edition of the WHO classification of haematolymphoid tumors, CD has been classified as a distinct class in tumor-like lesions with B-cell predominance [1]. This is not a single disease but rather three distinct clinicopathological entities: Unicentric Castleman disease (UCD), Idiopathic multicentric Castleman disease (iMCD), and KSHV/HHV-8 associated multicentric Castleman disease [2]. Classically characterized by lymph node hypertrophy, it may be associated with infection by human herpesvirus-8 (HHV8) in patients suffering from human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS). The unicentric form involves only one chain of lymph nodes, for example thoracic, mediastinal, or abdominal lymph nodes. In the multicentric or disseminated form, there is an involvement of a larger number of lymph nodes with more of systemic involvement. It has been extensively documented that patients with multicentric Castleman disease (MCD) frequently develop secondary malignancies [3, 4]. CD and lymphoma may exhibit synchronous or metachronous associations and may even mimic one another [5–10]. The occurrence of Hodgkin’s lymphoma (HL) alongside CD is uncommon and has been reported in only a limited number of case reports [3, 6–9].

Case Presentation

Case 1

A 44-year-old male patient presented to the hospital with generalized lymphadenopathy in the last 3–4 years. The patient has complained of on-and-off fever in the last 2 years. Recently, he also complained of yellowish discoloration of his eyes. Laboratory investigations showed normal total white blood cell count including absolute neutrophil counts; however, β2-microglobulin levels (14.0 mg/L) were raised. The patient also had anemia (hemoglobin 7.0 g/dL) with slightly elevated serum bilirubin levels (1.4 mg/dL) and conjugated bilirubin (0.7 mg/dL). Kidney and liver function tests (AST and ALT) along with lactate dehydrogenase levels were normal (186 UI/L). HIV and HHV-8 serologies were negative. Initial positron emission tomography (PET) scan revealed enlarged right cervical lymph nodes (level II, III, IV, V) measuring 4.6 × 3.4 cm with increased FDG uptake (SUVmax 5.4). Liver and splenic parenchyma were mildly enlarged and showed heterogenous FDG uptake. Serum protein and immunofixation electrophoresis revealed polyclonal hypergammaglobulinemia (serum IgG and IgA levels were elevated; however, IgM level was normal). No monoclonal band was noted. Kappa and lambda light chains were elevated on light chain assay. Rapid TB culture done on biopsy tissue showed no growth of acid-fast bacilli. Bone marrow aspirate showed a cellular reactive marrow with no atypical cells. In view of the high suspicion of lymphoma, the right posterior triangle lymph node was resected and sent for histopathological examination. Microscopically, the lymph node architecture was diffusely effaced (Fig. 1a). The interfollicular areas were markedly expanded and inhabited by sheets of mature-looking plasma cells admixed with some reactive lymphocytes (CD3 positive T cells) and few eosinophils (Fig. 1b, c). With a thorough search, many large atypical Reed-Sternberg cells having bi-lobed nuclei, prominent eosinophilic nucleoli with abundant cytoplasm were identified scattered in the interfollicular zones (Fig. 1d–f). Admixed multilobate and mononuclear Hodgkin cells were also noted (Fig. 1g, h). Widely dispersed residual lymphoid follicles with atretic hyalinised germinal centres and variably thick mantle cell layer were observed. Plasma cell population was positive for CD138 and showed polytypic expression of kappa and lambda light chains (kappa > lambda) (Fig. 2a). The Hodgkin cells were positive for CD30, CD15, PAX-5 (dim), and EBV (Fig. 2b–e) and showed negativity for CD3 and CD20. Thus, a final diagnosis of concomitant Classic Hodgkin lymphoma-mixed cellularity type and Castleman disease-plasma cell variant was rendered. The patient was started on 12 cycles of chemotherapy (Adriamycin, bleomycin, vinblastine, and dacarbazine), and on a 6-month follow-up showed a significant reduction in size and metabolic activity of right cervical lymph nodes, liver, and spleen and is doing well at present.

Fig. 1.

a Diffuse effacement of lymph nodal architecture (HE 40 ×); b, c Marked expansion of interfollicular areas and presence of sheets of mature-looking plasma cells admixed with few reactive lymphocytes and eosinophils (HE 100 × , 200 ×); d–f Scattered large atypical Reed-Sternberg cells (arrows) having bi-lobed nuclei with prominent nucleoli in the interfollicular zones (HE 100 × , 200 ×); g, h Occasional presence of multilobated Hodgkin cells (arrows) (HE 100 ×)

Fig. 2.

a CD138 positivity in plasma cell population (200 ×); b, c Hodgkin cells showing positivity for CD30 and CD15 (200 ×); d, e PAX-5 (dim) and EBV positivity in RS cells (200 ×)

Case 2

A 32-year-old female patient presented with complaints of left-sided vague abdominal pain for the last 1 month. Pain was associated with generalized weakness, malaise, easy fatigability, and bilateral lower limb pain. She had no complaints of fever, nausea, vomiting, constipation or diarrhea. Ultrasound (USG) abdomen revealed a peripancreatic mass measuring 6.5 × 4.2 × 3.0 cm. Laboratory investigations showed mild anemia (Hemoglobin 8.2 g/dL). Liver and renal function tests were normal. Serum tumor markers were also within normal limits (CEA: 0.75 ng/mL, CA 125: 10.2 U/mL, CA 15–3: 5.2 U/mL, and CA 19.9: 18 U/mL). Viral markers and autoimmune markers were negative. Triphasic computed tomography (TPCT) of the abdomen was done which showed a well-defined lobulated 5.7 × 3.8 × 3.8 cm mass in the gastro-hepatic space, superior to the neck and body of the pancreas, extending posteriorly to the left lobe of the liver. The mass was abutting the pancreatic parenchyma and showed an absence of fat planes. The lesion exhibited arterial enhancement and relative washout in the portal venous phase in contrast to hepatic parenchyma (Fig. 3a, b). These findings were suggestive of a neuroendocrine neoplasm or gastrointestinal stromal tumor. Endoscopic ultrasound (EUS) showed a mass in the body of the pancreas; consequently, fine needle aspiration cytology (FNAC) was attempted in the same sitting. Cytology smears showed few atypical cells in a lymphoid background, which was suggestive of a lymphoproliferative neoplasm. Subsequently, a whole body 18-Fluorodeoxyglucose positron emission tomography (18-FDG-PET) scan was carried out, which showed a large homogenously enhancing mildly FDG avid lobulated mass in the gastro-hepatic region, abutting the left lobe of the liver and the pancreatic head. No other lymph nodes were enlarged. Imaging and FNA findings appeared discordant along with the retroperitoneal location of the mass prompting the attending clinician to keep the neuroendocrine tumor of the pancreas, gastrointestinal stromal tumor, and lymphomas/lymphoproliferative lesions as differential diagnoses. The patient underwent an exploratory laparotomy; intraoperatively, a large mass was seen densely adherent to the neck, body of the pancreas, and the left lobe of the liver (Fig. 3c). Extensive adhesion with the major vascular structures was also visualized. The mass was separated from the retroperitoneum, pancreas, liver, and major vessels, excised, and sent for histopathological examination. Microscopic examination showed a large mass, which was encapsulated and composed of lymphoid tissue. There was lymphoid follicular hyperplasia and showed distinctive follicles with an atretic germinal center (Fig. 4a). Mantle zone was expanded and showed the presence of lymphoid cells which were small and mature and arranged as concentric rings (imparting an onion-skin arrangement) (Fig. 4b). Variably sized hyalinized blood vessels and numerous capillaries were noted in the follicle, mantle zone, and interfollicular area (Fig. 4c, d). Few atypical cells having lobulated nuclei with prominent nucleoli mimicking Reed-Sternberg cells were also observed in the interfollicular area (Fig. 4e, f). There was no evidence of malignancy or any pancreatic tissue in the specimen. On IHC, CD20 and CD3 showed a reactive pattern lymphocyte population of B cells and T cells, respectively (Fig. 5a, b). CD30 and CD15 were negative in those atypical cells while CD21 and S100 highlighted the follicular dendritic cells and scattered Langerhans cells in the interfollicular region, respectively (Fig. 5c, d). The morphological features were diagnostic of a hyaline vascular variant of Castleman disease. No further treatment was deemed necessary. The patient is presently doing well in a follow-up period of 6 months.

Fig. 3.

a Arterial phase of CECT abdomen (sagittal view) showing a well-defined, enhancing lobulated mass in the gastro-hepatic space superior to the body and the neck of the pancreas; b portal venous phase of CECT abdomen (sagittal view) showing relative washout of the lesion as compared to hepatic parenchyma; c Intraoperative image showing a lobulated mass, separate from the pancreas and closely adherent to vascular structures

Fig. 4.

a Lymphoid follicular hyperplasia showing distinctive follicles with atretic germinal center (HE 40 ×); b Expanded mantle zone showing the presence of small mature lymphoid cells arranged as concentric rings (imparting an onion-skin arrangement) (HE 200 ×); c, d Presence of numerous medium-sized vessels and capillaries in the follicle, mantle zone, and interfollicular area (HE 40 × , 200 ×); e, f Presence of few atypical cells having lobulated nuclei and small nucleoli in the interfollicular area (HE 400 ×)

Fig. 5.

a, b CD3 and CD20 showed reactive pattern in the lymphocyte population (40 ×); c CD21 highlighting the dendritic cells (40 ×); d S100 highlighting the Langerhans cells (40 ×)

Discussion

The most common presentation of CD is lymphadenopathy; however, the extranodal sites of involvement include the parotid, larynx, and meninges in the head and neck region, and pancreas in the retroperitoneal organs [11, 12]. It can affect individuals of any age; the localized form of the disease has a higher incidence in adolescents and young adults, whereas the multicentric form affects older individuals and patients with immunodeficiency, especially those suffering from AIDS. The exact etiology of CD remains largely undefined; the pathogenetic mechanism shows an inflammatory response involving chemical mediators (cytokines) particularly, interleukin-6 (IL-6) to an unspecified antigenic stimulus. IL-6 causes the proliferation and differentiation of B-cells (germinal centre) into plasma cells, resulting in hyperplastic follicles, thus leading to lymph node enlargement [13]. This cytokine also increases VEGF secretion, promoting angiogenesis, proliferation of vascular muscle cells, capillary proliferation, and endothelial hyperplasia. Additionally, human herpesvirus-8 (HHV-8) encodes a homolog of interleukin-6, leading to an increase in the systemic levels of IL-6 in cases of CD with HHV-8 infection [14].

Contrary to the hyaline vascular form of CD, the plasma cell variant represents less than 10% of cases and is frequently multicentric [2]. They have systemic manifestations (like fever, night sweats, hepatosplenomegaly), autoimmune phenomenon, recurring infections, and laboratory abnormalities. They can also be associated with the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes). HHV-8-associated Castleman’s disease is found mostly in HIV-positive individuals, generally shows constitutional symptoms, and has an aggressive disease course with more chances of developing lymphoma as compared to HHV-8-negative cases [15]. It has been well described that patients with multicentric CD often develop secondary malignancies, such as Kaposi sarcoma, plasmacytoma, Hodgkin lymphoma (HL), and non-Hodgkin lymphoma [3, 4]. The CD and lymphoma can show synchronous (coexistence) or metachronous (subsequent evolution) association or can even mimic each other [5–10]. The association of HL and CD is not common and has been documented in only a few case reports [3, 6–9]. Some cases of Hodgkin’s lymphoma can show Castleman-like features but are present focally, and the complete constellation of findings is not observed. However, Hodgkin’s lymphoma with coexisting Castleman disease shows diffuse histological findings of CD as seen in our case. Most of the cases of HL reported are of the interfollicular pattern and coexisted with the multicentric plasma cell variant of CD [7, 9, 16]. In our report also, one of the cases was of a plasma cell variant of CD with concomitant interfollicular HL with HHV-8-negative morphology on lymph node biopsy.

Pathogenetically, IL-6 cytokine has a pleiotropic effect on the immunological system. In Hodgkin’s disease, the reactive cells (lymphocytes, macrophages, eosinophils, and mast cells) within the tumor microenvironment greatly outnumber the malignant cell population (Reed–Sternberg cells) and mainly interact with RS cells via cytokine (IL-6) and chemokine cross-talk, thus promoting RS cell growth and survival [17]. The combination of findings consisting of interfollicular HL, HHV8-negative plasma cell variant of CD, and IL-6 involvement in pathogenesis suggests the emergence of a single-disease entity.

Lyapichev et al. described three cases of CD with concurrent HL where the pattern of involvement was focal and involved only a minor portion of the lymph node biopsy specimen, contrary to our case where the pattern of involvement of HL was diffuse [16]. From the diagnostic point of view, it is important for the pathologists to be aware of the possible occurrence of HL foci in cases of CD, so as to avoid missing the diagnosis of malignancy. Generally, an adequate open/excisional biopsy rather than a small needle biopsy is advocated to facilitate an accurate diagnosis. The use of immunohistochemical stains like CD30, CD15, and PAX-5 is indispensable in such cases in order to identify HL component.

The other probable diagnostic pitfall commonly observed in cases of hyaline vascular variant of CD is the presence of atypical cells [18]. In this variant, the interfollicular region is variably expanded with the presence of hyalinized blood vessels and marked proliferation of dendritic reticulum cells, dysplastic follicular dendritic cell networks, myoid cells, and T-lymphocytes. In some cases, even focal aggregates of plasmacytoid dendritic cells are noted in the follicular region. These cells are usually binucleated, with prominent nuclei, distinct small nucleoli, a moderate amount of cytoplasm, and indiscernible cytoplasmic borders. Due to the presence of binucleate dysplastic dendritic cells in the background of mature plasma cells and lymphocytes, CD closely mimics HL morphologically [5]. There are subtle morphological features to differentiate them. For example, the nucleoli of the RS cells are larger than the dendritic cells. The presence of eosinophils in the background favours the diagnosis of HL. Application of immunohistochemical stains (CD30, CD15, and dim Pax 5 positivity) is undoubtedly useful for the diagnosis of Hodgkin’s disease, while the dendritic cells show positivity for CD21 and CXCL13. We reported a similar case with the presence of atypical cells, mimicking the Hodgkin cells on morphology. Hence, it is important to be aware of this entity in order to avoid overdiagnosis of HL in such a setting.

It is worth emphasizing that different histomorphological types seen in CD represent different chronologic phases of the same disease, ensuing from changing host responses. It is also speculated that the plasma cell type represents a more active and aggressive phase of the disease and that the hyaline–vascular type represents a more indolent stage [2]. As CD is a rare and heterogeneous disorder, the standardization of treatment guidelines becomes difficult. However, in localized form, excision of the lesion is recommended. In multicentric disease, therapy requires a more extensive approach based on corticosteroid, radiation therapy, and chemotherapeutic drugs [2]. HL occurring within a backdrop of CD should be treated with a standard lymphoma chemotherapy regimen [8]. Other new potential targeted therapies are emerging for CD, with respect to the expression of epidermal growth factor receptor in the dendritic cells display [19].

Conclusion

Castleman’s disease is an infrequent heterogeneous entity with a complex pathophysiology. Although its association with lymphoma is linked to the multicentric variant and human immunodeficiency virus infection, the coexistence of Hodgkin’s lymphoma and CD in immunocompetent adults is very rare and has not been reported much in literature. This report details two cases of Castleman disease with intriguing histopathological observations in the interfollicular area. The first case displayed typical Reed-Sternberg cells within the interfollicular area, while the other exhibited atypical cells in the same region, potentially prone to oversight or misdiagnosis, particularly during biopsy. The presence of atypical cells in the hyaline vascular variant is a potential mimicker and can lead to misdiagnosis for an inexperienced pathologist. This emphasizes the critical need for a comprehensive examination of the interfollicular zone in all Castleman disease cases to prevent misdiagnosis, which could impact patient therapy.

Abbreviations

CD

Castleman’s disease

UCD

Unicentric Castleman disease

iMCD

Idiopathic multicentric Castleman disease

MCD

Multicentric Castleman disease

HIV

Human immunodeficiency virus

AIDS

Acquired immunodeficiency syndrome

HL

Hodgkin’s lymphoma

PET

Positron emission tomography

USG

Ultrasound

TPCT

Triphasic computed tomography

EUS

Endoscopic ultrasound

FNAC

Fine needle aspiration cytology

18-FDG-PET

18-Fluorodeoxyglucose positron emission tomography

IL-6

Interleukin-6

RS

Reed–Sternberg

HHV8

Human herpesvirus-8

Author Contribution

Conceptualization: MAO, AA, and SR; data curation: MAO, AA, NM, and PS; project administration: NM, PS, and SR; writing—original draft: MAO and SR; writing—review and editing: MAO and SR; approval of final manuscript: NM, PS, and SR.

Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics Approval and Consent to Participate

For this case report, formal consent from a local ethics committee is not required. The patient has given his consent for the images and other clinical information to be reported in the journal.

Consent for Publication

The authors certify that they have obtained the appropriate consent from the patient. The patient understands that the name and initials will not be published, and due efforts have been made to conceal the same.

Competing Interests

The authors declare no competing interests.