What is the difference in the appearance of the blasts in types L1,L2, and L3 ALL?
L1 = Small blasts
L2 = Large blasts
L3 = Leukemic form of Burkitts Lymphoma with the same t(8:14) location. All mature B-cell ALL
Good prognostic factors with ALL include hyperdiploidy, the t(__:__) translocation, being female, and the L1 subtype.
Poorer prognostic factors include age <1 or > 10 years old. Chromosome t(___:__) positive, or translocation t(__:__), WBC count > 50,000 on presentation, mature B-cell leukemia, T-cell leukemia, and/or being african american or hispanic.
t(12:21) translocation = good
t(9,22) aka Philadelphia Chromosome = Bad
t(4:11) = Bad
Induction therapy for the treatment of ALL includes what 4 drugs?
Vincristine, a glucocorticoid, L-asparaginase, and a 4th agent depending on the risk group, including an anthracycline (daunorubicin or doxorubicin).
Maintenance therapy for ALL is usually 18-24 months and uses oral _____ and weekly ____ with intermittent pulses of _____ and _______.
Oral 6-MP (mercaptopurine)
Intermittent pulses of Vincristine and glucocorticoid
Which ALL patients recieve CNS chemoprophylaxis or preventative therapy? What do they typically use?
EVERY ALL PATIENT regardless of the initial CNS findings.
Use a single-agent intrathecal methotrexate or triple agent chemotherapy.
The main site of relapse of ALL is ____. The predictive value is the length of time the remission lasted. What is the treatment? What if the relapse is in the CNS or testicles alone or relapse?
BM transplant is the standard for first relapse if early
Isolated CNS and testicular relapses are rarer but can potentially be cured by retreatment with chemotherapy.
What is the major long term complication of the following therapies:
Methotrexate or 6-MP?
Anthracyclines (doxorubicin and danorubicin)?
Epipodophyllotoxins (etoposide, VP-16)?
Methotrex/6-MP = Hepatotoxicity
Anthracyclines = cardiomyopathy
Epipodophyllotoxins = increased risk of secondary malignant tumors, specifically AML
The antimetabolite chemotherapeutic agents Methotrexate, 6-MP, and Ara-C cause myelosuppression as a toxicity. What do each inhibit?
Methotrexate - folic acid antagonist
6-MP - purine synthesis inhibitor
Ara- C - DNA polymerase inhibitor
What chemotherapy agent causes hemorrhagic cystitis as it's major toxicity? How does it work?
Cyclophosphamide - an alkylating agent that inhibits DNA synthesis.
Doxorubicin, Danurubicin, and Bleomycin are antibiotics that bind to ___. What is the major toxicity of each?
Dox and Dano cause Cardiomyopathies
Bleomycin causes Pulmonary fibrosis
Which Alkaloid inhibits microtubule formation and can lead to a peripheral neuropathy as a common toxicity?
L-aspariginase is an enzyme used for chemotherapy. What is it's common toxicity?
Pancreatitis, also increased glucose
Cisplatin inhibits DNA synthesis but can cause three toxic side effects which are:
Nephrotoxic, ototoxic, and neurotoxicity
Down Syndrome, Bloom Syndrome, and Fanconi's anemia all can predispose a patient to ALL or AML. What other condition increases your risk for ALL? What 4 other conditions can increase your risk for AML?
ALL = Ataxia-telangiectasia
AML = Diamond-Blackfan syndrome, Kostmann Syndrome, Paroxysmal nocturnal hemoglobinuria, & neurofibromatosis
t(15:17) is found in most cases of what FAB Classification of AML? Associated with DIC at presentation.
M3 - APL - acute promyelocytic leukemia
AML induction therapy is very intense and usually includes _____ and _____.
Anthracyclines (doxorubacin or danurubicin) and Ara-C (cytosine arabinoside)
Which AML patients get CNS prophylaxis?
All - even though CNS disease is low.
After the initial remission of AML, what is the next step in treatment? Patients with APL, M3 classification should recieve _____ and chemo instead. Kids with Down's syndrome also do well with chemotherapy alone.
Stem Cell Transplantation which can result in a 70% cure rate!
Inv 16 and 11q Chromosomes are found with what 2 FAB Classifications of AML that have associated CNS disease and gingival hyperplasia?
M4 and M5
Hyperkalemia, hyperphosphatemia, and renal insufficiency due to urate nephropathy are seen in tumor lysis syndrome. Which certain tumors are the highest risk?
Burkitt lymphoma and T-Cell ALL
Inhibit this from happening with hydration and allopurinol or urate oxidase therapy.
Philadelphia chromosome CML is a disorder of pluipotent stem cells defined by what translocation?
t(9:22) the bcr-abl gene
Philidelphia Chromosome CML has a chronic phase for 2-4 years, during this time what treatment is the best?
Use of what two medications can help control the progression of this cancer?
What inhibitors have been shown to directly inhibit bcr-abl and induce complete cytogenic remissions in patients with CML.
The chronic phase can give way to an acute "blast crisis".
Allogenic BMT during the 1st year of the chronic phase can cause cure rates as high as 90%.
Hydroxyurea and interferon-alpha can control it
Tyrosine Kinase Inhibitors
JuvenileMyelomonocytic Leukemia occurs before the age of 2 with skin rashes and a large spleen. There is no blast crisis (unlike in CML). However only 10% survive without what intervention?
BMT with or without splenectomy.
Neurofibromatosis Type 1 patients are at an increased risk for what leukemia?
JMML - Juvenile Myelomonocytic leukemia.
The finding of Reed-Stemberg cells is indicative of what diagnosis?
Hodgkin's Lymphoma - "Owl Eyes"
Age determines the form:
< 14 y/o = Childhood (more boys - mixed cellularity MC)
Middle = Young Adult (nodular sclerosing is MC form)
> 55 = Older Adult
What is the MC physical exam finding in Hodgkin's Lymphoma on presentation? What are having the "B" symptoms indicative of?
Supraclavicular lymphadenopathy. May have a cough from mediastinal node involvement.
B sympstoms (wieght loss, night sweats, fever) usually mean more advanced disease and poorer prognosis.
Pel-Ebstein fevers are the periodic fevers they get. Some also report pain with alcohol ingestion and itching.
What is the staging system used for Hodgkin Lymphoma? How are the 4 stages determined? What children should get bone marrow biopsies?
Ann Arbor Staging
I = 1 node
2 = 2 + on one side of diaphragm
3 = Both sides of diaphragm - add chemo to radiation for treatment
4. Disseminated - treat with combination chemotherapy
Those with stage III or IV or whom have "B" symptoms.
Early stage Hodgkin's Lymphoma is treated with radiation alone. Bulky stage II or higher is treated with chemo as well. What are the two MC used combinations and their major side-effects?
ABVD- Adriamycin (cardiomyopathy), Bleomycin (pulm toxicity) Vinblastine, and Dacarbazine.
MOPP (nitrogen Mustard, vincristine (Oncovin), Procarbazine, and Prednisone. SE include increased risk of AML and infertility.
Non-Hodgkin Lymphoma is the MC type of lymphoma in pediatrics. There are more males/females (?) effected. What 2 syndromes and 2 infections are linked to it?
Males > Females 3:1
Ataxia-telangiectasia and Wiskott-Aldrich Syndrome
HIV or other immunosuppresed disease
EBV - HIGHLY correlated in Africa
FYI: Most cases of Non-Hodgkin's Lymphoma are high grade diffuse neoplasms that can my lymphoblastic, large cell, or small non-cleaved (Burkitt).
The MC form of Non-Hodgkin's lymphoma is _____ lymphoma in which 90% arise from the relatively mature B cells in ________. What is a common complication with treatment?
Peyer Patches within the GI tract - MC in the ileocecal junction. 10% will come from Waldeyer rign (tonsils/adenoids).
Fastest growing tumor (can double in 2 days!) so tumor lysis syndrome is common.
Which form of lymphoma presents with an anterior mediastinal mass with 80% being from T-cell origin. Commonly seen in adolescent males.
FYI: the other 20% of lymphoblastic lymphomas are B-cell and show up in the skin and bone.
TENDER lymphadenopathy is associated with what form of lymphoma?
Large Cell Non-Hodgkin Lymphoma
What is the preferred method of treatment for Non-Hodgkin's Lymphoma? What Chemotherapy combination is used when NHL requires chemotherapy?
Chemotherapy with or without surgical resection
Radiation is limited to CNS disease (FYI any bone or CNS involvement = stage IV lymphoma)
CHEMO = CHOP aka Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone. This is then followed by 6-MP and methotrexate.
Remeber BURKITTS has a super high risk for tumor lysis syndrome so make sure that you prophylax!
With neuroblastomas, the best prognosis is in kids < 1 years old! Increasing copies of the ___ oncogene correlates with a poorer prognosis. Ploidy of the tumor confers a better prognosis. Chromosome __ deletion is a poor prognostic sign.
In infants < 1 years old with neuroblastoma, it is common t have a small primary tumor with dissemination limited to the liver and ____. This stage is referred to as __ and has a good prognosis generally.
In general stages 1,2, and 4s are good prognosis but the rest are poorer
Intractable secretory diarrhea, opsomyoclonus, and horner syndrome are all paraneoplastic syndromes associated with what tumors?
(horner is from cervical area involvement impinging on the nerve)
- VIP syndrome causes the diarrhea and bloating
Diagnosis of a neuroblastoma requires histiological evidence of neural origin and the ginding of what in urine?
Catecholamine metabolites HVA (homovanillic acid) and VMA (vanillymandelic acid).
What makes up WAGR syndrome?
Wilms tumor, aniridia, GU abnormalities, and Mentral Retardation
What tumor is a part of Dents-Drash syndrome?
Wilms tumor, nephropathy, and Hemi-hermaphroditism make up Denys-Drash Syndrome.
In wilm's tumors, stage I are limited to the kidney and completely resectable, II extend beyond but are completely resectable, III have tumor confinded to the abdomen and Stage IV have hematogenous spread - usually to the _____. Stage V has bilateral kidney involvement. What is more important than the stage in determining the prognosis for these patients?
- Tumor makeup is more important - the "triphasic" form with epithelial, blastemal, and stromal elements is favorable while anaplasia is poor prognostically.
What is the preferred treatment for a Wilm's Tumor? If chemotherapy is used and the patient has favorable histology at stage I or II then treat with ___ & ______ for __ weeks. Those with stage III or IV are given a combination with what 3 drugs for ___ weeks?
Vincristine & actinomycin D for 18 weeks
Vincristin, actinomycin D, and Doxorubicin for 21 weeks
Li-Fraunmeni Syndrome consists of maternal breast cancer, _____ in children, and others with adrenocorticical carcinoma. Germline mutations are present on the ___ gene.
Sarcomas - rhabdomyosacromas (or osteosarcomas)
Rhabdomyosarcomas arise from the same embryonic mesenchyme as ____. There are 4 histological types: Emryonal (MC), Botryoid (vagina/bladder/nasopharynx/middle ear), Alveolar (worst prognosis), and pleomorphic (rare - seen in adults).
Striated skeletal muscle
What determines the staging of a rhabdomyosarcoma?
What chemotherapy is indicated for all children with rhabdomyosarcomas? Local control with radiation and surgical excision (PARAMOUNT!) are also used.
Based on extent of residual disease after resection:
Group I = complete resection
Group 2 = microscopic residual
Group 3 = gross residual
Group 4 = distant metastases
VAC = Vincristine, actinomycin D, and high-dose cyclophosphamide.
Patients with AIDS and those that are immunosuppressed secondary to renal transplants are at risk for what type of tumors that are MC in the retroperitoneal cavity and typicaly arise in the GI tract.
Osteosarcomas usually occur in the _____ region of ____ bones. Their cells are ____ cells producing osteoid.
metaphyseal region or long bones
A "Sunburst" pattern on an x-ray of a bone is classic (but not diagnostic) for what cancer?
Ewing sarcomas are undifferentiated sarcomas of bone or soft tissue made up of small round cells of _____ origin. A majority of patients have a r(__,___) translocation. The rest have a t(21,22).
undifferentiated - probably neural crest
The ___ of long bones and flat bones (ribs/pelvis) are more commonly effected in Ewing's sarcoma.
Compared to osteosarcoma they are also more likely to have paraspinal and vertebral primary tumors.
An x-ray showing a primary lytic lesion with peristeal reaction on a bone aka "onion skinning" is suggestive of what?
What is an osteochondroma?
A very common bone tumor that is benign. Usually never recognizd and asymptomatic. Occur MC in metaphysis of long bones and have a cartilage cap. Leave them alone unless they are large enough to cause symptoms.
Benign solitary lesions of hyaline cartilage that occur centrall in the bone (MC in hands) are ______.
Enchondromas - usually not the answer on the boards but given as a distractor.
FYI: Ollier disease (mult enchondromas and short stature w/limb deformities) & Maffucci Syndrome (mult echondromas with angiomas) both can lead to malignant transformation of the enchondromas. Otherwise they are usually just observed.
Unremitting bone pain that is worse at night and responds to aspirin is usually a _______.
Osteoid Osteoma - a BENIGN mass
FYI: An X-ray will show a round or oval metaphyseal or diaphyseal lucency with surrounding sclerotic bone. Treatment is removal.
What tumor is associated with Neurofribromatosis Type 1?
How about NF Type 2?
Type 1 = Optoc Gliomas
Type 2 = Bilateral vestibular schwannomas
Others includie meningiomas, etc.
Tuberous sclerosis is associated with what tumors?
Subependymal Giant Cell Tumors - benign but grow big
What two tumors are associated with Turcot Syndrome?
Medulloblastoma & glioblastoma multiforme.
Von Hippel-Lindau is associated with what type of tumors?
Hemangioblastomas in the cerebellum, medulla, and spinal cord.
What is "sunsetting" of the eyes and what is it a symptom of?
Sunsetting is impairment of the upward gaze and downward deviation of the eyes. It is an early sign of increased intracranial pressure.
What is parinaud syndrome and what is it indicative of?
A triad of:
- impaired upward gaze
- dilated pupils with better reactivity to accomondation than to light
- retraction or conversion nystagmus with lid retraction
Caused by compression or infiltration of the midbrain tectum - usually meaning PINEAL TUMORS
Dissemination to the leptomeninges with CNS tumors causes what clinical symptoms?
Intermittent mental status changes, neck back or radicular pain, weakness, and bowel/bladder dysfunction
Preoperative corticosteroids are often given to brain tumor patients to reduce the intracranial pressure and tumor edema. These steroids are then tapered slowly after surgery. Too fast of a taper can cause a chemical meningitis in tumors located where?
Posterior fossa tumors.
NOTE: In all cases surgery and chemotherapy are preferred over radiation in INFANTS with brain tumors.
Neuroectodermal tumors are the MC malignant CNS tumors in kids. The worst prognosis are with the _____ which occur in the _____ and are usually disseminated at diagnosis. The MC are _______ which appear where?
Pineoblastomas (occur in pineal gland)
Medulloblastomas (occur in posterior fossa)
What is the common presenting clinical picture with a medulloblastoma? What is the treatment?
Morning headache, vomiting, lethargy, ataxia, head-tilt from 4th nerve dysfunction. 75% have hydrocephalus.
Surgical resection is the goal. Then do post-operative MRI w/gadolinium to check for leptomeningeal involvement and a LP. Radiation after surgery is a mainstay.
Tumors arising from the linig of the ventricular system are known as _______. 75% occur in the posterior fossa and the rest are supratentorial.
Ependymomas (arise from ependymal lining of ventricles)
A tumor arising in the cerebellum of a child is usually a _________. How do you treat it?
Cerebellar astrocytoma (usually the pilocytic juvenile form)
Resect it - only need radiation after if you can't get it all out.
What is the treatment of choice for a brainstem glioma?
They do not respond well to surgery so don't resect it unless you can take it out completely and it is benign. Treat with radiation or chemotherapy instead.
A patient with a diencephalic glioma should be examined for signs of what syndrome?
Neurofibromatosis Type 1 since optic pathway tumors are a part of the syndrome. Treat with radiation (surgery may risk vision even more).
What type of astrocytoma has the most malignant potential?
Glioblastoma Multiforme - treat surgically.
A patient with elevated hCG and Alpha-fetoprotein has what type of a pineal tumor?
Germ Cell Tumor - usually a germonoma
Treat with radiation
Remember: Pineal tumors present with parinaud syndrome (impaired upward gaze, better reactivity to accomodation than light, and nystagmus w/lid retraction).
Benign tumors derived from squamous epithelial cells in the suprasellar region of the brain are _____. Their growth usually is invasive and can impinge on other structures. Often associated with endocrine abnormalities. MC complication of surgical resection is what?
MC = diabetes insipidus
The retinoblastoma gene (Rb) is located on the long arm of ________ and functions as a tumor suppressor gene. Those with the germ cell line ___ mutation are at a very high risk of developiong secondary malignancies.
Chromosome 13 - remember it is a "two hit" method of obtaining itin the heritable form. 25% are hereditary and bialteral, 15 % are unilateral and hereditary, and 50% are unilateral and non-hereditary.
What is the treatment for a retinoblastoma?
Treat w/enucleation if unilateral, if bilateral try chemo w/ carboplatin, vincristine, and etoposide. Laser or cryotherapy are surgical options too.
In an infant with a teratoma, if it is located in what region will the risk for malignant transformation increase to 50% once the infant is over 2 months?
Sacrococcygeal teratoma - treat with chemo if this happens. Otherwise oftne benign.
Germinomas in the ovary are referred to as ______ and in the testes as ______. Often tumor marker negative (B-hCG and AFP). What extragonadal location is the most common?
Ovary = dysgerminoma
Teste = Seminoma
An ovarian, testicular, or sacroccyx tumor with a high AFP but absent B-hcg is a _____.
What about a tumor with a high B-hcg and an absent AFP?
Endodermal Sinus tumor aka Yolk Sac Tumor
Choriocarinoma - has syncyiotrophoblast tissue as well
A patient with a 46 XY or 46XY/XO karyotype that has dysgenic gonads present thus has a ______. What is the treatment?
Gonadoblastoma - Usually phenotypically a woman
Remove the gonads. Can be seen in Turner's Syndrome.
Nasopharyngeal carcinoma is associated with what inection?
EBV - usually seen in China
A child with a pancreatic tumor should be worked up for what syndrome associated with them?
Pancreatoblastomas occur only in childhood and are emryonal tumors that secrete what?
What syndrome is made up of a primary brain tumor (medulloblastoma) and multiple colorectal polyps?
Multiple intestinal polyps and tumors of the mandible and soft tissue/bone makes up what syndrome?
A child less than 2 years old with multiple liver lesions and a normal AFP most likely has ______. An older child with a solid mass and elevated AFP most likely has ______. A teen on BCPs with a hepatic mass has an ______.
FYI: metastaic disease to the liver in a kid < 2 years old is most likely due to a neuroblastoma.
Treat hemangioendotheliomas with resection if symptomatic. If you can not resect it or a coagulopathy is present give _____. If there is no response use ____ or ____.
Interferon-alpha or Vincristine.
Hepatocellular carcinoma is associated with what infection?
Hepatitis B - surgical resection is the only curable option. However 1/3 are unresectable and chemo is not beneficial.
(FYI: Elevated AFP is present in 1/2 of those with hepatocellular carciona).
OF NOTE: Chem with resection is the management for a hepatoblastoma - the other liver tumor with elevated AFP
What are the three types of Langerhans Cell Histiocytosis, what cells are increased, and how do you diagnose it?
Unifocal, Multifocal (formerly Hand-Schuller-Christian disease) & systemic.
Increased Langerhans cells - dendritic cells along with macrophages, lymphocytes, granulocytes, eosinophils, and multinucleated giant cells.
Diagnosis is confirmed by finding CD1a by immunophenotyping or Birbeck granules on electron microscopy.
FYI: clinically it ranges from painless, single bone involvement to multisystem involvement of brain/lungs/skin/bone/liver/etc
What is the finding on X-ray with unifocal langerhans cell histiocytosis?
What is the treatment for lesions causing pain? What about ones that threaten the spinal cord? What about skin lesions?
Punched-out lytic lesions of the bone
Pain: NSAIDs, curettage
Spinal Cord: low-dose radiation
Skin: Topical steroids, resistant can get topical nitrogen mustard.
What are the three findings in multifocal langerhans cell histiocytosis?
What is seen in infants?
Skull lesions, Diabetes insipidus (polyuria/polydipsia), exophthalmos.
Some get seborrheic rashes. Some present with pulmonary findings.
Infants have bleeding of the gums, eruption of teeth
What is the brain MRI finding in multifocal langerhans cell histiocytosis?
Posterior pituitary gland changes
Hemophagocytic lymphohistiocytosis has a primary and secondary form. The primary form is inherited AR and is associated with consanguity. Secondary is associed with EBV and various bacteria infections. What is the pathology? What are some lab findings?
Lesions with activated macrophages and lymphocytes are found in the liver, spleen, lymph nodes, bone marrow, and CNS. (different that langerhans cell histiocytosis because there is no dendritic cell involvement).
Labs: pancytopenia, hyeperferritinemia, hyperTG, and hypofibrinogenemia.
Diagnosis of Hemophagocytic Lymphohistiocytosis requires what 6 findings?
Peripheral blood cytopenia of two or more lineages
Hypertriglyceridemia or hypofibrinogenemia
Hemophagocytosis without evidence of malignancy in bone marrow, spleen. or lymph nodes
massively elevated serum ferritin
What is the treatment for hemophagocytic lymphohistiocytosis?
In primary HLH they die within months if not treated!
Give combination chemotherapy with steroids and etoposide for 8 weeks and intrathecal methotrexate for CNS involvement. BMT may be curative if remission occurs.
For secondary HLH use chemotherapy. BMT is not an option.