Introduction
Castlemans disease (CD) was described by
Benjamin Castleman in 1954. The disease today is enumerated among lymphoproliferative disorders. The disease shows various clinical and histological pictures, with a localized type (involvement of one lymph node group) described more frequently than the multicentric one. Unicentric presentation responds well to surgical resection and is associated with a benign course. The multicentric presentation requires systemic therapy and prognosis is guarded.1 Variable benefit has been achieved with single agent chemotherapy, combination chemotherapy, interferon (IFN)-alpha, rituximab, anti-IL-6 receptor antibodies, and thalidomide.2 We report a case of multicentric Castlemans disease which showed complete remission on treatment with tumour ‘vaccine’ prepared from patients own excised lymph nodes.
Case Report
A 52 year old female patient presented in 1997 with complaints of on and off low-grade fever of twelve weeks duration associated with tiredness, backache and decreased appetite. There was no history of loss of weight/haemoptysis. Her physical examination revealed palpable axillary lymph nodes. The nodes were firm in consistency, matted, non-tender with a normal overlying skin. Ultrasound of the abdomen picked up enlarged hypoechoic para aortic lymph node of size 2.5 x 1.5 cms. HIV status of the patient was negative. Biopsy of the left axillary lymph node was done at that time. Histopathological examination showed lymph node architecture to be fairly well preserved with appreciable follicular hyperplasia spread throughout. There was increased vascularity of the lymph node parenchyma with prominent capillary venules. These arborising vessels traversed the parenchyma with an occasional one seen in the centre of the follicles. Some of them showed mild thickening with hyalinization. The mantle zone appeared widened with few atypical lymphocytes. The germinal centre showed transformed lymphocytes. These features were suggestive of angio follicular lymphoid hyperplasia or Castleman’s disease.
Patient continued to have on and off fever. An ultrasound examination done on 27/Sep/2000 showed multiple para aortic, para caval, retro peritoneal, pelvic and iliac group of lymph nodes, the largest of which measured 5.8 x 1.9 cm in the para aortic region (Fig. 1 and Fig. 3). Multiple lymph nodes were also palpable in both the axillae.
Meanwhile, a research was going on in our hospital in which sarcomas were implanted into vistar rats and a tumour vaccine was prepared from these sarcomatous tissues. This tumour vaccine when injected intradermally into the rats was shown to decrease the size of the implanted sarcomas. Moreover, when the progeny of these rats were pre vaccinated with this ‘vaccine’ it was found that they failed to take up the externally implanted sarcomas implying that they had developed immunity to the sarcoma.
Taking inspiration from the success of these experiments and their results, it was decided to start the treatment of the patient with the tumour vaccine indigenously prepared in our hospital from the patient’s own excised lymph node. All the treatment options, their effectiveness and costs were explained to the patient and her relatives. She was also apprised of the results of our animal experiment that were the basis for this novel therapy. The treatment was started after obtaining the due informed consent from the patient.
The method for preparing the tumour ‘vaccine’ is simple and straightforward. An enlarged lymph node from the patient’s axilla was resected, irradiated and its unwanted components removed. It is stored in deep freezer and brought back to room temperature prior to use.
The tumour vaccine, 0.5 ml intradermally, was given at fortnightly interval and was supplemented with a monthly dose of 40 mg of Bacillus Calmette Guerin (BCG) vaccine sub cutaneously. Complete blood count of the patient was evaluated every 2 weeks. The patient was monitored for the disease progression/regression with the help of abdominal ultrasonography wherein the number and sizes of lympnodes were compared with the previous scan. Ultrasound examination done 7 months after starting the vaccine therapy showed an overall reduction in the sizes of the lymph nodes except for the right para caval adenopathy. Ten months post therapy the nodes in the axilla had decreased in size. Tumour vaccine was stopped after 22 months by which time the nodes in the axilla had become non palpable. After this the vaccine had to be stopped as its stock had exhausted. An abdominal ultrasound examination done 8 months after stopping the tumour vaccine showed regression in the size of the lymph nodes (Fig. 2 and Fig. 4).
However, the lymph nodes began to increase in size and number after 14 months of discontinuing the vaccine therapy and had reached the pre-treatment size by 20 months. It was decided to start the tumour vaccine therapy once again. A left axillary lymph node biopsy was done and tumour vaccine was prepared from the excised lymph nodes. A complete regression of the para aortic, coeliac and iliac lymphadenopathy was obtained by 6 months of tumour vaccine therapy, and a considerable regression in other regions as documented by the ultrasonography.
Tumour vaccine was continued till date and at the time of writing this report, the patients ultrasonography shows complete regression of intra abdominal lymphadenopathy except one enlarged lymph node just above the aortic bifurcation.
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Fig. 1 : An ultrasound scan prior to treatment shows massive retroperitoneal lymphadenopathy.
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Fig. 2 : An ultrasound scan of the same regions as in Fig. 1 after 16 months of treatment by ‘vaccine’ shows complete remission of the lymphadenopathy |
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Fig. 3 : A trans-abdominal ultrasound of the pelvis prior to treatment shows massive pelvic lymphadenopathy.
BL=Bladder, LN=Lymph nodes
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Fig. 4 : An ultrasound of the pelvis after treatment with tumor ‘vaccine’ shows complete remission of the pelvic lymphadenopathy. BL=Bladder, UT=Uterus |
Discussion
Castleman’s disease (CD) was described from Benjamin Castleman in 1954.1
Synonyms:
- Angiofollicular Lymph Node Hyperplasia
- Angiomatous Lymphoid
- Castleman Tumor
- Giant Benign Lymphoma
- Hamartoma of the Lymphatics
- Giant Lymph Node Hyperplasia
The disease today is enumerated among lymphoproliferative disorders and has known aetiology, but an interleukin-6 (IL-6) dysregulation and a reaction to viral antigens (HHV8) especially in patients with immunodeficiency is suspected. It is observed in adult and young people, in male or female with equal frequency; the appearance in childhood is extremely rare. The disease shows various clinical and histological pictures, with a localized type (involvement of one lymph node group) described more frequently than the multicentric one. Histological examination distinguish a “hyaline-vascular type” that represents approximately the 91%, “a plasma cell type” that represents approximately the 9% has an aggressive clinical outcome, and the “mixed types”. Initial symptoms are nearly absent, but not for the plasma cell type.1
The plasma cell type of Castleman’s Disease may be associated with fever, weight loss, skin rash, early destruction of red blood cells, leading to unusually low levels of circulating red blood cells (haemolytic anaemia), and/or abnormally increased amounts of certain immune factors in the blood (hypergammaglobulinaemia).
The pathology found with the unicentric presentation is most commonly that of the hyaline vascular variant. It responds well to surgical resection and is associated with a benign course. The multicentric presentation is rarely composed of lymph nodes with hyaline vascular pathology, but rather with the plasma cell of mixed pathology. This presentation requires systemic therapy and prognosis is guarded. Associated systemic symptoms are common. There is an increased incidence of Castlemans disease in patients with HIV. The human herpes virus-8 is associated with nearly all of the HIV-associated CD cases and nearly 50% of non-HIV cases. Interleukin (IL)-6 has also been shown to play a significant role in the pathogenesis of the disease. MCD is associated with Kaposi’s sarcoma herpes virus (KSHV) infection, which is alternatively termed human herpes virus 8 (HHV8). This virus encodes a homologue of interleukin 6 (VIL 6), which may mediate some systemic features of MCD. Paraneoplastic and autoimmune entities are not uncommon in the disorder.2
A literature review by Anungiata et al yielded 31 cases of Castleman’s disease with an abdominal localization. Retroperitoneal, mesenteric and pelvic sites have been reported and the diagnosis was incidental in almost all cases and detected at US, CT scan or MRI an angiography. If the lymphadenopathy was less than 5 cm, centripetal, homogeneous contrast enhancement was apparent during CT scan or MRI, versus dyshomogeneous enhancement for a lymph node with a diameter above 5 cm.3
The diagnosis of Castleman’s disease is established by biopsy and treatment is often based on published case reports only, as there are no randomized trials of therapy. Surgery has less of a role in MCD than in localized disease, but debulking by splenectomy may be useful to alleviate haematological sequelae. Systemic treatments for MCD have included chemotherapy, anti-herpes virus treatments to reduce the KSHV viral load, highly active antiretroviral therapy (HAART) to reduce HIV viraemia and latterly monoclonal antibodies against both IL6 and CD20. The introduction of HAART has altered the natural history of HIV infection; however, its impact on MCD is difficult to ascertain.4
Variable benefit has been achieved with single agent chemotherapy, combination chemotherapy, interferon (IFN)-alpha, rituximab, anti-IL-6 receptor antibodies, and thalidomide. Patients with CD are at increased risk for developing frank malignant lymphoma.2
We found that the treatment of Castleman’s disease by this indigenously prepared tumour vaccine was effective, safe and easy to carry out. Although our patient did show a recurrence of lymphadenopathy after a remission of about 6 months, the tumour vaccine was restarted and the patient again showed remission of lymphadenopathy. And therein lies the greatest advantage of this therapy; the vaccine can be prepared as and when required and the therapy can be repeated. Other advantages of this therapy include the ease and simplicity of vaccine preparation, the absence of deleterious side effects, cost effectiveness and above all the remission of the disease. Although recurrence of lymphadenopathy was observed, it is promptly treated by a fresh course of tumour vaccine.
Conclusion
Although various therapeutic alternatives like chemotherapy, anti-herpes virus therapy and anti-retroviral therapy have been proposed the optimization and consensus in treatment of these patients remains a target for the future.
References
- Cammisuli E, Catania V, Santuccio A, Pennisi S. Castleman’s disease: a case report. Ann Ital Chair 2003 Nov.-Dec.;74 (6) : 713-6.
- Dispenzieri A, Gertz MA. Treatment of Castleman’s Disease. Curr Treat Options Oncol 2005 May; 6 (3) : 255-66.
- Annunziata G, Martino P, Palazzo S, et al. US with contrast medium in the diagnosis of abdominal Castleman’s disease. Arch Ital Urol Androl 2005 Mar; 77 (1) : 76-8.
- Waterston A, Bower M. Fifty years of multicentric Castleman’s disease. Acta Oncol 2004; 43 (8) :
698-704.
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