A 26 Year Female with an Unusual Cause of Isolated Neck Mass

​

Case Presentation

​

​

Presenter:

​

Dr.Zannatun Nesa

Resident,Phase-B

Department of Haematology,BSMMU

Patient Profile

• Name: Ricta Moni
• Age: 26 year
• Sex: Female
• Religion: Islam
• Address: Gunapara ,Gopalganj

Chief complaints:

• Neck swelling for 9 years
• Generalized weakness for last 2 months

Neck swelling:

• This lady is having swelling in left side of neck for pretty long time around 9 years. It was initially small in size, maintained this size and shape without producing any symptoms since that period of time. So it was left ignored without any intervention
• For the last one year, she noticed that the mass is increasing in size gradually and occupying the posterior triangle of neck
• Now she became worried and decided to consult with a physician
• Though the mass is still asymptomatic and nontender

• She also noticed generalized weakness and easy fatigability for couple of months.
• She could perform her daily activities without having significant difficulties.

• No history of fever, night sweats and significant weight loss.
• Also no cough, contact with any open case of PTB
• Neither she has any local compressive symptoms or neurological features

​

• Past medical history:
• Unremarkable with no significant childhood disease.

​

• Menstrual History:
• Patient is in reproductive age with normal menstrual cycle

​

• Patient has came from middle class family and has completed her primary education

​

• Immunization History:
• Patient is immunized as per EPI schedule
• Transfusion History:
• No blood transfusion during her ailment
• Family History:
• All her family members including parents and sibling are of good health

• General examination reveals:
• Moderately anemic
• Non Icteric
• No Bony tenderness present
• Thyroid gland is not enlarged
• There is scar mark of biopsy in posterior triangle of left side of neck
• All vital parameters are normal

• Abdominal Examination reveals:
• Abdomen is normal in size and shape,
• Umbilicus central
• There is no organomegaly
• Upper border of liver dullness is in Rt 5^th ICS

• All other systemic examination was unremarkable

What could be the possible diagnosis?

Investigation Profile

• Peripheral blood film:
• RBC: Anisocytosis with anisochromia
• WBC: Mature with increased in number. Predominant cells are neutrophil
• Platelet: Normal

Comment: Neutrophilic leukocytosis

Investigation Profile

​

​

Imaging study

• Chest X ray
• Normal finding
• Ultra sonogram of W/A:16/10/19
• Normal. No organomegaly or intra-abdominal lymphadenopathy

Whole body FDG PET-CT

• FDG avid cervical and bilateral inguinal lymph nodes;likely to be active lymphoma
• Low FDG avid nodule in right lung ,needs follow up and further evaluation
• Hepatomegaly with fatty change

Bone Marrow and Trephine Imprint Report

• Inadequate marrow particle however aspirated marrow blood reveals erythropoiesis active and dimorphic with some dysplastic changes. Granulopoiesis is active and maturing into segmented form. Megakaryocyte and lymphocytes are normal. Ectopic and parasites are not found.

Trephine biopsy:

• Hypoplastic marrow

Cytopathology report

Histopathology Report

• Gross
• Lymph node measuring about 4.5cm in diameter. Cut surface is grayish yellow, solid and homogenous
• Microscopic
• Sections of the lymph node shows feature of low grade follicular lymphoma

​

​

​

​

​

​

Immunohistochemistry Report

• Microscopic description: Section revealed lymph node. The node contains many lymphoid follicles ,a few of which regressively transformed and having sclerosed border. At places multiple germinal centers are found to be surrounded by a single mantle zone-overall histologic features are suggestive of a reactive process like Castleman disease

​

Immunohistochemistry :

• Follicles are composed of CD20 positive B cells with negative centers of regressively transformed germinal centers

​

• CD10 positive cells are present at the center of those BCL2 negative follicles. The other follicles/nodules are B cells positive for BCL2 but negative for CD10 and positive for IgM .

​

• Inter-follicular zone is occupied by CD3 positive T cells with distinct paucity of CD20 positive cell

• No CD10 positive cell is present in the inter-follicular area .

​

• CD21 shows compact and expanded network of follicular dendritic cells as expected in Castleman disease.

Immunohistochemistry

• Morphology:

Section of lymph node shows extensive onion peel rings of mantle cells around atrophic follicle centers, hyaline vessels wall changes in follicle and para cortical venule prominence with lymphocyte and some plasma cells in the para cortex

• On the basis of:
• History
• clinical examination
• Bone marrow study
• Immunohistochemistry

Final Diagnosis:

Unicentric or Multicentric Castleman Disease?

Introduction

• Castleman disease (CD)
• Also known as angiofollicular lymph node hyperplasia or giant lymph node hyperplasia
• First reported Benjamin Castleman, in 1954
• It comprises a rare and heterogeneous cluster of lymphoproliferative disorders,

characterized by lymphadenopathy

unique histological features and

associated with cytokine-driven constitutional symptoms

biochemical disturbances

Epidemiology

• The incidence of CD is estimated at 21–25 cases per million person-years
• 23% of those cases potentially representing multi centric CD
• The median age

For UCD is much lower (30–34 years)

For HIV-negative MCD (49–66 years),

HIV-positive MCD falling in between (36–40 years)

• The sex distribution is approximately equal, slight male predominance

HIV associated cases

• There is a predominance of HIV- and HHV-8-negative MCD in the Polynesian population, with more favorable disease outcome.

​

• Although other geographic variations likely exist, it is unclear whether these relate mainly to epidemiological characteristics or if pattern of clinical presentation differs according to location

Types of Castleman disease

The three subtypes are as follows:

​

1)Unicentric CD (UCD) involves a single region of enlarged lymph nodes

2)Human herpesvirus 8 (HHV-8)–associated multicentric Castleman disease (HHV-8-associated MCD)

• Involves 2 or more regions of enlarged lymph nodes
• Immunocompromised individuals, such as those with Human immunodeficiency virus (HIV) infection

3)HHV-8–negative/idiopathic multicentric Castleman disease (iMCD)

• Multiple regions of enlarged lymph nodes

Cause of iMCD is unknown known, but hypothesized etiologies include acquired mutations in a clonal cell population, inherited mutations leading to autoimmunity or autoinflammation, or a pathogen.

​

Etiology and pathogenesis

• The overall understanding of the etiology and pathogenesis of CD remains limited
• MCD may be subdivided by HHV-8 status, reflecting a role of this virus
• All HIV-positive MCD cases are strongly associated with HHV-8 infection
• The distinct phenomenon of HIV- and HHV-8-negative MCD has been termed “idiopathic MCD”
• UCD is not typically associated with HIV or HHV-8 infection
• The discovery of the link to HHV-8 and role of IL-6 have provided valuable insights into CD pathophysiology

HHV-8 in MCD and other associated disorders

• HHV-8 or Kaposi’s sarcoma-associated herpes virus, is a gamma herpesvirus
• Strongly implicated in the pathogenesis of acquired immunodeficiency syndrome-related primary effusion lymphoma ,Kaposi’s sarcoma as well as a subset of MCD cases
• All HIV-positive MCD cases are strongly associated with HHV-8 infection
• The distinct phenomenon of HIV- and HHV-8-negative MCD has been termed “idiopathic MCD”

• HHV-8 has the capacity to infect many different cell types, including B-lymphocytes, macrophages, and endothelial cells
• Kaposi’s sarcoma is of endothelial origin while primary effusion lymphoma and MCD are B-cell lymphoproliferative disorders
• In MCD, HHV-8 appears to preferentially infect IgM positive memory B-cells
• Induce their proliferation and differentiation into the characteristic plasmablast phenotype observed

The pathogenic contribution of IL-6

• Excess IL-6 production is observed within the germinal centers of involved lymph nodes
• Following lymph node resection in a patient with UCD, there is the reduction in patient symptoms and
• Fall in serum IL-6, acute phase reactants such as C-reactive protein (CRP) and hypergammaglobulinemia

• Overproduction of hIL-6 may occurs via activation of the nuclear factor kappa B pathway

​

• Also latency-associated nuclear antigen (LANA)-mediated up regulation of IL-6 transcription

​

• Promotes the secretion of vascular endothelial growth factor (VEGF), resulting in angiogenesis

​

• This may contribute to the prominent capillary proliferation that is a histological characteristic found in hyaline vascular subtype of CD.

• The anemia in MCD appears to be mediated by IL-6-driven hepcidin overproduction

​

• Administration of anti-IL-6 monoclonal antibody in patients with anemia and elevated serum hepcidin levels resulted in a rapid decline in hepcidin levels and correction of anemia

​

• Anti-IL-6 monoclonal antibody therapy also abolishes CRP production

​

• All these establish it as a convenient marker of IL-6 bioactivity and facilitating monitoring of pharmacodynamic effects

Pathological Subtypes

Clinical manifestations

• UCD present with isolated lymphadenopathy

​

• It may be asymptomatic or have symptoms relating to mass effects on surrounding structures

​

• The main sites of disease are the chest (29%),neck (23%), abdomen (21%), and retroperitoneum (17%)

​

• other lymph node groups (axillary, inguinal) and the pelvis are also potential sites of involvement

• Systemic symptoms are a common feature of MCD

​

• “B”symptoms such as fever, night sweats, and weight loss

​

• Generalized lymphadenopathy and hepatosplenomegaly

​

• Vascular leak syndrome (ascites, pericardial effusions, pleural effusions, and/or peripheral edema)

​

• Anemia ,immune thrombocytopenia and acquired factor VIII deficiency

​

• Bronchiolitis obliterans, glomerulonephritis and pemphigus

• MCD may be seen in association with the POEMS syndrome, which comprises polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes

​

• A clinicopathological variant of CD has also recently been reported in Japan, characterized by low-volume lymphadenopathy with CD histology (usually mixed-type or, less commonly, the hyaline vascular variant) in association with thrombocytopenia, ascites, myelofibrosis, renal dysfunction, and organomegaly, termed the TAFRO syndrome

Diagnosis

• Common laboratory findings include

Anemia,thrombocytopenia, hypoalbuminemia, polyclonal,

hypergammaglobulinemia, and

• Raised CRP.
• Raised circulating IL-6 and VEGF
• Imaging findings may reveal lymphadenopathy and organomegaly, as well as other features of disease, such as sclerotic bony lesions or pulmonary infiltrates
• PET scan

• The diagnosis of CD is made on analysis of involved lymph node tissue showing classic histological features.
• Histopathologically, the lymph nodes demonstrate a contellation of "CD-like" features along a spectrum, including small or large germinal centers, follicular dendritic cell (FDC) prominence, hypervascularity, polyclonal plasmacytosis, and/or expansion of polyclonal B cells and T cells.

​

• Lymph node features of the different histopathological subtypes of UCD are as follows:

​

• Hyaline vascular – Atrophic germinal centers, onion-skinning mantle zones, hypervascularization, and FDC prominence
• Plasma cell – Hyperplastic germinal centers as well as occasional atrophic germinal centers and interfollicular plasmacytosis
• Mixed – Lymph nodes demonstrate features of both the hyaline vascular and plasma cell subtypes

​

• Immunohistochemical staining for LANA or polymerase chain reaction testing
• Detection of plasma HHV-8 viral DNA is not helpful

Overview of current therapeutic strategies and outcomes

​

Unicentric Castleman disease

1)Surgery: Complete surgical resection is curative for UCD( 10-year overall survival rates in excess of 95%.3)

• If this is not feasible, the optimal treatment strategy is not well-defined
• Debulking surgery particularly if there are local symptoms

2)Systemic options: (as used for MCD)may also be utilized

​

3)Radiotherapy :Alternative treatment option in unresectable cases of UCD

​

Treatment of multicentric Castleman disease

• A range of systemic therapies have been utilized in MCD
• Cytotoxic chemotherapy
• Antibodies directed against CD20 as well as IL-6 and its receptor
• Immunomodulators
• Bortezomib
• Antiviral agents

Chemotherapy

1. Chemotherapeutic options include the following:
• Low-dose single-agent chemotherapy, daily oral etoposideor intermittent etoposide or vinblastine these may facilitate symptom relief, but disease control tends to be lost rapidly after treatment cessation.
• Single-agent cladribine
• Combination chemotherapy, such as CHOP or equivqlent such as CVAD,COP, chlorambucil +prednisolone

2.Rituximab

• Significant activity in HIV-positive and idiopathic MCD
• Used either as monotherapy or in combination with chemotherapy
• In combined with chemotherapy like intravenous etoposide or liposomal doxorubicin in the HIV-positive population

​

3.Antiviral agents

• Limited trials of antiviral agents in HIV- and HHV-8- associated MCD have been undertaken (high-dose zidovudine and valganciclovir )

4)Other

• Corticosteroids may offer effective symptom relief .Case reports and small series of interferon α, thalidomide, lenalidomide, bortezomib and autologous stem cell trasplantation have also been published

5)Emerging use of biologics:(Anti-IL-6 therapy)

• The advent of monoclonal antibody therapy targeting the IL-6 pathway has significantly impacted the treatment of patients with idiopathic MCD. Agents that have been studied include siltuximab, and tocilizumab,

Long-term outcome

• UCD enjoy excellent long-term outcomes after complete resection 10-year overall survival rates greater than 95%
• Unresectable UCD cases, radio - therapy may offer good long-term response rates (82% overall survival at 20 months)
• The HIV- and HHV-8-associated subtype of MCD has the worst prognosis, earlier prior to rituximab patient dies within 2 years of diagnosis.

• Introduction of rituximab improves these outcomes somewhat, with 2-year overall survival over 94%,
• Finally anti-IL-6 therapy, a systematic literature review identified a 3-year disease-free survival rate of 45.7% in HIV-negative patients

​

THANK YOU ALL