Castleman’s disease - surgical treatment, case reports

Summary

The authors describe their experience with surgical treatment of benign rare lymph proliferation - Castleman’s disease (CD). It occurs in unicentric and multicentric forms. The very low incidence of the disease makes it very difficult to design larger prospective studies. Cases of two leading localizations of the unicentric form of CD - intrathoracic and retroperitoneal with special emphasis on the preoperative diagnosis and imaging options are described. This article underlines the curative potential of surgical treatment where a complete resection of the affected lymph node leads to eradication in almost 100% of the cases. The discussion is focused on the forms of CD - different localization, clinical symptoms and course of disease. It discusses the differential diagnosis, particularly difficult in the multicentric form, emphasizing the need to exclude malignant lymphoma. The etiopathogenesis of the disease is presented, mentioning its association with HIV (Human Immunodeficiency Virus) infection and HHV-8 (Human herpers virus 8) infection and the importance of overproduction of proinflammatory cytokines. The importance of surgical therapy for the unicentric form of CD is highlighted as compared to the multicentric form, where the surgeon´s task involves taking a biopsy - required for an accurate diagnosis.

Key words:
Castleman’s disease – lymphoproliferation – lymphadenopathy – surgical treatment

Introduction

Castleman’s disease (CD) is a rare non-clonal lymph proliferative disorder of unknown etiology first described in 1954 by Benjamin Castleman [1,2,3]. It is a benign tumorous process of lymphocyte cell lines, whose multiplication leads to excessive expansion of lymph nodes. This is found most frequently in the mediastinum, neck, abdomen and retroperitoneum [4,5]. This disease is also known as angiofollicular hyperplasia and may be associated with HIV (Human Immunodeficiency Virus) infection, HHV-8 (Human herpesvirus 8) and POEMS syndrome (Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome) [6,7]. The incidence of this disease is not yet established.

The disease occurs in two clinical forms with different prognoses, treatments and symptoms: a unicentric form, i.e. solitary, localized, and a multicentric form, generalized [1,8,9]. This distinction is important for prognosis and determination of the type of therapy. In the unicentric form, surgical extirpation “in toto” is the method of choice. However, in the multicentric form, the role of surgery is limited to obtaining a biopsy or resection of a lesion to reduce the pressure on the surrounding structures as a symptomatic treatment, without curative potential. According to histopathology, the hyaline vascular type is the most frequent with an incidence of 70–90%, plasma cell and mixed types are distinguished.

The following two case reports present the most common locations of unicentric Castleman’s disease.

Case report 1

A 57-year-old male with no history of serious diseases or subjective complaints underwent a urological screening. The ultrasound of the abdominal cavity revealed an approximately 10 cm retroperitoneal expansion. Biopsies were done with suspicion of the hyaline vascular variant of CD.

Abdominal PET-CT scans detected a retroperitoneal bulky shaped formation 9x8x10cm in size, compressing the surrounding inferior cava vein, biliary tract, pancreas and duodenum, without enlargement of the peripheral lymph nodes, confirmed by clinical examination (Fig. 1a, 1b, 2). During surgery, a bulky tumor was found in the right retroperitoneal subhepatic area, with significant compression to all the surrounding structures (Fig. 3a, 3b). After gradual release of the tumor from surrounding structures, it was removed in one piece, including peri-tumorous nodules corresponding to the surrounding lymph nodes.

Histological examination confirmed CD. The lesion histopathologically corresponded with the conventional hyaline-vascular type; however, due to the presence of frequent polyclonal plasma cells interfolicullary, it cannot be ruled out that it is a “transitory” type (according to some authors). Screening for B clonality showed no clonal character.

The postoperative period exhibited an uncomplicated course with only minor problems regarding the laparotomy, which regressed after conservative local therapy.There is no further requirement for adjuvant therapy and the patient´s follow up continues at the department of Hematooncology without detection of disease recurrence. The patient feels well.

Case report 2

A 27-year-old man with a positive family history (father and grandfather had lung cancer) investigated in the University Hospital Brno for chest pain, weakness, shortness of breath on exertion, without cough, after untreated catarrh of the upper respiratory tract. The patient was a non-smoker, otherwise healthy, without any regular medication. The chest X-ray revealed a spherical shadow 4 cm in diameter in the right hilum (Fig. 4). Antibiotic treatment was started. The chest CT showed a nodal tumor formation in close proximity to the structures of the right hilum; probably benign (Fig. 5a, 5b). Bronchoscopy showed no direct signs of a tumor, only a flare swelling of bronchus 6 and basal right bronchus. According to histology and cytology, only inflammatory changes were detected without any oncological findings. The follow-up chest X-ray confirmed a tumor of stationary size. The differential diagnoses considered were hamartoma, adenoma, hemangioendothelioma, a neuroendocrine tumor and possibly a carcinoid. The patient was indicated for surgery.

Peroperatively, an infiltrate of 3x4x2 cm in size was located in the interlobium of the middle and lower lobe (the right lung) between vessels and the bronchus of the lower lobe and showed no evidence of infiltration to the surrounding tissue. Lymph nodes and a sample of infiltrate were sent for cryosection which confirmed the sample as CD. The infiltrate was extirpated “in toto” with lymphadenectomy of the surrounding mediastinal lymph nodes. The postoperative course was uneventful. Definitive histology confirmed the hyaline vascular variant of CD, with no signs of malignancy. The patient is in remission, feeling well.

Discussion

This article presents two case reports of unicentric (solitary) forms of CD located in the retroperitoneum and mediastinum, which were radically surgically resected at our department. The unicentric CD form is characterized by a slow, painless enlargement of one lymph node or nodes in one group. The unicentric form of CD is usually not associated with systemic symptoms. The symptoms are usually diverse and begin with compression of adjacent structures. They may include pain, shortness of breath, coughing, dysphonia, dysphagia, diarrhoea, vomiting, postprandial discomfort, weight loss and ischemia due to compression of the main arteries [6,10,11]. According to available literature, the unicentric form is predominantly found in patients between 30 and 40 years of age [11].

The disease can occur anywhere in the lymphatic system. Characteristically, the most common localizations of its unicentric form are: 50% in the chest and neck, 37% in the retroperitoneum and abdominal cavity [11,12] and 10% in parotid gland [5], axilla, groin or small pelvis [11]. Interleukin-6 (IL-6) plays a role in the etiopathogenesis of unicentric CD. Moreover, the incidence among females is slightly higher. The unicentric form, unlike the multicentric one, is not associated with HIV or HHV-8 infection. The diagnosis is based on clinical findings and imaging techniques that reveal infiltrating processes using - CT, MRI, PET-CT. Infiltration may appear on CT as a hypervascularized and heterogeneous tumor containing necrosis, fibrosis and calcification. It is also possible to detect thickening of the peritoneum. Due to its uncharacteristic picture, CD diagnosis is rarely considered at first. The differential diagnosis more frequently considers malignancies such as sarcomas and other mesenchymal tumors, lymphomas, neuroendocrine tumors, including metastatic disease [4,11].

If significant fibrosis and peri-tumorous adhesions to the neighbouring structures are present in CD, intraoperative cryosection is beneficial. CD diagnosis during intraoperative biopsy can prevent an unnecessary extensive resection of adjacent organs, which is not necessary when treating benign tumors. It remains controversial whether to perform preoperative biopsy. Most surgeons prefer a surgical resection without preoperative biopsy when there is a suspicion of malignity and imagining techniques show resectable infiltration [4,13]. The treatment of choice for solitary CD is complete surgical removal of the affected lymph node. Radical surgical resection (R0) is potentially curative; a 5-year survival rate is up to 100% [7,11,12]. However, relapses can occur after subtotal or partial resection. Histologically, the most common type of this variant is the hyaline vascular type (up to 90%), which has a good prognosis. In the presence of tumor neovascularization, protruding vessels develop and adhesions to the surrounding structures occur. Resection of the hyaline vascular type of CD may be associated with a larger perioperative blood loss. In patients, where surgical resection would be excessive risk, radiotherapy appears to be a suitable alternative, which shows a complete remission in 50% of cases [6,11]. The literature also describes cases in which neoadjuvant therapy using Rituximab has the effect of reducing the infiltrate and increasing the success of subsequent R0 resection in case of primary inoperable CD infiltration [4,14].

The second clinical form is multicentric CD. This form often has systemic symptoms: – anemia, fever, night sweats, weight loss, fatigue, generalized lymphadenopathy, polyclonal hypergammaglobulinemia, hypoalbuminemia, thrombocytopenia, elevated erythrocyte sedimentation rate, elevated CRP, hepatomegaly, splenomegaly, peripheral edema, impaired renal function, polyneuropathy, etc. [7]. The multicentric form occurs predominantly in patients in the 5^th and 6^th decade. The most common histological type is plasma cell variant [6,11]. This form is often refractory to treatment as well as intensive chemotherapy. Surgery for multicentric forms is rather limited to gaining a biopsy or debulking resection of the symptomatic infiltrate compressing the surrounding structures. It has no curative potential [6,11,12]. The multicentric form of the disease has a significantly worse prognosis, and especially in combination with HHV-8 positivity is a risk factor for transformation to lymphoma [1,11]. It may be accompanied by immunodeficiency, secondary amyloidosis etc. Despite the introduction of an aggressive form of treatment, mortality, disease relapse and malignant transformation is high with a 5 year survival of around 40% [1,11,15].

Chemotherapy (regimens designed for the treatment of non-Hodgkin’s lymphoma), antiviral, biological (monoclonal antibody rituximab) and immunomodulating therapies (thalidomide) constitute the main treatment modalities. Furthermore, the multicentric form of CD is usually not considered among the first diagnoses due to nonspecific and variable symptoms. Despite characteristic findings on imaging studies (hypervascularized tumor masses with fibrous adhesions), lymphoma and other tumors – sarcomas, teratomas, also carcinoma, neuroendocrine tumors, or metastases are considered first. In the differential diagnosis of lymphadenopathy, it is important to distinguish multicentric CD from malignant lymphoma, sarcoidosis, as well as rheumatoid arthritis, reactive lymphadenopathy, HIV infections, lupus erythematosus and chronic infections [11]. In patients with multicentric CD, it is appropriate to perform laboratory testing for HHV-8, HIV and IL-6.

For the pathologist, a diagnosis of CD may not be easy either. The diagnosis may be clear in case of unicentric hyaline vascular variant with expressed morphological signs. Especially in the plasmocellular variant, the morphological features are non-specific and a clinical suspicion or repeated biopsy of lymph nodes with the greatest activity on PET scans can lead to the correct diagnosis [11,12].

Learning points

CD is a rare non-clonal lymph proliferative disorder of unknown etiology. It is a benign tumorous process of lymphocytes, their multiplication leads to an excessive expansion of the lymph nodes. This is found most frequently in the mediastinum, neck, abdomen and retroperitoneum. This disease is also known as angiofollicular hyperplasia and may be associated with infection by HIV, HHV8 and POEMS syndrome. The disease occurs in two clinical forms with different prognoses, treatments and symptoms: a unicentric form, i.e. solitary, localized, and a multicentric form, widespread. In the unicentric form, surgical extirpation “in toto” is the method of choice. However, in the multicentric form, the role of surgery is limited to obtaining a biopsy and resection of the lesion to reduce the compressive force on the surrounding structures as symptomatic treatment, without curative potential. According to histopathology, hyaline vascular type is the most frequent with an incidence of 70−90%.

Conclusion

CD is an illness of unknown etiology and incidence. Current findings are based on case studies. Due to the rarity of this disease, it is challenging to design a prospective study. It is a lymph proliferative disease characterised by enlargement of one or more lymph nodes. It is important to think about this disease in the differential diagnosis when finding a tumorous mass in the retroperitoneum or mediastinum, but also in lymphadenopathy with nonspecific systemic symptoms: fever, anemia, and weight loss. In unicentric CD, prognosis is dependant on a complete surgical resection of the mass, which has a curative potential unlike in the multicentric form - where the role of surgery is generally to verify the diagnosis.

Abbreviations:

CD - Castleman’s disease

HIV - Human Immunodeficiency Virus

HHV-8 - Human herpesvirus 8

POEMS syndrome - Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome

IL-6 - Interleukin-6

Conflict of Interests

The authors declare that they have not conflict of interest in connection with the emergence of and that the article was not published in any other journal.

Lumir Kunovsky, M.D.

Department of Surgery, University Hospital Brno Bohunice,

Jihlavska 20,

625 00 Brno

e-mail: lumir.kunovsky@gmail.com