Castleman Disease Presenting in the Neck: A Report of 3 Cases and a Literature Review.

BACKGROUND Castleman's disease (CD) is a reactive lymph node hyperplasia initially identified by Castleman in 1956. CD predominantly affects individuals 20-50 years of age, with low incidence in children. This case report describes 3 cases of CD treated in our hospital and reviews the relevant literature. The purpose of this case report was to enhance clinical understanding and treatment of CD in the head and neck in children. CASE REPORT To enhance clinical understanding and improve treatment of CD in the head and neck region in children, we present the cases of 3 patients who were admitted to the hospital, primarily presenting with a neck mass. Preoperatively, the patients collectively exhibited non-specific findings. Surgical interventions were performed with Cases 1 and 3 undergoing left functional (radical) neck lymph node dissection, in contrast to Case 2, in which bilateral functional (radical) neck lymph node dissection was executed. Pathological examination confirmed the diagnosis of CD in each of the 3 patients. Following surgery, a follow-up period ranging from 3 months to 1 year revealed that all patients had successfully recovered, with no recurrence. CONCLUSIONS Castleman disease is a rare disease in children and difficult clinical diagnosis. Some patients with unicentric Castleman disease (UCD) can be treated with surgery, and those with multicentric Castleman disease (MCD) need chemotherapy, but at present there is no widely accepted treatment plan.

Unicentric Castleman's disease in the parotid gland associated with psoriasis: a case report.

BACKGROUND: Castleman's disease is a rare lymphoproliferative disorder that is often misdiagnosed because of its untypical clinical or imaging features except for a painless mass. Besides, it is also difficult to cure Castleman's disease due to its unclear pathogenesis. CASE PRESENTATION: We present a Castleman's disease case with diagnostic significance regarding a 54-year-old Chinese male who has a painless mass in his left parotid gland for 18 months with a 30-years history of autoimmune disease psoriasis. Computed tomography scan showed a high-density nodule with clear boundaries in the left parotid and multiple enlarged lymph nodes in the left submandibular and neck region. General checkup, the extremely elevated serum interleukin-6 and lymph node biopsy in the left submandibular region gave us an initial suspicion of Castleman's disease. Then the patient underwent a left superficial parotidectomy. Based on histopathologic analysis, we made a certain diagnosis of Castleman's disease and gave corresponding treatments. In 18 months of follow-up, the patient showed no evidence of recurrence, with the level of serum interleukin-6 decreased. CONCLUSIONS: Clinicians should be aware of the possibility of Castleman's disease when faced with masses or enlarged lymph nodes in the parotid gland to avoid misdiagnosis, especially in patients with autoimmune diseases and elevated serum interleukin-6.

A unicentric center, multicenter, and mixed-type Castleman disease: Three case reports and a review of the literature.

RATIONALE: Due to the lack of specificity symptoms and site of onset of castleman disease (CD), it is difficult to diagnose and poses unique challenges for both patients and clinicians, leading to confusion in diagnosis and delays in treatment. To enhance understanding, we present 3 cases of CD treated at our hospital, including a single-center, multicenter, and mixed-type CD. PATIENT CONCERNS: Case 1: A 53-year-old female patient was admitted with a chief complaint of "abdominal pain and fever for 10 days." Marked enlargement of inguinal lymph nodes on both sides was observed. Case 2: A 58-year-old female patient was admitted with the main complaint of "discovering a left lower abdominal mass during a routine checkup for the past 10 days." Upon deep palpation, a palpable mass of approximately 5.0 * 3.0 cm was identified in the left lower abdomen. Case 3: A 40-year-old male patient was admitted with the main complaint of "progressive right upper abdominal and lumbar back pain for over 6 months." Computed tomography examination revealed multiple nodular soft tissue masses between the abdominal aorta and inferior vena cava, with the largest measuring 5.0 * 4.0 cm. DIAGNOSES: Based on the immunohistochemical results, the diagnoses for the 3 patients are as follows: Case 1: Multicentric Castleman's Disease (Mixed Type). Case 2: Pelvic Retroperitoneal Castleman Disease (Hyaline Vascular Type). Case 3: Castleman Disease Multicentric Type. INTERVENTION: Case 1: cyclophosphamide 0.6-1 g + vincristine 2 mg + methylprednisolone 50 mg/5 days. Cyclophosphamide 1 g + prednisone 30-50 mg/5 days. This alternating chemotherapy cycle is repeated every 6 months. Case 2: Laparoscopic pelvic mass excision surgery. Case 3: Surgical excision of the mass. OUTCOMES: Case 1: After a 43-month follow-up, the patient's general symptoms have improved compared to before, but regular chemotherapy is still necessary at present. Case 2: The patient did not take any medication postoperatively, and there has been no evidence of metastasis or recurrence during the 18-month follow-up. Case 3: The patient did not take any medication, and there has been no evidence of metastasis or recurrence during the 21-month follow-up. LESSONS SUBSECTIONS: The lack of specific signs on imaging studies and nonspecific blood tests increases the difficulty of diagnosis. However, tissue biopsy remains a feasible option. Therefore, we recommend conducting thorough examinations for suspected CD patients to reduce misdiagnosis and determine the CD type for effective targeted treatment.

Enfermedad de Castleman, fisiopatología, avances en el diagnóstico y tratamiento / Castleman's disease, pathophysiology, advances in diagnosis and treatment

La enfermedad de Castleman (EC) engloba a un conjunto heterogéneo de procesos linfoproliferativos que comparten rasgos histológicos bien definidos. Se considera una enfermedad rara o minoritaria u su incidencia no es del todo conocida, aunque se estima en menos de uno por cada 100.000 habitantes. Tiene una distribución bimodal (30-40 años y luego los 60-80 años). Su incidencia es similar en ambos sexos, aunque la variante unicéntrica parece tener ligero predominio en mujeres con proporción 2:1. La EC se clasifica en una forma hialinovascular (siendo esta la más frecuente) y otra plasmocelular, relacionadas con el virus de la inmunodeficiencia humana (VIH) y el virus herpes humano tipo 8 (VHH-8), que junto a otros mecanismos autoinmunitarios desarrollan la hiperproducción de interleucina-6 (IL-6) por parte de los linfocitos B. Existen diferentes líneas de tratamiento, donde destaca el uso de anti IL-6, siendo el siltuximab el más utilizado y catalogado como el fármaco huérfano de esta patología.(AU)

Castleman's disease (CD) encompasses a heterogeneous set of reactive lymphoproliferative processes that share well-defined histologic features. CD is considered a rare or minority disease. The incidence of CD is not fully known, although it is estimated at less than 1 per 100,000 inhabitants. It has a bimodal distribution (30–40 years and then 60–80 years). The incidence is similar in both sexes, although the unicentric variant seems to have a slight predominance in women with a 2:1 ratio. CD is classified into a hyalinovascular form (this being the most frequent) and a plasmocellular form, related to the HIV and VHH-8 viruses, which together with other autoimmune mechanisms develop hyperproduction of interleukin-6 (IL-6) by B lymphocytes. There are different lines of treatment, where the use of anti IL-6 stands out, being siltuximab the most used as orphan drug in this pathology.(AU)

Acquired Hemophilia: A Rare Complication of Pediatric Idiopathic Multicentric Castleman Disease.

Acquired hemophilia is caused by acquired autoantibodies to 1 of the factors of the coagulation cascade, usually factor VIII or IX, and is an exceedingly rare phenomenon in children. The finding of an acquired factor VIII inhibitor in a pediatric patient with idiopathic multicentric Castleman disease has never been reported. Patients with acquired hemophilia can have life-threatening bleeds that are refractory to blood product support, requiring bypassing agents to manage bleeding symptoms. We present the novel finding of acquired hemophilia resulting from an autoantibody to factor VIII in a pediatric patient with idiopathic multicentric Castleman disease and discuss the optimal management of bleeding in a patient with acquired hemophilia.

Urologic Presentation of Unicentric Pediatric Castleman Disease in the Setting of Acute Renal Colic.

An 11-year-old otherwise healthy female presented with renal colic and during computed tomography imaging evaluation, she was found to have a right distal ureteral stone with associated hydroureteronephrosis, medially deviated ureter, and 4-cm solid retroperitoneal mass. The mass was palpable on physical exam and was further categorized with magnetic resonance imaging, ultrasound, and laboratory testing. A multidisciplinary team approach, including pediatric surgery, radiology, oncology, and urology, led to the patient undergoing a right retrograde pyelogram, ureteroscopy with stent placement, and laparoscopic excision of retroperitoneal mass. Her pathology revealed lymphoid hyperplasia with histologic features of Castleman disease.

A case report: Castleman disease treated by the trinity of internal and external treatment of "Fuzheng, phlegm-resolving, and detoxification method".

RATIONALE: Castleman disease (CD) was first included in the CSCO lymphoma diagnosis and treatment guidelines in 2021. Its diagnosis relies on lymph node pathological examination. Observation, surgical resection of the lesion, radiotherapy, chemotherapy, and medical therapy (e.g., rituximab, siltuximab, steroids) can be used. Due to the traumatic, incurable, and recurrent nature of surgical treatment, drug therapy has many side effects and is expensive. Exploring effective traditional Chinese medicine (TCM) comprehensive treatment methods for this disease is important and necessary. PATIENT CONCERNS: The main symptom was recurrent lymphadenopathy, which had been surgically removed 5 times in the past. This time, lymph node enlargement occurred again, and the local hospital recommended surgical resection again. The patient could not tolerate another surgical treatment. Other targeted treatments are not available due to financial constraints. DIAGNOSES: The case was diagnosed as CD by pathological examination, which is an important basis for the diagnosis of this disease. INTERVENTIONS: The patient was treated with surgery in the early stage several times, later came to our hospital for the trinity of TCM integrated treatment program, which combines oral TCM with external application of TCM and intravenous drip of TCM as a syndrome of positive deficiency and phlegm-toxin internalization, and the therapeutic principle. OUTCOMES: After nearly 3 years of comprehensive treatment with TCM, the enlarged lymph nodes could not be touched, and there was no fatigue, fever, or weight loss. During this period, the patient did not undergo surgery, chemotherapy and other western medicine treatment, and lived a normal life. It not only met the patient's expectation but also confirmed that the TCM treatment was indeed effective. LESSONS: This case report confirms that TCM is safe and effective in the treatment of CD, which is worthy of promotion. In clinical practice, the individualized treatment for the patient, the duration of treatment, and the different disease states also affect the treatment outcome.

TAFRO syndrome is associated with anti-SSA/Ro60 antibodies, in contrast to idiopathic castleman disease.

TAFRO syndrome is an acute systemic inflammatory disease characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, and organomegaly. There have been increasing reports that TAFRO is a disease distinct from idiopathic multicentric Castleman disease and that TAFRO patients may be positive for anti-SSA antibodies. To assess anti-SSA antibody positivity and the clinical characteristics of the two diseases, we retrospectively compared 7 TAFRO and 10 iMCD patients in our hospital. The mean age of onset of TAFRO and iMCD was 48.0 (interquartile range [IQR], 41-53) and 45.0 (IQR, 35-53) years, respectively. The TAFRO and iMCD groups had 6 (86%) and 4 (40%) male patients, respectively, and the following pretreatment laboratory values: platelet count, 3.8 (IQR, 2.2-6.4) and 35.5 (IQR, 22.2-42.8) × 104/µL, respectively; C-reactive protein, 10.2 (IQR, 6.8-21.4) and 9.5 (IQR, 6.2-13.6) mg/dL, respectively; IgG, 1431 (IQR, 1112-1815) and 4725 (IQR, 3755-5121) mg/dL, respectively. RNA immunoprecipitation (5 cases for anti-SSA) or protein array (5 cases for anti-SSA/Ro60) detected anti-SSA antibodies in six (86%) TAFRO patients but not in iMCD patients; it did not detect anti-SSB antibodies in any of the patients. None of the patients were diagnosed with Sjögren syndrome. All iMCD patients treated with tocilizumab (TCZ) responded well. Meanwhile, two of six TAFRO patients treated with TCZ showed inadequate responses; thus, both patients were switched to rituximab, following which they achieved remission. TAFRO and iMCD have different clinical features. TAFRO may be categorized as a severe phenotype of the anti-SSA antibody syndrome.

IgG4-related lymphadenopathy.

IgG4-related lymphadenopathy is a nodal manifestation of IgG4-related disease (IgG4RD) which is characterized by increased polytypic IgG4+ plasma cells and IgG4+/IgG+ plasma cell ratio in lymph nodes and morphologically manifested as various patterns of reactive lymphadenopathy: Castleman disease-like, follicular hyperplasia, interfollicular expansion, progressive transformation of germinal centers and inflammatory pseudotumor-like. It typically presents with solitary or multiple, mild to moderate lymph node enlargement in otherwise asymptomatic patients. The serum IgG4 level is frequently elevated but C-reactive protein often remains normal. In patients not having a history of IgG4RD or manifestation of extranodal IgG4RD, a diagnosis of IgG4-lymphadenopathy should only be made with great caution given the non-specific morphologic features that can overlap with ANCA-associated vasculitis, interleukin-6 syndromes, Rosai-Dorfman disease, inflammatory myofibroblastic tumor, syphilis, lymphoma, and plasma cell neoplasia. Elevated IgG4 parameters, appropriate morphologies, and clinical correlation are essential to make the diagnosis of IgG4-lymphadenopathy more specific and clinically meaningful.

Unicentric Castleman Disease: Illustration of Its Morphologic Spectrum and Review of the Differential Diagnosis.

CONTEXT.­: Unicentric Castleman disease (UCD) is a dynamic entity with a wide spectrum of morphologic findings. UCD can be further subdivided into hyaline-vascular and mixed/plasmacytic variants. Hyaline-vascular UCD has both follicular and interfollicular (stromal) changes, and occasionally these lesions show a skewed representation of either the follicular or stromal compartments. Plasmacytosis is usually minimal in the hyaline-vascular variant. The mixed/plasmacytic variant of UCD is composed of sheets of plasma cells often associated with a variable number of follicles with regressive changes. OBJECTIVE.­: To illustrate the differential diagnosis of UCD, as it is quite broad and includes lymphomas, plasma cell neoplasms, stromal neoplasms such as follicular dendritic cell sarcoma and vascular neoplasms, immunoglobulin G4-related disease, infections, and other rare lesions. An additional objective is to enhance awareness of the morphologic features of UCD in excisional and in small core-needle biopsy specimens, the latter of which may inadvertently target follicle- or stroma-rich areas, causing diagnostic challenges. DATA SOURCES.­: In this review, we provide readers a concise illustration of the morphologic spectrum of UCD that we have encountered in our practice and a brief discussion of entities in the differential diagnosis. CONCLUSIONS.­: UCD exhibits a broad spectrum of morphologic changes, and awareness of these morphologic variations is key to avoid misdiagnosis.

The application of a multidisciplinary approach in the diagnosis of Castleman disease and Castleman-like lymphadenopathies: A 20-year retrospective analysis of clinical and pathological features.

BACKGROUND: Castleman disease (CD) comprises a group of rare and heterogeneous haematological disorders, including unicentric (UCD) and multicentric (MCD) forms, the latter further subdivided into HHV8-MCD, POEMS-MCD and idiopathic-MCD (iMCD). However, according to the Castleman Disease Collaborative Network guidelines, the diagnosis of CD can only be achieved through collaboration between clinicians and pathologists. METHODS: We applied these clinical and pathological criteria and implement with clonality testing to a retrospective cohort of 48 adult and paediatric Italian patients diagnosed with reactive lymphadenitis with CD-like histological features. RESULTS: We confirmed the diagnosis of CD in 60% (29/48) of the cases, including 12 (41%) UCD and 17 (59%; five HHV8-MCD, three POEMS-MCD and nine iMCD) MCD. Of the remaining 19 cases (40%) with multiple lymphadenopathy, 5 (26%) were classified as autoimmune diseases, 1 (5%) as autoimmune lymphoproliferative disorder, 1 (5%) as IgG4-related disease, 11 (83%) as reactive lymphadenitis and 1 (5%) as nodal marginal zone lymphoma. CONCLUSIONS: Our study emphasizes the importance of the multidisciplinary approach to reactive lymphadenitis with CD-like features in order to achieve a definitive diagnosis and choose the appropriate treatment.

Concordance between transbronchial lung cryobiopsy and surgical lung biopsy in patients with idiopathic multicentric Castleman disease: A report of four cases.

BACKGROUND: Idiopathic multicentric Castleman disease (iMCD) is a rare polyclonal lymphoproliferative disease often associated with pulmonary involvement. Recently, transbronchial lung cryobiopsy (TBLC) has been reported to be useful for the diagnosis of diffuse interstitial lung disease. However, there have been no reports of pathological assessment of TBLC for iMCD. METHOD: To clarify the efficacy of TBLC in the diagnosis of iMCD, we retrospectively reviewed four iMCD patients who had undergone both TBLC and surgical lung biopsy (SLB). RESULTS: The median age was 44 years; 2 males and 2 females. Two or three TBLC specimens were taken from each patient. All patients had no complications other than minimal bleeding. The size of the TBLC specimens was approximately 5-6 × 3-4 mm, and the alveolar region, and centrilobular and perilobular areas were adequately sampled. As with SLB, the extent of lung lesions and inflammatory cell infiltration could be sufficiently evaluated by TBLC. The presence of lymphoid follicles could also be assessed by TBLC; however, the germinal centers with lymphoid follicles were difficult to evaluate. The TBLC specimens could also be evaluated for immunostaining, especially IgG4 immunostaining, to rule out IgG4-related lung disease. Pulmonary pathological grading showed a high concordance rate between major pathological findings of TBLC and SLB. The pathologist's confidence level of TBLC for the diagnosis of iMCD was high in all cases. CONCLUSIONS: TBLC exhibits a high concordance rate with SLB in the pathological evaluation of iMCD, which may be useful for the diagnosis of iMCD.

A Multicentric Castleman Disease Associated with Mixed Warm and Cold Antibody-Mediated AHA Responsive to Siltuximab.

Castleman disease is non-clonal lymphoproliferative disorders defined by hypertrophy of lymph nodes. The multicentric form (MCD), in which multiple lymph node stations are involved, is not associated with HHV8 infection, but considered idiopathic, although IL-6 appears to play a central role in its pathogenesis. Here, we report the case of a patient who presented with mixed autoimmune hemolytic anemia (AIHA) and adenopathy that was very challenging to diagnose due to very low values of hemoglobin and refractoriness of obtaining any improvement of AIHA with standard first and second lines of therapy (steroids, rituximab, immunoglobulin, erythropoietin, and cyclosporine). When we safely proceeded to lymph node biopsy, a diagnosis of MCD was established. This permitted the treatment with siltuximab, an anti-IL-6 monoclonal antibody. After only 1 week, hemoglobin raised and he was discharged. After 1 year, he was still in remission. This case underlines the challenges in diagnosis of MCD, and the first case of response to siltuximab after the failure of rituximab to relieve mixed AIHA.

Retrospective cohort evaluation of non-HIV Castleman disease from a single academic center in Beijing, China.

The purpose is to ascertain the clinical impact of Castleman disease (CD) by reassessment of the real-world data from Peking University First Hospital (PKUFH). The results will contribute to the standardization of diagnosis and treatment on CDs. Based on the last 15-year retrospective real-world data from Peking University First Hospital (PKUFH), we reclassified and re-evaluated the clinical and pathological information of patients with pathologically suspected diagnosis of CD. A total of 203 patients were included in our study, in which the diagnosis of CD was confirmed in 189 cases, including 118 patients with unicentric CD (UCD, n = 118, 62.4%) and 71 patients with multicentric CD (MCD, n = 71, 37.6%). A total of 44.1% (n = 52) of UCDs in our cohort were complicated with paraneoplastic pemphigus (PNP). The treatment of UCD is primarily surgical, with a 5-year overall survival (OS) of 88.1%. Patients with PNP had a poorer prognosis than those without PNP (82.9% (95% CI 123-178) vs 92.8% (95% CI 168-196), log-rank p = 0.041). The rate of concurrent systemic symptoms was 74.6% (n = 53), and renal involvement occurred in 49.3% (n = 35) MCD patients. The MCD treatments were mainly chemotherapy regimens, with a 5-year OS of 77.6% (95% CI, 143-213). Patients with UCD demonstrate a better overall prognosis than patients with MCD. But the prognosis of those complicated with PNP was poor. The differential diagnosis of MCD is extensive. MCD treatment in China is heterogeneous. The inaccessibility of anti-IL-6-targeted drugs in China may contribute to the poor prognosis for patients with MCD.A preprint has previously been published (Guo et al. 34).

Whole-Exome Sequencing Reveals the Genomic Profile and IL6ST Variants as a Prognostic Biomarker of Paraneoplastic Pemphigus-Associated Unicentric Castleman Disease.

Unicentric Castleman disease (UCD) is a rare lymphoproliferative disorder. Paraneoplastic pemphigus (PNP) is a major complication associated with poor UCD prognosis. However, the genomic profiles and prognostic biomarkers of PNP-associated UCD remain unclear. In this study, we performed whole-exome sequencing analysis for 28 matched tumor-normal pairs and 9 tumor-only samples to define the genomic landscape of Chinese patients with PNP-associated UCD. An integrative analysis was performed to identify somatic variants, the mutational signatures, and key pathways in tumors. Besides, we analyzed the relationship among mutated genes, clinical characteristics, and prognosis. Sixty-one somatic mutant genes were identified in >1 patient with PNP-associated UCD. Specifically, IL6ST and PDGFRB were the most frequently mutated genes (32%), followed by DPP6 (18%) and MUC4 (18%). Signaling molecules and interactions, cellular processes, and signal transduction pathways were enriched. Furthermore, we found that poor overall survival was related to IL6ST variants (P = .02). Finally, we classified PNP-associated UCD into 4 genomic subgroups: IL6ST, PDGFRB, IL6ST-PDGFRB, and an unknown subgroup. In summary, we defined the molecular profile of PNP-associated UCD and identified a potential molecular biomarker for predicting prognosis, which may provide therapeutic targets for treating this severe disorder.

Outcomes in Kaposi's sarcoma-associated herpesvirus -associated primary effusion lymphoma and multicentric Castleman's disease in patients with human immunodeficiency virus (HIV) in a safety-net hospital system.

OBJECTIVE: To describe cases of Kaposi's sarcoma-associated herpesvirus (KSHV)-associated multicentric Castleman's disease (MCD) and primary effusion lymphoma (PEL) in patients with HIV from a large, safety-net hospital system in Dallas, Texas, USA. METHODS: We conducted a retrospective review of patients with HIV-associated PEL and/or MCD. RESULTS: Twelve patients with PEL and 10 patients with MCD were identified. All patients were male and 17 of 20 were men who have sex with men; 66.7% of PEL patients and 50% of MCD patients had concurrent KS at the time of diagnosis; 42% of patients with PEL and 20% of patients with MCD died during the follow-up period. We noted improved survival in our cohort compared to previous studies, particularly in our PEL patients with a median survival of 11.4 months compared to 3-6-month median survival historically. Median follow-up time for MCD patients was 17.5 months. This improved survival is despite suboptimal antiretroviral therapy (ART) adherence at diagnosis, with only 50% of patients on ART at the time of MCD/PEL diagnosis. CONCLUSION: These data highlight the importance of early recognition of PEL and MCD, and the larger-scale efforts needed to better understand the pathogenetic drivers of clinical outcomes in patients affected by KSHV-related diseases.