Mesenteric Castleman disease: Two case reports and review of literature

Abstract

BACKGROUND

Castleman disease (CD) is a rare lymphoproliferative disorder most commonly occurring in the mediastinum and hilar regions. Mesenteric involvement is rare, and diagnosis primarily relies on histopathological examination.

CASE SUMMARY

We report two cases of mesenteric CD with gastrointestinal symptoms accompanied by weight loss. Case 1 underwent complete surgical resection of the lesion. Postoperative pathology confirmed the hyaline vascular type, and the prognosis was favorable. Case 2 also underwent complete surgical resection initially, with postoperative pathology confirming the plasma cell type. However, the disease followed an aggressive course. A second surgery was performed five months later, and postoperative pathology confirmed mesenteric peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). The patient died postoperatively due to acute renal failure.

CONCLUSION

To our knowledge, this is the first reported case of mesenteric CD transforming into PTCL-NOS, highlighting the complexity and heterogeneity of the clinical course of mesenteric CD. These findings provide insights into the personalized treatment and clinical management of this disease.

Key Words: Castleman disease; Mesentery; Peripheral T-cell lymphoma; Immunohistochemistry; Case report

Core Tip: Castleman disease (CD) is a rare lymphoproliferative disorder. Certain variants, notably plasma cell-type CD, are associated with a potential risk of malignant transformation into lymphoma. The clinical course and prognosis of CD vary substantially across histological subtypes. Management strategies differ accordingly: Unicentric CD is generally treated with surgical excision, whereas idiopathic multicentric CD often necessitates anti–interleukin-6 monoclonal antibody and/or combination chemotherapy. We present two cases of mesenteric CD, one of which progressed to peripheral T-cell lymphoma, highlighting the critical importance of monitoring in patients with rapid postoperative progression and the need for long-term follow-up.

INTRODUCTION

Castleman disease (CD) is a rare and heterogeneous lymphoproliferative disorder. Its clinical symptoms and imaging findings are often non-specific, leading to misdiagnosis such as gastrointestinal stromal tumor, malignant lymph node metastasis, and tuberculous lymphadenitis, among others. The definitive diagnosis of CD mainly relies on characteristic histopathological findings, including the hyaline vascular (HV), plasma cell (PC), and mixed types[1]. Based on the extent of lymph node involvement, human herpesvirus 8 (HHV-8) infection status, and clinical presentation, CD is classified into unicentric CD (UCD) and multicentric CD (MCD). MCD is further subdivided into HHV-8⁺ MCD, polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes syndrome-associated MCD, and idiopathic MCD (iMCD). iMCD can be reclassified into thrombocytopenia, ascites, reticulin fibrosis, renal dysfunction, organomegaly syndrome, and not otherwise specified[1,2]. Compared to the indolent course of UCD, MCD has a more aggressive clinical course. This aggressive phenotype is closely related to the overproduction of interleukin-6 (IL-6)[3] and often manifests as repeated relapses, rapid progression to fatal disease, or malignant transformation (e.g., secondary lymphoma)[4]. It is important to note that patients with HHV-8⁺ MCD have a significantly increased risk of lymphoma transformation[5]. CD occurring in the mesentery is clinically rare. This article reports two cases of mesenteric CD exhibiting significant heterogeneity in their disease course and prognosis, with one case rapidly progressing to mesenteric peripheral T-cell lymphoma (PTCL). A case of mesenteric CD secondary to PTCL, not otherwise specified (PTCL-NOS) has not previously been reported. This report emphasizes the importance of long-term regular follow-up for such patients to monitor for potential transformation into malignant lymphoma.

CASE PRESENTATION

Chief complaints

Case 1: A 65-year-old male presented in November 2021 with abdominal pain and distension for 20 days.

Case 2: A 64-year-old male presented in March 2010 with poor appetite, hiccups, and abdominal distension and pain.

History of present illness

Case 1: The patient experienced abdominal pain and distension for 20 days, accompanied by weight loss of 10 kg.

Case 2: The patient had poor appetite and hiccups for six months, accompanied by right upper abdominal distension and pain for over one month, and weight loss of 6 kg.

History of past illness

Case 1: The patient had a history of coronary heart disease and diabetes mellitus.

Case 2: The patient reported no significant past medical history.

Personal and family history

Both patients have long-term history of smoking and alcohol consumption. No relevant family history was noted.

Physical examination

Case 1: Tenderness below the xiphoid process and in the lower abdomen was observed. No palpable superficial lymphadenopathy or abdominal mass was detected.

Case 2: Tenderness was observed in the right mid-abdomen. No palpable superficial lymphadenopathy or abdominal mass was detected.

Laboratory examinations

Case 1: Complete blood count showed the following: Hemoglobin was 97 g/L (reference range 110-160 g/L), hypersensitive C-reactive protein (CRP) was 70.70 mg/L (reference range 0-3.0 mg/L). Liver function tests showed an albumin level of 33.1 g/L (reference range 32.0-55.0 g/L). Tests for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), syphilis, and human immunodeficiency virus (HIV) infection were all negative.

Case 2: Complete blood count showed a hemoglobin level of 104 g/L (reference range 110-160 g/L). Liver function tests revealed an albumin level of 30.8 g/L (reference range 32.0-55.0 g/L). Carbohydrate antigen 125 was 45.5 U/mL (reference range 0.00-30.20 U/mL). Tests for HBsAg, HCV, syphilis, and HIV infection were all negative.

Imaging examinations

Case 1: Contrast-enhanced abdominal computed tomography (CT) revealed a heterogeneously enhancing mass measuring 5.7 cm × 5.5 cm in the left pelvis, multiple enlarged lymph nodes in the abdomen and retroperitoneum (Figure 1), irregular mesenteric thickening, and a large amount of ascites.

Figure 1 Contrast-enhanced abdominal computed tomography scan. The axial view shows a 1.4 cm × 1.1 cm lymph node (yellow arrow) in the retroperitoneum.

Case 2: Abdominal CT showed no positive findings. Positron emission tomography (PET)/CT revealed localized jejunal wall thickening in the left lower abdomen with significantly increased fluorodeoxyglucose (FDG) metabolism, with maximum standardized uptake value (SUV) of 3.4; additionally, a 1.1 cm × 1.4 cm enlarged lymph node was seen in the mesentery with synchronous high FDG metabolism [maximum SUV (SUVmax) 2.0]. Malignancy with mesenteric lymph node metastasis was highly suspected.

FINAL DIAGNOSIS

Case 1

Based on clinical, imaging, histological, and immunophenotypic features, the patient was ultimately diagnosed with HV type CD.

Case 2

Based on clinical, imaging, histological, and immunophenotypic features, the patient underwent complete surgical resection of the lesion. Postoperative pathology initially confirmed PC type CD. However, the disease progressed aggressively. A second surgery five months later confirmed mesenteric PTCL-NOS.

TREATMENT

Case 1

For definitive diagnosis, laparoscopic exploration was performed on December 8, 2021. Intraoperatively, a 6 cm × 8 cm hard tumor was found in the upper rectum, a 3 cm × 3 cm abscess in the left pelvis, congested and edematous pelvic wall, and rough peritoneum. Laparoscopic rectal tumor resection (including part of the sigmoid colon and mesorectum) + abscess drainage + abdominal wall nodule biopsy + ileostomy were performed.

Histological examination: Postoperative mesenteric tissue pathology showed scattered lymphoid follicle formation. Proliferating small blood vessels were seen in the follicular centers, with swollen vascular endothelium and hyaline degeneration. Surrounding small lymphocytes were arranged in an onion-skin pattern. Interfollicular small vessels were hyperplastic (Figure 2A). Immunohistochemistry showed: Bcl-6(-), CD10(+), CD117(-), CD20(+; Figure 2B), CD21(+, showing FDC network; Figure 2C), CD3(+), CD34(-), CD5(+), CD99(+), CK20(-), CK7(-), CXCL-13(-), HHV-8(-), Kappa(+), Ki-67(+, 20%), Lambda(+), MPO(-), PAX-5(+), PD-1(-), and TdT(partially +). The T-cell receptor gene rearrangement test was negative. The B-cell receptor gene rearrangement test was negative. In situ hybridization showed EBER(-).

Figure 2 Histopathological and immunohistochemical examinations. A: Scattered lymphoid follicles are formed. The follicular centers show proliferating small blood vessels with swollen endothelial cells and hyaline degeneration, surrounded by concentric layers of small lymphocytes (onion-skin layering). There is active proliferation of small vessels in the interfollicular areas (hematoxylin-eosin, × 20); B: CD20-positive B cells (× 20); C: CD21-positive highlighting follicular dendritic cell meshwork (× 20).

Case 2

Based on clinical, laboratory, and imaging findings, malignancy with metastasis was highly suspected. For definitive diagnosis, exploratory laparotomy was performed on March 29, 2010. Intraoperatively, significant adhesion and obstruction of the jejunum 20 cm distal to the ligament of Treitz were found, forming a dense adhesion with the tip of the appendix. The intestine proximal to the obstruction was dilated, and was approximately 8 cm in diameter. Appendectomy and full-thickness resection of the adherent bowel segment and involved mesenteric tissue were performed. The patient refused chemotherapy postoperatively. In June 2010, the patient developed distending pain in the mid-lower abdomen. Physical examination revealed a 6 cm × 8 cm hard, fixed mass in the right lower quadrant. Repeat PET/CT showed new soft tissue masses in the mid-lower abdomen and right iliac fossa with abnormally high FDG metabolism (SUVmax 12.7 and 6.2, respectively). New multiple enlarged lymph nodes were seen in the retroperitoneum and along the iliac vessels in the pelvis (largest 2.5 cm × 1.8 cm), with increased FDG metabolism (SUVmax 10.1). Bone marrow biopsy indicated nucleated cell volume < 20%, only a small number of hematopoietic cells were seen, erythroid cells outnumbered granulocytic cells, megakaryocytes were not observed, and reticulin fibers were not increased. Based on these findings, CD recurrence was considered, and one cycle of cyclophosphamide, adriamycin, vincristine, and dexamethasone (CHOP) chemotherapy was administered (cyclophosphamide 1 g on day 1, doxorubicin 70 mg on day 1, vincristine 2 mg on day 1, prednisone 150 mg on day 1-5). In August 2010, the patient again experienced abdominal distension and pain, lower limb edema, and intestinal obstruction. Considering CD progression, a second exploratory laparotomy was performed on September 2, 2010. Intraoperatively, swelling at the root of the mesentery near the original intestinal anastomosis, mesenteric thickening with partial necrosis, and a micro-perforation at the mesenteric border were found, with slight dilation of the proximal small intestine. Partial small intestine resection and full-thickness resection of the involved mesentery were performed.

Histological examination: Pathology from the first surgery showed lymphoid follicular hyperplasia with markedly expanded interfollicular zones and diffuse infiltration by numerous mature PCs. Immunohistochemistry showed: Nodal cortex: CD20(+), CD79a(+); paracortex: CD3(+), CD43(+); follicular dendritic cells (FDCs): CD21(+), CD35(+); follicular center cells: CD10(+), Bcl-6(+); PCs: CD38(+), CD138(+), MUM1(+); Bcl-2 scattered(+), Cyclin D1(-). Pathology from the second surgery five months later showed tumor cells extensively infiltrating the mesenteric lymph nodes and adipose tissue, with destruction of normal follicular architecture. Atypical lymphocytes were diffusely distributed. Tumor cell immunomarkers were as follows: CD3(+), TIA-1(+), GrB(+), PAX-5(-), CD20(-), CD79a(-), CD10(-), TdT(-), Bcl-2(+), MUM-1(-), CD138(-), MPO(-), Cyclin D1(-), and Ki-67(+, 70%).

OUTCOME AND FOLLOW-UP

Case 1

A follow-up abdominal CT scan 6 months after discharge showed no significant abnormalities. Ileostomy reversal and adhesiolysis were performed. As of the last follow-up in June 2024, the patient is alive and well.

Case 2

On September 12, 2010, the patient developed oliguria. Laboratory tests revealed serum potassium levels of 7.21 mmol/L (reference range 3.5-5.5 mmol/L), serum phosphorus levels of 2.61 mmol/L (reference range 0.6-1.6 mmol/L), and serum creatinine levels of 394.8 μmol/L (reference range 44-133 μmol/L). By September 22, 2010, the serum creatinine had further risen to 759.3 μmol/L, and acute renal failure was considered potentially attributable to tumor lysis syndrome. The patient subsequently elected to discontinue active treatment and died.

DISCUSSION

CD is a non-malignant lymphoproliferative disorder with limited epidemiological data[6,7]. The reported global annual incidence of CD is approximately 21-25 per million[8]. The distribution of UCD and MCD varies geographically. Among the 6500-7700 cases reported annually in the United States, UCD accounts for approximately 75%, while the total number of CD cases in Japan is similar, but UCD constitutes only 30%[9]. CD can occur at any age, with UCD predominantly affecting young adults aged 30-39 years. Population-based studies show no significant gender difference in CD[10]. The etiology and pathogenesis of CD are not fully understood. Existing data suggest UCD is essentially a neoplastic disorder driven by FDCs[2,11]. IL-6 is a core pathogenic driver in some iMCD patients; other mechanisms may be involved, such as T-cell activation, dysregulation of signaling pathways (e.g., mTOR and JAK-STAT pathways), and genetic predispositions such as NCOA4 and TRAF germline mutations[11,12].

Clinically, UCD typically presents as localized lymphadenopathy. Most patients are asymptomatic systemically, laboratory tests are often normal, and the course is indolent. In contrast, MCD has an aggressive course, usually presenting with systemic inflammatory responses such as fever, night sweats, weight loss, accompanied by multi-system involvement including anemia, abnormal liver and kidney function, elevated inflammatory markers [e.g., erythrocyte sedimentation rate (ESR) or CRP], and protein metabolism abnormalities (e.g., hypoalbuminemia or hypergammaglobulinemia)[13]. Therefore, clinical symptoms and laboratory indicators are valuable for typing. Additionally, baseline IL-6 level testing is recommended as it may serve as a disease biomarker[6].

The most common site of CD involvement is the thorax (30%-70%), followed by the abdomen and pelvis (12%-39%)[14]. Mesenteric involvement is rare, and its anatomical specificity makes preoperative diagnosis challenging. Ultrasound is suitable for initial rapid assessment of palpable lesions. Studies show that HV-UCD lesions often appear on ultrasound as well-defined, solid, hypoechoic masses, with internal hyperechoic spots visible in about 33.3% of cases[15]. CT typically shows pelvic/abdominal UCD as well-defined, solitary masses with homogeneous enhancement, which may be heterogeneous if fibrosis or necrosis is present. Abdominal MCD presents with diffuse lymphadenopathy accompanied by hepatosplenomegaly and ascites[14]. Furthermore, calcifications can be seen within lesions in 5%-10% of CD patients[16]. Some studies found that hyper vascular lymph nodes with surrounding infiltrative fat stranding are characteristic of CD, occurring in over 70% of HV cases[17]. PET/CT has superior sensitivity (96%) compared to CT (78.6%)[18]. Typical CD on PET/CT shows mild-moderate uptake (median SUVmax ranging between 3 and 8)[19]. Importantly, high SUV values or increased SUV on delayed phases may indicate disease progression or lymphoma transformation[20,21]. An elevated spleen/Liver SUVmax ratio has greater prognostic value than SUVmax alone and is an independent predictor of CD severity[18].

Regarding pathological subtypes, the HV type shows atrophic germinal centers penetrated by radially arranged hyalinized vessels, concentric or "onion-skin" mantle zone hyperplasia (rich in CD20⁺ B cells), and proliferating abnormal FDCs (expressing CD21 and CD23) within atrophic follicles – a characteristic triad. The PC type features hyperplastic germinal centers with massive interfollicular infiltration by polyclonal PCs. The mixed type has features of both[22,23]. Subtype distribution: Approximately 90% of UCD is HV type, while MCD is usually PC or mixed type. All HHV-8⁺ MCD cases are classified as PC type[24-26]. Diagnosing this virus-driven subtype relies on the characteristic marker for HHV-8 infection – latency-associated nuclear antigen-1[23]. Note that several diseases can mimic CD's pathological features. Some lymphomas, like follicular lymphoma and mantle cell lymphoma, can show HV type CD like histopathological changes[1]. Definitive diagnosis requires comprehensive judgment combining immunohistochemistry and clonality analysis[26]. Differentiating IgG4-related disease (IgG4-RD) from CD requires assessment of tissue IgG4⁺ PC increase and significantly elevated serum IgG4 levels (characteristic of IgG4-RD), elevated serum IL-6/vascular endothelial growth factor (VEGF) levels (characteristic of CD), and organ involvement specific to IgG4-RD (e.g., pancreatobiliary lesions)[25]. Additionally, active systemic lupus erythematosus can induce mixed-type CD-like lymphoproliferation, differentiated by the absence of polyclonal hypergammaglobulinemia and lack of evidence for HHV-8 infection[27].

Treatment for CD varies by subtype. Radical surgery is the first choice for UCD, with a postoperative 5-year overall survival (OS) of > 90%. For unresectable cases, individualized treatment is needed: Observation for asymptomatic cases; rituximab ± steroids for symptomatic cases with mass effect; anti-IL-6 monoclonal antibodies (e.g., siltuximab or tocilizumab) are preferred for symptomatic patients with systemic inflammation (e.g., night sweats, fever, anorexia, or weight loss) accompanied by elevated CRP, ESR, or anemia[20]. iMCD requires treatment stratified by disease severity. For non-severe iMCD, first-line treatment is the anti-IL-6 monoclonal antibody siltuximab (11 mg/kg every 3 weeks), potentially combined initially with steroids for symptom control. Severe iMCD requires immediate high-dose steroids (e.g., methylprednisolone 500 mg/day) combined with siltuximab. If ineffective within 1 week, treatment is immediately switched to multi-drug chemotherapy, such as rituximab-CHOP or cyclophosphamide, vincristine, doxorubicin, and dexamethasone, etc.[28]. iMCD patients benefit from long-term treatment with siltuximab or tocilizumab[29]. For HHV-8⁺ MCD patients, induction therapy with rituximab plus liposomal doxorubicin, followed by maintenance therapy with zidovudine plus valganciclovir, can achieve a 5-year progression-free survival of 87%[30]. Survival data for MCD varies due to disease heterogeneity; previous studies indicated a 5-year OS of approximately 65%[31].

CD typically presents with reactive lymphoid hyperplasia. In a minority of cases, a monoclonal lymphoid population may be observed[32,33]. The latter is regarded as a critical warning sign indicative of malignant transformation, suggesting that the lesion may be in a transitional phase from benign hyperplasia to neoplastic proliferation. The mechanism of lymphoma co-occurring with or secondary to CD is not fully elucidated. Current research suggests chronic viral infections, such as HIV, Epstein-Barr virus, and HHV-8, drive abnormal B-lymphocyte proliferation through excessive activation of the IL-6 or VEGF pathway, ultimately inducing clonal malignant transformation[34]. Approximately 25% of MCD cases are associated with the development of non-Hodgkin lymphoma, most commonly of B-cell lineage[14]. Potential mechanisms underlying the transformation of CD into T-cell lymphoma remain incompletely elucidated. Emerging research suggests that the pathogenesis of certain T-cell lymphomas may involve a precursor phase characterized by sustained stimulation of the T-cell receptor by exogenous or self-antigens, accompanied by clonal evolution of T cells[35]. During this process, abnormally activated FDCs over-secrete key cytokines, including IL-6, VEGF, and CXCL13. This cytokine storm, predominantly driven by IL-6[36], establishes a chronic inflammatory microenvironment that ultimately promotes the malignant transformation of specific T-cell subsets. Our case report 2 has several limitations. Due to personal reasons, the patient did not undergo T-cell receptor gene rearrangement, clonality analysis, or next-generation sequencing investigations that are crucial for early diagnosis, treatment, and prognostic assessment of the disease. The risk of lymphoma transformation differs among CD pathological subtypes (PC-MCD: 9.5% vs HV-UCD: 1%)[37]. CD secondary to PTCL is extremely rare, with only 3 cases reported to date[34,38,39] (Table 1). The median time to PTCL transformation in these 3 MCD patients was 2.3 years (range: 1-4 years); the median survival was less than 3 months, with a mortality rate of 66.7% (2/3 cases), indicating a very poor prognosis. The rapid nodal dissemination, aggressive progression, and ultimate transformation to mesenteric PTCL in our case 2 suggest that for PC-type CD presenting initially as a localized lesion completely resected surgically, rapid disease progression warrants systemic evaluation and vigilance for possible malignant transformation.

Table 1 Clinical characteristics of three reported cases of Castleman disease complicated by secondary peripheral T-cell lymphoma.

Ref.	Age/sex	Site of involvement	Initial diagnosis	Treatment	Interval to lymphoma transformation (year)	Type of lymphoma	Treatment of lymphoma	Prognosis
Liu et al[34], 2020	68/female	Neck	HV-MCD	Untreated	2	PTCL-U	CHOP, then relapse, chidamide-based chemotherapy	Survived
Park et al[38], 2013	37/male	Neck, axillae, and groin	PC-MCD	CHOP post steroid failure	4	PTCL	IVAM followed by BEAM and auto-PBSCT	Died
Qian et al[39], 2003	76/male	Bilateral submandibular areas and groin	PC-MCD	Steroids	1	PTCL	Untreated	Died

HV-MCD: Hyaline vascular multicentric Castleman disease; PC-MCD: Plasma cell multicentric Castleman disease; PTCL-U: Peripheral T-cell lymphoma of unspecified type; PTCL: Peripheral T-cell lymphoma; CHOP: Cyclophosphamide, adriamycin, vincristine, and dexamethasone; IVAM: Ifosfamide, etoposide, cytarabine, and methotrexate; BEAM: Bendamustine, etoposide, cytarabine, and melphalan; auto-PBSCT: Autologous peripheral blood stem cell transplantation.

CONCLUSION

CD is a group of rare and heterogeneous disorders characterized by specific lymph node histopathological abnormalities. Diagnosis requires integrating symptoms, clinical manifestations of multi-system involvement, and imaging features, with histopathology remaining the gold standard. Differential diagnosis from lymphoma, IgG4-RD, and autoimmune diseases is crucial. Treatment strategies for CD are highly subtype-dependent: UCD is primarily managed with radical surgery, while unresectable cases require symptom-stratified intervention. iMCD management follows the principles of severity stratification and maintenance therapy. HHV-8⁺ MCD requires combined antiviral intervention. Given the risk of malignant transformation, long-term follow-up is essential. For patients with new hypermetabolic lesions post-operation or those resistant to therapy, priority should be given to clonality testing for early diagnosis.