Lymphomas, Nephroblastoma, Neuroblastoma and hepatoblastoma

By

Dr. Maryam Shehu

BHUTH JOS

OUTLINE

• Introduction
• Classification
• Aetiology/Pathogenesis
• Clinical features
• Investigation
• Treatment
• Prognosis
• Conclusion

LEARNING OBJECTIVES

• Know the clinical features of these tumours
• Know the differences between Nephro and Neuroblastoma
• Know how to evaluate a child with these tumours
• Overview of their treat

Lymphomas

• Malignant expansion of any of the lymphoid cell series- lymph nodes and lymphoid components of other organs

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• Presents with
• enlarged lymph nodes,
• extranodal massess or
• both

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Classification

A Light Microscopy Classification

• Hodgkin’s lymphoma (HL) – 15%-
• Non-Hodgkin’s Lymphoma (NHL)- 85%

B REAL-Revised European- American Lymphoma classification

• B-cell lymphomas
• T-cell lymphomas
• Hodgkin’s lymphomas

Aetiology/Pathogenesis

• The transformation of cellular behaviour
• occurs when the genes controlling cellular behaviour are altered in some way
• In many cases the cause can not be readily identified
• Certain factors have been implicated in the aetiology of lymphomas

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Aetiology/Pathogenesis

• Aetiological factors in lympomas
• Biological- viruses /bacteria
• Epstein Barr virus (BL, HL, NHL)
• Human T-cell Leukaemia virus type 1
• Human herpes virus type-8 – KS, Lymphoma
• H.Pylori- MALT-lymphoma
• Campylobacter jejuni

-Immunoproliferative Small Intestinal Disease (IPSID)

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Aetiology/Pathogenesis

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Aetiology/Pathogenesis

• Genetic predisposition- Cytogenetics and oncogenes
• Karyotypic abnormalities are found in 80-90% of non-Hodgkin’s lymphomas
• Gene rearrangements occur frequency
• Chromosomal translocation
• Burkitt’s Lymphoma- t(8;14)
• Follicular lymphoma- t(14;18)
• Mantle cell lymphoma- t(11;14)
• Chromosomal deletions

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Clinical Presentation

Hodgkin’s lymphoma

• Primarily a disease of lymph nodes
• Clinical presentation largely depends upon which group of nodes is predominantly affected
• The classical presentation is of painless lymph node swelling
• Majority of patients with HD present with a painless enlarging mass in the neck- usually cervical and supraclavicular nodes

Clinical Presentation

• Occasionally axillary and inguinal nodes may be initially involved
• The enlarged nodes are either single or confluent, rubbery and mobile
• Local symptoms of lymphatic/venous obstruction or pain may occur
• Systemic symptoms like anorexia, weight loss, lassitude or pruritus may occur
• Unexplained fever (PUO), with or without night sweats may be the presenting feature

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Clinical Presentation

• Pel-Ebstein fever (Cyclical fever), may be present
• In NHL, extra-nodal disease is common
• Gastro intestinal (GI) tract or other lymphoid organs, such as the spleen
• Lymphoblastic lymphoma, typically presents with a mediastinal mass or pleural effusion

Clinical Presentation

• In Equatorial Africa
• The classic picture of BL is of a rapidly growing jaw or maxillary tumour
• Children under the age of 5 years
• Abdominal disease is seen in about half of the patients with BL

Clinical Presentation

• Endemic BL may present as an abdominal mass
• Paraplagia may be a presenting feature of Burkitt’s lymphoma
• Paraplagia is of rapid onset, flaccid and accompanied by stool and urine incontinence
• CNS may be involved especially with relapsing diseases
• Intussusception, intestinal obstruction, and occasionally intestinal perforation

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Investigations

• Lymph node biopsy Histology shows the Reed-Sternberg cells in patients with HL- Reed-Sternberg cells are large, abnormal lymphocytes which contain more than one nucleus, or bilobed nucleus resembling ‘owl’s eye’ appearance)

Investigation

• In patients with BL

X-ray of jaw and chest, bdominal USS, CT scan, FNABC, lumbar puncture, ascitic fluid cytology, bone marrow aspiration

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Investigations

• Laboratory tests
• FBC- leukocytosis in 25%, leukopenia in 5%, eosinophia and monocytosis
• ESR- Elevated in 50%
• LFTs- Elevated Alkaline Phosphatase
• U and E, Creatinine, Ca, Po4, UA
• Screen for sepsis and TB

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Staging of HL

• Modifying features
• A No symptoms
• B Fever, drenching sweats or weight loss
• X Bulky disease
• E- Involvement of single, contiguous or proximal extranodal site

Uganda Staging for BL

Treatment

• The actual treatment of lymphoma is primarily chemotherapy with selective use of radiotherapy
• The surgeon may be involved in
• Diagnosis- Biopsy and staging laparotomy
• Resection of localized intra-abdominal disease
• Management of complications of either the disease itself or its treatment

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Treatment

Hodgkin’s Lymphoma

• With modern radiotherapy techniques, effective chemotherapy, proper clinical assessment and improvement in patient care, HL can be cured.
• Treatment is individualized
• Radiotherapy for localized disease (Stages 1 and IIA)
• Chemotherapy for generalized disease (Stages III and IV) and where radiotherapy is not available

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Treatment-HL

• 90% of Stages I and II patients survive at 5 years with radiotherapy alone
• Patients expected to relapse should have in addition combination chemotherapy
• Combination Chemotherapy
• MOPP (Nitrogen mustard, vincristine, Procarbazine and Prednisolone)- effective in inducing complete remission
• ABVD (Adriamycin, Bleomycin, Vinblastine, Dacarbazine)- accepted as first line treatment of choice

Treatment- NHL

Non-Hodgkin’s Lymphoma

• Chemotherapy is treatment of choice for BL
• Surgical debulking if disease is localized and resectable, followed by chemotherapy
• Cyclophosphamide is drug of choice for Burkitt’s lymphoma-single dose of 40mg/kg iv repeated for 3-4 courses at 2-3 weekly intervals or until complete regression
• Response is dramatic- 80-90% complete remission is usually achieved

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Treatment- NHL

• Combination chemotherapy became necessary due to resistance to single agent chemotherapy
• COM of choice
• Cyclophosphamide- 30mg/kg iv days 1 and 14
• Oncovin (vincristine)-2mg/m2 iv days 1 and 14
• Methotrexate- 15mg/m2 orally days 1,2 and 3

Nephroblastoma (Wilm’s Tumour)

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• Most common intraabdominal cancer seen in childhood
• Incidence – 1 in 10,000 children <15years
• Annual incidence(USA): 8/million children <15years
• 350-450 cases/year
• 75% seen in children<5years

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Nephroblastoma

• Age range:- 2 – 9years
• Peak age incidence – 4 years
• Incidence same worldwide but slight female preponderance in USA
• Affects more blacks and African Americans than whites.
• Least common among the orientals
• Locally, paucity of figures:- 5-8 cases/year

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Aetiology/Pathogenesis

• Hereditary – involves a prezygotic event
• Non-hereditary/Sporadic Wilm’s tumour – postzygotic event
• Hereditary WT seen in 20% of all cases
• Hereditary:- young patients, aniridia, familial,

genitourinary anomaly and

bilateral WT

Familial WT – rare (1% of WT cases)

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Associated Anomalies

• Aniridia – 1%
• Hemihypertrophy – 3%
• Beckwith Wiedemann Synd
• WAGR Syndrome (WT, aniridia,GUT, MR)
• Denys – Drash Syndrome:- (male pseudohermaphroditism, diffuse GN dx, WT) – 50% - 90% develop WT

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• Hypospadias
• Undescended testis
• Simpson-Golabi-Behemel Syndrome: macroglossia, visceromegaly and coarse facial features
• Perlman’s Syndrome: fetal gigantism, renal harmatomas, nephroblastomatosis

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Clinical Features

• Asymptomatic abdominal mass
• Accidental finding
• Otherwise well child
• Microscopic or gross haematuria
• Hypertension
• Late presentation
• Constitutional symptoms
• Fever
• Weight loss

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Clinical Features

• Acute Presentation – tumour rupture

-Acute abdominal pain

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-Rapidly enlarging abd.mass

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-Subcapsular haemorrhage

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-Severe anaemia

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-Fever.

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Investigations

• Abd. USS
• IVU
• Contrast enhanced CT scan
• CXR
• U and E, Creatine, Ca, Po4,ALP, UA
• LFT
• FBC
• Screen for sepsis and TB

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Staging

I – Tumour confined to the kidney and

completely excised

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II – Tumour extends beyond the

capsule but completely excised

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III – Tumour extends beyond the

capsule with incomplete excision

IV – Distant metastasis to the

lungs, liver, bone and brain

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V – Bilateral renal involvement

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Treatment

• Resuscitation- Transfusion, TLS, Treat infection with antibiotics, Nutrition
• Chemotherapy – Vincristine(V), Doxorubicin (D), Actinomycin D(A), Etoposide(E) and Cyclophosphamide(C)
• Surgery - Nephrectomy
• Radiotherapy

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Bilateral Tumour

• Surgical management is controversial
• Bilateral nephrectomy with renal transplantation
• Ex vivo tumour excision with auto transplantation
• Preoperative chemotherapy with surgery. Assess response after 5 weeks using CT and check for cytoreduction

Prognostic factors

• Histologic type - FH

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• DNA index – worse with aneuploidy

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• Gene expression – expression of high levels of tyrosine kinase receptor increases mortality

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• Stage of the disease

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Challenges

• Late presentation
• Socio economic status of patients
• Paucity of epidemiological and multicentre studies to examine the tumuor biology in the African population
• Relative non availability of the various imaging studies for diagnosis
• Relative non availability of drugs
• Compliance to treatment and follow up

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Neuroblastoma

• Embryonal tumour
• Derived from sympathogonia (neural crest) cells
• Second most common solid tumour of infancy
• Appears anywhere along the sympathetic chain and adrenal medulla
• 25% diagnosed by 1yr, 50% by 2 years and 90% by 8 yrs

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Introduction

• 1 in 100,000 in US

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• Annual Incidence – 10.95/million Children under 15years

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• 27.27/million Children between 0 – 4years

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• More common in boys

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• May be sporadic with 2% familial

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Aetioogy

• Embryonal tumor of the sympathetic nervous system arising from neural crest
• Neuroblasts can be identified in a 7-week foetus
• Form neuroblastic nodules by 12 weeks
• Nodules increase in size until 15-17 weeks gestation
• Neuroblastoma in situ seen in 100% adrenal gland at 17-20 weeks gestation
• Neuroblastoma in situ is seen in the adrenals of 1:39 newborns and 1:263 at 3 months of infants who die from other causes

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Associated Anomalies

Rare

• Beckwith – Wiedemann Syndrome
• Hirschsprung’s Disease
• Foetal Alcohol Syndrome
• Infants of mothers on anticonvulsants – Phenlhydantoin
• Congenital central hypoventilation syndrome (Ondine’s curse)
• von Recklinghausen’s disease
• Hypomelanosis of Ito

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Pathology

• Macroscopic

- Purple, highly vascular and friable

- Nodular fleshy white

- Haemorrhage and necrosis in larger

tumours

- Tumour calcification – Fine and stippled

• Microscopy
• Homer-wright pseudorosettes (differentiated tumour cells surrounding neutrophils)

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Pathology

- Scattered ganglion cells orimmature chromaffin cells

- Schwann cells- amt correlates with degree of differentiation

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• Most common human tumour to undergo spontaneous regression

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Staging

INSS

• I – Tumour confined to organ of origin- complete

excision, no micros. residuals with no LNs

• IIA – Unilateral tumour, complete excision, no LNs
• IIB – Complete/Incomplete excision with ipsilateral

tumour only

• III – Extends beyond organ of origin and crosses the

midline

• IV – Distant metastasis – bone, soft tissues, LNs,
• IV-S – I/II with involvement of skin,Liver &BM limited to infants<1 year

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Clinical features

• Primary Sites

- Retroperitoneum – 75%

* Adrenal medulla – 50%

* Paraspinal ganglia – 25%

- Posterior mediastinum – 20%

- Cervical and Pelvic regions – 5%

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Clinical features

Clinical features

• Abdominal mass: 50% - 70%
• Abdominal pain
• Vomiting
• Respiratory Distress
• Dysphagia
• Altered defaecation or urination
• Paraplegia

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Clinical features

• Horner’s Syndrome (miosis, ptosis and hemi-anhidrosis)
• Exophthalmos and raccoon eyes
• Heterochromia of the Iris
• Acute Cerebellar Ataxia
• Dancing Eye Syndrome
• Diarrhoea
• Weight loss
• Hypertension

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Clinical features

• Features of spread to adjacent and distant organs –
• skin (Blue – berry muffin),
• liver,
• bone marrow,
• LNs
• Orbit (Black eye- raccoon/panda eye)

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Investigations

• Tissue biopsy with histological confirmation
• Presence of unequivocal tumor cells within BM
• Increased levels of urinary catecholamine

metabolites (VMA,HVA)

• CXR
• Plain Abdominal X-ray-mass with speckled calcification
• Abdominopelvic USS
• Contrast enhanced CT Scan
• Magnetic resonance imaging
• Bone marrow aspiration

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Differential diagnosis

Depends on the presentation

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• Wilms tumour

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• Non Hodgkins lymphoma

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• Rhabdomyosarcoma

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• Non osseous Ewing sarcoma

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Treatment

• Modalities –Surgery

- Chemotherapy

- Radiotherapy

- BM transplantation

- Immunotherapy

• Tumour may regress spontaneously (IV-S)

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HEPATOBLASTOMA

• A tumour that originates from liver or gall bladder
• Third most common intra- abdominal neoplasm
• Affects children 6/12 -3yrs, (mean age 19/12)
• Hepatocellular carcinoma more frequent than hepatoblastoma in Asia and Africa
• Has the potential to spread to other organs causing multiple kinds of cancer

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HEPATOBLASTOMA

• 100 cases reported each year in US
• Usually starts as a golf ball sized tumour on the right lobe of the liver
• Prematurity and low birth weight
• Associated with some genetic disorders/ over growth syndromes
• Beckwith-Wiedemann syndrome
• Familial adenomatous polyposis

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Clinical presentation

• Asymptomatic abdominal mass
• Weight loss, anorexia, emesis, abdominal pain
• Hypertension (rare)
• Distant metastasis
• Lungs, intraperitoneal, lymph node, brain
• Thrombocytosis
• Elevated alpha- fetoprotein

classification

Based on degree of differentiation

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• Embryonal (30%)
• Fetal (54%)
• Anaplastic/small cell undifferentiated type (6%)
• Macrotrabecular (10%)

Investigations

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• Abdomino pelvic Ultrasound
• CT Scan or MRI
• Alpha- fetoprotein
• Other routine investigations and based on site of metastasis

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Staging

• Stage 1
• Complete gross resection with clear margins
• Stage 2
• Gross total resection with microscopic residual disease at the margins
• Stage 3
• Gross total resection with nodal involvement, tumour spill, incomplete resection
• Stage 4
• Metastatic disease

Prognosis

• Depends on

- Age

- Stage of the disease at diagnosis

- Site of primary tumour

- Biologic feature – N-myc, DNA ploidy and tyrosine kinase receptor

Conclusion

• Malignant tumours are the second most common cause of death in children worldwide.
• High index of suspicious is required
• Community education is important for early diagnosis and better outcome in our society
• Especially because of the challenges faced for diagnosis and treatment