Leukemia/Lymphoma
This gene mutations are included in the diagnostic criteria for juvenile myelomonocytic leukemia (JMML).
JMML can be due to somatic mutations in PTPN11, KRAS, or NRAS, and germline mutations in CBL and NF1.
A germline mutation in NRAS or KRAS are not included in the diagnostic criteria for JMML, nor is a somatic mutation in TP53.
An 8-month-old infant presents with a distended abdomen, and a CT of the abdomen shows a mass in the right lobe of the liver. The alpha-fetoprotein is 350,000 ng/mL. You review the case with the surgeon, who believes that the tumor is resectable, and you decide to proceed with upfront resection. Pathology shows completely resected pure fetal histology hepatoblastoma. A CT of the chest is negative, and the alpha-fetoprotein serum concentration is declining appropriately after surgery.
You recommend the following for the patient.
Observation.
Pure fetal histology hepatoblastoma is associated with an excellent prognosis.
Patients with stage I disease (as is the case for this infant) can be observed without adjuvant chemotherapy. Administration of two cycles of adjuvant chemotherapy is the recommended treatment for all other cases of stage I non-small cell undifferentiated hepatoblastoma.
Intensive treatment according to rhabdoid tumor guidelines is a consideration for patients with advanced small cell undifferentiated hepatoblastoma.
Radiation therapy is not commonly used in the upfront management of hepatoblastoma.
A 5-day-old boy has been called by the state lab to be evaluated because of absent T-cell receptor excision circles (TRECs) on newborn screening. Lymphocyte subsets show:
Absolute lymphocytes: 2,300
CD3: 3%
CD4: 2%
CD8: 1%
CD19: 92%
CD16/56: 2%
You tell the family their child likely has this disease.
Severe combined immunodeficiency (SCID)
TRECs are now analyzed in newborn dried blood spots in more than 90% of births in the United States as a screen for T-cell lymphopenia and suspicion for SCID.
This profile is characteristic of a patient with SCID, T-, B+ and NK-, likely X-linked SCID in a boy. The absolute T-cell count is very low: 3% of 2,300 = 69 cells/μL.
2-year-old male with severe hemophilia A has a right ankle bleed. He receives 3 doses of a factor VIII concentrate at the correct dose and dosing interval, however his bleed worsens.
The following agent is the best option to prevent further bleeding.
Emicizumab (Hemlibra) is currently the only effective way to prevent bleeding in hemophilia A patients with inhibitors.
MOA: brings factor IXa and factor X together to mimic factor VIII.
This faculty member broke her pinky toe with a math textbook.
Cheryl Peretz
3-year-old female who received a kidney transplant 4 months ago presents with fever. Blood cultures are negative and fevers persist despite antibiotics. A CT scan is performed to look for a source of infection and reveals abdominal lymphadenopathy as well as several liver nodules. A biopsy reveals EBV-positive polymorphic posttransplant lymphoproliferative disease (PTLD).
You recommend this agent as the most appropriate initial treatment.
Reduction of immunosuppression is usually the first intervention and can result in complete regression of disease.
For those patients who do not respond to reduction of immunosuppression, low-dose chemotherapy and immunotherapy (including the anti-CD20 antibody, rituximab) can achieve durable remission in about two-thirds of patients.
12-year-old female presents with a 9-month history of weight loss, occasional nausea and vomiting, and progressive abdominal distention. Imaging studies show a large right-sided liver mass without lung metastases.The alpha-fetoprotein (AFP) serum concentration is 37 ng/mL.
This is the most common genetic alteration associated with this likely tumor.
Hepatocellular carcinoma (HCC) is the most commonly diagnosed liver tumor in adolescents- fibrolamellar variant (FL-HCC) accounts for approximately 25% of HCCs.
DNAJB1-PRKACA fusion is diagnostic of FL-HCC.
For fun- CTNNB1 is the most commonly mutated gene in hepatoblastoma.
You receive a phone call from the mother of a former patient who was diagnosis with non-Hodgkin lymphoma at 4 years old and underwent an unsuccessful bone marrow transplant after the lymphoma recurred. The mother is concerned about her 11-year-old son, who has just been evaluated for recurrent sinusitis and impetigo and found to have low IgG and IgA levels. The mother reminds you that her brother died of fulminant hepatitis after contracting infectious mononucleosis while in college.
You tell the mother that her 11-year-old son has this likely diagnosis?
X-linked lymphoproliferative syndrome.
The family history of multiple male relatives on the maternal side that were affected is highly suspicious for an X-linked disease.
X-linked lymphoproliferative syndrome due to mutations in the SH2D1A gene, leading to lack of expression of the SAP protein, is associated with fatality after Epstein-Barr virus, lymphoma, and hypogammaglobulinemia or dysgammaglobulinemia. Consequently, these patients usually present with overwhelming illness after primary infectious mononucleosis.
1-year-old boy presents to the emergency department with irritability and vomiting, and a CT scan demonstrates a large intracranial parenchymal hemorrhage. The mother reports that his only other bleeding symptom was prolonged bleeding from the umbilical stump.
There is no family history of excessive bleeding.
These are the results of your the coags you order.
Normal PT/PTT.
Factor XIII deficiency. The family history suggests a disorder inherited in an autosomal recessive pattern. The location of the two hemorrhages (intracranial and umbilical stump) are classic for factor XIII deficiency.
This person went sky diving during their summer research internship in Wisconsin.
Maria Castellanos
12-year-old female presents with 6 months of red-to-brown raised skin lesions that become hemorrhagic, crusted, and disappear after 3 to 4 weeks. During the past week, she has had fatigue, fevers, anorexia, and a 10-lb weight loss. Physical exam reveals several raised, red-brown lesions with about 1-cm subcutaneous firmness on the patient’s arms, a 4-cm skin lesion on her abdomen that has a necrotic center, and a 3-cm axillary node. Metastatic workup reveals axillary and cervical lymphadenopathy.
This is the most likely diagnosis for this patient.
Several lymphomas can involve the skin, ALCL is the most common in children.
t(2;5) translocation resulting in the fusion NPM-ALK protein is usually present.
Note that Hodgkin lymphoma and some DLBCL lymphoma can express CD30, but all of the other lymphomas in this question generally do not present with cutaneous involvement.
12-year-old-male is being evaluated for a history of epistaxis and bilateral enlarged cervical lymph nodes. On further evaluation he was noted to have a large nasopharyngeal mass, and a trans nasal biopsy showed an undifferentiated nasopharyngeal carcinoma.
You order this test as part of the patient’s initial diagnostic work up.
Epstein-Barr virus serology.
A 10-year-old boy seropositive for CMV underwent matched unrelated donor bone marrow transplant for treatment of aplastic anemia and was discharged on day +30. You are seeing him weekly in outpatient clinic and he has CMV viremia on PCR on serial screens that are rising rapidly. He has no evidence of CMV organ involvement. He is on acyclovir currently.
You decide to start another agent.
Standard induction treatment for CMV reactivation is ganciclovir IV or valganciclovir orally.
Letermovir is not an appropriate induction agent.
A 15-year-old girl with heavy menstrual bleeding is found to have a bleeding disorder with the following labs:
PT: 10 seconds (normal 8-13 seconds)
PTT: 32 seconds (normal 24-38 seconds)
von Willebrand factor antigen: 93%
von Willebrand factor activity: 29%
Factor VIII activity: 84%
von Willebrand multimers: present in normal amounts
Platelet aggregation studies: normal platelet aggregation
Factor XIII activity: 103%
Labs confirm she has this type of von willebrand disease.
Type 2M- discrepancy between the von Willebrand factor antigen, which is normal, and the von Willebrand factor activity, which is very low.
Remember- desmopressin is not effective in type 2M vWD because secreting more dysfunctional von Willebrand factor from the endothelial cells.
This person got locked in the Olympic Stadium in Athens and had to scale a fence to get out.
Ro Jain
Novel immunotherapeutics currently are being used in acute lymphoblastic leukemia (ALL) therapy, including bispecific T-cell engaging therapies. Cytokine release syndrome is a known complication of this therapy.
This cytokine is most associated with the acute onset of the inflammatory response and can be targeted with this agent.
Elevated levels of IL-6 are associated with CRS and the use of tocilizumab, an IL-6 receptor antibody, can ameliorate the symptoms.
23-year-old patient presents with pain and a 3.5-cm lytic lesion in the talus. Biopsy shows Ewing sarcoma with an EWS-ERG fusion. Staging studies show no evidence of metastatic disease.
Between tumor size, age, bone involvement, stage, fusion protein, the most unfavorable prognostic factor is...
Age
The most important unfavorable prognostic feature for this patient is age greater than 18 years.
Tumors larger than 8 cm generally considered unfavorable.
Localized Ewing sarcoma arises in bone or soft tissue or presence of EWS-FLI1 or EWS-ERG fusions, have not been clearly shown to affect prognosis.
Patients with Langerhans cell histiocytosis (LCH) who have lesions of the orbit, temporal bone, or mastoid have a higher incidence of diabetes insipidus than those having skull lesions in other locations.
They are also at risk for this non-endocrine problem.
Neurodegenerative syndrome- symptoms include ataxia, dysmetria, dysarthria, and learning difficulties.
Brain MRIs show abnormal FLAIR and T2 intense signal changes in the brain regions listed above. The cause of neurodegeneration is infiltration of the brain by BRAF+ myeloid dendritic cells migrating through blood vessel walls.
A 32-year-old woman who had immune thrombocytopenia (ITP) 2 years ago and is now in remission delivers a healthy male infant. The infant has no findings on physical examination. CBC is normal with the exception of a platelet count of 125,000/mm3. The infant is vigorous and alert.
You are asked if any additional work up/labs are needed for the infant.
Maternal history of ITP in this scenario makes a diagnosis of neonatal autoimmune thrombocytopenia more likely. Even though the infant’s mother is in remission, this does not entirely eliminate her ability to make antiplatelet antibodies.
Neonatal autoimmune thrombocytopenia is less likely to be associated with severe thrombocytopenia, rarely leads to intracranial hemorrhage, and usually can be managed with conservative measures. Therefore this infant does not need treatment, platelet transfusion, or head ultrasound at this time.
Infants should be watched closely because the platelet count reaches a nadir at 3 to 4 days of life.
2-year-old girl is diagnosed with T-cell lymphoma and therapy is initiated. She is meeting all her physical growth parameters and developmental milestones. Prior to her diagnosis of lymphoma, she was hospitalized twice for pneumonia. You notice that her gait appears more wide-based than normal for a toddler.
You suspect she may have this cancer predisposition syndrome.
Ataxia-Telangiectasia
T-cell malignancies, immunodeficiency, and progressive ataxia.
You are treating a 4-year-old with multiply relapsed B-ALL with tisagenlecleucel. The strongest predictor for failure after CAR T-cells is...
NGS-MRD positivity at 3 months after CAR T-cell treatment.
You are seeing a 24-year-old patient in your cancer survivorship clinic who was treated for a non-metastatic high grade Ewings sarcoma arising from the left scapula 4 years ago. He has been maintained in continuous remission since undergoing treatment with multiagent chemotherapy and definitive radiation to the tumor for local control.
He is doing well clinically with no complaints and asks about his risk for late effects from therapy doing well clinically with no complaints and asks about his risk for late effects from therapy.
Standard of care chemotherapy for Ewing sarcoma consists of interval compressed VDC-IE.
This treatment regimen contains a high cumulative dose of alkylator chemotherapy (cyclophosphamide and ifosfamide)- High incidence of infertility.
Secondary malignant neoplasms due to both chemotherapy and radiotherapy are important long term risks of treatment, but occur at much lower incidence than infertility.
Cardiomyopathy due to anthracyclines are also less likely particularly with the use of dexrazoxazne.
A 4-year-old boy comes for evaluation due to refractory autoimmune hemolytic anemia despite treatment with steroids. According to his family, he has been in and out of the doctor’s office because of swollen glands for about a year. On examination you detect massive splenomegaly in addition to cervical adenopathy.
Laboratory testing shows Coombs positive anemia and a platelet count of 32,000, with mean platelet volume of 11 fL. Lymphocyte subsets show normal numbers of T cells, B cells, and NK cells. IgG is elevated for age.
This is the most likely diagnosis.
Autoimmune lymphoproliferative syndrome (ALPS).
Other considerations:
Wiskott-Aldrich syndrome- autoimmunity including immune cytopenias, typically the platelet volume is very low, massive splenomegaly would be unusual.
CVID- autoimmune cytopenias, adenopathy, or splenomegaly, but the primary feature of CVID is humoral immune defect, with low IgG and low IgA or IgM.
SCID- hypogammaglobulinemic due to lack of T-cell help. It would be highly unusual for a child with SCID to present at 4 years of age.
2-year-old with severe hemophilia A has had 3 joint bleeds in the last 3 months. He received six doses of factor to treat these bleeds and responded well. You decide to initiate prophylaxis with every-other-day factor infusions at 40 IU/kg/dose.
A month after initiation, the patient returns to the clinic, and the family reports that he has two additional bleeds in his right ankle.
You order this test as the next step in your management.
Bestheda Assay.
Any patient with hemophilia on prophylaxis who is having breakthrough bleeding that is frequent or unexpected should be evaluated for the presence of an inhibitor.
This person first met their partner while they were naked on a table in public dispensing beer from a keg.
Natalie Wu