Abstract
OBJECTIVE To enhance the understanding of Castleman’s disease (CD), and to improve its diagnosis and management.
METHODS Clinical features and related information on diagnosis and treatment of 14 cases of CD were retrospectively analyzed and the literature reviewed.
RESULTS Based on the clinical classification, localized CD was found in 8 of the 14 cases. Both the results of lymph node biopsy and histopathology indicated they were a hyaline-vascular type. The multicentric type CD was detected in 6 cases, among which 4 were plasma cell type and 2 mixed type based on histopathologic examination. There were a variety of clinical situations in the 14 cases, with a lack of specificity. They were previously misdiagnosed as other diseases, and final diagnosis depended on a histopathologic examination. The 8 patients with localized CD underwent excision, without recurrence up to now. The 6 patients with multicentric-type CD were treated with glucocorticoids or combined chemotherapy, and all achieved remission.
CONCLUSIONS CD has complicated clinical manifestations and is difficult to diagnose. Lymph node biopsy is important for early diagnosis. An optimal curative effect can be achieved with a suitable therapeutic option, based on histopathology and clinical classification.
keywords
Castleman’s disease (CD) is a rare and cryptogenic atypical lymphatic tissue hyperplasia. Missed diagnosis and misdiagnosis occur frequently owing to its clinical rarity, diverse expression, pathomorphological characteristics, and lack of specificity. Since the first description of CD by Castleman[1] in 1956, reports of this disease have emerged in succession in China and overseas, but most have been case reports. Since 1990, 14 patients with CD were admitted in our hospital. Our report of the cases and a review of the literature follows, so as to better understand the pathogenetic condition and to improve CD diagnosis and treatment.
MATERIALS AND METHODS
General data
The 14 patients (7 males and 7 females) with CD were admitted in our hospital during the period from January 1990 to September 2006. Their ages ranged from 24 to 65 years, with mean and median ages of 39 and 40 years. The course of their disease ranged from 1 month to 8 years. These cases were misdiagnosed on admission as malignant lymphoma (ML), histocellular necrotic lymphadenitis, lung cancer, tuberculosis, pleural endothelioma, nodule disease and leiomyoma, as well as neurodermitis, etc. The period ranging from the first visit to final diagnosis of CD was 15 days to 6 months.
Clinical situation
The pathogenic condition of the 14 cases varied greatly. Superficial lymphatic tissue hyperplasia occurred as the first manifestation in 4 cases, occasional swelling during a physical examination in 3, an abdominal pain in 3, cough and chest distress in 2, complaint of abdominal distention in 1 and a prominent manifestation of a skin rash in 1. Symptoms of local compression occurred in 8 patients with localized CD, such as cough, distress, abdominal distention and pain, etc. All of these 8 cases showed no systemic symptoms and were pathologically diagnosed as hyaline vascular CD. In the 6 cases with multicentric CD, fever was found in 4, night sweats and emaciation in 3, and anemia in 2, with a pathologic diagnosis of the plasma cell-type or mixed-type CD.
Concerning physical signs, regional nodular enlargement was present in the 8 cases with localized-type CD, with sizes of 3 × 2 cm to 12 × 10 cm and without pain upon palpation. Several nodular enlargements were found in the 6 cases with multicentric CD, with nodular fusion and also with no palpatory pain. Slight-moderate soft splenic swelling was seen in 3 cases with palpation at 2 to 4 cm below the ribs. A hepatic soft swelling was seen in 2 cases with palpation at 3 to 4 cm below the ribs. The clinical symptoms and signs noted above related to the pathological typing and prognosis.
No abnormal laboratory results were found in the 8 cases with local-lesion type CD. The count and classification of white cells, and the blood platelet count for the 6 cases of multicentric CD were within normal limits. Anemia was found in 2 cases, with a hemoglobin (HB) value of 74 to 87 g/L. The results of antihuman-globulin test, i.e. the Coombs’ test, were negative in both cases. The HB was normal in the other 4 cases. The erythrocyte sedimentation rate (ESR) was increased in all 6 cases, with an increased rate ranging from 48 to 108 mm/h. Moreover, the globulin level was significantly elevated at a range from 60.5 to 116 g/L. Immunofixation electrophoresis suggested the presence of multiclonal lymphocytes. The Ben-Jones protein test was negative. In the 3 cases with hypoproteinemia, the blood albumin value ranged between 23 to 31 g/L.
Based on examinations of bone marrow cell morphology (BMCM), there was an active hyperplasia in all the cases, showing a slight increase in plasma cells in 4 cases that ranged from 5% to 12%, and a form of mature plasm cells (immunofixation electrophoresis indicated that the cells were multiclonal lymphocytes, instead of monoclonal; A multiple myeloma was ruled out as there was no skeletal destruction).
The results of a BMCM examination basically were normal in 2 cases. The tuberculin test was negative in all 14 cases and the human immunodeficiency virus (HIV) was negative in 10 cases, but the other 4 cases were not evaluated. There was a significant increase in the serum IL-6 of the 3 patients with multicentric CD, and the other 11 received no evaluation. Complications of systemic lupus erythmatosus (SLE) occurred in 1 case of multicentric CD.
Regional ultrasonic-B and X-ray examinations, and CT scans were conducted in all 14 cases. Lymphatic tissue hyperplasia was found in 10, ML in 8 and inflammation in two of these 10 cases. Neoplasms were found in the other 4 cases, namely lung cancer, pleural endothelioma, nodule disease and leiomyoma. All 14 cases had not been previously diagnosed as CD.
RESULTS
Histopathologic characteristics
Eight of the 14 cases were CD of the hyaline-vascular type. The germinal center (reaction center) of the nodulus lymphaticus shrank back and vanished, or mostly disappeared. The external lymphocyte band was widened, with a lamellar arrangement around the germinal center and an onionskin-like or “popcornlike alteration.” It was usually seen that one or several blood vessels extended from the reaction center, with a vascular endothelial cellular swelling, widened vessel wall and an encapsulation by transparent and acidophilic materials. There was an interfollicular blood capillary hyperplasia, with a hyaline degeneration. There were disparate lymph nodes, plasma cells, eosinophilic granulocytes and immunoblasts.
Four of the other 6 cases were CD of a plasma cell type, the reaction center of lymphoid nodules was normal or rather large, and the external lymphocytic band was thin, without vascular proliferation and paraplasmic deposition in the central follicle. A mass of plasma cell proliferation occurred in the region between the follicles, and there were few lymphocytes and immunoblasts. Only 2 of the 14 cases were a mixed-type CD, which combined the features of the above two, i.e. with an atypical lymphatic nodular-like structure. Apart from flaky plasma cells between the follicles, there was a vascular proliferation-like hyalinization. An integration of lymphatic elementary structure and overt follicular hyperplasia were the common histopathologic characteristics of CD.
Immunohistochemical examinations showed that there was a multiclonal lymphocytic proliferation in all cases. The follicles and the B-mantle cell CD20, CD45RA proliferating around it were all positive, and there were sporadic CD45RO-positive T cells and B-lymphocytes between the follicles. Both the hyaline-vascular and plasma cell-types of CD showed a CD38-positive staining, suggesting its multiclonal charateristics. There was a sporadic staining distribution in the hyaline-vascular CD cases, and there was clear CD38-positive staining in the plasma cell-type CD cases. For pathologic H&E staining and immunohistochemical results, see Figs.1 to 5.
Hyaline-vascular type(H&E staining ×200).
Plasma cell type(H&E staining ×200).
Hyaline-vascular type(H&E staining ×400).
Plasma cell type(H&E staining ×400).
Immunohistochemical staining (CD38) ×100.
Treatment and outcome
The 8 localized CD patients underwent surgery, with complete tumor resection. A further definite diagnosis was made by postoperative histopathologic examinations. To date no recurrences have occurred upon follow-up, with all having no health problems. In the 6 patients with multicentric CD, 3 received a combined chemotherapeutic regimen, such as CHOP or COP, with 6 to 8 courses. At present the lymphatic tissue hyperplasia has disappeared and chemotherapy ceased. No evidence of recurrence was found in follow-up. One patient with SLE complications received glucocorticoid treatment, resulting in immunologic indices with minimized lymphatic tissue swelling and a stable condition using 15 mg/d of prednisone. The other patient received CHOP and Mabthera treatment for 3 courses, resulting in lymph node diminution. Treatment is still continuing. The blood sedimentation, globulin and hemoglobin were normal in the above 5 cases. The last one of the 6 patients received a CHOP regimen with combined chemotherapy of 6 courses. A recurrent skin rash occurred from time to time. After administration of 30 mg/d prednisone, the rash disappeared, but would reappear if the dose of prednisone was below 15 mg/d. The patient displayed a slight anemia over the past year. The Coombs’ test was negative and the outcome of the BMCM examination was approximately normal. Administration of a 15 to 20 mg/d prednisone has continued to date. See Table 1 for information on clinical diagnosis and treatment of the 14 CD patients.
Information on clinical diagnosis and treatment of the 14 CD cases.
DISCUSSION
Etiological factors and pathogenesis
In 1956, it was Casteman who first described the atypical lymphoproliferative disease now known as Castleman’s disease, giant lymph node hyperplasia, angiofollicular lymph node hyperplasia, angiomatous lymphoid hamartoma, as well as Castleman’s lymph node hyperplasia, etc. At present the etiological factor and pathogenesis of CD is unknown. Viral infections or autoimmune and cytokine dysregulation are possible causes of the lymphocytic hyperplasia. Current studies have shown that IL-6, HIV, human herpes virus type 8 (HHV-8, Kaposi’s sarcoma-associated herpes virus) may play a key role in the disease’s progression,[2-3] and other cell factors such as tumor necrosis factor β, γ-interferon and macrophage colony stimulating factor (M-CSF) may also be involved in its onset. The conclusive statistical data on the incidence of CD is still unavailable. There is no gender difference in the morbidity, and ages of most CD patients range from 35 to 55 years, though the disease may occur at any age. In our case study, no common etiological factors were identified. One case showed complications with SLE and in 3 cases there was a clear increase of the serum IL-6 level. The percentage of localized CD was greater in females in our study, whereas the percentage of multicentric CD was greater in males.
Clinical features
The obvious clinical feature of CD is the painless giant lymphatic tissue hyperplasia, which can be found in any part of the lymph node area. It is most commonly seen in the thoracic mediastinum, and the extranodal tissues, such as the throat, pericardium and muscles etc., but occasionally seen in secondary places, including the neck, abdomen and armpit etc. Based on the clinical situation, it can be classified as a localized or multicentric type.
Histodiagnosis of CD is very important. Pathologically the disease is usually divided into two main types, i.e. the hyaline-vascular and plasma-cell type, and a mixed subtype made up of the two types[4]. Hyaline-vascular CD is the most common, accounting for about 90% of the cases. Most of the clinical manifestations show a slow enlargement of individual lymph nodes, which form a giant tumor, usually with a diameter of 3 to 10 cm and a few as large as 25 cm. Most cases are not associated with general symptoms, but with a local lesion, with different signs and symptoms, lacking specificity and diversity in lymphatic tissue hyperplasia.
Plasma cell CD is rare, accounting for approximately 10% of the cases. Most of the clinical manifestations show multicentric or multisystem lesions, with slow enlargement of lymph nodes at several places to form a giant lump and general symptoms, such as long-term fever, debility and emaciation. Splenohepatomegalia occurs occasionally, with the manifestations of anemia, multiclonal hyperimmunoglobulinemia, hypoalbuminemia and multisystem involvements, such as the nephrotic syndrome, immunologic hematocytopenia or thrombotic thrombocytopenic purpura.
In accord with the literature, the clinical situations of our patients were diverse, with an involvement of all systems and lack of specificity. The 8 cases with localized CD were all hyaline-vascular CDs. In 4 of the 6 cases with the multicenter-type CD, pathologic findings showed the plasma cell-type CD, and the other 2 were the mixed type. Our experience regarding idiopathic and painless lymphatic tissue hyperplasia indicates that lymph node biopsy should be conducted as complete as possible. In cases in which there was failure to achieve a correct diagnosis, node puncture biopsy usually destroyed the lymph nodes.
Diagnosis of CD can only be made based upon a histopathological examination. Differentiation of CD with other benign tumors was difficult to achieve using a conventional imageological examination. However spiral CT scans or MRI examinations might be of assistance for diagnosis of CD, e.g. apparent intensification of a distinctive tumor was observed, which was close to arterial augmentation, with delayed reinforcement points. Cytogenetic and immunophenotypic assays should be conducted in pathology laboratories to better understand the nature of this disease.
Differential diagnosis
Careful differentiation should be made between CD and other immune system diseases, such as ML, various reactive lymphatic tissue hyperplasias, rheumatic diseases, all kinds of plasma cell dyscrasias and AIDS etc. The main point for a pathological differentiation between the CD and ML include the following: In ML, the lymphatic structure is almost entirely destroyed, with a rare vascular hyperplasia, and hyperplasia of the monoclonal lymphocytes or of the R-S cells. With plasma cell dyscrasia there is an increase in monoclonal globulin, without multiclonal development. The Ben-Jones protein test is positive and dysmorphic or immature plasma cells can be detected by myeloid or lymphocytic morphological examination. These findings are used to differentiate CD from ML. It’s worth noting that the pathologic alterations with CD are not specific, e.g., the hyaline-vascular type resembled small blood vessel hyperplasia caused by an AIDS infection of lymphatic follicles, while the plasma cell-type CD was similar to an extensive quantity of plasma cell infiltration in the lymph nodes with rheumatoid arthritis. Therefore a correct diagnosis could only be made by combining the clinical and pathologic features, and if necessary, with a repeated sampling at various body sites. Before obtaining the pathological findings, the cases in our study had been previously misdiagnosed as ML, vascular leiomyoma, tuberculosis, nodule disease and pleural endothelioma etc., with the longest misdiagnosis made a half a year before.
Therapeutic regimen
Surgical treatment can be performed if CD is localizaed, or if surgery is not conducted, the patients might receive irradiation therapy[5]. In our study 8 patients with the local-lesion type CD underwent excision, with an excellent curative effect, and no relapses have occurred to date. In cases of the multicentric type, glucocorticoid treatment can be used with continuous remission in some patients. Combined chemotherapy might be employed for non-responsive cases, such as a CVP regimen, i.e. cyclophosphamide plus vincristine and prednisone, or a CHOP regimen. Mabthera is a human anti-CD20 monoclonal antibody which has a definite therapeutic effect for CD[6]. The Mabthera regimen in combination with CHOP was used to treat one of our CD cases, once a month using 375 mg/m2 each time. After 3 courses of treatment, all of the lymph nodes were completely minimized. Other treatments include thalidomide, interferon, tretinoin, ganciclovir,[7] IL-6 receptor antibody[8], and bone marrow transplantation etc.
Prognosis
It has been suggested by some medical specialists that CD is an atypical lymph node hyperplasia, with a condition between being innocuous and malignant[9]. Previous reports have indicated that CD has a course of disease of different durations. Some patients may have a long-term survival, others may die within a year. It is based on the pathologic type, clinical classification and treatment plan. The localized CD patients have a better prognosis, and may enjoy a disease-free survival, while those with multicentric CD may have complications with multiclonal hyperimmunoglobulinemia and may suffer a poor prognosis. In individual cases, it even can develop into ML, Kaposi sarcoma, dendritic reticulum cell sarcoma and angiolipoma etc.[10]
Immunohistochemistry and gene rearrangement studies usually have shown that CD is the source of monoclonal cells. In addition it may bring about a severe concurrent infection, renal failure and systemic exhaustion within several months or some years, resulting in death. Therefore multicentric CD has been regarded as an invasive disease.
Follow-up of our 14 cases has shown that all patients have survived to date. The immunoglobulin level obviously increased in 6 of our patients with multicentric-type CD. However, immunohistochemical examination indicated that most of the proliferative lymph nodes were multiclonal, and the therapeutic efficacy was also ideal, with a complete remission of the patients’ condition. Also some researchers suggest, based on histopathological theory, that most CD cases present as a benign disease, similar to hamartoma cases, and therefore CD should be regarded as a benign tumor.
- Received April 13, 2007.
- Accepted April 19, 2007.
- Copyright © 2007 by Tianjin Medical University Cancer Institute & Hospital and Springer
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