Qiao-Feng Su,Zhen Lei＊,Wei-Yi Yang,Shuang He,Yan-Li Luo

1Department of Respiratory,Affiliated Hospital of North Sichuan Medical College,Nanchong,Sichuan,637000,China.

Abstract Castleman disease, also known as angiofollicular lymph node hyperplasia, is a rare lymphoproliferative disease with a poorly understood etiology.We herein report a 27-year-old male with a six months history of painless and gradually enlarged lymph nodes presented recurrent cough and expectoration with fever and chills for ten days.The patient was recurrent fever even received empiric anti-inflammatory therapy.Then the right cervical follicles biopsy and pathological examination revealed Castleman disease Plasma cell variant.Castleman disease is a rare disorder that is hard to diagnose early.Now,we will review this case, summarize Castleman disease and propose a feasible diagnostic protocol.

Key words:Castleman disease,Case report,Plasma cell type

Background

Castleman disease (CD) is a rare nonclonal lymph proliferative disorder of unknown etiology, which was first described as a pathologic entity in 1954 and was defined by Dr Benjamin Castleman in 1956.CD is a rare lymphoproliferative disorder that can involve single (unicentric) or multiple lymph nodes(multicentric).In addition, it can be classified into 3 histopathological patterns: hyaline-vascular type,plasma cell type, and mixed variant.Type of hyaline-vascular is the most common, accounting for approximately 90%, and presents equally in men and women.Most patients present as a local mass without systemic symptoms or laboratory abnormalities.Haline vascular type of unicentric Castleman disease develops in all lymph nodes, especially in the mediastinum, can also occur in the cervical, retroperitoneal, and axillary regions.However, plasma cell type accounts for less,about 8%–10%.Most patients of the plasma cell type associated with systemic symptoms and laboratory findings.The clinical manifestations usually presented with fever, night sweats, fatigue, weight loss,splenomegaly, anemia, and hypergammaglobulinemia.The disease commonly presents as a solitary mass.Castleman disease can be confused with many other diseases, especially plasma cell variant Castleman disease.It has obvious clinical manifestations and abnormal laboratory findings, and accounts for less, so we cannot easily to get a diagnosis in the early stage about it.Now, we herein will report a rare case of plasma Cell variant Castleman disease.

Case presentation

A 27-year-old male with a six months history of painless, unexplained, gradually enlarged lymph nodes presented recurrent cough and expectoration with fever and chills for ten days before admission.He had a three-year history of hepatitis B and achieved physically stable after treatment.He had a surgery history for thyroid cyst.He had no family history of malignancy.

Physical examination was normal except several enlargement of lymph nodes of bilateral cervix and axillary.These enlarged lymph nodes were about 3-7 cm in diameter, were hard in texture, with clear boundaries, and can move from side to side.There is no tenderness in the masses, and the local skin color is normal.The cardiac and lung exam was unremarkable.Abdominal exam could palpate hepatosplenomegaly and bilateral inguinal lymphoproliferative.The four extremities exhibited equal pulses without evidence of leg edema.

Initial laboratory evaluation displayed normocytic normochromic anemia, other was unremarkable (Table 1).Sputum culture result was negative for Acid Fast Bacilli and mycobacterium species.Connective tissue disease screening displayed antinuclear antibody suspected positive, the remaining items were no abnormalities.The serum tumor markers of carcinoembryonic antigen, tissue polypeptide antigen and squamous cell carcinoma antigen were within the normal ranges.

Table 1 Initial laboratory results

Figure 1 The chest computed tomography images of the patients.

Figure 2 Bone marrow smears displayed a number of maturity plasma cells (high power field’s arrow)

Immunoassay showed surface antibody of hepatitis B was positive and the amount of immunoglobulin was increased(Table 2).

Table 2 Immunoassay results

Chest radiograph showed heart and lung were no abnormalities.Chest computed tomography (Figure 1)described multiple well-defined lymphoproliferation distributed in both mediastinal and bilateral axillary,so that did rule out lymphoma.

Superficial soft tissue of ultrasound showed these areas of proximity the bilateral cervical vessels,axillary and inguen had several lymphoproliferative.Echocardiography displayed a small amount of pericardial effusion.Abdominal ultrasound showed hepatosplenomegaly and a small amount of pelvic fluid.

The patient was given empiric anti-inflammatory therapy after admission.However, he was recurrent fever with Tmax 38.6℃; it was heavier in the afternoon and evening, following the next week.Combined with the patient's clinical presentation,chest computed tomography and ultrasound, we could not rule out lymphoma or myeloma.Then we did bone marrow biopsy (Figure 2).Bone marrow smears under high power fields displayed bone marrow hyperplasia,erythroid 27.5%and lymphocytes 13%.The proportion of plasma cells was 5.5%, which did not fully support the diagnosis of myeloma.

In order to find the pathology evidence, we selected the right cervical follicles biopsy and sent the biopsy to department of pathology.Histologically evaluation showed plasmacytosis in medullary sinus (Figure 3).Immunohistochemical stains performed that CD138,CD38 and CD3 highlighted the interfollicuar plasma cells.CD20, CD79a and pax5 highlighted interfollicuar (Figure 4).These pathological findings were consistent with the diagnosis of Castleman disease Plasma Cell variant.Unfortunately, the patient was discharged for further treatment after diagnosis.

Figure 3 Histologically evaluation showed plasmacytosis in medullary sinus.A,HE*200.B,HE*400.

Figure 4 Immunohistochemical stains reveal that the proliferated lympocytes were positive for castleman disease 138(A)and pax-5(B)

Discussion

In 1954, Castleman and Towne described CD as a non-clonal lymph node hyperplasia for the first time[1].It is also known with a variety of other descriptive names, including “giant lymph node hyperplasia”,“lymph node hamartoma”, “angiofollicular mediastinal lymph node hyperplasia” and “angiomatous lymphoid hyerplasia”.The pathogenesis is unknown, but substantial evidences point that disorder immune regulation could led to enlarged B-lymphocyte and plasma-cell proliferation in lymphatic tissue.

The etiology and pathogenesis of CD is probably diverse.It is important that inflammatory mediators involved in the pathogenesis of CD.Experimental studies have shown that increased production of IL-6 could stimulate the manifestations of CD [2].Many studies have showed that Human Herpes Virus-8(HHV-8) has closely relationship with CD.The majority of the CD cases associated with HHV-8 infection were simultaneously HIV infections [3].It is morphologically classified into Unicentric and Multicentric according to the extent of lymph node involvement.There are 3 maior pathologic variations of CD [4]: the hyaline vascular type, the plasma-cell type and less often a combination of both types (the mixed type).Approximately 90% of cases are hyaline vascular, it is more common in unicentric than multicentric.The plasma-cell type (less than 10%) is commonly found in multicentric.Our case was multientric and plasma-cell type because there were multiple lymphoproliferative and plasmacytosis of pathology.

The disease often has no specific clinical manifestations, whether unicentric or multicentric.The unicentric hyaline vascular type is usually manifestations of one or several enlarged lymph nodes.They may be asymptomatic or produce local symptoms such as pain, fever and fatigue and so on.Systemic symptoms and laboratory tests are no abnormalities[5].On the other hand, the systemic symptoms of the multicentric plasmacytic type are often severe.The majority of patients have fever, weakness, anorexia and weight loss.Almost patients have multi- site lymphadenopathy.Virtually any organ can be affected especially hepatosplenomegaly [6].Laboratory abnormalities commonly found anemia, elevated erythrocyte sedimentation rate (ESR), proteinuria and polyclonal agammaglobuinemia [7].The patient had the basic performances above mentioned.

In this report, fever was mainly manifestation;multifocal lymphadenopathy and hepatosplenomegaly were found on examination.The etiologies of the patient are divided into infectious and nor-infectious.Because of this patient had the history of hepatitis B,hepatitis B virus led to hepatosplenomegaly as the first consideration.However, his hepatic function was normal without jaundice that does not support the diagnosis.The patient had symptoms of infection, but neutrophils were not elevated and anti-infective effect is poor, so it was considered the specific infection diseases or others.Tuberculosis should be considered,however, sputum culture result was negative for Acid Fast Bacilli and mycobacterium species and there are no significant tuberculosis infection according to chest radiograph or computed tomography, therefore these do not support the diagnosis.

Further, the patient had lymphadenadenopathy accompanying multiple organ abnormalities, so connective tissue, tumor and hematological disorder should be considered on nor-infectious aspect.Yet,connective tissue disease screening displayed antinuclear antibody suspected positive, the remaining items were no abnormalities, this result don't support the such disease.Simultaneously, the serum tumor markers of carcinoembryonic antigen, tissue polypeptide antigen and squamous cell carcinoma antigen were within the normal range, chest computed tomography has no significant lesions; these do not support the diagnosis of solid tumors.Lymphoma and myeloma are considered for hematological diseases.Bone marrow biopsy is a common means of detection hematological diseases.Although immunoglobulin was elevated in serum, a number of mature plasma cells(approximately 5.5%) in bone marrows smears are not supported myeloma.Last, we adopt right cervical follicles biopsy and immunohistochemical stains, the pathology report confirmed CD plasma cell variant.

Image studies frequently display a variety of tissue abnormalities, in addition to lymphadenopathy,nodules and calcification are occasionally seen[8].For typical castleman disease lesions, fluorodeoxyglucose positron emission tomography scanning usually reveals low to moderate specific uptake values in affected tissues [9].No technique is sufficiently to diagnose the deeply located lesions based on their manifestations.The final diagnosis also need to biopsy.Our case was definitive diagnosis by biopsy.

The treatment of CD is directed toward the specific symptoms that are presentation in each individual.Unicentric CD is generally treated with excisional surgery or irradiation that lead to rapid resolution of symptoms and laboratory abnormalities, the type of CD is always curable [10].Multicentric CD always requires systemic therapy, which may include corticosteroid, radiation therapy and chemotherapy drugs such as cyclophosphamide, vincristine and prednisone, cyclophosphamide, doxorubicin,vincristine and prednisone or monotherapy(chlorambucil, cyclophosphamide,2-chlorodeoxyadenosine, carmustine, vincristine,bleomycin, liposomal doxorubicin, oral etoposide and vinblastine) [3].Unfortunately, the patient was discharged for further treatment after diagnosis.

Although CD is a rare disease, it is important that the differential diagnosis of CD in mind when experiencing unexplained fever and multiple lymphoproliferative.Biopsy is still the primary means of diagnosis CD,and the etiology remains to be further examined in future studies.