Introduction
Castleman disease (CD) comprises a group of rare lymphoproliferative disorders with
diverse clinical presentations, histopathological features, and treatment approaches.
CD is traditionally classified into unicentric CD (UCD), involving a single lymph
node or region, and multicentric CD (MCD), which affects multiple lymph node regions.
MCD is further categorized into human herpesvirus 8 (HHV-8)-associated, idiopathic
MCD (iMCD) and polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell (PC)
disorder, skin changes (POEMS)-associated MCD (POEMS-MCD). The diagnosis of CD from
other lymphoproliferative diseases is pathologically challenging. UCD is typically
managed through surgical excision or monitoring, while MCD requires more complex treatment,
including immunomodulators or chemotherapy, based on the clinical severity and organ
involvement. However, standardized protocols remain elusive, especially in resource-limited
settings like India. This case series presents four patients with CD, detailing their
clinical presentations, laboratory tests, imaging, treatment, and outcome with comprehensive
review of literature. The study underscores the challenges in diagnosis and management
while emphasizing the need for individualized care strategies.[1]
[2]
Case Series
Case 1: A Case of Symptomatic UCD Treated with Rituximab
A 41-year-old female patient with no notable medical or family history presented with
a 4-year history of chronic lower back pain. Over the preceding 6 months, she experienced
an 8 kg (13% of body weight) unintentional weight loss but denied fever, night sweats,
or appetite changes. Physical examination was unremarkable. Laboratory tests revealed
a normal complete blood count (CBC) and biochemistry panel, except for an elevated
erythrocyte sedimentation rate (ESR). Abdominal ultrasound identified multiple retroperitoneal
lymph nodes near the upper pole of the left kidney, the largest measuring 4 × 3 cm,
with normal-appearing liver, spleen, and kidneys. The uterus was structurally normal,
but endometrial thickness was 18 mm. Contrast-enhanced computed tomography (CECT)
of the chest and abdomen demonstrated several enlarged para-aortic lymph nodes, the
largest measuring 5.2 × 3.8 cm, accompanied by fat stranding. Additional findings
included a left thyroid nodule (16 × 10 mm), a left ovarian corpus luteum cyst, sacralization
of L5 (Castellvi type IIIB), diffuse osteopenia, and degenerative vertebral changes.
18-Fluorodeoxyglucose positron emission tomography-CT (18FDG-PET-CT) scan revealed mild hypermetabolism in the para-aortic nodes (maximum standardized
uptake value [SUVmax] 4.0), moderate activity in the left thyroid nodule (SUVmax 6.7),
physiological endometrial uptake (SUVmax 4.1), and left adnexal uptake (SUVmax 6.8)
([Fig. 1A–E]). Histopathological examination of a para-aortic lymph node biopsy confirmed unicentric
hyaline vascular CD (HVCD), demonstrating distorted nodal architecture, hyperplastic
follicles with onion-skinning mantle zones, and interfollicular vascular proliferation
([Fig. 2]). Immunohistochemistry (IHC) showed CD10 and BCL6 positivity in germinal centers,
BCL2 expression in mantle zones, and a polarized Ki67 proliferation pattern ([Fig. 3]). Tests for HHV-8 and human immunodeficiency virus (HIV) were negative. The patient received four
weekly cycles of rituximab, completed in July 2023, with marked symptomatic improvement.
Follow-up CECT scan performed 6 weeks posttreatment showed stable nodal size without
progression. At most recent evaluation, she remained asymptomatic and continues routine
surveillance to monitor long-term outcomes.
Fig. 1 18-Fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/ contrast-enhanced computed tomography (CECT)
findings in a patient with hyaline vascular Castleman disease. (A) Axial fused PET/CECT image showing mild to moderate FDG uptake in a near homogeneously
enhancing retroperitoneal lymph nodal mass. (B) Corresponding axial CECT scan showing a near homogeneously enhancing retroperitoneal
mass. (C, D) Coronal and sagittal PET/CECT images (arrows) indicating the hypermetabolic lymph
node. (E) Maximum intensity projection (MIP) image highlighting the region of increased tracer
uptake.
Fig. 2 Histopathological features of the hyaline vascular variant of Castleman disease.
(A) Lymph nodes showing lymphoid follicles with expanded interfollicular area showing
vascular proliferation—4 × . (B) Characteristic “lollipop sign”—penetrating vessel encroaching into the follicle—20 × .
(C) Prominent hyaline vascular proliferation—10 × . (D) Image showing pronounced vascular proliferation in the interfollicular area—40 × .
Fig. 3 Immunohistochemical profiles in hyaline vascular Castleman disease. (A) BCL6, demonstrates germinal center activity with a characteristic polarized pattern,
supporting the diagnosis of the hyaline vascular variant of Castleman disease (HVCD)—20 × .
(B) BCL2, showing expanded mantle zone—20 × . (C) CD3, highlights the interfollicular T cell zones, which are notably expanded in
HVCD—10 × . (D) CD10, highlights germinal center B cells, confirming follicular hyperplasia in HVCD
and aiding differentiation from follicular lymphoma—20 × .
Case 2: A Case of UCD Treated with Surgery
A 29-year-old female patient presented with a 6-month history of menorrhagia accompanied
by a 10-kg weight gain, with no comorbidities or family history of malignancy. Initial
imaging studies, including ultrasound and CT scan, revealed a 4.5 × 4 cm exophytic
lesion arising from the body of the pancreas and abutting the left lobe of the liver,
along with bilateral polycystic ovaries. A subsequent CT scan further characterized
a 3.7 × 3.7 × 3.4 cm mass in the neck and proximal body of the pancreas, raising the
possibility of a nonfunctional neuroendocrine tumor or a solid pseudopapillary tumor.
The uterus appeared bulky with a mildly thickened endometrium, and a left adnexal
cyst, likely representing a hydrosalpinx. In January 2024, the patient underwent an
exploratory laparotomy with excision of the peripancreatic tumor. Postsurgical PET-CT
imaging demonstrated low-grade FDG uptake in bilateral level II lymph nodes and subtle
nodularity in the thymic tissue, with mild liver enlargement but normal liver parenchyma.
The pancreatic region showed postsurgical changes without abnormal FDG uptake or enhancement,
and no active disease elsewhere. Histopathological examination confirmed CD, HV type.
IHC revealed CD20 positivity within follicles and CD3 positivity in interfollicular
areas, with a Ki67 proliferation index of 4% in hotspot areas. CD21 and CD23 highlighted
an expanded follicular dendritic cell meshwork. The HHV-8 test was negative, ruling
out Kaposi sarcoma-associated herpesvirus involvement. Routine blood tests were normal,
HIV serology was negative, and bone marrow evaluation showed moderate euthyroid hyperplasia
with normal myeloid maturation. The patient was referred for further management, and
follow-up PET-CT imaging, as well as the last clinical and sonological assessment
in January 2024, showed no evidence of disease recurrence.
Case 3: A Case of CD Presenting as Paraneoplastic Pemphigus
A 21-year-old female patient presented with a 4-month history of hyperpigmented patches
across her body, accompanied by oral and genital ulcers. She had no significant past
or family medical history. Examination revealed erythematous and hyperpigmented patches,
severe oral and pharyngeal mucositis, and an extensive, itchy rash with atypical targetoid
lesions on the trunk and extremities. Her condition worsened acutely following an
episode of herpes stomatitis. A mucosal biopsy from the right cheek revealed lichen
planus with acanthosis, hyperkeratosis, basal cell degeneration, and a band-like lymphocytic
infiltrate, while a skin biopsy from the abdomen confirmed erythema multiforme. Abdominal
ultrasound detected a pelvic mass, further evaluated by CECT and PET-CT, which revealed
a low-grade FDG-avid mass in the left paravertebral and presacral region, abutting
the left psoas muscle and displacing the left ureter suggestive of UCD. A CT-guided
biopsy of a left iliac fossa lesion showed lymphoid tissue with follicles, hyalinized
centers, “onion skinning,” increased vascularity, and PCs. IHC was positive for CD20,
CD3, and CD138, with negative for HHV-8, confirming HVCD. Following four weekly doses
of rituximab, an excision biopsy revealed effaced nodal architecture, regressed follicles,
and atypical follicular dendritic cells. IHC confirmed CD3, CD2, CD5, and CD7 positivity
with dual CD4 and CD8 populations, indicating CD. Enzyme-linked immunosorbent assay
for anti-envoplakin was positive and negative for anti-BP 180, anti-BP 230, anti-desmoglein
1, anti-desmoglein 3, and anti-collagen VII suggesting paraneoplastic pemphigus. Her
skin lesions resolved and oral mucositis improved but persisted. She is currently
on oral prednisolone in tapering doses.
Case 4: A Case of CD on Follow-Up for 9 Years
A 68-year-old female patient was evaluated for central chest pain with mild nonproductive
cough in 2015 at an outside hospital. Cardiac workup was negative. An X-ray revealed
mediastinal mass. CECT scan of the thorax and abdomen showed a left posterior mediastinal
mass of 6 × 4 cm. Biopsy with IHC suggestive of CD HV type. She was treated with low-dose
steroids for 5 years and has been in stable disease. Her medical history is otherwise
unremarkable, with no significant past or family history and no comorbidities. CT
scan done in 2024 showed a heterogeneously enhancing lesion with linear calcifications
in the left posterior mediastinum, measuring 5.1 × 3.1 × 5.5 cm. There is no evidence
of mediastinal or hilar lymphadenopathy, pleural abnormalities, or pericardial effusion
suggestive of stable disease. She was referred to our department for further treatment.
A PET-CT scan revealed a metabolically active, heterogeneously enhancing lesion with
multiple focal calcifications in the left posterior mediastinum, measuring 5.2 × 3 × 4.9 cm
(SUVmax 6.5) with preserved fat plane to the mediastinal structures with no mediastinal
and hilar lymphadenopathy. The patient remains clinically stable and is under regular
follow-up.
The cases are summarized in [Table 1].
Table 1
Summary of cases
|
Sl. no.
|
Age
|
Sex
|
HIV status
|
HHV-8 status
|
Castleman type
|
Histopathologic type
|
Immunohistochemistry
|
FDG PET findings (SUVmax)
|
Treatment
|
Current disease status
|
|
1
|
41
|
F
|
Negative
|
Negative
|
Unicentric
|
Hyaline vascular type
|
CD10/BCL6 + (germinal centers), BCL2 + (mantle zones), Ki67 polarized
|
Para-aortic nodes (4.0)
|
Rituximab × 4 cycles
|
Stable on surveillance
|
|
2
|
29
|
F
|
Negative
|
Negative
|
Unicentric
|
Hyaline vascular type
|
CD20 + (follicles), CD3+ (interfollicular), Ki67 4%,CD21/CD23+ (dendritic cells)
|
Low-grade FDG uptake in lymph nodes
|
Surgical excision
|
Stable on surveillance
|
|
3
|
21
|
F
|
Negative
|
Negative
|
Unicentric
|
Hyaline vascular type
|
CD20/CD3/CD138 + ,post-Rituximab:CD3/CD2/CD5/CD7 + with dual CD4/CD8 populations
|
Low-grade FDG-avid paravertebral/presacral mass
|
Rituximab + prednisolone
|
Skin lesions resolved, mucositis improved (on steroids)
|
|
4
|
68
|
F
|
Negative
|
Negative
|
Multicentric
|
Hyaline vascular type
|
CD20 + (follicles), CD3+ (interfollicular), Ki67 4%,CD21/CD23+ (dendritic cells)
|
Mediastinal lesion (SUVmax 6.5), para-aortic/paratracheal nodes (SUVmax 3.7)
|
Low-dose steroids (5 years)
|
Disease stable on latest PET-CT scan
|
Abbreviations: BCL2, B cell lymphoma 2 protein; BCL6, B cell lymphoma 6 protein; CD10,
cluster of differentiation 10; CD138, cluster of differentiation 138; CD2, cluster
of differentiation 2; CD20, cluster of differentiation 20; CD21, cluster of differentiation
21; CD23, cluster of differentiation 23; CD3, cluster of differentiation 3; CD4, cluster
of differentiation 4; CD5, cluster of differentiation 5; CD7, cluster of differentiation
7; CD8, cluster of differentiation 8; FDG, fluorodeoxyglucose; HHV-8, human herpesvirus
8; HIV, human immunodeficiency virus; Ki67, proliferation marker Ki-67; MCD, multicentric Castleman disease; PET, positron emission tomography; SUVmax,
maximum standardized uptake value; UHVCD, unicentric hyaline vascular Castleman disease.
Note: Clinicopathological and radiological features of Castleman disease cases.
Reference; Dispenzieri A, Fajgenbaum DC. Overview of Castleman disease. Blood. 2020;135(16):1353–64.
Discussion
The disease was first described by Benjamin Castleman during mid-1950s. In the course
of studying tumors of thymus gland, which presented as enlarged mediastinal lymph
nodes resembling thymic tumors grossly, radiologically, and microscopically.[3] Extensive studies followed the discovery in the past five decades, unraveling further
disease characteristics. Determining the epidemiology of CD is a challenging feat
due to the limited data available about the disease, particularly from low-mid income
countries. The incidence of CD varies depending on the region, with the United States
reporting an annual incidence of around 7,000 cases, UCD being 70 to 80% of these
cases and the rest MCD. The data from Japan gives a similar incidence but with MCD
cases more than 70%.[4] A clear gender disparity of the disease is not easily visible, UCD appears to have
equal gender distribution while MCD depicts a slight male predominance. HHV-8 though
shows a male predominance with around 70 to 80% of the cases while iMCD shows a moderate
female predominance. Age distribution of CD is a wide spectrum with the disease occurring
at any age, but mostly seen in individuals of between mid-30s and 60s, even though disease have been reported in adolescent age group. Majority
of the UCD cases belong to 4th decade whereas MCD cases in comparatively older patients,
in their 6th decade of life.[5]
[6]
[7]
[8]
The disease is classified based on the proposition of the Castleman Disease Collaborative
Network, primarily depending on the extent of lymph node involvement into UCD, where
only a single lymph node or a solitary region of lymph nodes and MCD, which involves
multiple lymph nodes across different regions. MCD is further classified into HHV-8
virus positive group, subdivided among HIV positive and HIV negative cases. Other
variants of MCD includes POEMS-associated MCD linked to a wide spectrum of symptoms
and iMCD subdivided into thrombocytopenia, anasarca, fever, reticulin fibrosis of
the bone marrow, organomegaly (TAFRO) and iMCD–non-TAFRO.[9]
The pathogenesis of each type varies significantly. UCD usually presents with a slow
growing lymph node with characteristic histopathology, mostly harmless.[10] UCD does not usually exhibit systemic symptoms and is often discovered incidentally.
Multiple etiological mechanisms have been proposed but the exact mechanism is still
obscured. Viral mechanism initially proposed is weakened due to the absence of certain
markers like T bet (T-box expressed in T cells), the neoplastic hypothesis involving
follicular dendritic cells is currently favored. Mutations in the PDFRB gene encoding
platelet-derived growth factor (PDGF) receptor β in CD-45 cells and overexpression
of interleukin-6 (IL-6) and epidermal growth factor receptor have been identified
in several UCD cases.[1]
[4]
[9]
HHV or Kaposi sarcoma-associated herpesvirus is among the key etiological factors
of MCD. This virus is found to be present in all HIV associated cases and around half
of all the HIV-negative MCD cases. The cells involved belong to B cell lineage, B
cells, and plasmablast cells.[1]
[9] HHV-8 positive plasmablasts which were found to be predominantly localized in the mantle
zone of B cell follicles express high levels of cytoplasmic immunoglobulin M (IgM)
and are limited to producing a single type of light chain, that is, they are light
chain restricted, whereas HHV-8 negative mature PCs in the interfollicular region
are IgM negative and produce multiple types of light chain, that is, polytypic. The
infected plasmablasts exist as isolated cells, microscopic aggregates also called
microlymphomas, or in other cases as frank plasmablastic lymphomas.[11] HHV-8 encodes for viral IL-6 (VIL 6), which is a homologue of human IL-6, and thus
contributes to the inflammatory symptoms seen in HHV-8 MCD cases. These cells stain
for latency-associated nuclear antigen, VIL 6, B lymphocyte marker CD-20.[1]
[4]
[9]
[11]
POEMS syndrome is found to be linked with MCD and is reported among half of the POEMS
cases.[12] POEMS syndrome is a rare paraneoplastic disorder due to underlying PC dyscrasia.[1]
[4]
[9] The diagnosis of POEMS syndrome is confirmed when the patient present with both
polyneuropathy and monoclonal PC disorder, at least one of the three major criteria
which includes CD, sclerotic bone lesions, or elevated vascular endothelial growth
factor (VEGF), and minor criteria, that is, organomegaly, extravascular fluid overload,
endocrinopathy, and skin changes papilledema of thrombocytosis.[12] Cases where both the mandatory criteria are met but pathologically diagnosed with
CD, it must be classified as CD variant of POEMS syndrome if other features of POEMS
syndrome exist.[13] Both angiogenic and inflammatory cytokines are found in the condition which are
VEGF, IL-1, IL-6, and tumor necrosis factor.[14] Nearly all cases are light chain restricted, which contribute to concurrent MCD
and POEMS syndrome.
iMCD, which accounts for one-third of all MCD cases, is a polyclonal lymphoproliferative
disorder with an unknown etiology. They are negative for both HIV and HHV-8.[1]
[15] Two clinical subtypes of iMCD are iMCD-TAFRO and iMCD–non-TAFRO. iMCD TAFRO presents
with features of thrombocytopenia, anasarca, fibrosis of bone marrow, renal dysfunction,
organomegaly, and normal immunoglobulin levels. while the latter presents with thrombocytosis
hypergammaglobulinemia and less severe fluid accumulation.[9]
[15] Elevated IL-6 levels are detected in some patients while being normal or marginally
raised in other cases, suggesting that other factors may too be involved in the pathogenesis.[1]
[9]
[15] Studies also state a history of autoimmune disease in 30% of iMCD patients making
a possibility that iMCD may be due to an underlying autoimmune condition triggering
a cytokine storm. Hypotheses of an unidentified virus causing the disease also have
been considered.[15]
The disease diagnosis is only confirmed when the lymph node is pathologically reviewed
after an excisional biopsy.[1]
[4] Histologically, the disease is classified into subtypes HV, PC, and rarely a mixed
variety, based on the lymph node morphology and architectural destruction pattern.[1]
[16] Predominantly seen in UCD, that is, 90% of UCD is of HV subtype and is mostly benign
in nature. Histologically characterized by distinctive follicles with expanded mantle
zones of small lymphocytes forming concentric rings forming the so-called “onion skinning”
around the atretic germinal center, penetrated radially by hyalinized vessels creating
a lollipop follicle appearance. This is also associated with vascular proliferation,
perivascular hyalinization with occasional intravascular calcification. Evidences
suggest follicular dendritic cell dysplasia within germinal centers may lead to proliferations
or even malignancies. PC variant is more commonly seen in MCD. Histologic features
of PC are less distinctive. Histologically, PC shows lymph node with preserved architecture
with expanded mantle zones, hyperplastic germinal centers, and sheets of PCs in the
interfollicular areas. Vascular proliferation is mild with hyalinization may be present.
Mostly the PCs are polytypic but light chain constrictions may occasionally be seen.[1]
[4]
[16] Mixed variant exhibiting histologic characteristics of both HV and PC variants.
HV is found to be less aggressive than its PC counterpart and offers a better prognosis
even though histologic subtype is a less suitable prognostic indicator[16] ([Fig. 4]).
Fig. 4 Classification and treatment of Castleman disease.
UCD cases mostly presents with no elaborate clinical symptoms unlike MCD where the
patients present with significant symptoms.[17] UCD usually presents with solitary lymphadenopathy commonly in the mediastinum but
also in other regions such as the cervical, axillary, abdomen, etc. Some cases may
rarely present with signs of inflammation, anemia, hypergammaglobulinemia, and pulmonary
findings in approximately 18%. Patients with MCD presented almost always with systemic
symptoms. iMCD and HHV-8 MCD present with an overlap of symptoms, including enlarged
lymph nodes, signs of inflammations, anemia, hypoalbuminemia, hypergammaglobulinemia,
and renal dysfunction. Thrombocytopenia, fluid accumulation, pulmonary findings, cutaneous
abnormalities, and neuropathy were also reported in patients even though infrequently.[1]
[4]
[18]
[19] iMCD is further classified into iMCD TAFRO, clinically more aggressive, and iMCD
NOS. Evidences also suggest the association of iMCD with autoimmune disorders with
these cases presenting with rash, mucosal injury, and positive autoantibodies.[20] Paraneoplastic pemphigus, an autoimmune bullous disease affecting the skin and mucous
membrane causing painful bullae; ulcers were found to be associated in some cases
of CD, mostly found in HV variant and UCD subtype.[4] Anemia, polyclonal hypergammaglobulinemia, thrombocytopenia, hypoalbuminemia, elevated
C-reactive protein (CRP), etc. are the common laboratorial findings. Rise in the levels
of cytokines such as IL-6 and VEGF are also detected. Patients require a thorough
evaluation, including history, physical examination, and tests such as CBC, ESR, CRP,
direct Coombs test, liver function tests, creatinine, serum protein electrophoresis,
HIV serology, and urinalysis. Imaging, such as CT or PET/CT, is essential, with pulmonary
function tests for those with respiratory symptoms. 18FDG-PET-CT aids in identifying disease activity, guiding biopsy, and monitoring response.
Biopsies should target areas of highest uptake. Imaging may reveal lymphadenopathy,
organomegaly, sclerotic bone lesions, or pulmonary infiltrates. Lymphoma is the key
differential, requiring FDG-PET and pathology for confirmation.[4]
[21]
Regular monitoring with yearly CT scan is indicated in asymptomatic patients with
normal laboratory values and currently no chances of compression-related symptoms.
Complete surgical excision remains the mainstay treatment for symptomatic UCD. The
clinical and laboratory abnormalities may return to normal after excision. It provides
an excellent 10-year survival of 90%. Debulking surgery is an alternative when a complete
excision is not feasible especially in cases with compression of critical structures.[4]
[21] Radiotherapy can be used in symptomatic cases when surgery is not feasible.[22] Inflammation-related disease can be treated with anti-IL-6 agents like siltuximab
or tocilizumab, which provide symptomatic relief and arrest lymphadenopathy.[4] We generally use rituximab as the other two agents are costly. The prognosis of
peripheral lymphadenopathy is better than those cases with central lymphadenopathy.
Rituximab administration for cases with HHV-8 positive cases significantly improved
the prognosis and survival rate up to 90%. The drug targets the B cell CD20 antigen.
Regimen involves weekly rituximab 375 mg/m2 for 4 weeks in mild cases, administration of etoposide along with rituximab for severe
cases. Suppression of B cell by rituximab therapy may lead to the activation of latent
HHV-8 and hence there is a risk for development of Kaposi sarcoma.[1]
[4]
Based on the severity, the disease is classified into severe iMCD and nonsevere iMCD.
TAFRO subtype being commonly presented as severe subtype. The disease is categorized
as severe subtype if the patients present with two or more out of the five criteria,
which includes performance score, that is, Eastern Cooperative Oncology Group ≥ 2,
stage 4 renal dysfunction, anasarca/ascites/pleural or pericardial effusion, hemoglobin
≤ 8, and pulmonary involvement.[23] Siltuximab, which acts through an anti-IL-6 mechanism, is the first-line drug for
both severe and nonsevere iMCD. Regimen involves 11 mg/kg once every 3 weeks. Corticosteroids
are given as an added therapy. Tocilizumab, which is given at a dose of 8 mg/kg every 2 weeks along with corticosteroids, is given if siltuximab is not available.
Response toward the treatment must be assessed by symptomatic, biochemical, and radiological
criteria. Patients with nonsevere disease and not reacting to first-line therapy must
be given rituximab at a dose of 375 mg/m2 once a week for 4 to 8 weekly doses, supplemented with corticosteroids, immunomodulatory,
and suppressive agents including cyclosporine and thalidomide. Patients with severe
disease and no response to first-line therapy, concurrent high-dose corticosteroid
therapy may be given. A standard therapy for iMCD TAFRO is still not established.[4]
[24] The POEMS-associated cases must be treated like myeloma therapy. Commonly used regimens
are bortezomib, cyclophosphamide, and dexamethasone/bortezomib, lenalidomide, and
dexamethasone. High-dose melphalan with autologous peripheral stem cell transplantation
is an effective treatment modality for consolidation therapy in severe cases.[1]
[4]
Continuous renal replacement therapy (CCRT), an extracorporeal blood purification
technique, effectively removes inflammatory cytokines, including IL-6, endotoxins,
and other mediators, while optimizing fluid balance and restoring homeostasis. Utilizing
high cutoff and medium cutoff membranes, CRRT targets cytokine-mediated inflammation
and multiorgan dysfunction. It can be used as a bridge therapy for patients unresponsive
to cytotoxic chemotherapy or anti-IL-6 therapies.[25] Bortezomib with dexamethasone can be used in the second line for refractory iMCD
unresponsive to siltuximab.[26] Testing for markers like VEGF, PDGF, and mutations in PDGFRB gene could help differentiate UCD from other similar disorders.
For MCD, its complex nature has led to the discovery of subtype-specific biomarkers,
for example, IL-6. CXCL13, a key player in immune regulation, has been found to rise
during iMCD flares and could predict how patients respond to treatment. Meanwhile,
the mammalian target of rapamycin pathway and serum IP-10 are tied to the hypervascular
iMCD-TAFRO type, and IL-6 has been linked to the PC iMCD-NOS type[27]
[28]
[29]
[30]
[31].
This study highlights the clinical heterogeneity of CD through four diverse cases,
emphasizing histopathological and imaging-driven diagnosis, multidisciplinary collaboration,
and long-term follow-up insights. However, its retrospective design, small sample
size, and institutional bias limit generalizability, particularly for off-label therapies
like rituximab in UCD. Future multicenter studies should validate treatment protocols,
explore molecular drivers (e.g., PDGFRB mutations, cytokine pathways), and standardize
biomarkers (CXCL13, IL-6) for risk stratification. Research must address unresolved
areas: HHV-8's role in HIV-negative MCD, autoimmune-CD interplay, and long-term safety
of immunomodulators. Findings are most applicable to resource-constrained settings,
underscoring the need for adaptable algorithms and equitable access to advanced therapies
globally.
