Part 22. Neoplastic Diseases and Tumors

민수진 선생님

PART 22. Neoplstic Diseases and Tumors.

Chapter 445. Epidemiology

# incidence rate of malignant tumor

    ; 14/100,000 in children under 15yr. (1986-1987)

# the precise cause of childhood cancer is unknown

# specific genetic event

    ; retinoblastoma

        - Rb tumor-suppressor gene

    ; Li-fraumeni-syndrome

           - p53 tumor-suppressor gene

# *childhood cancer environmental factors보다 host factors 중요하다.

Environmental Factors

Table 445-1

Ionizing Radiation

   .radiation dose & frequency of leukemia were related in a linear fashion.

   .type & latency of leukemia were related to age at exposure

   .leukemia radiation exposure 5년이 peak incidence time이다.

   .breast cancer; 10 이전에 노출된 중년의 여성에서 빈도 증가

   .thyroid tumor

   .brain tumor

Ultraviolet Radiation

   .exposure of sunlight-skin cancer

   .genetic predisposition(eg, xeroderma pigmentosa,other congenital defect in DNAS repair)

    있는 경우 ultraviolet  neoplasm risk 높다.

Drug

  .DES-clear cell adeno ca. of the vagina only proven transplacental carcinogen

  .Neuroblastoma-fetal hydantoin synd.

                 .fetal alcohol synd.

.immunosuppressive agent; eg, NHL

.anabolic androgenic steroid; liver tumor

.alkylating agent & epipodophyllotoxins

    ; can cause second neoplasm

Diet

.high fat intake, obesity-breast

                        colon  ca

                        uterus

Viruses

1)RNA viruses; lymphatic leukemia & lymphoma

                 -type C RNA virus in animal

                  leukemia/lymphoma-retrovirus

                  Kaposi sarcoma  AIDS

                  CNS lymphoma

2)DNA viruses; EBV IM(미국), Burkitts' lymphoma(아프리카)

                Lymphepithelioma

                Hodgkin's dz.

                HBV-H.C.C

 

3)papova viruses; warts, papilloma

                 type 6 & 11-laryngeal papilloma

                              condyloma acuminatum

                 carcinoma of the uterine Cx.

                     (sub type 16, 18)

Chapter 446. Molecular Pathogenesis

Oncogenesis

# oncogene

    ; endogenous human DNA sequence arising from protooncogene

    ; develope to tumorigenesis

# Rhabdomyosarcoma

    ; activating ras oncogene point mutation

# Burkitts lymphoma

    ; chr. translocation t(8:14)(q24q32) in protooncogens(C-myc) on chromosome 8

Table 446-1

Table 446-2

Tumor Suppressor Genes

.cancer발생을 억제하는 tumor suppressor gene(antioncogene) down regulation

 malignant growth 자극시킨다.

.retinoblastoma; submicroscopic deletion in chr 13

.Rb gene 1)nuclear phosphoprotein with DNA biredig activity(cell cycle regulation

           중요하다.

          2)정상인에 존재하며, cell growth 관장하는 retinoblastoma환아에서는 없다.

Li-fraumeri synd.; 가족적으로 다양한 childhood solid tumor 발생.(bone , breast, lung

                   cancer)하는 임상증후군으로, p-53 tumor suppressor gene germline

                   mutation 나타난다.

                  -p53 tumor suppressor gene product apoptosis(programmed natural

                   cell death) 관장하는 , 이것의 결여로 인해 excessive tumor cell                        growth 생긴다.

Other Mechanisms And Implications

.underlying genetic disorder malignancy 연관되어 있는 경우가 많은 , 이것은 oncogenesis 다른 mechanism 암시한다.

.ex1)xeroderma pigmentosa, ataxia-telangiectasia,Bloom synd. Fanconi anemia malignancy  risk 높다.

.ex2)immmunodeficiency state Wiskott-Aldrich synd, congenital X-linked immunodeficiency경우 lymphoid malignancy 확률이 높다.

.malignancy 환아의 evaluation , familial association congenital synd. 확인해야 한다.

Chapter 447. Principles Of Diagnosis

.most childhood cancers are curable

.Px relates most strongly to tumor type, extent at diagnosis, effectiveness of tx.

.대부분의 physician 환자를 처음 대할 , cancer 떠올리지 않기에, 놓치는 수가 있는

 , atypical course 기억해야 한다.

Table 447-1

osteosarcoma, Ewing's sarcoma 10대에 생기고, 나이가 physical activity 왕성하므

 , bone pain시기와 trauma시기가 중복되는 수가 많다.

   -radiologic exam 도움을 있다.

.nasopharynx or middle ear tumor inf. 유사하다.

  지속되는 이통, 이루, retropharyngeal swelling시는 malignancy 의심해야 한다.

.cervical lymph node enlargement시는 inf. lymphoma 구분해야 한다.

 (Sx. 지속시 LN.bx. 시행한다.)

.leukemia 초기 증세가 low grade fever, bone pain, joint pain 국한될 있으며, PB에서

 blast 보일 수도 있다. anemia, neutropenia, mild thrombocytopenia 있을 BMA

 해야 한다.

.bx 앞서 metastasis유무 보기 위한 stage work up 해야 한다.

->surgeon operation,  resection범위를 결정하게 된다.

.Dx. 중심은 histologic type이다.

Chapter 448. Principles Of Treatment

# the gene of all forms of tx.

  -to remove or destroy as much tumor as possible

  -with least damage to normal cells.

448.1 Chemotherapy

Table 448-1

<phase I study>; low dose에서 start해서 max. tolerate dose까지 측정

<phase II study>; specific tumor type tx. efficacy 측정

<phase III study>; protocol 기존의 약과 같이 schedule 입력시켜 효과측정한다.

Acute Complications & Supportive Care

# Early complications

    ; metabolic disorders

  ; bone marrow suppressions

  ; immunosuppressions

# Tumor Lysis Syndrome

    ; substantial breakdown of tumor cells

           --> tubular precipitates of uric acids crystals

           --> impaired renal functions

    ; *symptomatic hyperphosphatemia, hypocalcemia, hyperkalemia

    ; *often in hematologic malignancy

    ; large solid tumor 가능하다.

           - e.g.) Burkitt's lymphoma, germ cell tumor, neuroblastoma

    ; Treatment

           - adequate hydration & allopurinol before chemotherapy

# bone marrow suppression

    ; Granulocytopenia(500/mm3이하)

    ; life threatening inf. 생길 있다.

=>febrile granulocytopenic pt. broad spectrum antibiotics 사용해야 하며, 1 이상

   지속시는 antifungal agent 고려해야 한다,.

.특히, candida 혹은 aspergillus species 흔하다.

.opportunistic inf.; pneumocystitis carinii

   ->그래서, bactrim 예방적으로 사용

. 항암치료 환아에서, varicella 노출되면 varicella zoster immunoglobulin 맞고, 임상증세 생기면 입원해서, iv acyclovir 투여한다.

3)항암 치료후 pt. 대부분의 평소 B.Wd 10% 소실한다.( tx associated nausea, vomiting)

 -intensive CTx, total body irradiation, abd. head, neck irradiation tx환아는 malnutrition  위험하며 TPN 필요하다.

Late Sequelae

; radiation-related problems

    - *not obvious until patients is fully grown

    - e.g.)

           / marked asymmetry of irradiated & non irradiated area & extremity

           / hypothyroidism or sterility

           / *growth retardation from pituitary hormone deficiency

           / neurological & intellectual dysfunction

; chemotherapy can cause severe organ damage

  - high-dose MTX : leukoencephalopathy

    - anthracyclin : myocardial damage

  - bleomycin : pul. fibrosis

    - asparaginase : pancreatitis

    - cisplatin : hearing loss

    - irreversible change

; baseline test, adequate monitoring 필요

; *serious late effect

    - second cancer

  - the risk is cumulative

           / *0.5% per yr to 12% at 25yr

448.2 Bone Marrow Transplantation

.in general, the younger the patient, the more favorable the response.

.Autologous BMT; BM 치명적인 용량의 radiation tx 혹은 chemotherapy시행할 ,

 먼저 환아의 BM 따로 보관한 , tx 다시 autologous marrow reinfusion

  ->ALL, AML, neuroblastoma, Hodgkin's dz, Non Hodgkin's dz, Ewing's sarcoma,

    brain tumor

.문제점; 이식한 BM residual malignant cell relapse 있다는 .

.allogenic BMT-환자의 HLA "match"되는 donor로부터 골수룰 이식받음.

 -the best donor is major MHC 같은 sibling(확률 ; 20-30%)

 -morbidity; GVHD, marrow rejection

 -matched sibling donor라서, 어느 정도의 alloreactivity 있다.( minor HLA typing

  틀리므로 )

 -serious post transplantation problems;

.graft versus host disease

  ;어린 환아일수록 발생하고, 최근에는 cyclosporin 투여로 발생이 감소되고 있으나,

   GVHD 발생이 감소할수록 cancer relapse 증가

1)acute GVHD(1st & 2nd Mo. after transplantation

 ;target organ-skin, GI tract, liver

  tx)steroid or anti T-cell monoclonal antibody

2)chronic GVHD(3-4Mo. after transplantation)

    ; resembles autoimmune dz.

     (ex; scleroderma, MG)

.all patients are at risk for life-threatening infection until recovery of immune

 function

 

<application of BMT>

.In congenital immunodeficiency, BMT is the only curative option

.In hematopoietic malignancies, the role of BMT is more difficult to define

 (Randomazied clinical trials are lacking)

.tx. decision are based on Pt's history, condition, prognosis, donor availability

Chapter 449. The Leukemias

; common childhood cancer

; 33% of pediatric malignancy

; *ALL-75% of leukemia, peak incidence-4yr

; *AML-20% of leukemia, increasing incidence from adolescent

; anual incidence

    - 42/만명 (백인)

  - 24/만명 (흑인)

        --> due to lower incidence of ALL in black

449.1 ALL

; first curable disseminted cancer with chemotherapy & irradiation

; Asso. with diseases

    - immunodeficiency ; congenital hypogammaglobulinemia, ataxia-telangiectasia

    - consititutional chromosomal defect ; trisomy 21

Pathology

; subclassed according to morphologic, immunologic, genetic feature of leukemic blast.

; definite diagnosis-BMA

; FAB system(morphologic subtypes)

    1) L1 - predominantly small with little cytoplasm

    2) L2

           - larger & pleomorphic with increased cytoplasm

    - irregular nuclear shape, prominent nucleoli

    3) L3

           - *finely stippled and homogenous nuclear chromatin

           - prominent nucleoli

           - *deep blue cytoplasm with prominent vacuolization

; chromosomal abnormalities

    - 80-90% in childhood ALL

Clinical Manifestation

; *signs and symptoms of their disease for less than 4wk at the time of diagnosis

    - 66% of children

; first Sx

    - usually nonspecific

    - anorexia, irritability, and lethargy

; progressive bone marrow failure

    - pallor(anemia), bleeding(thrombocytopenia), fever(neutropenia, malignancy)

; petechiae or mucous membrane bleeding - 50%

; fever - 25%

; occasionally prominent lymphadenopathy

; splenomegaly

    - usually extending less than 6cm below the costal margin

    - 66%

; *less common hepatomegaly

; *significant bone pain and arthralgia

    - 25%

; rarely, signs of increased intracranial pressure

    - headache and vomiting

    - indicate leukemic meningeal involvement.

# Children With T-Cell ALL

    ; older and more often male

    ; 66% anterior mediastinal mass

Table 449-1

Diagnosis

-on initial exam, most have anemia, about 25% have Hb levels below 6g/g이하

-thrombocytopenia,  25% have platelet counts greater than 100,000/mm3

-diagnosis of leukemia is suggested by the presence of blast cells on a peripheral blood

 smear but is conformed by examination of bone marrow

-If the marrow cannot be asperated or specimen is hypocellular, bone marrow bx. is

     required

-a chest radiograph is necessary to determine whether there is a mediastinal mass

-bone radiograph

-CSF should be examined for leukemic cells

Differential Diagnosis

# aplastic anemia, myelofibrosis, infectious mononucleosis

# Pediatric Tumors That Can Infiltrate Marrow

    1) neuroblastoma

  2) *rhabdomyosarcoma

  3) Ewing sarcoma

  4) rarely retinoblastoma

Treatment 

# Average Risk Of Relapse (=standard group)

    ; between the ages of 1 & 10 yr

    ; under 100,000/mm3

    ; lack evidence of mediastinal mass or of CNS leukemia

    ; B-progenitor cell immunophenotype

Table 449-2

-a combination of prednisone, vincristine(oncovin), and asparginase should produce

      remission in about 98% of children with standard-risk ALL.

-in the absence of prophylactic treatment, the CNS is the initial site of relapse in more

     than 50% of patients.

-Most patients with T-cell ALL relapse within 3-4yr if treated with a standard-risk

     regimen.

-With more intensive multidrug regimen

-B-cell cases with L3 morphology and surface immunoglobulin expression once had a

     poor prognosis.

Relapse

    ; bone marrow

           - *common site of relapse

    ; experience bone marrow relapse during treatment, intensive chemotherapy followed by

 bone marrow transplantation

    ; CNS and the testes

           - *important extramedullary sites of relapse

-the common early manifestations of CNS leukemia increased intracranial pressure and         include vomiting, headache, papilledema, and lethargy.

-convulsions and isolated cranial nerve palsies may occur with CNS leukemia or as side       effects of vincristine.

# CNS relapse

    ; should be given intrathecal chemotherapy weekly for 4-6wk      until lymphoblasts have disappeared from the CSF

    ; cranial irradiation

    ; intrathecal TX.

# Testicular relapse

    ; generally produces painless swelling of one or both testicles

    ; conformed by bx

    ; Treatment

           - *include irradiation of the gonads

Prognosis

# Treatment

    ; *important prognostic factors

# clinical features

    ; initial WBC counts

    ; age

           - older than 10yr, younger than 12mo : poor

# Chromosomal Rearrangement

    ; 11q23 region : poor

    ; hyperdiploidy with more than 50 chromosomes : favorable

    ; *two poor chromosomal translocations

           - t(9;22) or Philadelphia chromosome

           - t(4;11)

    ; *B-progenitor cell ALL with the t(1;19) : favorable

449.2 Acute Myeloid Leukemia

-annual incidence of five to six cases per million in children younger than 15 yr.

-AML constitutes 15-20% of all childhood leukemias.

-there are no clear racial or gender differences.

-the distribution of cases by age is consistent throughout childhood.

-the incidence of AML exceeds 1)trisomy 21, 2)fanconi anemia, 3)Diamond -Blackfan anemia,  4)Kostmann syndrome, and 5)Bloom syndrome.

-children previously treated for another malignancy are also  at increased risk;

-the incidence of secondary AML approaches 5% after tx. of some malignancies.

-incidence of secondary AML pe within 10 yr of the initial malignancy

-associated with specific therapies(alkylating drugs such as cyclophosphamide, agents

 that inhibit DNA repair such as etoposide).

Clinical Manifestations

; typically signs and symptoms attributable to bone marrow failure

; *less common bone pain

; *common liver and spleen enlargement

; *less common lymphadenopathy

; unexplained gingival hypertrophy or parotid gland swelling

; chloroma

    - localized mass of leukemic cells

    - *retro-orbital, epidural location

           / *common

    - maybe precede leukemic cell infiltration of bone marrow

; initially with only anemia, leukopenia, or thrombocytopenia

    - MDS

Diagnosis

-the presence of at least 30% leukemic blast cells in the bone marrow

-morphology and cytochemical analysis(histochemical stain positive for myeloperoxidase,

 Sudan black, or nonspecific esterase)

# FAB system divides AML into eight subtypes, M0 to M7

Table 449-3

-the number of patients with the M0, M1, and M2 subtypes approximates the number

 of M4 and M5 cases.

-FAB types accounts for 80% of childhood.

-The M3 and M7 subtypes are less common, and M6 is rare.

-Hemorrhagic diathesis(disseminated intravascular coagulation at presentation or later);

  acute promyelocytic leukemia(M3)             

-Translocation between chromosomes 8 and 21, typically present in the M2 subtype,

  is closely associated with chloroma.

# Myelodysplastic syndrome

    ; some resemblance to AML, but the bone marrow contains a lower percentage of blast cells and has characteristic dysplastic features, including megaloblastosis

    ; chromosomal changes

           - *trisomy 8 and complete or partial deletion of chromosome 5 or 7

                   / common in secondary myelodysplastic syndromes and secondary AML

# juvenile chronic myelogenous leukemia(JCML)

    ; unlike adult type CML

    ; similar to those of AML and myelodysplastic syndrome

    ; *Philadelphia chromosome is not present in JCML

Treatment

-chemotherapeutical regimens; anthracyclin (daunorubicin, idarubicin) and cytarabine.

-Retinoic acid as initial treatment for acute promyelocytic leukemia may reduce

     the risk of the hemorrhage but is not curative.

-autologous or allgenetic bone marrow transplantation

-intrathecal chemotherapy is necessary to prevent CNS relapse.

Prognosis

-poor

-with aggressive therapy, 40-50% of patients who achieve remission(3-40%overall cure

     rate.)

449.3 Chronic Myelogenous Leukemia(CML)

-CML is a clonal malignancy of the hematopoietic stem cell characterized by a

     specific translocation, the t(9;22)(q34;q1), Philadelphia chromosome.

-CML is more common in adults and  accounts for only 3%of cases of childhood leukemia.

-progression to a myeloid or lymphoid blast crisis

  *Pathology

-characterized by myeloid hyperplasia with increased numbers of differentiating

      myeloid cells in blood and bone marrow.

-the pathognomonic Philadelphia chromosome is easily detectable in more than 95% of

     cases

-Southern blot analysis or polymerase chain reaction technique reveal the bcr-abl

     rearrangement.

Clinical Features

-Sxs of hypermetabolism, including wt. loss, anorexia, and night sweats.

-Sxs of leukostasis, such as visual disturbance or priapism, occur rarely.

Diagnosis

-elevated white blood cell counts exceed 100,000/mm3, with all forms of myeloid cells

     seen in the blood smear.

-PLT counts may also be abnormally high.

-elevated serum levels of vitamin B12 and uric acid and reduced or absent leukocyte

     alkaline phosphatase activity.

-the bone marrow is hypercellular, with normal myeloid cellsin all stages of differrentiation.

-megakaryocytes may be more numerous.

-cytogenetic or molecular studies showing the Philadelphia chromosome.

Treatment

-chemotherapy with busulfan(Myleran), or hydroxyurea.

449.4 Congenital Leukemia

-extremely rare disease, diagnosed within the 1st mo  life at a rate of 4.7 per million

     live birth.

-Myeloid leukemia appears marked leukocytosis, petechiae, ecchymoses, and

  extramedullary involvement massive hepatosplenomegaly, cutaneous nodule, and CNS

  leukemia.

-occurs primarily in neonates with trisomy 21 or chromosome 21 mosaicism.

-Most transient myeloproliperative disorders undergo spontaneous remission within a few wks.

-poor prognosis,especially, leukemic cell chromosomal rearrangement affecting the q23region

 of chromosoe 11

Chapter 450. Lymphoma

; the third most common cancer in children

450.1 Hodgkin Disease

Epidemiology

# peak age

    ; *the middle to late 20s

  ; age of 50yrs

# *whites male

# *EB virus may be involved in the pathogenesis

Pathology

# 4 histologic subtypes

    1) lymphocytic predominance

        ; mature lymphocytes or a mixture of lymphocytes and benign histiocytes

                   - occasionally Reed-Sternberg cells

           ; 10-20%

           ; *clinically localized disease

           ; more common in male & younger patients

           ; *best prognosis

    2) nodular sclerosing type

       ; *common type

           ; 50% of younger patients, 70% of adolescents

           ; special cytologic feature

                   - *clear space surrounding “lacunar cell: variants of the R-S cell

  3) mixed cellularity

    ; second common

           ; 40-50%

    ; *inflammatory bacground of lymphocytes, plasma cells, eosinophils, histiocytes, malignant reticular cells

                   - *abundant R-S cells

           ; more likely advanced disease & extranodal extension

    4) lymphocyte depletion

           ; *least common and least favorable form

       ; fewer than 10% of patients

    ; numerous bizarre malignant reticular cells along with R-S cells

                   - relatively few lymphocytes

         - various degree of partly hyalinized fibrosis

 - arises in lymph nodes in allmost all cases

   extranodal primary sites : fewer than 1% of patients

                             -> spleen, lever, lung,bone,and BM

 - the manner of spread : direct anatomic extension

        -> adjacent lymphnode : the first site of spread in most patients

                                 along adjacent lymphoid channels

 - systemic Sx (B-sx) : night sweat, fever, recent wt loss of more than 10% of BW

Clinical Manifestations

    ; painless enlarged cervical or supraclacicular lymph node, occasionally nodes of the axillary or inguinal areas

           - common presenting finding

           - firm, nontender, usually discrete

 - mediastinal LN enlargement -> produce a cough, usually non-productive

 - pruritus : an unusual early complaint

             if pruritus occurs alone -> no B category

 - if pulmonary involvement -> establishment of stage

  ; BM involvement

           - neutropenia, thrombocytopenia and anemia

    ; immune disorders

           - immunohemolytic anemia

    - immunothrombocytopenia

    - nephrotic syndrome

    ; *impaired cellular immunity

           - *varicella-zoster infection

    - fungal infection

                   / cryptococcosis, histoplasmosis, candidiasis

    ; transiently depressed humonral immunity

Diagnosis

; suspected in the patient with persistent unexplained lymphadenopathy

; in a significant percentage of patients

   -> a history of relatively recent antecedent serologically proven infectious

       mononucleosis(+)

   -> 따라서 infectious mononucleosis 앓은 enlarged LN 줄어들지 않은 경우

       Bx 시행하여야 한다.

; chest X-ray

    - *performed before biopsy

    - explore possibility of mediastinal involvements & examine airway potency

# blood counts

    ; not helpful but characteristic changes in WBC counts

           - neutrophilic leukocytosis, lymphopenia, and sometimes eosinophilia and monocytosis

# increased acute phase reactant

  ; ESR, serum copper, and serum ferritin ; nonspecific but markers of disease activity

# Staging Procedure After Confirmed Diagnosis

  ; roentgenogram of the chest

  ; CT scan of the chest

    ; CT or MRI of abdomen

    ; lymphangiography

           - lymph node involvement

                   / not be filled with contrast materials

    ; staging laparotomy

           - determine with certainty the presence or absence of infradiaphragmatic disease

           - *현재는 findings 치료 방향을 좌우할 경우에만 시행

    ; BM biopsies

Table 450-1

Treatment

    ; localized disease (stage I or IIa)

           - radiation alone to standard fields with doses of 3500-4406 rad

           - radiation + combination chemotherapy

    ; advanced disease

           - MOPP

                   / nitrogen mustard, vincristine(oncovin), procarbazine, prednisone

         - ABVD

                   / doxorubicin(adriamycin), bleomycin(blenoxane), binblastine(vleban), dacarbazine

           - MOPP/AVDG alternating with low-dose (2000-2500cGy) radiotherapy

                   / more useful

                   / cure rate 70-90%

                   / why?

                           : potential growth defects and risk of second solid tumor are reduced by limiting the radiotherapy

                           : risk of infertility and leukemogenesis is decreased by reduced exposure to alkylating agents

                           : exposure to drugs with potential cardiopulmonary toxicity is limited

Prognosis

 - more than 90% of patients : complete initial clinical remission

 - most patients with disease in stages and will be crued

 - in stages ; 75% cured

 - in stage : at least 50% cured

# complications of treatment

 - the complications of irradiation

   ; irradiation of upper body node : restriction of lung capacity

                                    cardiac involvement

                                    late hypothyroidism

   ; in younger child, disturbance of the growth of the vertebra, the clavicle, breast bud

   ; 따라서 성장문제 때문에 children에게서는 standard dose radiation 주지 않는다.

 -irradiation of the ovaries-> sterility or premature menopause or both.

 - complication of chemotherapy ; late pulmonary toxicity : bleomycin

                                 late cardiac toxicity : doxorubicin

                                 MOPP : sterility in male

 - staging laparotomy : splenectomy ; sepsis with pneumococcus or H.influenza

                        abdominal adhesion

# secondary malignancy

    ; *5-10yr after treatment

    ; 1.2-13% at 10yr

    ; acute myeloid leukemia

           - *frequently

450.2 Non-Hodgkin Lymphoma

; malignant clonal proliferations of primarily T or B lymphocytes

# High Risk Diseases

    ; ataxia-telangiectasia

    ; Wiskott-Aldrich syndrome

    ; combined immune deficiencies

    ; X-linked lymphoproliferative(XLP) syndrome

         - marked sensitivity to EBV-induced disease

           - fatal infectious mononucleosis case 57%

Pathology

# Difference from adults

    ; diffuse, extranodal, high-grade tumors type

# high-grade NHL subtype

  small noncleaved cell (Burkitt and non-Burkitt subtypes)

           ; B cell tumor

       ; express surface immunoglobulin

           ; contain one of three chromosomal translocations

                   - *t(8;14), t(2;8), t(8;22)

           ; involved c-myc oncogene, immunoglobulin gene (mu heavy chain, kappa light chain, lambda light chain)

  Lymphoblastic lymphoma

           ; T-cell origin

           ; *contain a translocation involving a T-cell receptor gene

    Large cell NHL

           ; T-cell, B-cell, non-B, non-T cell phenotypes

           ; t(2;5)(p23;q35) asso. with CD30

Clinical Manifestations

    ; ★▲common primary site

           - *abdomen(31.4%), mediastinum(26%), head/neck region including Waldeyer ring and/or cervical lymph nodes (29%), non cervical LN(6.5%)

    ; striking association between histologic subtype and disease sites

           - lymphoblastic type

                   / head and neck region or ant. mediastinum

           - SNCC

                   / abdomen and/or head and neck

           - large cell type

                   / any anatomic location

    ; mediastinal mass

           - pleural effusions,respratory distess,superior vena cava syndrome,

    ; Abdominal mass( ileocecal region)

           - abdominal distension, nausea, vomiting change in bowel habits

  ; BM involvement

           - anemia or thrombocytopenia

    ; central nervous system disease

           - headache, ICP 증가, cranial nerve palsies

Diagnosis

Table 450-2

Treatment

    ; common TLS

    ; CNS prophylaxis

    ; multiagent chemotherapy

           - cyclophosphamide-based COMP regimen

                   / SNCC type

           - intensive multiagent LSA2L2 regimen

                   / Lymphoblastic type

           - CHOP regimen (cyclophosphamide, doxorubicin, vincristine, predisone)

                   / *effective protocols for large cell type

Prognosis

 ·2-yr event-free survival (EFS) : 90% for children with limited-stage disease

                                   70% for those with stage and

 ·improvement in the treatment of advanced-stage SNCC NHL ; 90% 2-yr EFS

                                   (70% for those with central nervous system disease)

CHAP. 451. Neuroblastoma

; * extracranial solid tumor of childhood (8-10% of all children cancer)

; *frequently diagnosed neoplasm in infants

; median age

    - *2 yrs (90% : before 5yr)

; 8.7/million children (new case 500-600 /yr U.S.A)

; *spontaneous regresstion - 10%(주로 1세이하, stage I or IVs)

; higher in males and in whites

; *some familial

    - asso. /c *neurofibromatosis, nesidioblastosis, hirschsprung disease

; microscopic clusters in adrenal gland of fetuses

    - 1 of 200 neonates at autopsy

    - normal

; mass screening programs

    - urinary catecholamine metabolites(VMA)

    - at 6 mo in japan

Pathology

; originate in neural crest cells of sympathetic nervous system

    - anywhere from post. fossa to coccyx

; site

    - *abdomen (70% : adrenal gland 50%), thorax(20%)

; *hematogenous spread - bone marrow, skeleton, liver

; *tumor cells in peripheral blood - more than 50% at diagnosis or relapse

# histological features

    ; small round cells with abundant granules

    ; forming *Homer-Wright rosettes

    ; calcification and necrosis with extensive hemorrhage

    ; EM

           - peripheral dendritic processes

           - containing longitudinally oriented microtubules,

    - small, spherical membrane-bound granules with electron-dense cores

                   --> representing cytoplasmic neurosecretory granules(catecholamines)

                   --> secretes catecholamines, neuron-specific enolase(NSE), ferritin

; catecholamines metabolites in urine

    - vanillylmandelic acid, homovanillic acid

; monoclonal Ab to cell surface antigen*(glycosphingolipid, diganglioside, synaptophysin, NSE, neurofilament)

; Cytogenetic Abnormality

    ; 80%

  1) partial deletion of the short arm of chromosome 1, chromosome 17

    2) genomic amplification of the N-myc oncogene ; indiator of poor prognosis

Clinical manifestations and Diagnosis

; hard, painless mass in the neck

    - localized intrathoracic mass on chest radiograph

; large palpable mass in flank or abdomen

; *metastasis in 65-70% at diagnosis

# Direct invasion Sx

    ; proptosis and ecchymosis - orbit involve

    ; lower limb paresis - paraspinal tumor -> epidural extension

    ; *horner syndrome - lesion in cervical or upper thoracic sympathetic ganglia

    ; unilateral epistaxis or occlusion of nasal passage - tumor in nasopharynx

    ; *firm, blue-tinged subcutaneous nodules resembling blueberry muffins in neonates & infants

    ; *anemia, thrombocytopenia - bone marrow infiltration

# Indirect Sx due to substances

    ; acute cerebellar encephalopathy

           - *cerebellar ataxia, rapid and random eye movement, myoclonic jerks

           - 4%

    ; *severe diarrhea with extreme hypokalemia & achlorhydria

           - due to VIP

    ; *hypertension due to catecholamine

# Physical Examination

    ; LN enlargement, hepatomegaly, abdominal or flank mass

    ; periorbital ecchymoses, scalp nodules

# Lab. finding

    ; anemia, thrombocytopenia

    ; DIC

    ; elevated LDH, ferritin, NSE, BUN, creatinine

    ; *increased homovanillic acid & vanillymandelic acid in urine

           - *useful markers of neuroblastoma

# Imaging study

    ; chest radiograph

    ; CT of chest, abdomen-pelvis

    ; bone scan

           - detecting the primary tumor

           - defining the extent fo skeletal metastasis

    ; MRI

           - detecting intraspinl extension, vessel encasement or displacement, bone marrow involvement

    ; MIBG(meta-iodobenzylguanidine)

# Confirm Diagnosis

    ; tissue biopsy

    ; *any surgical procedure 하기전에 반드시 BM aspiration & biopsy 시행하여 전이여부를 확인해야 한다.

# Definite Diagnosis

    ; histologic studies of tumor tissue

    ; documentation of bone marrow involvement plus increased urine or serum catecholamine level

# DNA Determination Of Tumor Materials

    ; DNA content(tumor cell ploidy)

    ; presence of N-myc amplication

    ; cytogenetic analysis

Staging

# Pediatric Oncology Group (POG) system

    stage A ; grossly resected tumor

    stage B ; localized unresectable tumor

    stage C ; metastasis to noncontiguous intracavitary lymph nodes

    stage D ; metastasis beyond lymph nodes

    stage Ds ; infants with small adrenal primary with metastatic disease limited to skin

               liver or bone marrow

Table 31-6 by PO

Bone involvement of neonatal neuroblastoma

           --> poor prognostic factor

Treatment

; main modalities

    - surgery(localized tumor), chemotherapy, radiotherapy

# Primary surgical resection Ix

    ; abdominal tumors localized to one side of the midline

    ; abdominal tumors crossing the midline without encasement of major blood vessels

    ; tumor in chest

    ; to determine status of intracavitary LN that not attached to primary tumor

           - liver biopsy should be in infant

; second-look or delayed surgery

# Chemotherapy

    ; infants with disseminated disease or children with localized unresectable disease

           - cyclophosphamide, doxorubicin

    ; older children with locally advanced & disseminated neuroblastoma

           - combination

           - *cyclophosphamide, doxorubicin, cisplatin, etoposide, ifosfamide, melphalan, vincristine, carboplatin

# Experimental approaches

    ; extensive chemotherapy with or without BMT

    ; Radioactive MIBG

    ; Monoclonal Ab directed against neuroblastoma cell surface proteins

# Radiotherapy

    ; *most neuroblastomas are radiosensitive

Prognosis

; age and stage

    - * significant predictors of outcome

; *younger than 1yr : good prognosis than same stage children

    - low stage infants - more than 90%

    - infant with metastatic disease - more than 50%

; Biologic And Genetic Markers

    - DNA content(ploidy)

           /hyperdiploid(DNA index more than 1)

                   : 80% survival expectancy compared with 20% for diploid tumors

    - N-myc amplication

           / *poor outcome in all age/stage tumors

96 Table 31-11 by PO

Chapter 452. Neoplasms Of The Kidney

452-1 Wilms' Tumor

. accounts for almost all neoplasms in childhood.

. equal frequency in both sexes.

. annual incidence ; 7.8 million children under the age of 15yr.

# association with congenital anomalies

    ; *genitourinary anomalies(4.4%) : common

  ; hemihypertrophy(2.9%)

  ; sporadic aniridia(1.1%).

# deletion one of two loci in chromosome 11

    ; *33% of Wilms' tumors

    1) hemizygous constitutional deletions of one loci, *11p13

           - asso. with two syndrome

                   / *WAGR syndrome

               : Wilms' tumor, aniridia, G-U malfomations, mental retardation

         / *Denys-Drash syndrome

                           : Wilms' tumor, nephropathy, genital abnormalities

    2) deletion of one loci, *11p15

    - association of Wilms' tumor with Beckwith-Wiedemann syndrome, congenital syndrome (several types of embryonal neoplasms, hemihypertrophy, macroglassia, visceromegaly)

    3) Third locus

    -involved in familial Wilms' tumor

Pathology

# the classic Wilms' tumor

    ; solitary growth in any part of either kidney

    ; sharply demarcated and variably encapsulated

    ; common small areas of hemorrhage

  ; usually distort the renal outline.

# favorable-histologic

  ; *triphasic, epithelial, blastemal

    ; *presence of stromal elements

    ; resemble abortive glomeruli

# unfavorable histologic

    ; occur in older, nonwhite

    ; 3 times the normal size

    ; hypochromatic nuclei, abnormal mitoses

    ; 2 subtype

           - Rhabdoid tumor

                   / composed of cells with fibrillar eosinophilic inclusions

                   / *often in very young patients

           - Clear cell sarcoma

                   / spindle cell patterns with striking vasocentric arrangements

                   / male predominance

                   / *tendency to metastasize to bone

# staging system (NWTS group)

    stage 1 ; limited to kidney,

            completely excised with capsular surface intact.

  stage 2 ; extends beyond the kidney,

            but can be completely excised.

  stage 3 ; non hematogenous extension of tumor,

            confined to abdomen

  stage 4 ; hematogenous metastases,

            which most commonly involve the lung.

  *stage 5 ; bilateral renal involvement, 5-10%

Clinical Manifestations

; median age at Dx ; 3yr (Wilms tumor)

; *asymptomatic abdominal or flank mass

    - *frequent sign

; smooth and firm and rarely crosses the midline

. mean diameter ; ll cm

. 50% - abdominal pain, vomiting, or both

. 신경아 세포종에 비해 연령이 높고 less ill 하게 보임

. Hypertension (60%)

   -owing to pressure of the tumor on the renal a.

Diagnosis

   . microscopic 혹은 gross hematuria (1025%)

   . ultrasonography ; the mass is intrarenal. (신경아 세포종과의 감별이 중요)

   . CT scan ; most helpful.

               -CT without enhancement ; arise from kidney as inhomogeneous masses

                                          with areas of low density indicating necrosis.

   . areas of hemorrhage and small focal calcifications ;

               ->generally less common and less prominent than in neuroblastoma.

               -CT with enhancement ;

   . slight enhancement of tumor is noted.

   . often a sharp demarcation between the tumor and normal parenchyma.

                 - primary usefulness of CT in Wilms tumor ;

                   . establish the intrarenal origin of the tumor->rule out neuroblastoma.

                   . detect multile masses

                   . determine the extent of tumor.

                   . evaluate the opposite kidney.

# differential diagnosis

    ; hydronephrosis

    ; renal cysts

    ; mesoblastic nephroma

    ; other renal malignancies ; renal cell carcinoma

                         sarcoma

                         lymphoma

    ; Neuroblastoma (가장 중요)

# pulmonary metastases ;

   .evident on roentgenogram in 1015% of patients at time

     of diagnosis.

   .more common in neuroblastoma.

   .CT scan of chest ; plain radiograph 발견하기 어려운

                      the dome of the diaphragm

                      아래쪽의 metastatic lung lesions

                      발견하는데 도움이 된다.

hepatic metastasis 의심시

  -CT of abdomen

evaluation of bone and BM.고려.

  -persistent bone pain

  -unfavorable histologic subtype

paraneoplastic syndrome

  -1.produce erythropoietin->polycythemia

   2.secondary hypercalcemia

      -임상적으로 von Willebrand disease 유사한 양상 보임.

Treatment

# surgical removal of the kidney

    ; usual immediate treatment

    ; pulmonary metastases 존재하더라도 시행

# *Wilms tumor is sensitive both chemotherapy and to radiotherapy

# radiotherapy

    ; *술후 모든 환자에게 시행

# chemotherapy

    ; NWTS groups에서 combination therapy single agent therapy보다 효과적으로 인정

    ; *vincristine+dactinomycin : patients with localized disease

    ; *vincristine+dactinomycin+doxorubicin : advanced disease

    ; stage 1

           - a short postoperative course(6mo or less) of combination chemotherapy

          postoperative radiotherapy is not necessary.

    ; stage 2 and 3

           - postoperative radiation with chemotherapy.

    ; stage 4

           - radiotherapy+ combination chemotherapy with 3 or 4 drugs for 15mo.

# preoperative therapy

    ; not recommended for patients with unilateral disease.

    ; treatments of choice for pt. with bilateral disease.

Prognosis

# ★▲significant prognostic variables

    ; Histologic subtype and stage

# 재발시 poor prognosis

452.2 Other Renal Neoplasms

Nephroblastomatosis

. immature renal elements (nephrogenic rests)

        -33% of unilateral Wilms tumor에서 발생

        -대개 bilateral

. precursor lesions

        -unifocal and deep within renal parenchyma (intralobar rest)

        -multifocal (perilobar rest)

 

* Mesoblastic Nephroma

. grossly and microscopically resembling

    -leiomyoma

    -low-grade leiomyosarcoma with trapped nephrons.

. EM fibroblasts 혹은 myofibroblasts 보임.

. 남아

. renin production

Renal Cell Carcinoma

. 10대에 발생

. abdominal mass and hematuria

        -initial finding

. 어른의 renal cell ca, 비슷한 현미경 소견과 임상 경과를 가짐.

Chapter 453. Soft Tissue Sarcomas

. 50%이상이 rhabdomyosarcoma

453.1 Rhabdomyosarcoma

Epidemiology

; *common soft tissue sarcoma

. male (많이 발생)

# site

    ; head and neck (40%)

  ; genitourinary tract (20%)

  ; extremities (20%)

  ; trunk (10%)

    ; retroperitoneal

# risk patients

    ; neurofibromatosis

    ; maternal breast cancer in the Li-Fraumeni syndrome.

Pathology

# "small round cell tumors" on light microscopy.

    ; 96 DDx

           - *Ewing sarcoma, neuroblastoma, neuroectodermal tumor, non-hodgkin lymphoma

# histologic subtypes ( 4 가지 )

  1.embryonal; about 60% of the tumors, intermediate prognosis.

  2.botroid; 6%

            commonly seen in the vagina, uterus, bladder, nasopharynx, middle ear.

  3.alveolar; about 15%

            most often trunk and extremities, in older children.

            the most poor prognosis, 특징; t(2;13) chromosomal translocation.

  4.pleomorphic; adult form, 1% of cases.

  -undifferentiated tumor; about 20%.

Clinical Manifestation

; *painful or not painful mass

    - *common presenting feature

. nasopharynx tumor; nasal congestion, mouth breathing, epistaxis, difficult

                     swallowing and chewing.

. extension into the cranium; cranial nerve paralysis, blindness, IICP sign

# orbit

    ; *proptosis, periorbital edema, change in visual acuity, local pain

# middle ear

    ; pain, loss of hearing, chronic otorrhea, tumor mass in ear canal.

. larynx; unremitting croupy cough and progressive stridor.

. trunk or extremities; 처음 한동안은 hematoma 오인하기 쉽다.

. genitourinary tract; hematuria, obstruction of the lower urinary tr,

                    recurrent UTI, incontinence

. paratesticular tissues; a rapidly growing mass in the scrotum.

. vagina; a grape like mass, vaginal bleeding, obstruction of the urethra or rectum.

. tumor 어느 위치에 있든지 상관없이 early dissemination 발생하며

    pulmonary  metastasis 발생하는 the presenting symptom pain or

    respiratory distress

Diagnosis

. in head and neck;

   -roentgenogram 

   -CT scan; check for intracranial extension.

              look for bony involvement at the base of skull.

. for abdominal tumor; ultrasound and CT scanning.

. in the bladder; cystourethrogram.

. before surgery;

             -a full skeletal metastatic survey.

             -radionuclide scans of the skeleton

             -a chest roentgenogram and CT.

             -BM exam.

. the most essential element of the diagnostic workup;

             -the exam of tumor tissue.

Treatment

. based on the primary tumor location and disease stage("clinical group")

       .group 1 tumor; complete local excision+chemotherapy.

       .group 2 and 3; local irradiation+systemic chemotherapy+surgery

       .group 4; systemic chemotherapy+irradiation

.intrathecal chemotherapy시행

   -primary disease in parameningeal sites(nasopharynx, paranasal sinuses etc)

   -with intracranial extension.

Prognosis

. resectable tumor; prolonged tumor free survival in 80-90%

. unresectable tumor라도 orbit 같은 favorable site 발생하는 경우 high likelihood of cure 가진다.

. disseminated disease; a poor prognosis.

. older children;

     -a worse prognosis

     -greater frequency of lesions of the extremities and of alveolar histology.

453.2 Other Soft Tissue Sarcomas

  *NRSTS ( nonrhabdomyosarcoma soft tissue sarcomas )

        -3% childhood malignancy

. median age at Dx; 12

. M:F=2.3:1

. histologic types

    -synovial sarcoma(42%)

    -fibrosarcoma(13%)

    -malignant fibrous histiocytoma(12%)

    -neurogenic tumors(10%)

 호발부위

    -trunk or lower extremities

Chapter 454. Neoplasms Of Bone

; 2nd decade of life

; male (우세)

Table 454-1

454.1 Osteosarcoma

# 호발부위

    ; metaphyseal region of rapidly growing bones

       - distal femur, proximal tibia, proximal humerus

# Genetic And Hereditary Conditions

    ; *increased risk among children with bilateral retinoblastoma

           - *loss of normal Rb tumor-suppressor gene

    ; *increased risk of Li-Fraumeni syndrome

           - *germline mutations of p53

# Others Risk Conditions

    ; Paget disease

  ; enchondromatosis

  ; multiple hereditary exostoses

  ; osteogenesis imperfecta

  ; local irradiation for Ewing sarcoma

Pathology

. highly malignant spindle cell neoplasm

. arises in the cortical/medullary region of long bones

   - break through bone cortex and invade surrounding soft tissues

. skip lesion

    - may occur at some distance from the primary tumor mass

. high-grade osteosarcoma 분류

   ; 1. osteoblastic

     2. chondroblastic

     3. fibroblastic

. rare subtype

   - parosteal;

              a well differentiated, extramedullary tumor,

              low metastatic potential

              surgical resection alone is often adequate therapy

   - periosteal;

              histologically,more pleomorphic.

              more aggressively clinically.

   - telangiectatic;

              bloody, cystic lesion.

              radiographically, no new bone formation

              --> confused with aneurysmal bone cyst.

              poor prognosis.

. multifocal sclerosing osteosarcoma;

      - 동시에 여러 장소에서 tumor 발병하는 형태를 말하며,

         주로 osteoblastic pattern 나타낸다.

Clinical Manifestations

; *localized pain and swelling

    - *common presenting symptom

; P/Ex

      - local swelling, tenderness, warmth

      - limited range of motion

. CBC, Chemistry; 대개 Nl

. metastases occur most often

      -lungs and other bones

Diagnosis

. persistent unexplained bone pain,

   particularly when associated with a palpable mass

   -> suspection->roentgenographic exam of that bone.

. typical findings on X-ray;

     -broken through the cortex,

       calcification in the surrounding soft tissues.

     -sclerosis of bone and periosteal new bone formation.

. stage 결정하기 위한 최소한의 검사;

     -a radionuclide scan and a roentgenographic study

     -CT scan of the chest.

. CT scan with contrast enhancement of the affected extremity;

     -define the extent of medullary involvement.

     -assist in surgical planning.

. serum alkaline phosphatase activity;

     -increased.

     -a marker to follow the effect of therapy.

. conformation; by histologic exam.

Treatment

# surgery

    ; mainstay

# radiotherapy

    ; *not useful due to radioresistance tumor

# combined CTx

    ; due to micrometastasis at diagnosis

    ; *수술자체만으로는 5 생존율이 20%미만

# 97 Advantage of adunvant chemotherapy

    ; immediate treatment for ocult metastatic disease

    ; tumor response

    ; limb-sparing surgery

Prognosis

. best with low-grade tumors, such as parosteal osteosarcoma.

. high-grade osteosarcoma and no evidence of metastasis.

      -66% cured

454.2 Ewing Sarcoma/Peripheral Neuroepithelioma

; a family of highly malignant small round cell undifferentiated neoplasms

; more common in male

; *often in 2nd decade of life

; ★▲often sites

    - *flat bones(pelvis, chest walls, vertebrae)

    - diaphyseal region of long bones

; soft tissues tumors

   -most often in the trunk.

   -50%이상이 chest주위에서 발생함.

.Ewing sarcoma

  -전형적으로 extensive soft tissue component가짐.

  -lung bone 가장 전이가 되는 부위

Pathology

# special histochemical staining for DDx from rhabdomyosarcoma, neuroblastoma, lymphoma

    ; *specific staining for cell-surface glycoprotein p30/32MIC2(HBA 71)

# specific chromosomal translocation

  ; t(11;22)(q24;q12)

           --> results in a *chimeric EWS and FLi1 gene product

Clinical Manifestation

; pain, swelling, tenderness in involved sites

; fever

; the two conditions most often mistaken clinically for Ewing sarcoma

    - eosinophilic granuloma

  - osteomyelitis

; 때때로 항생제를 쓰면 Ewing sarcoma 증상이 좋아지는 경우도 있으므로 bacterial culture 에서 음성으로 나타나는 osteomyelitis 대하면 반드시 Ewing sarcoma 고려해야 한다.

Diagnosis

.clinical history and radiologic features

.확진;  surgical biopsy

.CT scan

.Bone scan

.BM; 전이가 의심될 .

.MRI; primary lesion extent 평가하는 가장 좋다.

      특히 , 치료에 대한 반응을 평가하는 유용하다.

Treatment

# response to both radiotherapy and chemotherapy.

    ; *amputation is rarely indicated

# Multiagent chemotherapy

  ; 4 drug CTx

           - cyclophosphamide, doxorubicin, vincristine, dactinomycin

    - 추가 약제;  ifosfamide and etoposide

. local RTx

    -효과적이긴 하지만 high-dose radiotherapy시행이 부작용

                   1)failure of bone growth

                   2)soft tissue fibrosis

                   3)secondary malignancy(특히, osteosarcoma)

.long-term F/U 필요

    -진단 10 혹은 이상에서도 재발이 있을 있기 때문.

Prognosis

454.3 Rare Bone Tumors

* Chondrosarcoma

.rare in children, usually seen during the second decade.

.most common in the pelvis.

.lung and bone으로 metastasis 가능하지만 대개는 local extension.

.histologic exam; osteosarcoma chondrosarcomatous component 많이 가지고 있기

                              때문에 주의를 요한다.

.Tx;

  -surgical removal

  -relatively radioresistant.

 

* Fibrosarcoma

.rare

.soft tissue에서 발생

.주치료 방법; surgical resection

Chapter 455. Retinoblastoma

# Average Age At The Time Of Diagnosis

    ; 11 mo for bilateral tumor

  ; *23 mo for unilateral tumor

# bilateral involvement

  ; 30%

  ; dominantly inherited predisposition to retinoblastoma

           - 20% of patients with unilateral disease

# Genetic Predispostion

    ; retinoblastoma occurred with *“13q-syndrome”

        --> suggesting the retinoblastoma locus on chromosome 13

    ; Rb gene

           - increased risk of other tumors

                   / osteosarcoma developed by 10yr of age in about of 1% of survivors

           - secondary malignancy

                   / 30% witin 30yr

  ; trilateral retinoblastoma syndrome

           - bilateral ocular disease + pineal tumors

Pathology

usually develops in the posterior portion of the retina

consists of  small, round, closely packed malignant cells with scanty cytoplasm

endopytic growth:

   -arises in the internal nuclear layers of the retina

   -> growing into the vitreous cavity

   -easily seen with the ophthalmoscope

exophytic growth

   -arising in the external nuclear layers and growing into the sub retinal space

    -> diagnosis is more difficult, because the tumor is hidden

endophytic tumor로부터 떨어져 나온 tumor fragment vitreous 내에서 떠돌다가

          다른 retina seeding 되는 경우 large tumor 형성하고 poor prognosis 나타낸다.

choroid extension 되어 있는 경우 hematogenous metastasis 경향을 보인다.

retinoblastoma 대개 metastasis 드물기 때문에 진단 당시 주관 심은 useful vision             보존하는 것이다

Clinical Manifestation

; presenting Sx

 -*leukokoria : yellowish white reflex in the pupil (due to tumor behind the lens)

; diminished or absent vision, strabismus

; more advanced tumor

    - pupillary irregularity, hyphema, pain

; very advanced tumor

    - proptosis, IICP sign, bone pain

; *both eye involvement at diagnosis

    - *more than 80%

Diagnosis

# leukocoria

    --> a careful fundoscopic examination in general anesthesia

# CT scans

    ; *evaluate the intra orbital extent of tumor

  ; *see whether optic nerve or bony structures are involved

    ; intratumoral calcification

# MRI

    ; define optic nerve invasion

# DDx Of Leukokoria

    ; retinal detachment

  ; persistent hyperplastic primary vitreous

  ; nematode endophthalmitis

  ; bacterial panendophthlmitis

  ; cataract

  ; coloboma of the choroid

  ; the retinopathy of prematurity

# Radionuclide bone scan

# bonemarrow exam

# CSF study

# carcinoembryonic antigen

    ; rarely found at diagnosis

    ; recur 다시 상승

Treatment

-standard tx. for unilateral disease: enucleation of the eye

-bilateral: salvage useful vision in at least one eye by using radiotherapy

            and / or cryotherapy

-심하게 침범된 쪽이 보다 dramatic response 보일 있기

   때문에 radiation therapy both eye 시행한다.

-한쪽 눈이 useful vision 남아 있지 않을 정도로 심하게 침범되거나

   complication으로 painful glaucoma 발생하면  눈을 enuculation한다.

             -enuculation gross or microscopic residual disease 남아 있으면

               radiation therapy 더불어 chemotherapy(cytoxan+doxorubicin) 고려된다.

Prognosis

; overall survival rate: 90%이상

Chapter 456. Gonadal And Germ Cell Neoplasms

Epidemiology

3% of childhood cancer

 but ,sacrococcygeal teratoma is the most common solid tumor in newborns

childhood & early adolescence :sacrococcygeal & ovarian tumor 빈도 수가

    많으므로  female predominance                            

14 이후 testicular tumor 많으므로 male predominance

risk for gonadal or germ cell tumor: gonadal dysgenesis & cryptorchidism

Pathology

Figure 456-1

 most germ cell tumor : benign lesion (cystic teratoma: most common)

 malignancy 경향은 primary site age 따라 다름

   ovarian germ cell tumor : 10 이하에서 대개 benign

                              adolescence에서는 30%에서 malignant

   sacrococcygeal tumor :malignancy 빈도가 10% at birth 

                                           50% at age 2 mon   

Choriocarcinoma

    ; highly malignant

  ; occurs after puberty in the testicle

           - but both before and after puberty in the ovary

    ; *high β-HCG level

Yolk Cell Carcinoma(Endodermal Sinus Tumor)

    ; schiller-duval bodies

    ; *elevated AFP

Embryonal Carcinoma

    ; poorly differentiated cells with epithelial appearance

Seminoma Of Testicle

    ; during or after adolescence

  ; clear cells aggregated in lobles & separated by fibrous stroma

    ; no associated with biologic markers

Dysgerminoma Of Ovary

    ; counterpart of seminoma

Teratoma

    ; usually benign

  ; *consist of at least two, & sometimes three germ cell layers

Clinical Manifestation & Diagnosis

testicular germ cell: intact-painless mass in scrotum, no signs of  

                            inflammation

                     older boy-swelling, pain ,tenderness

ovarian germ cell tumor: acute or chronic pain & enlarged abdomen

                          abdominal mass or fullness

sacrococcygeal germ cell tumor: most have external pelvic component

                                 involving buttocks or sacrum

                  D.Dx : meningocele, chordoma, duplication of

                       the rectum, neurogenic tumor,

                        lipoma, rhabdomyosarcoma, hemangioma 

 signs & sx.:constipation and/ or anuria

Dx: plain radiographs, chest CT scans, radionuclide bone scans

     MRI: identifying local tumor extension into the adjacent bone or

            intra spinal canal

     surgical excision or biopsy

     serum level of AFP & B-HCG

Treatment

Whenever possible, surgical excision

dysgerminoma & seminoma -traditionally Radiotherapy

Most patients with malignant germ cell tumors :combination chemotherapy

  (likelihood of subclinical dissemination at the time of diagnosis)

     -cisplatin, bleomycin, etoposide

Prognosis 

-depend on disease extent at Dx. & primary site

                 malignant germ cell tumor- 70-80% : alive without disease 5 yr after Dx

                 advanced disease -40-70% 5-yr survival rate

                * Other tumors of the gonad

                -sertoli tumor: benign

                               before the age of 6 mo.

                               columnar cells with tubular formation

                -leydig cell tumor: benign

                                   the ages of 4-9 yr

                                   sexual precocity

                                   surgical resection

                -benign ovarian cyst: 50% of ovarian tumors

                                     torsion-mimic an acute abdomen

                -granulosa-theca cell tumor: benign

                                            ovarian stromal origin

                                            precocious puberty

                -cystadenocarcinoma

                -hemangioma

                -lymphoma: ovarian enlargement  is the first manifestation

                           in small cases

                -gonadoblastoma-occur only with gonadal dysgenesis

                                 victimization, cryptorchidism, hypospadias

                                 and / or female internal or secondary sex organs

Chapter 457. Neoplasm Of The Liver

457.1 Hepatoblastoma

; *common primary malignant liver neoplasm

; mostly younger than 3yr

; male > female

; associated with congenital anomaly

    - *hemihypertrophy, Beckwith-Wiedemann syndrome, diaphragmatic & umbilical hernias, Meckel diverticulum, renal anomaly

; composed immature hepatic epithelial tissues

four histologic subtype: fetal ,embryonal,macrotrabecular,anaplastic

Clinical & Laboratory Characteristics

; *enlarging, asymptomatic abdominal mass

; pain, fever, weight loss, and/ or vomiting

    - 소수에서 나타난다.

; *jaundice - rare

; *isosexual precocious puberty due to β-hCG

; severe osteoporosis with pathologic fractures

; *elevated a-fetoprotein - 66%

; significant thrombocytosis, mild anemia, moderate leukocytosis

; X-ray

    - hepatic enlargement with tumor calcification(30%)

Treatment And Outcome

surgical excision of primary tumor is necessary to achieve a cure

-initially feasible in only 50%

 highly chemosensitive (cisplatinum with  either vincristine and 5-FU or doxorubicin)

3-yr survival rate:90% with initially resected tumor

457.2 Hepatocellular Carcinoma

; *often in older children 12-15yr

    - peak incidence *before age 4 yr

; 33%

    - *cirrhosis secondary to metabolic abnormality(galactosemia, tyrosinosis), glycogen storage disease, malnutrition, biliary atresia, giant cell hepatitis

Clinical Manifestation And Laboratory Data

   : abdominal distention, RUQ mass

     50%:abdominal pain; nausea, vomiting

     fever, weight loss, anorexia

     thrombocytosis is less common & elevated transaminase levels are

      more common in HCC

     serum-a-fetoprotein is elevated in about 50%

     Rt. lobe is the most common primary site

     Lung & L.N are the most common metastatic site

Treatment

 complete surgical excision is the only effective Tx

      respond to CTx are in 30-40%

457.3 Benign tumors

 -cavernous hemangioma

 -hemangioendothelioma

 -mesenchymal harmatoma

 -focal nodular hyperplasia

 -liver cell adenoma

Chapter 458. Gastrointestinal Neoplasm

458.1 Salivary Gland Tumor

458.2 Nasopharyngeal Carcinoma

    .high degree of association with EB virus

    .the histologic appearance : undifferentiated carcinoma.

    .the most early finding : cervical lymphadenopathy(usually unilateral)

    .early Sx and Sg : trismus, epistaxis, sorethroat, swallowing difficulty

    .Dx : Bx of cervical node

    .local extension : the base of the skull, surrounding soft tissue.

    .metastasis : LN(common), bone, lung.

    .the primary Tx : irradiation

458.3 Carcinoma Of The Stomach

    .extremely rare in children

    .usual Sx : noticeable mass

    .most common malignant lesion : lymphoma or soft tissue sarcoma(leiomyosarcoma)

458.4 Pancreatic Tumors

    .rare

    .usual site of origin : head of the pancreas

    .initial clinical findings : upper abdominal mass, weight loss, pain, icterus, obstructive                  jaundice(obstruction of the CBD)

    .Tx : resection when possible

          CTx agent-5FU, the nitrosoureas, doxorubicin, alkylating agent)

  =Pancreatoblastoma

    .a benign exocrine tumor located in the head of the pancreas

    .encapsulated and not communicated with the pancreatic ducts-can be removed without             interfering with pancreatic function

    .Sx : abdominal mass

    .Px : favorable after resection

  =β-Cell endocrine tumor

    .in the form of diffuse islet cell malformation or dysplasia

    .Dx : hypoglycemia

          high serum level of insulin even at low glucose levels.

         confirm-autonomous behavior of islet cell

    .Tx : pancreatectomy

458.5 Colonic Polyps

    .about 85% of all polypoid lesions in colon and rectum-the juvenile or retention polyp         .most common presenting Sx and Sg : bright red rectal bleeding.(painless)

    .become symptomatic when children are 3-5 yr of age

    .most can be removed through a sigmoidoscope.  a new polyp and polyps develops

     ( 25%) .not a premalignant lesion

    .adenomatous polyps-associated with the development of adenocarcinoma of the large             bowel

458.6 Adenocarcinoma Of The Colon And Rectum

    .represent fewer than 1% of malignant tumors in children

    .affected pt. present -bloody stools, melena, abdominal pain, anorexia, weight loss                  intestinal  obstruction

    .Dx : barium enema, direct endoscopic examination

          CT-detect hepatic metastasis, retroperitoneal lymphadenopathy, ovarian                    metastasis

    .predisposing condition :

      -familial multiple polyposis

      -ulcerative colitis

      -regional enteritis

      -Peutz-Jeghers syndrom

Chapter 459. Carcinomas

459.1 Clear Cell Adenocarcinoma Of The Vagina And Cervix

    .associated with intrauterine exposure to diethylstilbestrol

    .anomalies of the cervix may also occur in affected pt.

459.2 Carcinoma Of The Thyroid (In Chapter 524)

    .incidence is increased-head and neck irradiation

    .spontaneous thyroid cancer : F>M, papillary in nature, grow slowly

  .medullary carcinoma-associated with Marfan-like habitus, mucosal neuroma, MEN

459.3 Carcinoma Of The Adrenal Gland

   .occur at any age during childhood-more common during the first few years

   .associated with-hemangiomas of the skin,

                   hemihypertrophy

                   urinary tract anomalies

                   astrocytoma

                   girls predominate

   .affected children present sings of adrenal hyperfuntion(Cushing syndrome, virilization,

    feminization)

   .Px is dependent on tumor size, extend of tumor, resectability

Chapter 460. Cancer Of The Skin

460.1 Malignant Melanoma

   .during the first two decades

   .rapidly growing, easily traumatized, dark pigmented ulcerative lesion

   .giant hairy cell nevus syndrome or dysplastic nevus syndrome

     predispose to the development of melanoma

   .Tx : wide local resection

         metastatic disease-vincristine, cyclophosphamide, dactinomycin

460.2 Xeroderma Pigmentosum

   .an autosomal recessive

   .a defective mechanism for DNA repair

     -exposure to sunlight : UV radiation produces breaks in DNA

     -mutant malignant growth.

   .Tx : surgical resection

Chapter 461. Benign Tumor

461.1 Benign Tumors And Tumor-Like Processes Of Bone

Table 461-1

Osteoid Osteoma

   .in adolescents, esp in boys. (10-25yr)

   .usually involves the femur or tibia.

   .clinical feature : pain (more severe at night and relieved by aspirin)

            -localized tenderness, but signs of inflammation are unusual

   .roentgenogram : a sharply demarcated radiolucent nidus of osteoid tissue surrounded

                    by sclerotic bone

   .Tx : surgical (nidus must be completely removed to prevent recurrence)

Fibrous Dysplasia

   .most common developmental osseous anomaly

   .manifest in late childhood

   .association with a pathologic Fx-common cause of nonunion

   .Albright syndrome : polyostotic fibrous dysplasia + skin hyperpigmentation

                       + endocrine dysfunction

Benign Fibrous Cortical Defects

   .occur in 3040% of children

   .most commonly from 4-8yr of age

   .located in the distal femur

   .asymptomatic and heal spontaneously

   .chronic bone pain and pathologic Fx may be evident with large lesion

   .중요한 것은 malignant lesion 으로 오인하지 않는 것이다.

   .plain radiograph : ecentrically located, ovoid, have a loculated portion with a

                     sclerotic medullary border

Osteochondroma

:   .MC benign tumor of bone

   .2nd decade of life

   .often involves the distal metaphysis of the femur and proximal metaphysis of

    the tibia

   .epiphyseal plate closure 일어날 때까지 커짐

   .만약 epiphyseal closure 후에 다시 재발하면 malignant lesion 의심하고 excisional Bx

    시행함

   .x-ray : pedunculated or sessile

Enchondroma

   .MC in metadarpals, metatarsals, phalanges

   .lesion in the hand or feet : benign

   .lesion in the large long bones, in any diaphysis, or in membraneous bone : malignant

    potential 가지며, 조직학적으로도 malignant lesion 구별하기 어려움

   .Ollier disease : presence of multiple enchondroma

   .Tx : curettage for well-contained lesion, autologous bone grafting for extensive

         lesions in the metarcarpals or phalanges

Aneurysmal Bone Cyst

   .radiographically

     -lytic expansile lesion

     -lacks a sclerotic ring

   .Tx : curettage, bone grafting, cryosurgery

Simple Unicameral Bone Cyst

   .proximal humerus and proximal femur

   .cavity is unilocular or multilocular and contains fluid or blood

   .origin : unknown

   .attributed to traumatic hematoma

   .Sx : absent or scant

   .upper extremity cysts-not need Tx

    lower extremity pose a greater risk of Fx-Tx with curettage or excision

Fibromatoses

   .less then 1% of all pediatric solid tumor

   .MC neoblastic myoblastic-fibroblastic growth I children

   .characterized by the presence of multiple painless cutaneous papules located in the

    head, back and extremities

   .only definitive Tx : surgical excision

461.2 Hemangioma

; *common tumor in infants

; common site

    - *the skin : 60% head and neck

; solitary

; predominate in girls

; proliferative growth phase for 6-10mo

; involutional phase

    - 50% by age 5yr

    - *90% by age 10yr

; Treatment

    - prednisone

    - *INF alpha-2a(Roferan-A)

           / regression in most infants with life-threatening hemangiomas

    - surgical resection

    - laser photocoagulation

Kasabach-Merritt Syndrome

; Cavernous hemangioma, microangiopathic hemolytic anemia, thrombocytopenia, consumptive coagulopathy

; Treatment

    - supportive therapy directed toward improving the coagulopathy using PLT, cryoprecipitate, FFP

    - steroid

Hemangioendothelioma

   .initial Sx : jaundice, vomiting, diarrhea, abdominal swelling

   .radiograph : enlarged liver and calcification in the tumor

   .Tx : 1)initial-prednisone and or radiation

         2)surgical resection

         3)hepatic a, catheter embolization

461.3 Lymphatic Malformation (=Lymphangiomas)

; 2nd common benign vascular tumor in children

; localized or generalized

; common site

    - *the cervicofacial lesion, axilla, and thorax

; appear early in life

    - evident by the age of 3yr

; rarely regress spontaneously and obstruct aerodigestive tract

; Treatment

    - staged surgical resection

461.4 Thymoma

   .rare in children

   .equal frequency in boys and girls

   .associated conditions

     -myasthenia gravis

     -red cell aplasia

     -hypogammaglobulinemia

   .with tumor growth-progressive compression of surrounding tissue

     -cough, dyspnea, dysphagia, superior vena cava compression

   .slow growing, rarely metastasize, radiosensitive

   .TOC-surgical excision