2 Peds Malignancy Flashcards
1
Q
1 Second to accidents, what is the most common cause of death in children between 1 and 14 years of age?
A
Malignancy
2
Q
2 What is the most common sarcoma of childhood?
A
Rhabdomyosarcoma. Up to 35% are found in the head and neck.
3
Q
3 Which cell type gives rise to rhabdomyosarcoma, and what major histologic variants are described?
A
Primitive skeletal muscle cells (small, round blue cell tumor of childhood): embryonal, botryoid, alveolar, undifferentiated. Some include anaplastic. Embryonal and alveolar are the most common types, and embryonal type carries the best prognosis.
4
Q
4 Where does pediatric head and neck rhabdomyosarcoma most commonly occur?
A
Parameningeal (50%): Paranasal sinuses, nasopharynx, nasal cavity, middle ear, mastoid, infratemporal fossa (5-year survival: 49%; considered high risk) Orbit (25%) (5-year survival: 84%) Nonorbital, nonparameningeal (25%): Scalp, parotid, oral cavity, pharynx, thyroid, parathyroid, neck (5-year survival: 70%)
5
Q
5 What are the common initial symptoms associated with head and neck pediatric rhabdomyosarcoma?
A
Symptoms are due to progressive mass effect, local swelling, neurologic sequelae, or tissue necrosis. Bone marrow involvement can manifest as hematologic concerns.
6
Q
6 What are the most important negative prognostic factors associated with pediatric rhabdomyosarcoma?
A
Diagnosis during infancy or adolescence; metastatic disease at diagnosis; alveolar histology; disease identified in a parameningeal location (risk for intracranial spread), in the extremities, or in the retroperitoneum or trunk; recurrence or progression during therapy
7
Q
7 What diagnostic techniques are required to evaluate the primary tumor in rhabdomyosarcoma?
A
Biopsy: Open biopsy is done to ensure adequate tissue unless the lesion is small and difficult to access, in which case, needle biopsy may be acceptable. Imaging: CT scan and magnetic resonance imaging (MRI) to evaluate extent of disease
8
Q
8 What diagnostic techniques are required to evaluate locoregional and/or distant metastases in rhabdo myosarcoma?
A
Laboratory work (complete blood count [CBC], electrolytes, liver function, coagulation studies, renal function tests) Technetium-99 bone scan CT chest Positron emission tomography (PET)/CT scan Aspiration/biopsy of iliac bone marrow. Distant metastases are more commonly found in the brain, lung, bone, and bone marrow.
9
Q
9 Which group is credited with increasing the survival rate for patients with rhabdomyosarcoma from 30 to 70% since the 1970s?
A
The Intergroup Rhabdomyosarcoma Study Committee (now the Soft Tissue Sarcoma Committee of the Children’s Oncology Group)
10
Q
10 What is the clinical grouping or surgical pathologic staging system commonly used for staging rhabdo myosarcoma?
A
Table 2.1
11
Q
11 What is the tumor, node, and metastases (TNM) staging system for rhabdomyosarcoma introduced by the Intergroup Rhabdomyosarcoma Study IV?
A
Table 2.2
12
Q
12 Describe the staging system for rhabdomyosarcoma that combines the TNM and clinicopathologic groups to provide both prognostic and therapeutic recommendations.
A
Rhabdomyosarcoma prognostic stratification and standard treatment assignment (Prognosis, Event-Free Survival): Excellent (> 85%) Very good (75 to 85%) Good (50 to 70%) Poor (< 30%) This system allows for risk-directed therapy.
13
Q
13 Describe the favorable and unfavorable locations for head and neck rhabdomyosarcoma.
A
Favorable: Orbit and eyelid Unfavorable: Parameningeal
14
Q
14 True or False. In a patient with localized nonorbital, nonparameningeal head and neck embryonal rhabdomyosarcoma, if complete surgical excision can be achieved, radiation therapy may be avoided.
A
True. However, chemotherapy is recommended for all patients with rhabdomyosarcoma.
15
Q
15 Is elective neck dissection for clinically negative necks recommended in patients with nonparamen ingeal rhabdomyosarcoma of the head and neck?
A
No
16
Q
16 What are the most commonly used chemotherapeutic agents for treatment of rhabdomyosarcoma?
A
Vincristine, actinomycin D, cyclophosphamide
17
Q
17 What are the most common late complications in patients treated for rhabdomyosarcoma of the head and neck?
A
Short stature, regional tissue hypoplasia, poor dentition, malformed teeth, impaired vision, decreased hearing, and learning disorders
18
Q
18 What is the most common fibrous tumor of infancy?
A
Infantile myofibromatosis (solitary or multicentric; well circumscribed, spindle-shaped cells, including fibroblasts and smooth muscle cells on histopathology)
19
Q
19 What is the natural history of infantile myofibromatosis?
A
Most will involute by age 1 to 2 years. Visceral lesions causing functional impairment (e.g., pulmonary), may require surgical excision. For nonresectable, rapidly pro gressive, recurrent or symptomatic lesions, surgery, radia tion therapy and chemotherapy should be considered.
20
Q
20 What tumor type is composed of a mixed group of mesenchymal malignancies that are generally defined as either soft tissue (80%) or bony/ cartilaginous (20%) tissue?
A
Sarcomas. These tumors can arise from muscle, nerve, fat, vessel, fibrous tissue, bone, or cartilage.
21
Q
21 What is the most common initial manifestation of head and neck sarcoma?
A
Painless mass. Symptoms generally are related to the structures involved and uncommonly include pain. Referred otalgia may be seen in patients with oropharyngeal or hypopharyngeal lesions. Pain can also represent bony impingement of nervous structures.
22
Q
22 How are sarcomas defined in general terms?
A
Tissue of origin Histologic grade Anatomical subsite in the head and neck
23
Q
23 List examples of high-grade and low-grade sarcomas of the head and neck.
A
High grade
● Osteosarcoma* ● Malignant fibrous histiocytoma*
● Rhabdomyosarcoma* ● Angiosarcoma*
● Synovial sarcoma ● Alveolar soft part sarcoma
● Ewing sarcoma
Low grade
● Dermatofibrosarcoma protuberans ● Desmoid tumors
● Atypical lipomatous tumors
Require individual grading ● Chondrosarcoma ● Fibrosarcoma ● Neurogenic sarcoma ● Hemangiopericytoma
*Most common in the head and neck (50%)
24
Q
24 How does the anatomical subsite within the head and neck influence decision-making in the management of sarcomas?
A
The ability to resect the tumor fully, without causing undue morbidity, significantly influences surgical versus nonsur gical decision-making.
25
25 In the pediatric population, what percentage of sarcomas manifest in the head and neck?
Around 35% of sarcomas in children manifest in the head and neck; this rate is greater than that in adults.
26
26 What historical factors increase the risk of developing a sarcoma?
* History of radiation of the head and neck
* Li-Fraumeni syndrome (p53 mutation)
* Hereditary retinoblastoma (Rb-1 mutation)
* Neurofibromatosis type 1 (NF-1)
* Gardner syndrome
* Nevoid basal cell carcinoma syndrome
* Carney triad
* Hereditary hemochromatosis
* Werner syndrome
27
27 How might a sarcoma differ from a squamous cell carcinoma of the same anatomical subsite during examination of the upper aerodigestive tract?
Sarcomas will appear as a submucosal mass.
28
28 What radiographic workup is necessary for pediatric head and neck sarcomas?
CT scan: Soft tissue extent, nodal involvement, cortical bony involvement MRI scan: Soft tissue, bone marrow, perineural extension, orbital and intracranial involvement Fludeoxyglucose (FDG)-PET/CT scan: Staging, response to therapy, surveillance
29
29 What is the most likely site of metastasis from head and neck sarcomas, and how does this influence diagnostic workup?
Lung. Imaging of the chest is required: chest-X-ray for low grade lesions, CT for high-grade lesions.
30
30 During initial diagnosis of a soft tissue mass in the head and neck, why might core needle biopsy or excisional biopsy be preferred to FNA?
FNA may not provide enough tissue for extensive immu nohistochemical analysis, and it has a higher risk of being nondiagnostic. However, FNA is minimally invasive, can be performed without conscious sedation in some children, and has a reported sensitivity of 95%.
31
31 What mesenchymal vascular sarcoma arises from the pericytes of Zimmerman?
Hemangiopericytoma
32
32 Notably, 10 to 25% of all hemangiopericytomas are in the head and neck. What is the most common subsite?
Sinonasal tract
33
33 True or False. All hemangiopericytomas diagnosed in the pediatric population are acquired after birth.
False. 5% of all hemangiopericytomas are congenital and are considered benign.
34
34 How do pediatric hemangiopericytomas most commonly present?
Most are slow-growing, soft, subcutaneous, painless masses. Compared with adult-onset hemangiopericytomas, the pediatric variant generally follows a more benign clinical course.
35
35 How are pediatric hemangiopericytomas managed?
Surgical resection to negative margins is the mainstay of treatment for malignant lesions. Radiation and chemotherapy may improve local and distant control, although distant metastases are less common in the head and neck. Chemotherapy has been used for congenital lesions.
36
36 What aggressive malignant sarcoma arises most commonly in the axial long bones of the lower extremities and pelvis but can arise in extraosseous soft tissue sites, such as the sinonasal tract and paranasal sinuses, orbit, scalp, and paravertebral areas of the neck?
Ewing sarcoma
37
37 What is the tissue of origin for Ewing sarcoma?
This topic is controversial; possible origins include totipo tential mesenchymal cells and primitive neuroectodermal tumors.
38
38 What are the most common initial symptoms associated with Ewing sarcoma?
Pain and regional swelling
39
39 What proportion of patients with Ewing sarcoma manifest with metastatic disease?
Ewing sarcoma is considered metastatic at presentation in nearly all patients.
40
40 How is Ewing sarcoma managed?
Treatment comprises surgical excision with concurrent chemotherapy (vincristine, actinomycin-D, cyclophospha mide) and radiation therapy.
41
41 What tumor is a type of spindle cell sarcoma that is either associated with peripheral nerves or shows nerve sheath differentiation?
Malignant peripheral nerve sheath sarcoma is a malignant, aggressive tumor with a high rate of metastases.
42
42 Malignant peripheral nerve sheath tumors are masses that can be associated with pain and dysesthesia. How often is a nerve of origin identified?
~ 70%
43
43 What hereditary condition is a significant risk factor for the development of malignant peripheral nerve sheath tumors?
NF-1. Up to 40% of tumors develop in a preexisting neurofibroma.
44
44 What important prognostic factors predict poor outcome in patients with malignant peripheral nerve sheath tumors?
Tumor size \> 5 cm, tumor invasiveness (T2), concomitant NF-1, head and neck location
45
45 What is the management strategy for malignant primary nerve sheath tumors?
Surgical resection is the mainstay of treatment and a strong predictor of survival. Adjuvant chemotherapy or radiation therapy potentially has a role.
46
46 Alveolar soft part sarcoma arises from which tissue type(s)?
Myogenic and neural cells (controversial)
47
47 Although they are extremely rare, two-thirds of head and neck alveolar soft part sarcomas arise in which anatomical subsites and manifest with what common symptom(s)?
They manifest in the orbit and tongue as a painless mass.
48
48 What demographic is most commonly affected by alveolar soft part sarcomas?
Females aged 10 to 30 years
49
49 How are alveolar soft part sarcomas treated?
Surgical resection with adjuvant radiation therapy or chemotherapy (in phase I or phase II trials)
50
50 What are the two most common locations for osteosarcoma within the head and neck?
Mandible and maxilla
51
51 What are the most common initial symptoms associated with osteosarcoma of the head and neck?
2 to 6 months of a painless mass, dental pain, or loose teeth
52
52 What is the mainstay of therapy for osteosarcoma of the head and neck?
Aggressive surgical resection. Postoperative radiation ther apy is controversial. The addition of chemotherapy to surgery has been shown to be beneficial.
53
53 Despite advances in treatment, surgical resection, and reconstruction, survival for patients with osteosarcoma is poor. What prognostic factors have been identified?
Surgical margins (i.e., positive margins are associated with poor outcome), recurrence, primary tumor arising in previously radiated bone, and tumors arising in extra gnathic bone (i.e., less likely to achieve wide resection). No differences have been identified between pediatric and adult populations.
54
54 What is the most common lymphoproliferative malignancy of the head and neck in pediatric patients?
Lymphoma
55
55 What are common risk factors for lymphoma?
Radiation, Epstein-Barr virus, human immunodeficiency virus (HIV) or other immunosuppressive disorders, organ transplantation, common immunodeficiency syndromes (e.g., Wisckott-Aldrich syndrome, ataxia-telangiectasia, X-linked lymphoproliferative disease), organic toxins (e.g., phenols, benzene), autoimmune disorders (e.g., celiac disease, rheumatoid arthritis)
56
56 What cell types give rise to non-Hodgkin lymphoma?
B cells: 85% T cells: 15%
57
57 What is the typical age distribution of non-Hodgkin lymphoma?
Incidence increases with age.
58
58 According the National Cancer Institute, what are the most common types of non-Hodgkin lymphoma of childhood?
* Burkitt [t(8:14)] and Burkitt-like lymphomas
* Lymphoblastic lymphoma
* Diffuse large B-cell lymphoma
* Other (anaplastic large cell lymphoma)
59
59 How do pediatric lymphomas most commonly manifest?
● Rapid enlargement of extranodal tissue (e.g., Waldeyer ring) or nodal enlargement (persisting \> 4 to 6 weeks, generally \> 2 cm in diameter; nodes \> 1 cm should be considered suspicious) that may or may not be painful ● Mass effect is dependent on location (e.g., nasal obstruction, dysphagia, airway compromise, superior vena cava syndrome). ● Hepatosplenomegaly ● Central nervous system (CNS) involvement (cranial nerve palsies, mental status changes, rarely with seizures)
60
60 What are the two symptom classes used for staging lymphomas?
Class A: Asymptomatic (better prognosis) Class B: Weight loss, fever, night sweats (poorer prognosis)
61
61 Most non-Hodgkin lymphomas in the pediatric population arise in the abdomen; only 5 to 10% are located in the head and neck. What are the most common subsites in the head and neck?
Salivary glands, larynx, Waldeyer ring, paranasal sinuses, orbit, and scalp
62
62 Non-Hodgkin lymphoma workup includes a careful history and physical examination; imaging such as CT and gallium-67 scanning; and laboratory workup including cerebrospinal fluid analysis, urinalysis, CBC, and serum chemistries. However, definitive diagnosis rests on what key step?
Biopsy or tissue specimen (excisional biopsy) for histology, cytology, immunohistochemistry and genotyping
63
63 What infectious agent has been shown to be associated with both endemic (85%) and sporadic (15%) cases of Burkitt lymphoma?
Epstein-Barr virus
64
64 What chromosomal translocation is commonly noted in Burkitt lymphoma?
t(8;14)(q24;q32)
65
65 The 5-year survival rate in pediatric cases of non Hodgkin lymphoma is 80%; this rate varies depending on what important prognostic factor(s)?
* Age: Worse outcome if \< 12 months or \> 15 years
* Site of disease: Worse in mediastinum, CNS
* Lactate dehydrogenase (LDH) levels
* Unusual chromosomal abnormalities
66
66 How is pediatric non-Hodgkin lymphoma clinically staged?
67
67 What is the mainstay of management for non Hodgkin lymphoma?
Chemotherapy: CHOP (cyclophosphamide, doxorubicin [hydroxydaunorubicin, Adriamycin], vincristine (Oncovin), prednisone (or prednisolone) Radiation can be used for localized disease or emergencies involving respiratory, nervous system, or vascular compro mise.
68
68 What age group(s) is(are) most affected by Hodgkin lymphoma?
Bimodal distribution: Teenage adolescents and middle-age adults
69
69 Which sex confers a higher risk for Hodgkin lymphoma?
Male, 2:1
70
70 What causative agent is commonly associated with Hodgkin lymphoma?
Epstein-Barr virus
71
71 What tumors are most commonly associated with Epstein-Barr virus infection?
Burkitt lymphoma (non-Hodgkin lymphoma) Hodgkin lymphoma Nasopharyngeal carcinoma
72
2 How does Hodgkin lymphoma typically manifest?
About 80% of patients have cervical lymphadenopathy and ~ 40% with class B symptoms (night sweats, fever, weight loss). It can present with respiratory distress or superior vena cava syndrome resulting from mediastinal involvement.
73
73 What is the pathognomonic histopathology found in Hodgkin lymphoma?
Reed-Sternberg cells (“owl-eyes” = two or more nuclei with two or more large nucleoli) Eosinophilic inclusions Large, clonal, multinucleated cells B cell in origin, derived from germinal centers.
74
74 What is the histologic classification used for Hodgkin lymphoma?
WHO 2008 classification
1. Nodular lymphocytic predominant
2. "Classic" Hodgkin lymphoma: Rye modification of the Lukes-Butler classification
1. **Lymphocytic predominance** (\< 10%): Typically manifests with localized disease; high concentration of normal appearing lymphocytes, uncommon Reed-Sternberg cells, and no fibrosis; better prognosis
2. **Mixed cellularity** (20 to 40%): Typically manifests with extranodal involvement; mixed infiltrate; Reed-Stern berg cells more common
3. **Lymphocytic depletion** (\< 15%): Common in HIV pa tients; diffuse fibrosis, few lymphocytes, bizarre Reed Sternberg cells; poor prognosis
4. **Nodular sclerosis** (40 to 80%): Most common; lymphoid nodules separated by bands of collagen containing the Reed-Sternberg cells (lacunar cell variant); more commonly affects females than males
75
75 What is the clinical classification system used to stage Hodgkin lymphoma?
Ann Arbor Staging: ● Stage I: Single lymph node region or single extralymphatic organ or site (IE) ● Stage II: Two or more lymph node regions on the same side of the diaphragm or localized involvement of an extralymphatic organ or site (IIE) in addition to one or more lymph node region on the same side of the diaphragm ● Stage III: Involvement of lymph node regions on both sides of the diaphragm, with or without involvement of an extralymphatic organ or site (IIIE), involvement of the spleen (IIIS), or both ● Stage IV: Diffuse or disseminated involvement of one or more extralymphatic organs or sites, with or without associated lymph node involvement
76
76 In addition to a thorough physical examination, what radiographic studies are important for the workup of a patient with suspected Hodgkin lymphoma?
* Chest X-ray
* Chest and abdominal CT scan
* PET/CT
77
77 What is the overall 5-year survival rate for patients with Hodgkin lymphoma?
~ 80%
78
78 What prognostic factors are important in Hodgkin lymphoma?
* Better:
* Lymphocytic predominance types
* Worse:
* The presence of Reed-Sternberg cells
* Higher Ann Arbor stage
* Presence of class B symptoms
79
79 What is the management strategy for primary treatment of Hodgkin lymphoma?
Chemotherapy: MOPP (mechlorethamine, Oncovin [vin cristine], prednisone, procarbazine); ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine), fol lowed by targeted radiation therapy. Some authorities suggest single-modality radiation therapy for early disease.
80
80 What percentage of pediatric thyroid nodules are malignant?
About 26% (ranges have been published from \< 1%, citing a referral bias in children with risk factors for thyroid cancer, to as high as 36%; most of the literature suggests an increased risk of thyroid carcinomas in pediatric thyroid nodules compared with adults) Regardless of the exact percentage, the 2009 revised American Thyroid Association (ATA) recommends the same diagnostic and therapeutic approach for children as for adults (clinical evaluation, serum thyroid-stimulating hor mone [TSH], ultrasonography, FNA).
81
81 What are the most common benign thyroid nodules?
* Multinodular goiter (sporadic)
* Hashimoto thyroiditis
* Hemorrhagic, colloid, and simple cysts
* Follicular adenomas
* Hürthle cell adenomas
82
82 What is the most important environmental risk factor for the development of pediatric thyroid carcinoma?
Radiation exposure
83
83 What genetic syndromes are associated with an increased risk of medullary thyroid cancer?
* MEN 2A
* MEN 2B
* Familial medullary thyroid carcinoma
84
84 Name the syndrome associated with the following constellation of syndromes:
1. Familial adenomatous polyps, papillary thyroid carcinoma, autosomal dominant (adenomatous polyposis coli [APC]) gene
2. Primary pigmented nodular adrenocortical disease (primary adrenal hypercorticism); lentigines, ephelides, and blue nevi of the skin and mucosa; nonendocrine and endocrine tumors including papillary and follicular thyroid carcinoma
3. Premature aging (progeria), osteosarcoma, soft tissue sarcoma, and follicular or papillary thyroid carcinoma
4. Macrocephaly, autism or developmental delay, penile freckling or other benign skin lesions, vascular anomalies such as arteriovenous (AV) malformations or hemangiomas, and GI polyps
1. Gardner syndrome
2. Carney complex type 1
3. Werner syndrome
4. PTEN hamartoma syndrome (Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome)
85
85 What is the most common pediatric thyroid tumor (malignant or benign)?
Follicular adenoma (benign)
86
86 What is the most common malignant thyroid tumor in children?
Papillary thyroid carcinoma (83%):
* 60% papillary
* 23% follicular variant papillary.
Less commonly, follicular thyroid carcinoma (10%), medullary thyroid carcinoma (5%), and other rarer cancers may arise.
87
87 What factors increase the risk that a thyroid nodule is in fact thyroid carcinoma?
* Male
* Family Hx of thyroid cancer in one or more 1st-degree relatives
* Personal Hx of prev hemithyroidectomy for thyroid cancer
* Hx of radiation exposure (external beam, ionizing radiation, etc.)
* Associated genetic syndrome increasing the risk for thyroid cancer (e.g., MEN 2A, MEN 2B, Familial Medullary Thyroid Carcinoma [FMTC], Cowden, Carney, Werner, PTEN hamartoma syndrome, etc.)
* Firm, fixed, rapidly growing nodule
* Sx: new-onset hoarseness or vocal cord paralysis, dysphagia, odynophagia
* Lymphadenopathy (up to three-fourths of patients)
* FDG avidity on PET scanning
88
88 Does a 5-year-old diagnosed with thyroid carcinoma have a higher risk of advanced disease than an 18-year-old with the same tumor?
Yes. Prepubertal children are more likely to have advanced disease (regional metastasis, extracapsular extension, and invasion into surrounding tissue). Overall prognosis is still excellent.
89
89 Children diagnosed with medullary thyroid carcinoma generally have a solitary thyroid nodule or are diagnosed during workup for which three associated syndromes?
* MEN 2A (or Sipple syndrome): RET (rearranged during transfection) proto-oncogene mutation; parathyroid hyper plasia, pheochromocytoma, medullary thyroid carcinoma
* MEN 2B: RET proto-oncogene; mucosal neuromas, marfanoid habitus, thickened corneal nerves, medullary thyroid carcinoma, rare parathyroid hyperplasia
* Familial medullary thyroid carcinoma
90
90 What laboratory workup should be performed for a child in whom thyroid cancer is suspected?
* Thyroid function testing: tri-iodothyronine (T3), thyroxine (T4), TSH; generally normal in malignancy
* Calcitonin: Elevated in medullary thyroid carcinoma
* Thyroglobulin: If elevated, can be used for postoperative surveillance; _routine preoperative measurement is not recommended by the ATA_
* Carcinoembryonic antigen: Elevated in medullary thyroid cancer (except in advanced disease)
* 24-hour urine metanephrines: Functional pheochromocytomas or paragangliomas may result in hypertensive crises if untreated.
* Genetic screening: If patient is at high risk for hereditary disorders
91
91 What is the first step in the imaging workup for pediatric thyroid cancer?
Ultrasonography: location, number of nodules, size, micro calcifications, infiltrative margins, hypervascularity, extracapsular spread, regional metastases, height relative to width on transverse view; can also be used to guide FNA biopsy
92
92 True or False. FNA biopsy is less accurate for diagnosing thyroid malignancy in pediatric patients than in the adult population.
False. There is no difference in diagnostic accuracy. FNA is first-line test for tissue diagnosis and management planning. Patient compliance may require FNA with sedation.
93
93 True or False. Scintigraphy does not often help to distinguish malignant from benign thyroid disease.
True. Scintigraphy is useful for identifying ectopic thyroid tissue (ectopic lingual thyroid). Hot nodules can be malignant.
94
94 When should a CT scan be considered in the workup of pediatric thyroid cancer?
CT of the neck and chest should be considered with extensive disease, extracapsular spread, mediastinal involvement, or regional lymphadenopathy. The risk of pulmonary metastases is as high as 20% in some series and increases with regional metastases. Pulmonary metastases can also be detected using radioactive iodine scanning.
95
95 How are thyroid cancers in children staged?
TNM staging T-stage ● T1: \< 2 cm ● T2: 2 to 4 cm ● T3: \> 4 cm limited to the thyroid gland or with minimal extrathyroidal extension ● T4a: Any size; extrathyroidal extension to involve adjacent soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve ● T4b: Any size, extrathyroidal extension to involve the prevertebral fascia or encase the carotid artery or mediastinal great vessels N-stage ● N1a: Metastases to level VI ● N1b: Metastases to any cervical or mediastinal lymph node(s) M-stage ● M1: Distant metastases
Well-Differentiated: ● Stage I: Any T, any N, M0 ● Stage II: Any T, any N, M1 Note: Medullary thyroid carcinoma has the same TNM system, but stages I, II, III, IVA, IVB, and IVC are delineated.
96
96 The American Joint Committee on Cancer (TNM) system was developed to determine the risk of death, but it does not describe the risk of recurrence. How do the 2009 ATA guidelines describe this risk?
Low-risk
* No local or distant metastases
* All macroscopic tumor has been resected.
* No tumor invasion of locoregional tissues or structures
* Tumor does not have aggressive histology or vascular invasion.
* If 131I is given, there is **no uptake** outside the thyroid bed on the first post-treatment whole-body scan.
Intermediate-risk
* Microscopic invasion of tumor into the perithyroidal soft tissues at initial surgery
* Cervical lymph node metastasis or 131I **uptake** outside the thyroid bed done after thyroid remnant ablation
* Tumor with aggressive histology or vascular invasion
High-risk
* Macroscopic tumor invasion
* Incomplete tumor resection
* Distant metastases
* Possibly thyroglobulinemia disproportionate to what is seen on the post-treatment scan
97
97 In general, what is the extent of resection recom mended for a solitary thyroid lesion in a child?
Hemithyroidectomy. Subtotal or completion thyroidectomy should be performed if frozen or permanent pathology confirms thyroid cancer.
98
98 When might thyroid lobectomy alone be sufficient as surgical therapy in the pediatric population?
Small (\< 1 cm), low-risk, unifocal, intrathyroidal papillary carcinomas in the absence of prior head and neck irradiation or radiologic or clinical cervical lymphadenopathy
99
99 When should total thyroidectomy be considered in patients with indeterminant thyroid nodules?
Large tumors (\> 4 cm), when marked atypia is seen on biopsy, when the biopsy is read as "suspicious for papillary carcinoma," in patients with a family history of thyroid carcinoma, and in patients with a history of radiation exposure
100
100 Discuss the pros and cons of subtotal or near-total thyroidectomy.
Pros
* Potentially limit morbidity associated with recurrent laryngeal nerve injury and parathyroid devascularization
* Unlikely to increase recurrence rates
* May be able to maintain a euthyroid state
Cons
* Can interfere with postoperative radioactive iodine treatment for microscopic and distant disease
* May impact postoperative surveillance
101
101 When should you consider elective neck dissection in pediatric patients with well-differentiated thyroid carcinoma?
Lateral neck dissection should be performed **only for clinically positive nodal disease**. If such disease is present, elective dissection of levels IIA, III, IV, and VB should be performed. If there is disease in level IIA, some authorities recommend dissection of level IIB. Levels I, IIB, and VA should also be included if there is clinically evident disease. Central neck dissection (level VI) should be performed therapeutically for clinically involved central or lateral neck nodes and electively (ipsilateral or bilateral) for patients with advanced primary tumors (T3 or T4).
102
102 When should radioactive iodine be considered in the management of pediatric thyroid carcinoma?
Indicated:
* All patients with known distant metastases, gross extrathyroidal extension, and primary tumor size \> 4 cm
* Selected patients with 1- to 4-cm thyroid cancers confined to the thyroid with documented lymph node metastases or other high-risk features when the combi nation of age, tumor size, lymph node status, and individual histology predicts an intermediate to high risk of recurrence or death from thyroid cancer.
Not indicated:
* Solitary tumor \< 1 cm in diameter without high-risk features
* Multifocal cancer if all tumors are \< 1 cm and intra thyroidal without high-risk features
103
103 What are the potential side effects of radioactive iodine ablation for the management of pediatric thyroid cancer?
Short-term effects: Nausea (immediate, temporary), xerostomia, altered taste, dental carries, cytopenias, menstrual irregularities (temporary), decreased sperm counts (tem porary)
Long-term effects: Xerostomia, altered taste, cytopenias, nasolacrimal duct obstruction, increased lifetime risk of secondary malignancy (leukemias, salivary gland, urinary, and GI)
104
104 What is the extent of surgical intervention recommended for medullary thyroid carcinoma?
Total thyroidectomy (when there is high risk for multicentricity and recurrence) and elective bilateral central compartment dissection
Lateral dissection is reserved for clinically evident disease or lymph node metastases in the adjacent central neck compartment. Elective lateral neck dissection should include levels IIA, III, IV, and VB. The superior level VII nodes should also be addressed in this situation.
105
105 A 9-month-old female infant is brought to your office for consideration of prophylactic thyroidectomy to prevent the development of thyroid carcinoma. Why might you consider this operation?
RET gene mutation positivity
For MEN 2B (high-risk) mutations, resection may be considered in the first year of life (includes central neck dissection if patient is \> 1 year).
In MEN 2A or familial medullary thyroid cancer syndromes (lower risk), resection can be delayed until early childhood (age of 3 to 6 years is suggested in the literature, but no real consensus has been reached; timing of surgery depends on other risk factors; in general \< 8 to 10 years of age) unless a high-risk mutation is identified.
106
106 True or False. Because of their young age, risk for recurrence, and aggressive disease at diagnosis, pediatric patients diagnosed with thyroid carcinoma uniformly do poorly compared with their adult counterparts.
False. The survival rate for pediatric patients is better than that for adults. Long-term survival for well-differentiated thyroid carcinoma is \> 90%. Medullary thyroid carcinoma has relatively low 30-year survival rates, but the 5-year survival rate is \> 90%.
107
107 What are the two most common benign salivary gland tumors of childhood?
Pleomorphic adenoma and hemangioma
108
108 What is the risk of malignancy in pediatric epithelial salivary gland tumors compared with the risk in adults?
Pediatrics 50 to 60% vs. adults 15 to 25%
109
109 Name the most common and the second most common pediatric salivary gland malignancy.
Mucoepidermoid carcinoma and acinic cell carcinoma
110
110 What two salivary gland malignancies are seen almost exclusively in children?
**Sialoblastoma** (congenital, relatively high risk of local recurrence, risk of metastases) and **salivary gland anlage tumor** (benign, pedunculated nasopharyngeal tumor, simple surgical excision)
111
111 True or False. Pediatric salivary gland tumors in children are treated the same as in adults.
True
112
112 Although nasopharyngeal carcinoma represents only 1% of pediatric malignancies in the United States and Europe, it is more common in which geographic and international regions?
China, Southeast Asia, Alaska (Inuit population), North Africa, and some areas in the Mediterranean
113
113 What three subtypes of nasopharyngeal carcinoma does the WHO recognize?
WHO subtypes of nasopharyngeal carcinoma:
* Type 1: Squamous cell carcinoma
* Type 2: Nonkeratinizing carcinoma
* Type 3: Undifferentiated carcinoma (MC in Peds)
114
114 What virus is commonly associated with pediatric nasopharyngeal carcinoma?
Epstein-Barr virus
115
115 Where does nasopharyngeal carcinoma most commonly metastasize?
Bone and bone marrow, lung, liver, and mediastinum
116
116 What is the mainstay of treatment for pediatric nasopharyngeal carcinoma?
Biopsy for diagnosis and to assess recurrence
Radiation and chemotherapy for treatment
117
117 With modern treatment protocols, what is the estimated 5-year survival for pediatric nasopharyngeal carcinoma?
Event-free and overall survival greater than 90%
118
118 What solid, extracerebral pediatric tumor arises from neuroectodermal neural crest cells of the sympathetic nervous system (e.g., organ of Zuckerkandl, sympathetic chain, etc.) or adrenal medulla?
Neuroblastoma
119
119 What is the range of clinical outcomes associated with pediatric neuroblastoma?
Spontaneous resolution vs. rapid metastases (70% at Dx) and death
120
120 What are the common age groups affected by neuroblastoma?
50% by age 1 year, 80% by age 5 years
121
121 What are the common manifestations of neuroblastoma in the head and neck?
* Horner syndrome
* Asymmetric crying facies
* Heterochromia irides
* Mass effect
* Airway compression
* Pharyngeal com pression
* Proptosis
* Periorbital ecchymosis or "raccoon eyes,"
* Trismus
122
122 Where are the potential sites of distant metastases in neuroblastoma?
Head and neck: skull base, periorbital bones, maxillofacial bones, paranasal sinuses
Other: bone marrow, liver, skin, other organs
123
123 In addition to _neck_ CT and MRI, _abdominal_ CT and MRI, _chest_ X-ray, bone scans (technetium radio nuclide scan or I123-metaiodobenzylguanidine [MIBG] scan), and bone marrow aspirates, what additional tests are important in evaluating a patient with neuroblastoma?
* Histology (core needle or open biopsy, not FNA)
* Urinary catecholamine metabolites (vanillylmandelic acid, homovanillic acid)
* Possibly urinary dopamine, serum LDH, or serum ferritin
124
124 Although several genetic markers have been linked to neuroblastoma, which has the most significance when considering prognosis and risk stratification?
MYCN amplification
125
125 What is the staging system used for pediatric neuroblastoma?
International Neuroblastoma Staging System
* Stage 1: Localized tumor with complete gross resection, with or without microscopic residual disease; ipsilateral lymph nodes; not attached to the primary specimen; microscopically negative for tumor
* Stage 2A: Localized tumor with incomplete gross resec tion, ipsilateral lymph nodes, not attached to the primary specimen, microscopically negative for tumor
* Stage 2B: Localized tumor, with or without gross resection; ipsilateral lymph nodes; not attached to the primary specimen; microscopically negative for tumor
* Stage 3: Unresectable unilateral tumor infiltrating across the midline, with or without regional lymph node involvement; or localized unilateral tumor with contrala teral regional lymph node involvement; or midline tumor with bilateral extension by infiltration (unresectable) or lymph node involvement
* Stage 4: Any primary tumor with distant metastases to lymph nodes bone, bone marrow, liver, skin, or other organs (except as noted for stage 4S)
* Stage 4S: Localized primary tumor (1A–2B) with dissemination limited to skin, liver, or bone marrow in an infant \< 1 year of age
126
126 Why might it be reasonable to offer close observation for infants less than 12 to 18 months of age (excluding neonates \< 2 months of age) diagnosed with neuroblastoma?
Most of these tumors undergo spontaneous regression (stage 4S). High-risk features such as age \< 2 months, diploidy, undifferentiated pathology, and/or MYCN amplification are contraindications to observation.
127
127 What treatment options are available for patients with neuroblastoma based on the Children's Oncology Risk stratification schema (stage, age, histology, International Neuroblastoma pathology classification, and clinical picture)?
* Primary surgical resection or surgery combined with other treatment strategies
* Upfront chemotherapy to shrink the tumor followed by resection
* Multiagent chemotherapy as primary treatment
* Radiation for unresectable tumors that are unresponsive to chemotherapy, high-risk disease, or life-threatening compression
128
128 What benign tumor contains Schwann cells, mast cells, and fibroblasts?
Neurofibromas
129
129 What clinical criteria are required to diagnose NF-1?
Two or more of the following are required for a diagnosis:
* Six or more café-au-lait macules \> 5 mm (prepubertal) or \> 15 mm (postpubertal) in diameter
* Two or more neurofibromas of any type or one plexiform neurofibroma
* Axillary or inguinal freckling
* Optic glioma
* Two or more Lisch nodules (raised, pigmented hamarto mas of the iris)
* Distinctive bony lesion (i.e., sphenoid dysplasia, thinning of the long bone cortex with or without pseudoarthrosis)
* A first-degree relative with NF-1 based on these criteria
Note: 46% of children \< 1 year of age with sporadic NF-1 fail to meet these criteria; 95% meet criteria by 8 years and 100% by 20 years.
130
130 What gene is responsible for NF-1?
NF-1 gene on chromosome 17q11.2, which results in mutation of **neurofibronin**, a tumor suppressor gene; **autosomal dominant**
131
131 For a child with a large, light brown-pigmented macule suggestive of a cafe-au-lait spot, what conditions must be considered?
* Neurofibromatosis
* McCune-Albright syndrome
* Fanconi anemia
* Tuberous sclerosis
132
132 What are the four possible neurofibroma subtypes?
* Cutaneous
* Subcutaneous
* Nodular plexiform
* Diffuse plexiform (has the highest risk for malignancy)
133
133 What are the properties of a plexiform neurofibroma?
A plexiform neurofibroma demonstrates angiogenic and invasive properties. It can be **nodular** (with clusters along peripheral nerve roots, with or without compressive spinal symptoms, etc.), or **diffuse** (congenital lesion, involves long segments of nerves.
134
134 What is the rate of malignant conversion in NF-1?
10% (soft tissue sarcoma: malignant nerve sheath tumors; most commonly arise from plexiform neurofibromas)
135
135 When should neurofibromas be resected?
When causing **compressive** or **cosmetic** symptoms, neurofibromas should be resected. Diffuse plexiform neurofibromas are often impossible to resect completely.
136
136 What is the most common intracranial tumor associated with NF-1?
Optic pathway glioma (less common: astrocytomas, brain stem gliomas)
137
137 What are the most common extracranial tumors associated with NF-1?
* Rhabdomyosarcoma
* Gastrointestinal stromal tumors
* Chronic myeloid leukemia
* Pheochromocytoma
138
138 What pediatric tumor arises from all three germ cell layers and occurs most commonly in the soft tissues of the neck, face, infratemporal fossa, orbit, and upper aerodigestive tract when it occurs in the head and neck?
Teratoma
139
139 True or False. All congenital teratomas manifest with impressive respiratory distress and are benign.
False. Although most do present with respiratory distress requiring interventions such as tracheostomies or extracorporeal membrane oxygenation and EXIT (ex utero intrapartum treatment) procedures, a small number do metastasize and are therefore considered malignant. Malignancy does not indicate maturity of tissue on histopathology, which tends to reflect the age of the host.
140
140 Do all metastatic teratomas result in progressive disease and death?
No. Many actually differentiate in the metastatic location and do not result in significant harm. However, fatal disease has been reported in children, and aggressive malignant disease is more common in adults.
141
141 What is the treatment of choice for malignant congenital teratomas?
Surgical resection of the primary tumor is the treatment of choice, as in “benign” teratomas, with consideration of chemotherapy for metastatic disease. There are limited data to guide decision-making for malignant disease.
142
142 What congenital, subcutaneous lesions contain trapped epithelium and its adnexa (i.e., hair follicles, hair, sebaceous glands) and form along embryologic fusion lines?
Dermoid cysts
143
143 Where are the most common locations for dermoid cysts in the head and face?
Anterior fontanelle, bregma, upper lateral forehead, upper lateral eyelid, and submental region are the most common locations. Note: These cysts can occur in other body sites, such as the ovaries, anywhere in the face, along the skull base, or spinal axis.
144
144 How do dermoid cysts manifest?
These cysts are solitary, rubbery, firm, painless (unless infected) mases, nonpulsatile, noncompressible, present since birth, but often noted after minor trauma. If associated with a sinus tract, they may have a dermal pit with or without an associated tuft of hair. If the tract extends to the CNS (common in the midline or nasal dermoid cysts), the patient may have meningitis. Tumors with infratemporal extension can result in midface widening, hypertelorism, and other issues associated with mass effect and altered growth.
145
145 What is the most important imaging modality when evaluating a midline dermoid cyst?
MRI
146
146 When should you remove a dermoid cyst?
Surgical resection is recommended for all dermoids to decrease possible associated complications (e.g., infection, meningitis, bony erosion).
147
147 You are evaluating a 14-year-old girl with a well-defined tan (or yellow orange) verrucous/ papillomatous hairless plaque on her scalp. This lesion has been present since birth, but it was not particularly bothersome. However, as she has begun to go through puberty, it has become significantly more prominent. What is the likely diagnosis and explanation for this change?
Nevus sebaceous. Puberty results in hyperplasia of the sebaceous and apocrine glands within the lesion.
148
148 What is the potential risk of simply observing nevus sebaceous in children?
A (very low) risk of developing basal cell carcinoma. Other benign tumors may also develop from these lesions (syringocystadenoma papilliferum, trichoblastoma, nodular hydradenoma, sebaceous carcinoma, etc.). All can be removed by simple excision.
149
149 What is the preferred management of nevus sebaceous in children?
Observation and education are preferred over surgical excision (which is indicated for cosmetic concerns as excision may be easier in infancy or childhood or for the development of a benign or malignant neoplasm).
150
150 A worried mother brings her son for evaluation of several ”dots" she has noted on his face that were not present at birth. On evaluation, these "lesions" are light brown, homogeneous, and round. They are flat and appear rather symmetric. What is the likely diagnosis?
Acquired melanocytic nevi (typical/acquired) (i.e., freckles)
151
151 What is the most likely cause of a well-demarcated lesion on an infant’s neck or chest?
Congenital melanocytic nevi: an error in proliferation and migration of melanocytic progenitor cells (neuroectoderm) during embryogenesis
152
152 What are the size categories for congenital melanocytic nevi, and how do these categories relate to the potential for malignant conversion?
* Small: \< 1.5 cm
* Medium: 1.5 to 2 cm
* Large: \> 20 cm
* Giant: \> 50 cm
Malignant potential (melanoma, neurocutaneous melanocytosis, rhabdomyosarcoma) increases with increasing size. An increasing number of satellite lesions also increases the risk.
153
153 How are congenital melanocytic nevi managed?
Treatment should be individualized based on cosmetic and emotional impact, as well as the risk for malignancy. Options range from surgical excision to dermabrasion and chemical peels to simple observation.
154
154 Name the pediatric skin lesion that is generally smaller than 1 cm in diameter, dome shaped, and well circumscribed; it can be purple, red, black or brown; it is composed of spindled and/or large epithelioid cells; and it can be quite difficult to differentiate from melanoma.
Spitz nevus
155
155 What are the three subtypes of Spitz nevi?
* Conventional Spitz tumor (benign or low-grade melanocytic neoplasm)
* Atypical Spitz tumor (larger, irregular, more atypia, increased risk for local lymph node involvement, and often difficult to differentiate from melanoma)
* Malignant Spitz tumor/melanoma (histologically difficult to differentiate from melanoma, malignant lesion)
156
156 How are Spitz tumors managed?
* Conventional Spitz nevi should be excised with surgical margins of 3 to 5 mm.
* Atypical Spitz nevi should be excised with wider margins (up to 1 cm), with consideration for sentinel lymph node biopsy and completion lymphadenectomy for positive nodes. (Note: Up to 50% of sentinel lymph node biopsies will be positive, with questionable impact on survival/ outcome.)
* Malignant Spitz tumor/melanoma: Treat as malignant melanoma
157
157 Describe some common characteristics of a dysplastic nevus.
A skin lesion with a macular (flat, nonpalpable) component, irregularly distributed pigmentation, indistinct boundary ("fried egg"), size \> 5 mm, irregular border, and a back ground of erythema. This lesion is commonly seen on the scalp but not in chronically sun exposed areas such as the face.
158
158 What is the clinical significance of dysplastic nevi or a family history of melanoma?
It carries an increased risk for melanoma, although atypical nevi generally do not represent a premalignant lesion.
159
159 What is required to diagnose familial dysplastic nevus syndrome?
\> 100 melanocytic nevi, at least one clinically dysplastic nevus, and at least one nevus \> 8 mm
160
160 When is biopsy indicated for a dysplastic nevus?
Biopsy is done when clinically and dermoscopically it is difficult to differentiate the lesion from melanoma.
161
161 What is required for the diagnosis of familial atypical mole and malignant melanoma syndrome?
\> 50 common and/or atypical nevi + a history of melanoma in one or more first-degree relatives. (Autosomal dominant, genetic association: CDKN2A gene mutations).
162
162 What clinical criteria are required to diagnose nevoid basal cell carcinoma syndrome (,i.e., Gorlin syndrome, basal cell nevus syndrome)?
Two major or one major and one minor criteria:
Major criteria:
* More than two BCCs or 1 BCC in a patient \< 20 years old
* Odontogenic keratocyst of the jaw (histologically proven)
* Three or more palmar or plantar pits
* Bilamellar calcification of the falx cerebri
* Bifid, fused, or markedly splayed ribs
* First-degree relative with the disease
Minor criteria:
* Macrocephaly
* Congenital malformations (i.e., cleft lip/palate, frontal bossing, coarse facies, moderate/severe hypertelorism)
* Skeletal anomalies (i.e., Sprengel deformity, marked pectus deformity, marked syndactyly)
* Radiographic anomalies (i.e., bridging of the sella turcica, vertebral anomalies, modeling defects of the hands and feet, or flame-shaped lucencies of the hands and feet)
* Ovarian fibroma or medulloblastoma
163
163 What is the genetic defect associated with nevoid basal cell carcinoma syndrome?
PTCH1 (patched) gene, chromosome 9q22.3, tumor suppressor gene
164
164 What treatment options are available for nevoid basal cell carcinoma syndrome?
Surgical resection (wide local excision, Mohs surgery, laser ablation), topical therapy (imiquimod, tretinoin, 5-fluorouracil), photodynamic therapy, systemic therapy (oral retinoids, vismodegib). Radiation is largely avoided because of the risk of developing basal cell carcinomas. Note: Vismodegib has shown good efficacy in treating this disease.
165
165 You are examining a 5-year-old girl with a mobile, rock-hard mass on her lateral cheek in the deep dermis or subcutaneous layer of the skin. The mass has been present for some time and has shown slow growth. It has an irregular border and is completely asymptomatic. What is the likely diagnosis?
Pilomatricoma (mutations in the ϐ-catenin gene arises from the outer root sheath of hair follicles).
166
166 Although most pilomatricomas are isolated lesions located predominantly in the head and neck (lateral cheek, preauricular area, and periorbital area), when they occur as multiple lesions, what additional diagnoses should be investigated?
1. Gardner syndrome
2. Myotonic dystrophy
3. Rubenstein-Taybe syndrome
4. Turner syndrome
167
167 What is the recommended management for pilomatricomas?
Surgical excision. They do not spontaneously regress.
168
168 Infantile hemangiomas are the most common benign neoplasm in childhood and are differentiated from other vascular malformations by the presence of what molecular marker?
Glucose transport protein 1 (GLUT-1)
169
169 A 12-month-old infant is undergoing inpatient medical treatment of a bright red, large, vascular growth involving her right cheek and orbit. What is the medication, and what side effects may occur with this treatment?
Propranolol: hypoglycemia and rarely hypotension and bradyarrythmias
170
170 You are examining an infant with a well-demarcated, dome-shaped, yellow-brown (or reddish-orange) papule (or nodule) on the neck. What is the likely diagnosis?
Juvenile xanthogranuloma: Benign, spontaneously regressing lesion with an excellent prognosis, occasionally associated with neurofibromatosis
171
171 Juvenile xanthogranulomas of the head and neck can be single or multiple, involve ocular structures (more common with multiple lesions in children under 2 years of age), regress within 2 years, and can be confirmed on biopsy if the diagnosis is suspect. What findings would you look for on pathology to confirm the diagnosis?
Dense infiltrate of foamy histiocytes in the dermis and cells containing a wreath of nuclei surrounded by eosinophilic nuclei (Touton giant cells)
172
172 What autosomal recessive genetic disorder results in extreme sensitivity to sunlight (i.e., early freckling, intense/prolonged burns), the potential for neurologic sequelae (i.e., cognitive impairment, ataxia, choreoathetosis, sensorineural hearing loss, spasticity, seizures, and peripheral neuropathy), and a greatly elevated incidence of cutaneous malignancies (i.e., basal cell carcinoma, squamous cell carcinoma, and melanoma)?
Xeroderma pigmentosum
173
173 What is the genetic defect associated with xeroderma pigmentosum?
A defect in the DNA repair mechanism; **autosomal recessive**; eight genes have been identified (XPA–XPG, excluding XPF)
174
174 What management options improve the prognosis for patients with xeroderma pigmentosum?
Aggressive sun protection and early detection and management of cutaneous malignancies improve prognosis. Patients without neurologic involvement may have a good prognosis with this strategy.
175
175 Although pediatric head and neck melanoma is quite rare, what is the prognosis compared with adult populations?
Similar survival time but shorter disease-free intervals
176
176 How is pediatric head and neck melanoma managed?
Wide local excision, sentinel lymph node biopsy, neck dissection for positive sentinel nodes, and consideration of interferon α-2b in high-risk individuals
