CASTLEMANS DISEASE.

DR. GULZAR ALI MCPS RESIDENT NATIONAL MEDICAL CENTRE

 Also referred to as angiofollicular lymph node

hyperplasia (also known as angiofollicular lymph node hyperplasia or giant lymph node hyperplasia ) is an uncommon benign lymphoproliferative condition. It can affect several regions of the body although commonly described as a solitary mediastinal mass.

Background
Etymology

First described by Benjamin Castleman in

1956 follicular hyperplasia of lymph nodes with abnormally increased interfollicular vascularity Can be associated with Kaposi's sarcoma (KS), non-Hodgkin's lymphoma, Hodgkin's lymphoma, and POEMS syndrome.

Differential diagnosis
For thoracic lesions consider

If antero-superior : consider : differential for

an antero-superior medistinal mass

If posterior : consider : differential for a

posterior medistinal mas

The differential diagnosis for a posterior mediastinal mass includes neurogenic tumours schwannoma neurofibroma malignant peripheral nerve sheath tumour neuroblastic tumours neuroblastoma ganglioneuroma non-neurogenic tumours chordoma 2 phaeochromocytoma 3 paraspinal abscess descending aortic aneurysm oesophageal neoplasm hernias hiatus hernia Bochdalek hernia lymphadenopathy or lymphoma 1 extramedullary haematopoiesis foregut duplication cysts neurenteric cyst oesophageal duplication cyst thoracic meningocoele

The differential diagnosis for an anterior mediastinal mass includes: thymus thymoma : most common primary neoplasm of the anterosuperior mediastinum invasive thymoma thymic carcinoma thymolipoma / thymoliposarcoma thymic cyst benign thymic hyperplasia thymic carcinoid thyroid and parathyroid thyroid neoplasms thyroid goitre parathyroid neoplasms lymphoma Hodgkin lymphoma non-Hodgkin lymphoma (NHL) germ cell tumours mediastinal teratoma mature : 75% of mediastinal germ cell tumours immature teratocarcinoma (malignant teratoma) mediastinal seminoma mediastinal embryonal cell carcinoma mediastinal yolk sac tumour mediastinal choriocarcinoma mediastinal mixed cell type germ cell tumour thoracic aortic aneurysm

Epidemiology
The condition can potentially present at any

age but typically presents in the 3rd to 4th decades.

Pathology
The disease is of unknown etiology but the

most widely accepted theory is that Castleman's disease is a chronic low-grade inflammatory process. The disease is characterised by hypervascular lymphoid hyperplasia. There are two distinct sub-types of Castleman disease : uni-centric (UCD) and multi-centric (MCD). Uni-centric disease is more common

 There are also two recognised sub types

based on histology 1,2 hyaline vascular : commoner ~ 90% more uni-centric plasma cell : often multi-centric less enhancing may be more symptomatic 5

Location

The distribution is as follows :

thorax : ~ 70 % abdomen / pelvis and retroperitoneum : ~ 10 -

15 % neck : 10 - 15 %

Types of CD
Unicentric vs. Multicentric

Hyaline vascular vs. Plasmacytic vs.

Mixed cellularity variety based on histopathology HIV associated vs not

 Multi-centric disease may involve all of the

above, and is associated with a more complex clinical course and poorer prognosis.

Associations
POEMS syndrome

osteosclerotic myeloma
Kaposi sarcoma AIDS - espacially multicentric amyloidosis10
9

 A number of tests can help your doctor determine if

you have Castleman disease, although unicentric Castleman disease may be found incidentally. People with unicentric Castleman disease often notice no symptoms, and the diseased lymph node is found during screening or treatment for another illness, such as during a CT scan or during abdominal or chest surgery. Tests your doctor may conduct to diagnose either unicentric or multicentric Castleman disease include:

Physical examination
. Your doctor may examine not only your

swollen lymph nodes but also your other lymph nodes to determine their size and consistency.

Radiographic features
CT

Blood and urine tests

. Blood and urine tests may help your doctor

rule out other infections or diseases. They can also reveal anemia and abnormalities in blood proteins that are sometimes characteristic of Castleman disease.

Imaging techniques
. An X-ray, computerized tomography (CT)

scan or magnetic resonance imaging (MRI) scan of your chest, neck, abdomen and pelvis may detect the presence and number of enlarged lymph nodes. These tests can also determine whether organs, such as your liver or spleen, are enlarged. Positron emission tomography (PET) scans also may be used in diagnosing Castleman disease and later, to assess whether a treatment is working

Lymph node biopsy.

To differentiate Castleman disease from other

types of lymphatic tissue disorders, such as lymphoma.

For mediastinal lesions : CT chest

commonly seen as a mediastinal mass and

rarely as matted lymphadenopathy (with or without a dominant mass) in a single mediastinal compartment typical arborising calcification may be seen within the mass typically shows intense homogeneous enhancement following contrast dynamic CT demonstrates early rapid enhancement with washout in the delayed phase

For abdominal lesions : CT abdomen

most commonly, a single well defined

abdominal mass location is variable, and includes retroperitoneum, mesentery and porta hepatis
3

enhancement is homogeneous, or in larger

lesions ( > 5cm) may demonstrate central hypo-attenuation consistent with necrosis. variable pattern of calcification, including arborising calcification.

For multi-centric disease : multi-region CT

bilateral hilar and mediastinal

lymphadenopathy centrilobular nodules diffuse abdominal lymphadenopathy hepatosplenomegaly ascites

MRI
General signal characteristics include

T1 : iso to hyper intense relative to skeletal

muscle T1 C+ (Gd) : shows enhancement T2 : arborsing calcification may be seen as low signal

FDG - PET
There is some evidence that Castleman

disease is FDG avid, and therefore 18F-FDG PET may be useful in identifying the extent of multi-centric disease and for monitoring disease progression 7.

Unicentric CD
More common Presents as slow growing solitary mass

typically located in the mediastinium or mesenteries. No constitutional sm-s Not associated with progression to malignancy Treated by surgical resection with excellent results

Unicentric CD
Histologicaly Unicentric CD is of hyaline

vascular variety

Multicentric CD
Median age 50-60s ( younger if HIV+)

Widespread lymphadenopathy
Hepatosplenomegaly Can present with systemic sm-s: fatigue,

fever, wt loss, night sweats (overproduction of IL-6). Severe peripheral edema, anemia, hypoalbumenia, peripheral neuropathy

Multicentric CD
Also can be associated with

autoimmune hemolytic anemia multiple myeloma amyloidoisis Pemphigus POEMS

Multicentric CD
Diagnosis by biopsy: Histologicaly usually of

the plasmacytic type or mixed cellularity variety

Prognosis of Multicentric CD
rapidly progressive form can lead to death

within weeks (commonly in HIV+) Chronic persistent form with relapses is more common

HIV association
More likely to be associated with Multicentric

Castlemans Disease More likely to be caused by HHV8 Associated with poor prognosis and progression to malignancy Initiation of HAART may lead to fulminant multicentric CD

HHV-8 Role
Kaposi's sarcoma-associated herpesvirus also known

as HHV-8 HHV-8 is universally found in HIV+ MCD (but only in 40-50% of HIV- MCD) HHV-8 viral load corresponds to the presence of symptoms in CD HHV-8-infected immunoblasts are highly proliferative and may coalesce to form "microlymphomas," or develop into frank lymphoma

IL-6 Role
Possible link between overexpression of IL-6

to the systemic manifestations of CD HHV-8 expresses a viral IL-6 gene (vIL-6) that activates IL-6 receptor This can induce proliferation of human myeloma cell lines

Associated Malignancies
Kaposi's sarcoma (up to 70% in

HIV+/HHV+) Non-Hodgkin's lymphoma (15-20% of pt) Hodgkin's lymphoma (both MCD & UCD) POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes)

Treatment and prognosis

For unicentric Castleman disease treatment

is surgical, with good prognosis (can be curative). Multicentric Castleman disease may be treated with any combination of surgery, chemotherapy and prednisolone 6. Prognosis is relatively poorer.

25-year-old asymptomatic man with right posterior mediastinal hyaline-vascular Castleman's disease

60-year-old woman with thoracic plasma cell Castleman's disease who presented with chest tightness.

32-year-old man with anterior mediastinal hyalinevascular Castleman's disease who presented with anterior chest pain.

26-year-old asymptomatic woman with hyaline-vascular Castleman's disease in right major fissure incidentally found on chest radiographs; interlobar pleural mass with prominent vessels on lesion surface and marked adhesion to adjacent lung tissues were noted during surgery.

32-year-old asymptomatic woman with pericardial hyaline-vascular Castleman's disease incidentally found on chest radiographs; ovoid mass embedded within proliferated pericardial fat adjacent to right atrium was confirmed during surgery.

Therapy for Multicentric CD

Steroids (15-20% eff, not in HIV+)

IV Ig
Antivirals (acylovir/gancyclovir/foscarnet) in HIVand

HHV8 + population Rituximab (complete remission in few cases) CHOP or CVAD (90% eff) Anti-IL6 or anti-IL6 receptor antibody. Thalidomide (anecdotal)