Unicentric Castleman Disease And Microcytic Anemia: A Challenging Diagnosis

Introduction

Castleman disease (CD) is an uncommon lymphoproliferative disorder characterized by hypervascular lymphoid hyperplasia. CD can be classified into two subgroups that differ in their pathogenesis, prognosis, and presentation: unicentric and multicentric.1 Several histological variants are seen, including the hyaline vascular variant (HVV), plasma cell variant, and mixed variant1. Unicentric HVV, the most common variant, typically presents as a single enlarged lymph node that is most often found incidentally on radiographic studies or during surgical procedures and can be cured by surgery.2,3 Approximately 5000 cases of unicentric CD occur in the United States annually, with few cases documented in pediatric patients.3 In children, similar to adults, the most common subtype of CD is unicentric.4 Here we discuss a delayed diagnosis of a case of unicentric HVV CD with an atypical presentation involving anemia.5

Castleman disease, lymphoproliferative disorder, microcytic anemia, pediatrics

A 12-year-old boy with recent poor weight gain and vague abdominal pain was found to have microcytic anemia during the work-up of his short stature. He denied fevers and night sweats. Blood work showed low hemoglobin level of 6.3 gm/dL, low MCV (60.2 fL), leukopenia (2.5 × 103/μL) with neutropenia (0.5 × 103/μL) and thrombocytosis (401 × 103/μL), low serum iron (20 μg/dL), normal TIBC (304 μg/dL), and normal ferritin (68.6 ng/mL), elevated haptoglobin level (347 mg/dL) and a negative IgG DAT. Hemoglobin electrophoresis was negative for hemoglobinopathy. Peripheral blood smear revealed reactive lymphocytes. EBV IgG and IgM were positive. Parvovirus, HIV, and CMV were negative. Chest x-ray and thyroid studies were normal. Baseline autoimmune workup (RF, dsDNA, ANA as well as tTG-IgA for celiac disease) was negative. Uric acid and LDH were normal. CRP (118 mg/L) and ESR (143 mm/h) were elevated. He was referred to oncology after an ultrasonography of the patient’s abdomen demonstrated an ill-defined abdominal mass. A subsequent MRI of the abdomen and pelvis revealed a solid, minimally enhancing 5 × 3.6 × 4.3 cm retroperitoneal mass in the left para-aortic/mesenteric root region, just below the inferior border of the pancreas (Figure 1).

Fine-needle aspiration of the mass showed reactive/benign lymphoid proliferation with focal CD21-, CD35-, and D2-40 + dendritic meshwork, no immunophenotypic support for B-cell or T-cell neoplasia and Castleman disease could not be excluded. Positron emission tomography/computed tomography (PET/CT) scan demonstrated a unifocal, 4.5-cm lesion with a standardized uptake value of 8.5 (Figure 1). Given the concern for Castleman disease, the patient underwent laparoscopic resection of the mass. Pathologyshowed changes indicative of HVV CD (Figure 2).Within 2 months of mass resection, the patient’s IL-6 level decreased from 21 pg/mL to undetectable, hemoglobin level normalized, CRP level declined from 118 mg/L to 0.6 mg/L, and sedimentation rate decreased from 143 mm/h to 7 mm/h. PET/CT scan 1 month after excision showed no recurrence or new lesions. The patient’s laboratory values remained normal at last follow-up, 12 months after resection.

The infrequency with which CD is diagnosed in pediatric patients has hampered comprehensive clinical studies, leading to an incomplete understanding of the disease, its subtypes, and its prognosis. Unicentric CD is more common than multifocal CD in children. It usually presents clinically with compressive symptoms, which are investigated with imaging, rather than abnormal labs or physical findings. Our patient’s presentation was unique - microcytic anemia is more often seen in multifocal CD and in the absence of other significant symptoms - this delayed diagnosis for several months. The patient’s anemia resulted from IL-6–mediated hepcidin secretion, and his IL-6 level was elevated until removal of the mass6. Evaluation for short stature with anemia in this case prompted the abdominal ultrasound that identified the mass. Although this mass was identified with abdominal ultrasonography, it is important to note that abdominal CT is more sensitive for the HVV due to the rich vascularization of these masses. Unicentric HVV CD is generally more common in the fourth decade of life2, however, our patient was 12 years old at diagnosis. As seen in this case, surgical excision is preferable to needle biopsy to properly analyze the architecture of the entire germinal center and interfollicular zone, otherwise, the sample may be inadequate for diagnosis2. Removal of the mass was curative in our patient, leading to normalization of the patient’s laboratory values, however, unicentric CD is sometimes unresectable due to location or size and may require systemic therapy. While there is no standardized therapy, options include immunotherapy, corticosteroids, chemotherapy, or radiotherapy.3 Following excision, surveillance can be gradually spaced out as laboratory findings normalize; radiologic imaging 6 to 12 months later is sufficient to verify cure and no recurrence2. Patients with systemic involvement must be monitored closely postoperatively, with regular laboratory tests and imaging studies2. However, since little data and few reported cases have described systemic symptoms in unicentric CD, the long-term monitoring plan for this patient was based on the normalization of his laboratory values and reassuring clinical examination.

CD is rare in children but should be considered in the setting of systemic inflammatory processes and associated anemia. Treatment depends on compressive symptoms and resectability. Multidisciplinary approach involving surgery, pathology, hematology and oncology is essential when evaluating complex cases with uncertain etiology.

The authors have no COI or financial disclosures to report.

Informed parental consent was obtained to report these findings and pathology.

References

1. Munshi N MM, van de Velde H, Desai A, Potluri R, Vermeulen J. Use of a Claims Database to Characterize and Estimate the Incidence Rate for Castleman Disease. Leuk Lymphoma 2015;56(5):1252-1260.
2. Casper C. The Aetiology and Management of Castleman Disease at 50 Years: Translating Pathophysiology to Patient Care Br J Haematol 2005;129: 3 – 17
3. Carbone A, Borok M, Damania B, et al. Castleman disease. Nat Rev Dis Primers 2021;7:84.
4. Sopfe J, Endres A, Campbell K, et al. Castleman disease in pediatrics: Insights on presentation, treatment, and outcomes from a two-site retrospective cohort study. Pediatr Blood Cancer 2019;66:e27613.
5. Bjarnason I, Cotes PM, Knowles S, Reid C, Wilkins R, Peters TJ. Giant lymph node hyperplasia (Castleman's disease) of the mesentery. Observations on the associated anemia. Gastroenterology 1984;87:216-23.
6. Kalayoğlu Beşışık S, Yönal Hindilerden İ, Hindilerden F, Doğan İ, Beşışık F. A Rare Cause of Unexplained Refractory Iron Deficiency Anemia: Unicentric Plasma-Cell Type Castleman's Disease. Turk J Haematol 2016;33:257-8.
7. Parez N, Bader-Meunier, B., Roy, C. et al. Paediatric Castleman disease: report of seven cases and review of the literature. European Journal of Pediatrics 1999;158, 631–637.

This is a text version generated from the article. For the formatted version of record (with original tables & figures), download the PDF →