COX2-related multicentric mixed-type Castleman's disease in a young man
Jie Liu*, Shuang Han, Jie Ding, Kaichun Wu, Jiyan Miao and Daiming Fan* About the authors
Correspondence *State Key Laboratory for Cancer Biology, Department of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China
Email jieliu@fmmu.edu.cn or
Email fandaim@fmmu.edu.cn
Summary
Background A 34-year-old male presented with a 5-month history of fatigue, anorexia, low fever, night sweats, and oliguria with edema of the eyelid, exacerbated by abdominal distension and mild diarrhea of 3 weeks duration. Physical examination showed positive signs of ascites, palpable spleen, slight abdominal tenderness and mild rebound tenderness in the lower abdomen, and edema of the lower limbs. Initial laboratory tests revealed abnormal liver biochemistry and increased protein concentration in the urine. Chest X-ray showed minimal pleural effusion in both sides of the thoracic cavity, and ultrasound detected moderate ascites, several small lymph nodes in the retroperitoneum, and mild splenomegaly with widening of the splenic vein. A lymph node biopsy established the diagnosis, and cytokine analysis in the serum revealed COX2 as the possible mediator.
Investigations Abdominal paracentesis, chest X-ray, abdominal ultrasound, thoracic and abdominal CT scans, gastroscopy, colonoscopy, biopsies of the liver, bone marrow and lymph nodes, immunophenotype staining for lymphocytes, cytokine analysis.
Diagnosis COX2-related multicentric mixed-type Castleman's disease.
Management Chemotherapy and COX2 inhibitors.
Keywords:
angiofollicular lymph node hyperplasia, chemotherapy, COX2, COX2 inhibitor, multicentric mixed-type Castleman's disease
The case
A 34-year-old male presented to his primary care physician with a 5-month history of fatigue, anorexia with weight loss of 8 kg, low fever (37.0–37.6 °C), night sweats, and oliguria (400 ml/day) with edema of the eyelid. Three weeks prior to presentation, these symptoms became more severe and were exacerbated by abdominal distension and mild diarrhea with yellow stools 3–5 times per day, but no hematuria or hematochezia. The patient was referred to a large teaching hospital in Shaanxi Province, China for further investigations.
The patient's medical history was remarkable for an episode of pulmonary tuberculosis 20 years previously, and he reported that he had smoked one packet of cigarettes per day for the past 14 years and occasionally consumed alcohol. The patient's family history was unremarkable for cancer or hereditary diseases.
Upon physical examination, the patient's body temperature was 37.7 °C. Heart and lung function tests were normal. There was slight abdominal tenderness and mild rebound tenderness with positive signs of ascites and mild splenomegaly, and moderate edema of the lower limbs. The liver was not palpable, and there was no obvious swelling of the peripheral lymph nodes, changes to the skin, or red swelling of the joints. Initial laboratory tests revealed abnormal liver biochemistry and increased protein concentration in the urine (see Table 1 for complete laboratory test results).
Table 1 Patient's laboratory test results obtained during hospital evaluation.
Full tableFigures & Tables indexDownload Power Point slide (292K)
Chest X-ray showed the presence of small amounts of pleural effusion in both sides of the thoracic cavity. Abdominal ultrasound detected a medium seroperitoneum, six small lymph nodes approximately 0.9 cm 
1.0 cm to 2.0 cm 1.0 cm in the retroperitoneum, and mild splenomegaly with widening of the splenic vein.
Contrast CT and repeated ultrasound showed normal liver, cholecyst, pancreas, kidney and prostate morphology, but revealed moderate ascites and confirmed distension of the spleen and widened splenic vein. Gastroscopy revealed hemorrhagic gastritis, but a colonoscopy was unremarkable for changes in the colon mucosa. No tumor cells were found in the ascitic fluid. Biochemical analysis of the fluid revealed that the ascites was between exudate and transudate, with a SERUM–ASCITES ALBUMIN GRADIENT of 3.0 g/l (ascitic albumin 30 g/l; serum albumin 33 g/l). Repeated acid-fast staining for Mycobacterium tuberculosis was negative and a purified protein derivative test showed 10 mm induration in 72 hours. Repeated chemical indices of liver and kidney function remained abnormal, and hematoxylin and eosin staining of a percutaneous liver biopsy revealed extensively degenerated hepatocytes and infiltration of inflammatory cells around the portal regions (Figure 1). Bone marrow biopsy showed that the percentage of mesenchymal plasmacyte cells was increased to 17.4% (normal 0.71 
0.42%) and a large number of heteromorphic plasmacytes could be seen (Figure 2). Significant stromal edema and fibrous tissue hyperplasia, with a focal distribution, were also found. Tests for Bence Jones protein in the urine, and serum M protein, were negative. Serum calcium levels were normal, and X-ray examination revealed no evidence of osteolysis.
Figure 1 Percutaneous liver biopsy with hematoxylin and eosin staining.
(A) Revealing extensively degenerated hepatocytes and infiltration of inflammatory cells, such as plasmacytes (arrow) and granulocytes around the portal region. Magnification 400. (B) Plasma cell infiltration, highlighted by immunohistochemical staining with an antiplasmacyte antibody (DAKO, Glostrup, Denmark). Magnification 400.
Figure 2 Bone-marrow biopsy revealing heteromorphic plasmacyte aggregates and double immunofluorescent staining of COX2 in the plasma cells.
(A) Plastic-embedded bone marrow (hematoxylin–Giemsa–eosin staining) showing a large area of mega-plasmacyte aggregation, with loose chromatin and visible nuclei (arrow). Magnification 400. (B) Paraffin-embedded tissue showing plasmacytes highlighted by immunohistochemical staining with an antiplasmacyte antibody. Magnification 200. (C) Paraffin-embedded tissue showing strong immunohistochemical staining of COX2 with an anti-COX2 polyclonal antibody (Cayman, Ann Arbor, MI). Magnification 200. (D–F) Confocal laser-scanning microscopy of paraffin-embedded tissue showing strong immunofluorescent staining of COX2 with an anti-COX2 polyclonal antibody (D, red-channel, tetraethyl rhodamine isothiocyanate-labeled secondary antibody), plasmacytes highlighted by immunofluorescent staining with antiplasmacyte monoclonal antibody (E, green channel, fluorescein isothiocyanate-labeled secondary antibody), and double immunofluorescent staining showing plasma cells expressing COX2 (F, red plus green channel). Magnification 400. COX2, cyclooxygenase 2.
One month after admission, the patient developed ASTEATOSIS CUTIS with violet coloration of the forearm skin, and two separate palpable lymph nodes of approximately 0.5 cm 0.5 cm situated close to each other in the middle of the right side of the neck. Mild numbness of the toes and fingers and slight stiffness in the joints of both hands were also reported.
A lymph node biopsy revealed accrescent lymph follicles, with abnormal small blood vessel penetration accompanied by hyalinization (Figure 3) and plasmacyte proliferation and patchy distribution among the follicles (Figure 4). Cytokine analysis showed that serum levels of two COX2 (cyclooxygenase 2) products, thromboxane A2, monitored by measurement of thromboxane B2, and prostacyclin, monitored by 6-keto-prostaglandin F1
, were remarkably elevated in this patient. Double immunofluorescence staining showed plasma cells in both bone marrow and the lymph node expressing high levels of COX2 (Figures 2 and 4). The complete results of the serum cytokine analyses are listed in Table 2.
Figure 3 Lymph-node biopsy with hematoxylin and eosin and Ki-67 nuclear proliferation antigen staining.
(A) Hematoxylin and eosin staining showing abnormal blood vessel penetration into the follicles accompanied by hyalinization and multilayer lymphocytes with circular permutation surrounding the follicle to form onion-skin architecture (arrow). Magnification 200. (B) Proliferating cells in the germinal center highlighted by Ki-67 staining (DAKO, Carpinteria, CA). Magnification 200. (C) Proliferating blood vessels highlighted by Ki-67 staining. Magnification 200.
Figure 4 Lymph-node biopsy and staining for vascular endothelial cells with CD34 and double immunofluorescent staining of COX2 in the plasma cells.
(A) Hematoxylin and eosin staining of the lymph node showing blood vessel and plasma cell proliferation among the follicles. Magnification 200. (B) Immunohistochemical staining of the plasma cells with an antiplasma cell antibody. Magnification 250. (C) Immunohistochemical analysis of the blood vessels by anti-CD34 staining (DAKO, Glostrup, Denmark). Magnification 200. (D) Paraffin-embedded tissue showing strong immunohistochemical staining of COX2 with an anti-COX2 polyclonal antibody (Cayman, Ann Arbor, MI). Magnification 200. (E–G) Confocal laser-scanning microscopy showing plasma cells expressing COX2 (E, COX2 staining with red channel; F, plasmacytes highlighted with the green channel; G, co-staining of COX2 and plasma cells [red plus green channel], primary and secondary antibodies as in Figure 2). Magnification 300. COX2, cyclooxygenase 2.
Table 2 Evaluation of patient's serum cytokine levels.
Full tableFigures & Tables indexDownload Power Point slide (240K)
The patient was diagnosed with COX2-related multicentric mixed-type Castleman's disease and commenced COP chemotherapy (cyclophosphamide 200 mg once daily on the first, third, fifth and seventh days, vincristine 2 mg on the first day and prednisone 40 mg once daily for 7 consecutive days) 2 days after diagnosis. After 1 week, the patient experienced partial relief of most of his symptoms, but he did not tolerate this treatment well and COP was replaced with the MP regimen (melphalan 2 mg three times daily and prednisone 50 mg once daily for seven consecutive days) for the second cycle of chemotherapy. After two cycles, MP was combined with the COX2 inhibitor celecoxib (200 mg daily), which resulted in a markedly better response than MP chemotherapy alone.
After 21 cycles of MP and celecoxib, a bone marrow biopsy showed that the percentage of mesenchymal plasmacyte cells had decreased to approximately 1.3%, compared with 17.4% at diagnosis. There were no other obvious symptoms or lymphadenopathy, and treatment was therefore discontinued. The patient remains under close medical supervision and receives abdominal ultrasound and tests for hepatorenal biochemistry and blood-cell count once a month, and a bone marrow biopsy every 3 months.
Discussion of diagnosis
The symptoms with which this patient presented could have been caused by a variety of underlying disorders including malignancy, infectious disease, POEMS SYNDROME-related disorders, and hepatorenal, rheumatologic, cardiogenic, and metabolic diseases. In this case, however, the evidence indicated secondary, rather than primary, hepatorenal dysfunction, and negative results for indicators of autoimmune dysfunction made rheumatic diseases unlikely. A liver biopsy helped to rule out the possibility of metabolic disease. Confirmation of the diagnosis in such cases should be based on a combination of medical history, clinical findings, and histopathologic evaluation.
Differential diagnosis
Malignant diseases
Primary or metastatic peritoneal cancer commonly results in ascites, abdominal distension, fatigue and unexplained weight loss. In this case, however, these diagnoses were excluded because of the absence of tumor cells in the ascitic fluid, the normal titer of most of the tumor markers, and the fact that no evidence of abdominal malignancy was revealed by gastroscopy, ultrasound or CT scan.
Hodgkin's and non-Hodgkin's lymphoma begin as a malignant clonal expansion of B or T lymphocytes. The normal architecture of the lymph node is obliterated by dysplasia, lymphocyte amplification, or fibrosis. In this case, the lymph node biopsy revealed almost intact nodal architecture, and immunohistochemical (IHC) staining of Ig
and Ig
revealed polyclonal B cells and plasma cells. The immunophenotyping of CD20 (B cells), and CD45RO (T cells) gave the staining pattern of a normal lymph node, in which B cells are located predominantly in the lymph follicle and T cells mainly in the paracortical area. In addition, CD15 staining showed no Reed–Sternberg cells. Flow cytometry was not performed in this case, because the morphology of the lymph node and distribution of cells were clearly shown by IHC staining. Hodgkin's and non-Hodgkin's lymphoma were therefore excluded as possible diagnoses.
POEMS syndrome
POEMS syndrome, also known as Crow–Fukase syndrome, is associated with a group of disorders known as monoclonal gammopathies or plasma cell dyscrasias, of which multiple myeloma is the best known. Monoclonal gammopathy of undetermined significance is asymptomatic with the presence of serum or urine M protein. Multiple myeloma, a principal disorder of plasma cells, is characterized by myeloma cell proliferation and bone destruction mediated by cytokines. In this case, serum M protein was negative, CT evaluation did not demonstrate osteolytic changes, serum calcium levels were normal, and the urine was negative for Bence Jones protein. Monoclonal gammopathies were therefore considered unlikely.
Infectious disease
Mycobacterium infection, especially M. tuberculosis, can cause peritonitis, concomitantly inducing low fever, night sweats, abdominal distension and fatigue. In this case, however, tentative anti-tuberculosis therapy (isoniazid 300 mg once daily, pyrazinamide 500 mg three times daily and rifapentine 600 mg once weekly), from 1 week after admission to the final diagnosis 3 weeks later, was ineffective. Acid-fast staining, polymerase chain reaction testing and culture of the ascetic fluid were repeatedly negative for M. tuberculosis, as was IHC staining of the lymph node. The diagnosis of tuberculosis was therefore excluded.
Multiple mixed-type Castleman's disease
Castleman's disease, also known as angiofollicular lymph node hyperplasia, is a rare disorder with three identified histologic variants (hyaline vascular-type, plasma cell-type, and mixed-type) and two clinical types (localized and multicentric). Only occasional cases of mixed-type disease have been reported.1, 2 Clinically, in contrast to the localized form, multicentric Castleman's disease is a systemic illness that frequently presents with general signs, polyadenopathy, organomegaly, and occasionally POEMS syndrome. Importantly, multicentric Castleman's disease is aggressive and is usually high risk for malignant change.3 In this case, given the multisystemic manifestations and pathologic characteristics of vascular penetration with hyalinization and plasmacyte proliferation in the lymph nodes, multicentric mixed-type Castleman's disease was considered the most likely diagnosis. This case differs somewhat from most previous reports of Castleman's disease that relate to HIV or human herpes 8 virus infection and interleukin-6 mediated impairment,3, 4, 5 because in this patient IHC and polymerase chain reaction tests for human herpes 8 virus and Epstein–Barr virus (EBV) in the lesion were negative. EBV capsid antigen IgG was detected in the serum, but EBV DNA was not present in either the serum or the lesion, suggesting an unclear etiology. In addition, cytokine levels were not elevated, except for a marked upregulation of serum COX2 products (Table 2). COX2 and its derived prostaglandins play a key role not only in the inflammatory response, but also in tumorigenesis through stimulating cell proliferation and angiogenesis.6, 7, 8 In this case, the high proliferation of blood vessels shown in the lymph node biopsy, and clinical manifestation of a multi-organ inflammatory response, could have been induced by upregulation of COX2. Combined with the high levels of COX2 in the proliferated plasma cells of the bone marrow and lymph nodes, as demonstrated by double immunoflourescent staining (Figures 2 and 4), it could be concluded that this patient has a previously unreported type of multicentric Castleman's disease with COX2-mediated multi-organ impairment.
Treatment and management
At present, no therapeutic consensus exists for the multicentric forms of Castleman's disease,9 although chemotherapy usually administered for lymphoma or multiple myeloma has proven effective and well tolerated in some cases.1, 2, 9, 10 Reports in the literature suggest that COX2 plays a key role not only in the inflammatory response, but also in tumorigenesis through stimulation of cell proliferation, angiogenesis, enhanced cell invasiveness, and increased production of mutagens.11, 12 In this case, COX2 inhibition was indicated as an appropriate therapy by the high proliferation of blood vessels in the lymph node, clinical manifestation of a multi-organ inflammatory response, and high levels of COX2 expression in the bone marrow and lymph node. It would, however, have been unadvisable to limit treatment to COX2 inhibition alone, and therapy was therefore based on the MP regimen, with a COX2 inhibitor as an adjunctive agent. Here, this combination proved successful, and the patient's remaining symptoms of chest pain, abdominal distension, xeransis of the skin and eyes, and mild diarrhea, were much improved after the addition of the COX2 inhibitor.
Conclusion
This is a rare case of Castleman's disease with mixed-type pathological features and multicentric clinical features. COX2 was found to be involved in the pathogenesis of this disease, and the MP chemotherapy regimen, in combination with the COX2 inhibitor celecoxib, proved to be a promising therapy in this patient. Because of the complexity of its mechanisms and clinical manifestations, Castleman's disease should be suspected in patients with constitutional symptoms after other diagnoses have been excluded, and a novel choice of therapeutic compound, such as a COX2 inhibitor, should be considered.
Acknowledgments
We would like to thank Drs Binzhong Sun and Chuanshan Zhang for their assistance with this case study. This work was supported by the Program for New Century Excellent Talents (NCET) in University and a grant (No. 30371585) from the National Natural Science Foundation of China to Dr Jie Liu. Written consent for publication was obtained from the patient.
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Competing interests
The authors declared no competing interests.
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Subject areas under which this article appears: Hematology
