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 Table of Contents  
Year : 2023  |  Volume : 43  |  Issue : 6  |  Page : 292-295

Finding a needle in the haystack: A hidden follicular lymphoma

1 Department of General Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
2 Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
3 Division of Hematology/Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

Date of Submission12-Nov-2022
Date of Acceptance10-Dec-2022
Date of Web Publication03-Feb-2023

Correspondence Address:
Dr. Ping-Ying Chang
Division of Hematology/Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Chenggong Rd., Neihu Dist., Taipei 114
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jmedsci.jmedsci_249_22

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The classical morphological features of follicular lymphoma (FL) are well-recognized. However, identifying some morphological variants, such as FL with hyaline-vascular Castleman disease (HVCD) like features (FL-HVCD), is challenging. Hence, we report a 57-year-old male with FL-HVCD who presented with nontender swelling of the bilateral lower limbs, caused by enlarged intra-abdominal lymph nodes with venous compression. The excised lymph nodes showed onionskin-like mantle zones and hyalinized blood vessels, which was consisted with HVCD. Oral medications were prescribed; however, the patient was lost to follow-up after 6 months and was readmitted with anemia, thrombocytopenia, and leukocytosis 3 years later. A bone marrow biopsy was done, and the patient was diagnosed as having overt FL with bone marrow involvement. Physicians should be careful if HCVD patients present with systemic symptoms or generalized lymphadenopathy. Excluding the possibility of lymphoma is necessary because the different treatment strategy and prognosis from HVCD.

Keywords: Follicular lymphoma, hyaline-vascular Castleman disease, unicentric Castleman disease

How to cite this article:
Lin HY, Peng YJ, Wu YY, Chang PY. Finding a needle in the haystack: A hidden follicular lymphoma. J Med Sci 2023;43:292-5

How to cite this URL:
Lin HY, Peng YJ, Wu YY, Chang PY. Finding a needle in the haystack: A hidden follicular lymphoma. J Med Sci [serial online] 2023 [cited 2023 Dec 6];43:292-5. Available from: https://www.jmedscindmc.com/text.asp?2023/43/6/292/369139

  Introduction Top

Although follicular lymphoma (FL) with hyaline-vascular Castleman disease (HVCD) like features (FL-HVCD) was first described in 1994,[1] this rare morphologic variant of lymphoma has been reported in fewer than 20 patients since then.[2],[3],[4],[5],[6],[7] FL-HVCD is one of the most underrecognized variants of FL due to its rare occurrence. Hence, we report the case of a patient who was initially diagnosed with HVCD by lymph node biopsy but was confirmed to have overt FL with bone marrow involvement through a bone marrow biopsy 3 years later.

  Case Report Top

A 57-year-old man with a medical history of hypertension and type 2 diabetes mellitus presented with nontender swelling of the bilateral lower limbs for 3 months. On admission, physical examination revealed Grade III pitting edema of the bilateral lower limbs and palpable, movable, and nontender masses in the bilateral inguinal regions. Laboratory studies did not reveal any abnormalities, including abnormal blood cell profiles, liver function, renal function, and lactate dehydrogenase levels. Contrast-enhanced computed tomography of the lower limbs demonstrated subcutaneous lymphedema with no evidence of deep-vein thrombosis. However, enlarged confluent lymph nodes in the retroperitoneal and pelvic regions with vessel compression were identified [Figure 1]a. Histology of the excisional biopsy of inguinal lymph nodes showed variable-sized lymphoid follicles with interfollicular increased vascularity and some penetrating blood vessels into follicles [Figure 2]a. The areas of the germinal center were immunoreactive for Bcl-6, CD20, and CD10 [Figure 2]b, but negative for Bcl-2 [Figure 2]c. Based on these characteristics, the patient was diagnosed with Castleman disease (CD). Oral chlorambucil was then administered. Following discharge, the patient's clinical symptoms gradually improved after 3 months of treatment. However, 6 months after treatment, the patient was lost to follow-up.
Figure 1: Image work-up of the patient. (a) Contrast-enhanced computed tomography of the abdomen showed retroperitoneal lymphadenopathies (yellow arrow). (b) PET scan showed multiple FDG-avid lesions over neck, axillary, intra-abdominal lymphadenopathies and entire skeleton (c) PET scan showed a good metabolic remission after the completion of R-COP treatment. PET: Positron emission tomography, R-COP: Rituximab, vincristine, cyclophosphamide, and prednisolone

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Figure 2: Histopathological and immunohistochemical findings for inguinal lymph nodes on the first admission and readmission after 3 years. (a-c) Castleman disease on first admission. The enlarged lymphoid follicles had penetrative blood vessels (arrows) (a, H and E, ×100). The areas of germinal center (✽) are immunoreactive for CD10 (b, ×100), but not for Bcl-2 (c, ×100). (d-f) Follicular lymphoma after 3 years. The homogenous nodules lacking tangible-body macrophages and mantle zones (d, H and E, ×100). Vast majority of cells in the nodules are positive for CD10 (e, ×200) and Bcl-2 (f, ×200)

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Three years later, the patient was admitted to the emergency department after experiencing dizziness and bruising of his extremities for 2 days. Physical examination showed pale conjunctiva and multiple ecchymoses along the extremities. The laboratory studies showed a white blood cell count of 55,260/μl (normal, 4500-11,000/μl; neutrophil = 5.1%, lymphocyte = 84.7%), hemoglobin 6.1 g/dl (normal, 12-16 g/dl), platelet count 5000/μl (normal, 150-400 × 103/μl), and a leukoerythroblastic picture. Normal liver, renal, and coagulation function was observed. Contrast-enhanced CT of the abdomen revealed multiple lymphadenopathies in the para-aortic region, mesentery, retroperitoneal space, and bilateral inguinal region. An excisional biopsy of the inguinal lymph nodes was performed again. Bone marrow examination showed hypercellularity with a marked increase in atypical B-cell lymphocytes characterized by small- to medium-sized nuclei with irregular nuclear borders. Immunohistochemistry revealed positivity for CD 10, CD20, and negativity for Bcl-6. Flow cytometry of the bone marrow revealed positivity for CD5, CD10, CD19, CD20, CD22, and FMC-7, and negativity for CD23 and CD25. 18 F-positron emission tomography scan showed multiple fluorodeoxyglucose-avid lesions in the neck, axillary, and intra-abdominal lymph nodes and throughout the entire skeleton [Figure 1]b. FL, Ann-Arbor stage IVA with bone marrow involvement was diagnosed. After reviewing this case in a multidisciplinary team meeting, focal areas with homogeneous nodules lacking tangible-body macrophages and mantle zones were identified [Figure 2]d. The vast majority of the cells in the nodules were positive for CD10 and Bcl-2 [Figure 2]e and [Figure 2]f. Therefore, FL with hyaline vascular CD features was diagnosed. Leukocytosis, severe anemia, and thrombocytopenia improved after one cycle of chemotherapy with an rituximab, vincristine, cyclophosphamide, and prednisolone regimen (R-COP). The patient achieved good metabolic remission after six cycles of R-COP treatment [Figure 1]c and remained under tri-monthly rituximab maintenance for 2 years.

  Discussion Top

CD is a benign lymphoproliferative disease characterized by follicular hyperplasia with germinal center involution and marked follicular and interfollicular capillary proliferation. Three histopathological subtypes of CD have been identified: hyaline vascular (HV), plasma cell (PC), and mixed subtypes.[8] HVCD, which comprises 80%90% of CD cases, is characterized by increased follicular hyperplasia with atrophic germinal centers, penetrating hyalinized blood vessels (lollipop-like follicles), surrounding concentric layers of mantle zone lymphocytes (sometimes described as the onionskin mantle zone), and interfollicular vascular proliferation. In contrast, PC CD (10%-20% of CD cases) features hyperplastic follicles and a marked proliferation of interfollicular area PCs.[2] CD can be divided into unicentric CD (UCD) involving a single enlarged lymph node, often with HV histopathology, and multicentric CD (MCD) involving multiple lymph nodes, often with PC histopathology.[9] CD is currently categorized into several disorders that share a spectrum of characteristic histopathological features but have different etiologies, presentations, treatments, and outcomes.[9]

Few cases of FL-HVCD have been reported in the literature. Pina-Oviedo et al.[5] comprehensively reviewed the clinicopathologic features of 11 cases with FL-HVCD. The median age of the patients was 68 years, and multifocal lymphadenopathy was the most common presentation. These cases showed typical FL with centrocytes and centroblasts that were positive for CD10 or Bcl-6 and all were positive for Bcl-2. Furthermore, all these cases had some characteristic features of HVCD, such as lollipop-like follicles, onionskin-like mantle zone, and interfollicular increased vascularity. Our case had multifocal lymphadenopathy as the initial presentation and HVCD-like features on histopathological examination, which was similar to previous case reports. FL was diagnosed after disease progression with bone marrow involvement. Dominant HVCD-like histopathology may mask underlying lymphoma, leading to misdiagnosis.

On the other hand, many cases in the study by Pina-Oviedo et al.[5] presented with multifocal or systemic lymphadenopathy, which is uncommon in HVCD. HV histopathology usually has been discovered in UCD and manifests as an asymptomatic localized lymphadenopathy. CD may coexist with or develop subsequent lymphoma, including non-Hodgkin or Hodgkin types.[10] This occurs most often with MCD/PC but is rare with HV histopathology. Therefore, caution should be exercised in patients with HVCD who present with systemic symptoms and generalized lymphadenopathy. Additional studies should exclude the possibility of occult lymphoid neoplasms. Distinguishing FL variants with HVCD features from HVCD is essential because the treatment and prognosis are different. The under-recognition of FL-HCVD may delay FL therapy.

  Conclusion Top

In conclusion, we report a case of FL-HVCD. Physicians should consider the possibility of occult lymphoma before confirming the diagnosis of HVCD and initiating treatment strategies, especially if the clinical presentation is uncommon for the histopathologic features.

Declaration of patient consent

The authors certify that they have obtained appropriate patient consent forms. In the form the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed.

Data availability statement

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Warnke RA, Weiss LM, Chan JK, Cleary ML, Dorfman RF. Tumors of the lymph nodes and spleen. In: Rosai J, Sobin LH, editors. Atlans of Tumor Pathology. 3rd Ser. Washington, DC: Armed Forces Institute of Pathology; 1994. p. 85.  Back to cited text no. 1
Siddiqi IN, Brynes RK, Wang E. B-cell lymphoma with hyaline vascular Castleman disease-like features: A clinicopathologic study. Am J Clin Pathol 2011;135:901-14.  Back to cited text no. 2
Nozawa Y, Hirao M, Kamimura K, Hara Y, Abe M. Unusual case of follicular lymphoma with hyaline-vascular follicles. Pathol Int 2002;52:794-5.  Back to cited text no. 3
Kojima M, Sakurai S, Isoda A, Tsukamoya N, Masawa N, Nakamura N. Follicular lymphoma resembling with Hyaline vascular type of Castleman's disease. The morphological and immunohistochemical findings of two cases. Cancer Ther 2009;7:109-12.  Back to cited text no. 4
Pina-Oviedo S, Miranda RN, Lin P, Manning JT, Medeiros LJ. Follicular lymphoma with hyaline-vascular Castleman-like features: Analysis of 6 cases and review of the literature. Hum Pathol 2017;68:136-46.  Back to cited text no. 5
Koh J, Jeon YK. Morphologic variant of follicular lymphoma reminiscent of hyaline-vascular Castleman disease. J Pathol Transl Med 2020;54:253-7.  Back to cited text no. 6
Chapman JR, Alvarez JP, White K, Sanchez S, Khanlari M, Algashaamy K, et al. Unusual variants of follicular lymphoma: Case-based review. Am J Surg Pathol 2020;44:329-39.  Back to cited text no. 7
Keller AR, Hochholzer L, Castleman B. Hyaline-vascular and plasma-cell types of giant lymph node hyperplasia of the mediastinum and other locations. Cancer 1972;29:670-83.  Back to cited text no. 8
Dispenzieri A, Fajgenbaum DC. Overview of Castleman disease. Blood 2020;135:1353-64.  Back to cited text no. 9
Oksenhendler E, Boutboul D, Fajgenbaum D, Mirouse A, Fieschi C, Malphettes M, et al. The full spectrum of Castleman disease: 273 patients studied over 20 years. Br J Haematol 2018;180:206-16.  Back to cited text no. 10


  [Figure 1], [Figure 2]


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