1

Second to accidents, what is the most common cause of death in children between 1 and 14 years of age?

Malignancy

2

What is the most common sarcoma of childhood?

Rhabdomyosarcoma. Up to 35% are found in the head and neck.

3

Which cell type gives rise to rhabdomyosarcoma, and what major histologic variants are described?

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

Where does pediatric head and neck rhabdomyosarcoma most commonly occur?

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

What are the common initial symptoms associated with head and neck pediatric rhabdomyosarcoma?

Symptoms are due to progressive mass effect, local swelling, neurologic sequelae, or tissue necrosis. Bone marrow involvement can manifest as hematologic concerns.

6

What are the most important negative prognostic factors associated with pediatric rhabdomyosarcoma?

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

What diagnostic techniques are required to evaluate the primary tumor in rhabdomyosarcoma?

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

What diagnostic techniques are required to evaluate locoregional and/or distant metastases in rhabdomyosarcoma?

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

Which group is credited with increasing the survival rate for patients with rhabdomyosarcoma from 30 to 70% since the 1970s?

The Intergroup Rhabdomyosarcoma Study Committee (now the Soft Tissue Sarcoma Committee of the Children’s Oncology Group)

10

What is the clinical grouping or surgical pathologic staging system commonly used for staging rhabdomyosarcoma?

( Table 2.1)

11

What is the tumor, node, and metastases (TNM) staging system for rhabdomyosarcoma introduced by the Intergroup Rhabdomyosarcoma Study IV?

( Table 2.2)

12

Describe the staging system for rhabdomyosarcoma that combines the TNM and clinicopathologic groups to provide both prognostic and therapeutic recommendations.

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

Describe the favorable and unfavorable locations for head and neck rhabdomyosarcoma.

Favorable: Orbit and eyelid

Unfavorable: Parameningeal

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.

True. However, chemotherapy is recommended for all patients with rhabdomyosarcoma.

15

Is elective neck dissection for clinically negative necks recommended in patients with nonparameningeal rhabdomyosarcoma of the head and neck?

No

16

What are the most commonly used chemotherapeutic agents for treatment of rhabdomyosarcoma?

Vincristine, actinomycin D, cyclophosphamide

17

What are the most common late complications in patients treated for rhabdomyosarcoma of the head and neck?

Short stature, regional tissue hypoplasia, poor dentition, malformed teeth, impaired vision, decreased hearing, and learning disorders

18

What is the most common fibrous tumor of infancy?

Infantile myofibromatosis (solitary or multicentric; well-circumscribed, spindle-shaped cells, including fibroblasts and smooth muscle cells on histopathology)

19

What is the natural history of infantile myofibromatosis?

Most will involute by age 1 to 2 years. Visceral lesions causing functional impairment (e.g., pulmonary), may require surgical excision. For nonresectable, rapidly progressive, recurrent or symptomatic lesions, surgery, radiation therapy and chemotherapy should be considered.

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?

Sarcomas. These tumors can arise from muscle, nerve, fat, vessel, fibrous tissue, bone, or cartilage.

21

What is the most common initial manifestation of head and neck sarcoma?

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

How are sarcomas defined in general terms?

Tissue of origin

Histologic grade

Anatomical subsite in the head and neck

23

List examples of high-grade and low-grade sarcomas of the head and neck.

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

How does the anatomical subsite within the head and neck influence decision-making in the management of sarcomas?

The ability to resect the tumor fully, without causing undue morbidity, significantly influences surgical versus nonsurgical decision-making.

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

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

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

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

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

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 immunohistochemical 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

What mesenchymal vascular sarcoma arises from the pericytes of Zimmerman?

Hemangiopericytoma

32

Notably, 10 to 25% of all hemangiopericytomas are in the head and neck. What is the most common subsite?

Sinonasal tract

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

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

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

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

What is the tissue of origin for Ewing sarcoma?

This topic is controversial; possible origins include totipotential mesenchymal cells and primitive neuroectodermal tumors.

38

What are the most common initial symptoms associated with Ewing sarcoma?

Pain and regional swelling

39

What proportion of patients with Ewing sarcoma manifest with metastatic disease?

Ewing sarcoma is considered metastatic at presentation in nearly all patients.

40

How is Ewing sarcoma managed?

Treatment comprises surgical excision with concurrent chemotherapy (vincristine, actinomycin-D, cyclophosphamide) and radiation therapy.

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

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

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

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

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

Alveolar soft part sarcoma arises from which tissue type(s)?

Myogenic and neural cells (controversial)

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

What demographic is most commonly affected by alveolar soft part sarcomas?

Females aged 10 to 30 years

49

How are alveolar soft part sarcomas treated?

Surgical resection with adjuvant radiation therapy or chemotherapy (in phase I or phase II trials)

50

What are the two most common locations for osteosarcoma within the head and neck?

Mandible and maxilla

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

What is the mainstay of therapy for osteosarcoma of the head and neck?

Aggressive surgical resection. Postoperative radiation therapy is controversial. The addition of chemotherapy to surgery has been shown to be beneficial.

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

What is the most common lymphoproliferative malignancy of the head and neck in pediatric patients?

Lymphoma

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

What cell types give rise to non-Hodgkin lymphoma?

B cells: 85%

T cells: 15%

57

What is the typical age distribution of non-Hodgkin lymphoma?

Incidence increases with age.

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

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

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

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

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