Ghai Essential Pediatrics8th

Fig. 20.8: Leukocoria and squint in a 3-yr-old boy with retinoblastoma

Diagnosis

Diagnosis is established by characteristic ophthalmologic findings often requiring examination under anesthesia. Imaging studies such as ultrasound, CT/ MRI (preferred) scans are used for assessment of orbital, optic nerve and intracranial extension (Fig. 20.9).

Rarely children with hereditary retinoblastoma have pinealtumor (trilateral retinoblastoma) thatmaybe found on imaging. CSF and bone marrow evaluation shouldonly be done if indicated clinically or by other imaging studies (i.e. in advanced disease).

Where possible, both eyes should be examined under generalanesthesia. Properstagingrequiresultrasonography and imaging of the orbit and brain, for assessment of orbital and intracranial extension.

Second neoplasms are a major concern in retino­ blastoma survival. Approximately 30% of individuals cured of hereditary retinoblastoma will have a second malignancywithin 30 yr. Osteosarcoma is the commonest second malignancy; other second neoplasms include rhabdomyosarcoma and melanoma.

Fig. 20.9: Bilateral extraocular retinoblastoma with optic nerve involvement and intracranial spread

Treatment

The aims of treatment is survival with maintenance of vision. Treatment depends on size and location of the tumor and whether it is hereditary or sporadic. Retino­ blastoma is curable when the disease is intraocular. Therapeutic plans usually require a multidisciplinary approach. Treatment should behighly individualized. The majorconcern is toavoidenucleation andorexternalbeam radiation and trends are towards focal conservative treatment.

In casesofunilateraldiseasewithlargetumorswhereno useful vision can be preserved, enucleation must be performed early. Delay in this can lead to extraocular diseaseandultimatelylossoflife. Survivalfrommetastatic disease isextremelypoor. Inchildren withbilateraldisease systemic chemotherapy is used to shrink the tumors followed bylocal treatmentwithlaserphotocoagulationor cryotherapy in order to preserve vision. The eye with no useful vision should be enucleated in cases with bilateral disease. Systemic chemotherapy includes vincristine, carboplatin and etoposide. External beam radiation therapy should only be considered in cases where chemotherapy and focal therapy fail. Radiation therapy leads to orbital deformity and increased risk of second malignancyinpatientswithhereditaryformofthedisease. Several reports document longterm survival of patients with metastatic disease treated with high dose chemo­ therapy with autologous bonemarrow transplantation.

Routine eye examination should be done in these children till they are over 7 yr of age. All first degree relatives of children with known or suspected hereditary retinoblastomashould have eyes examined for retinomas or retinal scars. Patients with hereditary form of the disease are at a high-risk of other cancers particularly

osteosarcoma, soft tissue sarcomas, malignant melanoma and carcinomas.

Prognosis

Most tumors that are confined to the eye are cured. Cures are infrequent when extensive orbital/optic nerve extension has occurred or patient has distant metastasis. Reported mortality is 29% with involvement of lamina cribrosa, 20-30% with tumor invasion posterior to lamina cribrosa and 78% with involvement of cut end of optic nerve. CNS metastasis carries a very high mortality.With the advent of HSCT and aggressive chemotherapy the outcomesofextensivediseases are showing improvement.

Suggested Reading

Dimaras H, IGmani K, Dimba EAO, et al. Retinoblastoma. Lancet 2012;379:1436-46

Hurwitz RL, Shields CL,Shields JA, et al. Retinoblastoma. In: Prin­ ciples and Practices of Pediatric Oncology. Eds. Pizzo PA, Poplack DG. Lippincott Williams & Wilkins, Philadelphia, 2011;809-37

NEUROBLASTOMA

-----

Neuroblastoma is the most common intra-abdominal and extracranial solid tumor in children, accounting for 7-8% of all cancers. It is a malignant tumor of the autonomic nervous system derived from the neural crest. Neuro­ blastomais adiseaseofearlychildhoodwithapproximately 90% of patients presenting before 5 yr of age and almost 50% within the first2 yr of life. The etiology is not known but familial cases occur and there is an association with neurofibromatosis, Hirschsprung disease, heterochromia, fetal hydantoin andfetal alcoholsyndromes, and Friedreich ataxia. Rearrangement or deletion of the short arm of chromosome 1 has been found in 80% cases. Neuro­ blastoma is one of the very few childhood cancers that can undergo spontaneous regression.

Genetics

MYC-N oncogene is used as a biomarker for risk strati­ ficationin neuroblastoma. MYC-Namplificationisdefined as greater than or equalto 10 copies ofMYC-Nper nucleus and is associated with more aggressive disease, and poor outcome. Hyperdiploidy in the tumor tissue is associated with a favorable prognosis in children <2 yr of age at diagnosis. Loss of heterozygosity of lp, llq, 14q and gain of 17q are common in neuroblastoma and associated with worse prognosis.

Clinical Features

The clinical features are related to the localization of the sympathetic nervous system and site of metastasis. The most common sites of primary tumors are the adrenal gland (30%), paravertebral retroperitoneum (28%), posterior mediastinum (15%), pelvis (5%) and cervical area. Cervical neuroblastoma can present with Horner syndrome. The patient may be asymptomatic with a

paraspinal,localized intrathoracic or retroperitonealmass found incidentally. This presentation has an excellent prognosis. At the other extreme is an anxious, febrile patient with periorbital ecchymoses known as raccoon eyes (Fig. 20.10), scalp nodules, bone pain, limping and anemia from widespread metastasis. Neuroblastoma staging is discussed in Table 20.16.

Five percent of patients have stage IVS (S = special) disease. This is characterized by a small primary tumor in an infant with metastatic disease involving the liver, skin and bone marrow and regresses spontaneously. Infants younger than 2 months may show a rapid progression of intrahepatic disease causing respiratory distress (metastasis in liver). Another unusual presentation (5-15%) is the occurrence of spinal cord signs secondary

Fig. 20.10: Left eyelid appears like a 'raccoon's eye' in a child diagnosed with metastatic neuroblastoma

Table 20.16: International neuroblastoma staging system

Stage I: Localized tumor confined to the area of origin; complete excision, with or without microscopic residual disease; identifiable ipsilateral and contralateral lymph nodes negative microscopically

Stage II: Localized tumor with incomplete gross excision; identifiable ipsilateral and contralateral lymph nodes negative microscopically

Stage IIB: Localized tumor with complete or incomplete gross excision with positive ipsilateral regional lymph nodes; identifiable contralateral lymph nodes negative micro­ scopically

Stage III: Tumorinfiltrating across the midline with or without regional lymph node involvement; or unilateral tumor with contralateral regional lymph node involvement; or midline tumor with bilateral regional lymph node involvement

Stage IV: Tumor disseminated to distant lymph nodes, bone, bone marrow, liver or other organs (except stage IVS).

Stage IVS: Localized primary tumor as defined for stage 1 or 2 with dissemination limited to liver, skinand/orbone marrow (only in infants)

to 'dumb-bell' tumor growth. The primary paraspinal tumor grows through the intervertebral foramen and forms an intraspinal mass with neurologic signs. Metastasis present in 60-70% children, are usually to the skeleton (facial bones, skull), bone marrow and lymph nodes. Two paraneoplastic syndromes attributed to metabolic and immunologic disturbances are associated with localized disease opsoclonus-myoclonus and watery diarrhea associated with VIP secretion by the tumor. Opsoclonus-myoclonus syndrome is characterized by rapid eye movements, ataxia and irregular muscle movements and occurs in 2-4% of patients. Most children with opsoclonus-myoclonus have a favorable outcome with respect to their neuroblastoma but are left with longterm neurological deficits.

Diagnosis

The gold standard for the diagnosis of neuroblastoma is examination of tumor tissue by histopathology and immunohistochemistry. Other investigations include blood counts, urinary catecholamine excretion, bone marrow aspirationandbiopsy, abdominal ultrasound, and X-ray and bone scan for metastasis. Nuclear scanning with 123I or 131I MIBG detects tumors and metastasis accurately. CT scan ofchest, abdomen and pelvis is indicated to assess extent of disease (Fig. 20.11). MRI is preferred for paraspinal tumors to assess spinal cord compression. Quantitation ofserumneuron-specific enolaseandferritin, amplification of the MYC-N oncogene, tumor, cell ploidy and age-based histologic classification of the tumor are of prognostic value. Children with neuroblastoma can be divided into two groups: those with favorable and those with unfavorable features. The favorable group has a survival expectancy of 90% or more. It is characterized by young age (<1.5 yr), favorable stage (I, II and IVS), normal levels of serum ferritin and favorable histology. Older patients with stage III or IV disease, serum ferritin levels greater than 150 ng/ml and tumors of unfavorable histology have survival rates of20% or less.

Fig. 20.11: Computed tomography of abdomen shows suprarenal mass suggestive of neuroblastoma

Childhood Malignancles -

Treatment

Age and clinical stage are the two most important independent prognostic factors. Even with advanced disease, children less than 1-yr-old at diagnosis have a better outcome than those diagnosed later. Treatment modalities for neuroblastoma include chemotherapy, surgery and radiation therapy. Localized neuroblastoma has better prognosis; it can be treated with surgery alone and does not requirechemotherapy.Observation alone is needed for stage 4S patients. Chemotherapy is the chief therapy for most patientswithneuroblastomain advanced stage. Chemotherapy includes vincristine and alkylating agents in combination with anthracycline and epipodo­ phyllotoxins. Chemotherapy regimens widely used are OPEC (vincristine, cyclophosphamide, cisplatinum, teniposide (VM-26), CADO (vincristine, cyclophos­ phamide, doxorubicin) and PECADO (vincristine, cyclophospharnide, doxorubicin, cisplatinum, teniposide), etc. Other modalities include surgery, radiotherapy and autologous bone marrow transplantation.

Suggested Reading

Brodeur GM, Hogarty MD, Masse YP, Maris JM. Neuroblastoma. In: Principles and Practice of Pediatric Oncology. Eds. Pizzo PA, Poplack DG, Lippincott Williams and Wilkins, Philadelphia 2011;886-922

WILMS TUMOR

Wilms tumor (nephroblastoma) is the most common malignant tumor of the kidney, accounting for 6-7% of all childhood malignancies.Eightypercent ofpatients with Wilms tumor present under 5 yr of age; the frequency is similar in boys and girls. The peak age at diagnosis is 2-3 yr; 6% patients have bilateral disease. While a vast majority of Wilms tumors are sporadic, 1 2%- may be familial.Bilateraldiseaseis morecommoninpatientswith familial Wilms tumor.

The tumoris thoughtto developinthe foci of embryonal kidney tissue called nephrogenic rests. Up to 1% of newborns may have nephrogenicrests. Nephrogenic rests may transform into Wilms tumors.

WTl is the best characterized Wilms tumor gene. It is located at chromosomellp13 and encodes for a transcrip­ tion factor that is critical for normal development of kidneys and gonads. WT2 is localized to a cluster of genes at llpl5. Children with some genetic syndromes are predisposed to developing Wilms tumor. These include WAGR Wilms tumor, aniridia, genitourinary abnor­ malities like horseshoe or fused kidney and mental retar­ dation, del llpl3, Denys Drash syndrome (renal failure, renal mesangial sclerosis, male hermaphrodism, WTl misense mutation) and Beckwith-Wiedeman syndrome (hemihypertrophy, macroglossia, omphalocele, organo­ megaly, del llp15.5-WT2).

Loss ofheterozygosity (LOH) of lp and/or 16q andhigh expression of telomerase havebeenassociatedwith poorer outcome in children with Wilms tumor.

Clinical Features

Most patients present with an asymptomatic abdominal mass detected by parents or physician during routine examination. Features at diagnosis include hematuria (10-25%), hypertension (25%), abdominal pain (30%), fever (20%), anorexia and vomiting. Tumor thrombus extending into the inferior vena cava is foundin 4-10% of cases. Other features include anemia, thrombocytosis, acquired deficiency of von Willebrand factor and factor VII and polycythemia. Important differential diagnosis includes neuroblastoma, hydronephrosis, multicystic kidney and rarely abdominal lymphoma and retro­ peritoneal rhabdomyosarcoma. Features of congenital syndromes may be present in 13-28% of patients.

Investigations

Ultrasonography isthemostimportantinvestigationsince it can differentiate solid from cystic renal mass. CT scan and MRI provide detailed view of the extent of the tumor (Fig. 20.12). Contralateral kidney must be carefully evaluated on imaging studies. Metastasis in the liver can be detected on ultrasonography and CT scan. CT or MRI of the brain must be done in cases of rhabdoid tumor of the kidney (Table 20.17).

Fig. 20.12: Abdominal CT in 6-yr-old boy with hematuria and abdominal mass suggests Wilms tumor

Table 20.17: Investigations for suspected Wilms tumor

Prognostic Factors

Stage I: Tumorconfinedtokidneyandcompletelyexcised. Stage II: Tumor extends beyond kidney but completely excised.

Stage III: Tumor infiltrates renal fat; residual tumor after surgery. Lymph node involvement of hilum, para-aortic region or beyond.

Stage IV: Metastasisin lung orliver,rarelybone andbrain. Stage V: Bilateral renal involvement at time of initial diagnosis.

Besides staging another prognostic factor is pathology. 3% tumors showfavorable pathology (focal anaplasia) for which only surgical excision is necessary. Another 6% have unfavorable histology (diffuse anaplasia); these tumors are pleomorphic and ruptured and show early metastasistobones. Themajorityofpatientshavestandard histology, where precise treatment is determined by staging. Ploidy is another prognostic sign, diploid tumors have a better prognosis than hyperdiploid tumors.

Treatment

Therapy for Wilms tumor is based on stage of the disease and histology. The immediate treatment for unilateral disease is removal of the affected kidney. Many experts prefer preoperative chemotherapy because it diminishes the size of the tumor and allows better staging. By preoperative chemotherapy, using actinomycin D and vincristine for a period of 4 weeks, 85% of the patients may not require any local radiotherapy. Stage I and II tumors with favorable histology are usually treated postoperatively with vincristine and actinomycin D. The commonly used drugs for advanced Wilrns tumor are a combinationofvincristine,actinomycinDandadriamycin along with abdominal radiation. Abdominal radiation is used in stage IIIdisease. Pulmonary radiation is used for pulmonary metastasis.

With modem therapy, 80-90% of patients with Wilms tumor are cured. Overall approximately 90% of children with Wilrnstumorarelongtermsurvivors. Youngage,low stage and low tumor weight (<550 g) are favorable prognostic factors. Presence of anaplasia and loss of heterozygosity of lp or 16q increase risk recurrence.

Survivors of Wilms tumor have relatively few late effects.

Suggested Reading

Buckley KS. Pediatric genitourinary tumors. Curr Opin Oncol 2012; 24:291-6

Geller E, Kochan PS. Renal neoplasms of childhood. Radio! Clin N Am 2011; 49:689-709

SOFT TISSUE SARCOMA-----------

Pediatric soft tissue sarcomas are a group of malignant tumors thatoriginate from primitive mesenchymal tissue and account for 6-7% of all childhood tumors. Rhabdo-

myosarcomas, tumors of striated muscle (commonest childhoodsofttissuesarcoma), account for morethanhalf of all cases. The remaining nonrhabdomyosarcomatous soft tissue sarcomas (NRSTSs) account for approximately 3% of all childhood tumors; these include fibrosarcoma, leiomyosarcomas, synovial sarcomas and malignant peripheral nerve sheath tumors.

BONE TUMORS

Osteogenic sarcoma and Ewing sarcoma are the two major types of bone tumors in children and adolescents. Both tumors occur more common during the second decade of life and show male predominance.

Osteogenic Sarcoma

The peak incidence of osteogenic sarcoma is during adolescence, correlating with therapid bone growth; it is rare below the age of 5 yr. The distal femur and proximal tibia are the most frequent sites followed by proximal humerus and middle and proximal femur. Flat bones, e.g. vertebrae, pelvic bones and mandible may rarely be invol­ ved. Radiation exposure is a causal factor for osteogenic sarcoma. Localized painful swelling in the bone is the usual presentation, which may be mistakenly attributed to traumatic orinfectiveconditions,delaying thediagnosis by months. Metastasis occurs early to the lungs and other bones. Several gerrnline mutations of tumor suppressor genes are associated with increased incidence of osteo­ sarcoma. Hereditary retinoblastoma associated with the gerrnline mutation in the RBl gene have a significantly increased risk of osteosarcoma. Li-Fraumeni syndrome, a familial cancer syndrome associated with germline mutation of the p53 gene is also associated with osteo­ sarcoma. High dose radiation therapy such as that used for Ewing sarcoma or brain tumors predisposes to development of osteosarcoma. Benign bone lesions such as Paget disease, multiple hereditary exostoses, fibrous dysplasia and enchondromatosis can undergo malignant transformation and develop osteosarcoma.

Radiographic examination shows sclerotic or lytic bone lesions and periosteal new bone formation over the metaphyseal region. The differential diagnosis includes osteomyelitisand other bonetumors. Biopsy must be done to confirm the diagnosis. This is a pleomorphic, spindle cell tumor that forms extracellular matrix or osteoid. Imaging studies include CT chest and radionuclide bone scan to rule out metastasis.

Successful treatmentrequires multiagentchemotherapy with complete surgical resection. Amputation is rarely neededwithpresentdaymanagement comprising chemo­ therapy and surgery. Chemotherapeutic agents include doxorubicin, cisplatin, ifosfarnide, cyclophospharnide and high dose methotrexate. The tumor is unresponsive to radiotherapy. With current treatments, more than two­ thirds of patients presenting without metastasis have longterm survival.

Childhood Malignancies -

Ewing Sarcoma

Ewingsarcomais thesecondmostcommonmalignant bone tumor in children and adolescents. Ewing sarcoma occurs most often in the second decade, but can occur below the age of 10 yr. They most often arise from flat bones such as pelvis, chest wall and vertebrae and the diaphyseal region of long bones. Common sites of metastasis are lungs and other bones; bone marrow metastasis is not uncommon.

The typical presentation is with pain, swelling, a lump and/or a limp. Systemic symptoms such as fever and weight loss may be present. The duration of symptoms varies from few weeks to sometimes more than a year. Osteomyelitis andLangerhancellhistiocytosisparticularly eosinophilic granuloma are the differential diagnosis. Othersmallroundcelltumors, whichmetastasize into the bonemarrow are neuroblastoma, rhabdomyosarcomaand NHL. Plain radiographs may show destructive lesions of the diaphysis of bone in the form of lytic or mixed lytic and sclerotic lesions with a classical appearance called 'onion skinning' (Fig. 20.13). Biopsy must be done to confirm the diagnosis. Chest CT bone scan and bone marrow biopsy are performed to evaluate for metastasis. Reciprocal chromosomal translocation t(ll;22) (q24;q12) is pathognomonic of ES and is present in 85% of cases.

These tumors are responsive to both chemotherapy and radiotherapy. Localsurgeryis also an effective wayto treat Ewing sarcoma, however, surgical amputation is rarely indicated. Tumor control with radiotherapy requires moderately high doses ranging from 5500 to 6000 cGy. Multiagentcombination chemotherapy includes vincristine, dactinomycin, cyclophosphamide and doxorubicin.

Fig. 20.13: Radiograph of leg shows permeative lytic lesion with a prominent soft tissue mass extending from the bone and periosteal reaction. The 'onion-skin' or 'sun-burst' pattern indicates an aggressive process suggesting Ewing sarcoma

MALIGNANT TUMORS OF THE LIVER

Primary tumors of the liver are rare and account for approximately 1% of all childhood malignancies. Hepatoblastoma and hepatocellular carcinoma are the two most common malignant disorders of the liver. Over 80% of malignantlivertumorsinchildren are hepatoblastomas. Most commonly hepatoblastoma presents as an asympto­ matic abdominal mass in a young child. As the disease progresses child may develop symptoms such as abdominal pain, weight loss, vomiting and anorexia. Metastatic spread occurs to regional lymph nodes and lungs; patients do not have jaundice.

Serum a-fetoprotein (AFP) is a useful diagnostic marker that can be used for disease assessment during and after completion of therapy. AFP is elevated in almost all hepa­ toblastomas. Tumor thrombi extending into the hepatic veins and inferior vena cava may be present at diagnosis.

Diagnostic imaging should include CT or MRI of the abdomen along with the CT of the chest for evaluation of metastatic disease. Complete resection of thetumoreither by partial hepatectomy or by liver transplantation is critical for successful treatment of malignantlivertumors. Two more cycles of chemotherapy are administered after surgical resection.

Hepatocellular carcinoma is associated with chronic hepatitis B and C infections. Abdominal distention, pain, anorexia and weight loss are common presenting symptoms. Patients may present with acute abdominal pain secondary to tumor rupture and hemoperitoneum. Serum AFP is elevated in about 60% of cases. Liver enzymes may be elevated. Complete resection can only be achieved in about a third of the cases. Chemothera­ peutic agents active in this disease include cisplatin, etoposide, doxorubicin and 5 flourouracil. Other rare malignant liver tumors include rhabdomyosarcoma, embryonal or undifferentiated sarcoma and angiosar­ coma. Acute lymphocytic leukemia and neuroblastoma may present with diffuse or multifocal infiltration of the liver with liver dysfunction.

Suggested Reading

Hazdic N, Finegold MJ. Liver neoplasia in children. Clin Liver Dis 2011;15:443462

Litten JB, Tomlinson GE. Liver tumors in children. Oncologist 2008;13:812-20

HISTIOCYTOSES

The childhood histiocytoses are a rare and diverse group ofproliferative disorders characterized by infiltration and accumulation of histiocytes (monocytes, macrophages, dendritic cells, Langerhans cells) within various tissues. The International Histiocyte Society has proposed a classification for histiocyte disorders (Table 20.18).

Table 20.18: Classification of histiocytic disorders

Dendritic cell disorders

Langerhans cell histiocytosis (LCH) Secondary dendritic cell processes Juvenile xanthogranuloma

Solitary histiocytoma with dendritic phenotype

Macrophage related disorders

Hemophagocytosis syndromes (primary and secondary) Rosai-Dorfman disease

Solitary histiocytoma with macrophage phenotype

Malignant histiocyte disorders

Monocyte related leukemias Extramedullary monocytic tumors

Dendritic cell or macrophage related histiocytic sarcoma

Langerhans Cell Histiocytosis (LCH)

LCH is a rare nonmalignant disease characterized by a clonal proliferation of pathologic cells with the characteri­ stics of Langerhans cells in single/multiple sites and an unpredictable course. This is usually a sporadic and non­ hereditary condition. The clinical presentation is heterogeneous ranging from single-system involvement to a multisystem life-threatening disease. The hallmark of LCH is the presence of Birbeck granules on electron microscopyandpositivity for S-100proteinand CDla. The numberof cellswith Birbeckgranulescan vary in different lesions with limited numbers seen in tissues taken from liver,spleen,gastrointestinaltract or CNS.As aresultother pathognomonic surface markers are being sought. Langerin (CD207), a novel monoclonal antibody directed against a type II transmembrane protein associated with Birbeck granules, is considered sensitive and specific for Langerhans cells. This may be a key component of an immunocytochemical panel to diagnose LCH.

The spectrum of LCH (eosinophilic granuloma, Hand­ Schuller-Christian disease, Letterer-Siwe disease) reflects varying extents of the disease. The course of disease is unpredictable, varyingfromrapidprogressionand death, to repeated recurrence and recrudescence with chronic sequelae, to spontaneous regression and resolution. Pati­ entswithdiseasethatislocalized(skinorbone)haveagood prognosis and are felt to need minimum or even no treat­ ment. Incontrast,multipleorganinvolvement, particularly inchildrenunder2-yr-old,carriesrelativelypoorprognosis.

The most common involvement is of the skeleton (80%). Bonelesionscanbesingle or multipleaffectingskullbones, long bones, vertebrae,mastoidand mandible (Fig. 20.14A) The lesions may be painless or present with pain and local swelling; X-rays show sharp lytic lesions. Clinical manifestation includes vertebral collapse and spinal compression, pathologicalfractures in long bones, chronic draining ears and early eruption of teeth. Other mani­ festations include seborrheic skin rash (Fig. 20.14B) on

jaundice

scalp and back (60%), lymphadenopathy (33%), hepato­ splenomegaly (20%), tachypnea, air leaks, parenchymal lung infiltrates (15%), jaundice, abdominal distension, neurodegenerative symptoms and features of mal­ absorption. Bilateral infiltration of retroorbital area may cause exophthalmos. Gingivalmucous membrane may be involved with lesions, which look like candidiasis. Pituitary dysfunction may result in growth retardation and/or diabetes insipidus. Severe disease is characterized by fever, weight loss, malaise, failure to thrive and liver dysfunction. Liver involvement may result in sclerosing cholangitis and cirrhosis. Bone marrow involvement may lead to anemia and thrombocytopenia. Multiorgan dysfunction is associated with poor prognosis.

Diagnostic work up should include appropriate biopsies, complete blood count, liver function tests, coagu­ lation studies, skeletal survey, chest X-ray and urine specific gravity. In addition, evaluation of involved organ system should be under taken. These include ultrasound abdomen, CT chest and or abdomen and MRI brain. Bone marrow biopsies are required to exclude infiltration.

Treatment for localized disease or single bony lesion varies from observation, curettage, indomethacin, bisphosphonates, low dose radiation or systemic chemo­ therapy Multisystem disease is treated with chemo­ therapy, combining vinblastine, prednisone and 6 mercaptopurine. If there is response based on clinical evaluation and investigations these children are treated for a total duration of 12 months.

Hemophagocytic Lymphohistiocytoses

Hemophagocytic lymphohistiocytoses (HLH) is an aggressive and potentially fatal syndrome which results from an inappropriate prolonged activation of lympho­ cytes and macrophages which lack Birbeck granules and CDla positivity. Young children with HLH and known

gene mutations, or a family history of HLH are described as having primary HLH. Older children with HLH or children without identifiable mutations are described to have secondary/acquired HLH. Common causes of secondaryHLHareinfection,systemicjuvenile rheumatoid arthritis and SLE.

Clinical features include fever (91%), hepatomegaly (90%),splenomegaly(84%),neurological symptoms (47%), rash (43%) and lymphadenopathy (42%). HLH patients often develop liver failure with hyperbilirubinemia, pancytopenia, coagulopathy, renal failure, ARDS and features of encephalopathy. In the absence of a known gene mutation, a diagnosis of HLH can be made when atleast 5 of the 8 criteria are identified (Table 20.19).

Treatment comprises dexamethasone and etoposide. Cyclosporine may be added. Treatment of underlying infections should be undertaken. HLH patients require multiple transfusions of blood components and prophyl-

Table 20.19: Clinical criteria for the diagnosis of hemo- phagocytic lymphohistiocytoses

One of the two is required to establish the diagnosis:

1.Presence of pathogenic mutation in PERF, SAP or MUNC gene

2.Five of the following 8 criteria are fulfilled:

i.Fever

ii.Splenomegaly

iii.Cytopenias in at least two cell lines (hemoglobin <9

g/dl, platelets <100 x 109 cells/1 and/or neutrophils <1

x109 cells/1)

iv.Hypertriglyceridemia (fasting triglycerides >3 mmol/1 or >265 mg/dl) and/or hypofibrinogenemia (fibrinogen <1.5 g/1)

v.Hemophagocytosis in bone marrow or spleen or lymph nodes

vi.Low or absent activity of natural killer cells

vii.Serum ferritin >500 µg/1

viii.Soluble interleukin-2 receptor (CD25) >2400 units/ml

axis against Pneumocystis jirovecii and fungi. Other modalities having a role for familial HLH include antithymocyte globulin and stem cell transplantation.

Malignant Histiocytosis

These conditions represent malignancies of the monocyte macrophage system with proliferation of malignant histiocytes in many organs. Patients present with fever, weakness, anemia, weight loss, skin eruptions, jaundice lymphadenopathy and hepatosplenomegaly. Treatment is with intensive chemotherapy and CNS prophylaxis.

Suggested Reading

Abla0, EaglerRM,WeitzmanS. Langerhanscellh.istiocytosis:Current concepts and treatments. Cancer Treatment Reviews 2010;36:354-9

McClain Kenneth L, Allen Carl E, Hicks J. Histiocytic diseases. In: Principles and Practices of Pediatric Oncology. Eds. Pizzo PA, Poplack DG. Lippincott Williams & Wilkins, Philadelphia 2011;703-6

Satter EK, High WA. Langerhans cell h.istiocytosis: A review of the current recommendations of the Histiocyte Society. Pediatric Dermatology 2008;25(3):291-5

ONCOLOGIC EMERGENCIES

The survival of children with cancer has improved as a result of advances in diagnosis and newer therapies including hematopoietic cell transplantation and use of

growth factors. Oncologic emergencies may come as initial presentation of the malignancy, during course of the disease or as a consequence of therapy. A solid tumor may invade or compress vital organs like trachea, esophagus or superior vena cava. Effusions into the pleural space or pericardium may compromisefunctions of heart and lung. Metastasis into the brain may lead to cerebral edema and features of raised intracranialtension. Spinal cord involve­ ment by malignancy may lead to cord compression. Bone marrow involvement results in anemia, bleeding due to thrombocytopenia or coagulation abnormalities, leuko­ stasis, thrombosis,cerebrovascularepisodesand infections. Hormonal problems can occur because of paraneoplastic secretions. Metabolic complications may occur prior to or at onset of chemotherapy. Therapy related complications, include myocardial dysfunction (anthracyclines), extra­ vasation of drugs (anthracyclines, vinca alkaloids), hemorrhagiccystitis (cyclophosphamide), cerebrovascular accidents (methotrexate, 1-asparaginase) and pancreatitis (1-asparaginase, corticosteroids) may be encountered. Early diagnosis and urgent management of these condi­ tions will save the life of the child and allow for treatment of the underlying malignancy. Common oncologic emer­ gencies are discussed in Table 20.20.

Other emergencies include (i) Cardiac tamponade: This occurs due to massive pericardia! effusion, constrictive

Treatment

Hydration, alkalinization, allopurinol, rasburicase (if uric acid>10 mg/di), dialysis for renal failure

Hydration, hydroxyurea, leukopheresis, chemotherapy

Establish histological diagnosis by tissue sampling; administer corticosteroids. Avoidintravenous access in upper limbs; monitor for tumor lysis; chemotherapy; radiation

Dexamethasone; definitive management; surgery if required

Dexamethasone; surgical intervention; phenytoin

Broad spectrum antibiotics and antifungal agents

pericarditis from radiation, intracardiac thrombus or tumors. (ii) Syndrome of inappropriate antidiuretic hormone secretion may occur due to various chemotherapeutic agents (cyclophosphamide, vinca alkaloids, cisplatin) or with certain malignancies (craniopharyngioma, naso­ pharyngeal carcinoma). (iii) Gastrointestinal emergencies:

These include acute abdomen, ileus, massive hepato­ megalyand typhlitis. Infantswithstage IV neuroblastoma may present with massive hepatomegaly sufficient to cause respiratory compromise. Typhlitis presents usually with fever, neutropenia and acute abdominal pain. It is a necrotizing colitis caused by bacterial invasion of the caecum that may progress to bowel infarction and perforation.

Suggested Reading

CohenKJ, Helman I.J. Pediatric emergencies. In: Oncology Emergencies; Oxford University Press 2002;239-52

Seth R, Bhat AS. Management of common oncologic emergencies. Indian J Pediatr 2011;78:709-17

CHILDHOOD CANCER SURVIVORSHIP

-----

The overall survival of children with malignancies has increased. Over 80% children and adolescentswith cancer survive 5 or more years from diagnosis in many centers and are effectively cured of the disease. This is however at the cost of increased morbidity with various long/late effects ofcancer treatment. Longterm side effects are those complications of treatment that occur during therapy and persist even after thetreatmentis over. Late effects appear months or years after the completion of treatment. One­ third to half of childhood cancer survivors will experience a late/longterm effect of cancer therapy; of which up to half may be life-threatening.

These effects are more common with more intensive treatment regimens and more frequently seen with radiation therapy in young children. Neurocognitive deficits, growth retardation, cardiomyopathy, infertility and second malignancy are some of the most serious late adverse effects of therapy. Risk of cardiomyopathy and second cancer increases with increasing time from initial

Childhood Malignancies -

diagnosis. Up to 12% patients may develop a second cancer 25 yr after diagnosis of the first cancer.

The main goals of the Cancer Survivorship Program are to improve the health and well-being of childhoodcancer survivors by promoting adherence to a schedule of followup appointments and routine screening tests, educate patients, parents and health care professionals about the longterm effects of cancer treatment, integrate them appropriately into society, provide referrals to specialists as needed and offer psychological counseling and transition of patients to adult care when ready.

HEMATOPOIETIC STEM CELL TRANSPLANTATION

Hematopoietic stem cell transplantation (HSCT) refers to the administration of hematopoietic progenitor cells from bonemarrow,peripheral bloodorumbilicalcord from the same individual (i.e. autologous) or another donor (i.e. allogeneic) to reconstitute the bone marrow (see Chapter 12). AutologousandallogeneicHSCTareusedincreasingly to treat a variety of hematologic malignancies in children.

HSCT is indicated in the following pediatric malig­ nancies; (i) acute myeloid leukemia, following first or subsequent remission in patients with favorable cyto­ genetics such as translocation t(lS; 17) or inversion (16); or inpresence of residual disease; (ii) acute lymphoblastic leukemia, following first or subsequent remission in patients with Philadelphia chromosome positive disease, t(4:11) positivity, biphenotypic disease or >1% minimal residualdisease; as salvagetherapy forresistant disease;and following second or subsequent remission; (iii) chronic myeloid leukemia; (iv) certainlymphomas (e.g.peripheral T cell lymphoma,follicularlymphoma, diffuse large B cells lymphoma); and (v) some solid tumors (neuroblastoma, retinoblastoma, brain tumors, sarcomas).

The outcomesfollowingtransplantationhave improved due to advances in supportive care, refinement in techniques ofHLA matching and improved diagnosis and therapy for infectious morbidities. Disease stage at the time of HSCTand cytogenetic abnormalities are important determinants of disease relapse after transplantation.

ARTHRITIS

Approach to Diagnosis

Arthritis is a common complaint in children. It is said to be present if there is swelling or effusion in _a j? t o if there are any two of the following 4 features: (1) limitation of range of motion, (ii) pain, (iii) tenderness and (iv) increased heat. It can be secondary to an underlying illness (infectious or noninfectious), or may be a primary disease condition in itself. Clinical assessment based on a good history and physical examination would provide more diagnostic clues than indiscriminate laboratory tests. A convenient way to classify arthritis is based on the duration of illness at the time of presentation (Table 21.1).

Table 21.1: Classification of arthritis

Acute arthritis (usually <2 weeks)

Arthritis associated with acute rheumatic fever Transient ('toxic') synovitis

Arthritis associatedwithKawasakidisease, Henoch-Schonlein purpura

Septic arthritis (S. aureus, H. influenzae, N. meningitidis)

Subacute arthritis (2-6 weeks)

Reactive arthritis

Arthritis associated with systemic lupus erythematosus, dermatomyositis, polyarteritis nodosa

Bone pains associated with leukemia or neuroblastoma Arthritis associated with Lyme disease or brucellosis Sickle cell disease

Arthritis associated with hypogammaglobulinemia

Chronic arthritis (>6 weeks)

Juvenile idiopathic arthritis

Ankylosing spondylitis

Tubercular arthritis

Legg-Calve-Perthes disease

Psoriasis

Surjit Singh

Transient Synovitis

This is a common condition seen in young children and is characterized by sudden onset of pain in the hips, thighs or knees following an upper respiratory catarrh. It is a self limiting disorder, lasts only 2-4 days and must not be confused with a septic arthritis or acute osteomyelitis. Skin traction and judicious use of nonsteroidal anti­ inflammatory drugs (NSAIDs) brings prompt relief.

Septic Arthritis

This is usually seen in neonates and infants. It presents almost always as a monoarthritis and is accompanied by fever, tenderness and limitation of joint movement.Causes include gram-negative bacilli, group B streptococci (in

neonates), Haemophilus infiuenzae type B and Streptococcus pneumoniae (in infants) and Staphylococcus aureus (in older children). Ultrasonography, magnetic resonance imaging and radionuclide scans provide useful clues to the diag­ nosis. A diagnostic arthrocentesis is necessary to confirm the diagnosis (Table 21.2). Appropriate antimicrobials, aspiration and, in some cases (e.g. the hip joint), open drainage are required for treatment.

Tubercular Arthritis

This has become less common in our experience. It can result from an actual infection with Mycobacterium tuberculosis or from an allergic phenomenon (Poncet disease). The former type usually presents as a mono­ arthritis (e.g. hip or ankle joint) while the latter type presents as a polyarthritis with a strongly_rositi e Mantoux reaction. Arthrocentesis may be diagnostic (Table 21.2).

Reactive Arthritis

This is not as common in children as in adults. It is diagnosed on the basis of Berlin criteria: (i) peripheral arthritis: usually lower limb asymmetric oligoarthritis; (ii) evidence of preceding gastrointestinal or genitourinary