(BQ) Part 2 book Pediatric malignancies pathology and imaging presentation of content: Pediatric cancer in the head and neck, malignancies of the pediatric lower respiratory tract, gastrointestinal, pancreatic and hepatic malignancies in children, malignant renal tumors, germ cell and gonadal tumours,...
7 Pediatric Cancer in the Head and Neck Zhongxin Yu, David M Parham, and Marcia Komlos Kukreja Overview of Head and Neck Malignancies Head and neck malignancies typically occur in adults, often as a result of tobacco and/or alcohol exposure [1, 2] More recently, oncogenic human papillomavirus (HPV) exposure related to oral sex has been related to a rise in head and neck cancers among nonsmokers [3] These factors and others make the head and neck region a major focus for adult oncology In children, the situation differs, as head and neck cancers fortunately are quite rare However, more typical cancers of childhood such as embryonal rhabdomyosarcoma show a predilection for this anatomic region, as unusual neoplasms such as NUT-translocation carcinoma and melanotic neuroectodermal tumor Infections may also give rise to juvenile head and neck cancers; among these are oncogenic HPV infections, usually acquired at birth, and Epstein-Barr virus (EBV) infections, which may initiate poorly differentiated nasopharyngeal carcinomas In the following section we also discuss pediatric thyroid cancers, which may arise secondary to irradiation, autoimmune stimulation, or an inherited propensity for cancer For the purposes of discussion, the central nervous system and eyes are excluded, and the head and neck region may be conveniently divided into the nose, oral cavity, salivary glands, ear, and larynx In addition, it contains a bilobate thyroid gland, four parathyroid glands, and various ganglia, paraganglia, and lymphatic related structures All of these regions are housed within a skeletal or connective tissue framework, supplied by neurovascular structures, and mobilized by a complex series of muscles, including the tongue Any of these structures may become the site of origin of a pediatric cancer Embryologic development of the head and neck proceeds by an intricate orchestration of signals among the neural tube, adjacent neuroectoderm, cephalic mesoderm, proximal endoderm (the primitive pharynx), and the vestigial gills that comprise the branchial arches and pharyngeal pouches The posterior pharyngeal endoderm invaginates to form thyroglossal duct, which in turn elongates to form the thyroid Similarly, a laryngotracheal diverticulum forms just distal to the thyroglossal duct and gives rise to the tracheobronchial tree The branchial arches and pharyngeal pouches, respectively, give rise to the mandible, pharyngeal tonsils, ears, parathyroid glands, thymus, and C-cells of the thyroid Malformations and perturbations of these various processes may give rise to the premalignant soil from whence pediatric cancers arise Imaging of Head and Neck Tumors Z Yu, M.D Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma, OK, USA D.M Parham, M.D (*) Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, 4650 Sunset Blvd., #43, Los Angeles, CA 90027, USA Department of Pathology and Laboratory Medicine, University of Southern California, Los Angeles, CA, USA e-mail: daparham@chla.usc.edu M.K Kukreja, M.D Department of Radiology, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA Imaging has an important role in diagnosis, staging, treatment, and posttreatment follow-up in pediatric head and neck cancer When interpreting imaging studies for a suspected mass, some clinical findings should be taken into consideration, including age of the child, location of the mass, how long the mass has been present, and if there is a known syndrome associated with neoplasms [4] Ultrasound is widely used as the initial evaluation technique of a superficial neck mass in the pediatric population given its availability, sedation being not needed, and the absence of ionizing radiation Ultrasound can frequently differentiate a solid from a cystic mass Color Doppler ultrasound allows assessment of vascularity within a D.M Parham et al (eds.), Pediatric Malignancies: Pathology and Imaging, DOI 10.1007/978-1-4939-1729-7_7, © Springer Science+Business Media New York 2015 203 204 mass and is helpful in distinguishing lymph nodes from congenital lesions such as vascular malformations For deeper lesions and further characterization of superficial masses, computed tomography (CT) [5] and magnetic resonance imaging (MRI) are the preferred imaging modalities In head and neck malignancies, CT is useful to evaluate for bony involvement as well as to evaluate for the presence of calcifications within a mass Current CT scans allow very quick imaging of the neck and can usually be performed without sedation unless the patient is too young to cooperate Radiation should be minimized and intravenous contrast is mandatory in the evaluation of a neck mass with CT Images are acquired axially and coronal and sagittal reformations are usually performed MRI is frequently better for characterization of the primary cancer and its relationship to adjacent structures Both T1- and T2-weighted images are usually performed; however T2 images and postgadolinium fat-suppressed images are especially important when evaluating a neck mass MRI is also important in evaluating for the presence of intracranial extension of a cervical or skull base mass Since MRI of the neck requires more time to be performed, sedation is frequently needed in the pediatric population, especially in patients under the age of or [18F]Fluorodeoxyglucose ([18F]FDG) positron emission tomography [6] provides wholebody functional imaging and has a role in staging head and neck malignancies and monitoring response to treatment PET and PET-CT are commonly used in childhood head and neck malignancies, predominantly in staging and follow-up of lymphoma [7] It may also have a role in soft-tissue sarcomas [7] Plain radiographs have very limited role in the evaluation of head and neck malignancies Nasal Tumors Nasopharyngeal Carcinoma Definition: Nasopharyngeal carcinoma is a malignant epithelial tumor that arises in the nasopharyngeal mucosa and shows evidence of squamous differentiation by light or electron microscopy or tested by immunohistochemistry It is subclassified into three groups: keratinizing squamous cell carcinoma, nonkeratinizing carcinoma, and basaloid squamous cell carcinoma [8] Clinical features and epidemiology: Nasopharyngeal carcinoma is rare in the pediatric population but relatively common among tumors in that location It has a remarkable geographic and ethnic distribution, with high incidence in Southeast Asia and northern Africa [9, 10] While infection with EBV is known to be an essential risk factor, cofactors including HLA type, genetics, and environment are thought to play an important role, especially in low-incidence Z Yu et al populations such as the USA [11, 12] In high-incidence populations most patients are middle-aged adults, but in other populations there is a bimodal age-incidence curve with an early peak around ages 15–24 years and a second peak later in life around ages 65–79 years [13] In pediatrics, the tumors are more commonly of undifferentiated histology and associated with EBV infection, frequently occur in African American population, and often present with advanced loco-regional disease manifesting as cervical lymphadenopathy [14–16] Imaging features: Nasopharyngeal carcinoma in children presents as an asymmetric mass in the posterior nasopharynx and may extend into the posterior choana and nasal cavity (Fig 7.1a) The tumor may also extend into the adjacent parapharyngeal space and pterygopalatine fossa, features concerning for malignancy Invasion of the central skull base is common [17, 18] Mastoid opacification frequently occurs as a secondary finding [17] Lymphadenopathy is also common at the time of diagnosis [17, 18] The lateral retropharyngeal nodes are the most frequently affected, followed by high level II and high level V lymph nodes [17] On MRI, the nasopharyngeal mass is usually iso- or slightly hyperintense to adjacent muscle on T1-weighted images and hyperintense compared to muscle on T2-weighted images Enhancement on contrast-enhanced images is usually present [18] (Fig 7.1b) It may be difficult to distinguish from benign adenoid hypertrophy, the most common nasopharyngeal “mass” in children Some imaging features, including asymmetry and involvement of skull base and adjacent regions, are useful in differentiating NPC from adenoid hypertrophy Differential diagnosis also includes lymphoma and sarcomas, which can have a similar appearance (Fig 7.1c) but are more common in younger children while NPC is more common in adolescents [18] Gross and microscopic features: Nasopharyngeal carcinoma usually arises from the lateral wall of the nasopharynx, especially the fossa of Rosenmüller Grossly, it may form a smooth bulge or nodule in the mucosa, with or without surface ulceration Sometimes there is no visible lesion found, and the diagnosis is made by random biopsy in suspicious areas [19] Microscopically, there are three distinctive subtypes: keratinizing squamous cell carcinoma (SCC), non-keratinizing carcinoma, and basaloid SCC Keratinizing SCC resembles the usual well-differentiated SCC arising in other locations There is obvious squamous differentiation with intercellular bridges and abundant keratinization at the light microscopic level This type of tumor often occurs in an older age group and may not be associated with EBV infection Non-keratinizing carcinoma, which represents the large majority of nasopharygeal carcinoma, is associated with EBV infection in practically all cases It may be subclassified Pediatric Cancer in the Head and Neck Fig 7.1 (a, b) Nasopharyngeal carcinoma (a) Contrast-enhanced CT in a teenage boy demonstrating an asymmetric enhancing right nasopharyngeal with extension into the retropharyngeal soft tissues A right maxillary retention cyst or mucosal polyp is incidentally noted (b) Axial T1W postcontrast MRI image in the same patient shows the enhancing nasopharyngeal mass as well as delineates better the involvement of adjacent structures Encasement of the carotid sheath vessels can be appreciated (arrow) (c) Contrast-enhanced CT image in a 12-year-old girl with an asymmetric enhancing nasopharyngeal mass similar in appearance to a nasopharyngeal carcinoma but confirmed by biopsy to be lymphoma (d) Nasopharyngeal carcinoma, nonkeratiniz- 205 ing undifferentiated subtype The tumor cells form irregular islands intimately intermingled with inflammatory infiltrates The tumor cells are relatively large with scant, lightly eosinophilic cytoplasm and indistinct cell borders, vesicular nuclei, and prominent nucleoli Keratin formation is difficult to be identified on routine H&E-stained section (e) Nasopharyngeal carcinoma, metastatic to the neck lymph node Immunohistochemical stains with pan-cytokeratin AE1/AE3 antibody shows uniform strong reactivity in the tumor cells (brown color), but no staining in surrounding lymphocytes (f) Nasopharyngeal carcinoma, metastatic to the neck lymph node EBV in situ hybridization for EBER shows positive nuclear reaction in tumor cells (blue color) 206 into differentiated and undifferentiated types, the latter accounting for majority of cases This subclassification is generally considered unnecessary, because it lacks clinical significance and lesions may show heterogeneity in different areas in the same biopsy or in different biopsies taken at different time intervals [20, 21] However, a recent study showed worse prognosis with differentiated histology [22] Tumor cells in non-keratinizing carcinoma typically form solid sheets or irregular islands intimately intermingled with variable numbers of inflammatory infiltrates rich in lymphocytes Sometimes the lymphocytes may dominate the entire lesion and obscure the epithelial nature of the cells, mimicking a lymphoma Undifferentiated subtype cells exhibit a syncytial appearance with scant, lightly eosinophilic cytoplasm and indistinct cell borders, vesicular nuclei, and prominent nucleoli (Fig 7.1d), whereas differentiated subtype cells demonstrate some level of cellular stratification or pavement arrangement, often described as resembling transitional cell carcinoma of the bladder Tumors may have focal or extensive spindle cell morphology or form papillary fronds Other occasional finds include scattered spherical amyloid globules [23], epithelioid granulomas [24], and prominent infiltration by eosinophils and plasma cells [25] The basaloid variant is the rarest type of NPC, as only a few cases are reported in the literature [26, 27] This type of tumor is morphologically identical to neoplasms occurring in other head and neck sites but show a lower clinical aggressiveness The tumors were composed of two types of cells, basaloid and squamous cells The basaloid cells are small with hyperchromatic nuclei, inconspicuous nucleoli, and scant cytoplasm The cells form closely packed solid sheets, irregular islands, nests, or cords, occasionally with peripheral palisading A component of conventional SCC foci is invariably present in the basaloid variant, and the junction between the squamous and basaloid cells may be abrupt Careful examination of the entire specimen to find the areas with conventional SCC may aid diagnosis Another feature of basaloid SCC is the presence of stromal hyalinization with small cystic spaces containing PAS and Alcian blue-positive material Comedo-type necrosis is frequent Immunohistochemistry and other special stains: The tumor cells show uniform strong reactivity for pan-cytokeratin AE1/AE3, cytokeratin 5/6, and p63, focal or weak reactivity for low-molecular-weight cytokeratins and EMA, and no reactivity for cytokeratins and 20 [28–30] (Fig 7.1e) Most tumors, especially non-keratinizing carcinoma, show a positive nuclear reaction for EBV-encoded early RNA (EBER) by in situ hybridization [31–33] (Fig 7.1f) High-level expression of ERCC1 may be associated with more aggressive clinical behavior [22] Molecular diagnostic features and cytogenetics: Although of no diagnostic value, rearrangement and deletion on Z Yu et al chromosome have been consistently nasopharyngeal carcinoma [34–37] noted in Prognostic features: The mainstay of treatment for nasopharyngeal carcinoma is concomitant chemotherapy and radiation, with or without neoadjuvant chemotherapy Progressive improvement has been reported both from endemic and nonendemic areas The outcome in pediatric patients is usually better than that of adults, and the presence of metastatic disease in cervical lymph nodes at diagnosis apparently does not adversely affect prognosis Development of therapyrelated complications including second malignancy is of special concern in long-term survivors [16, 38–41] NUT Midline Carcinoma Definition: NUT midline carcinoma is a rare aggressive subset of poorly differentiated SCC, genetically defined by rearrangement of the Nuclear Protein in Testis [42] gene at chromosome 15q13 [43] Clinical features and epidemiology: NMC is a newly described carcinoma commonly occurring in children and young adults, with a median age of 16 years (range 0.1–78) at the time of diagnosis [5, 44–46] The majority of tumors arise in the midline structures in head and neck or in the thorax, and nearly one-half of the cases present with either lymph node or distant metastases [45, 46] Rarely, the tumors arise in salivary glands, liver and pancreas, testis, and bladder [44, 47–50] None of the cases tested to date have been associated with EBV or HPV infection [51] Imaging features: Imaging appearance of NUT midline carcinoma is nonspecific, and very few case reports are present in the imaging literature Imaging features include heterogeneous low density on CT and heterogeneous but predominant T1 hypointensity and T2 hyperintensity on MRI with heterogeneous enhancement [52] Metastasis may occur in any part of the body and metastatic intraspinal and intracranial involvement have been described [52, 53] The intracranial lesion may demonstrate restricted diffusion [52] Intralesional calcification has also been reported [52] NMC has been shown to be avid on PET imaging [52, 54] Molecular genetics: NUT midline carcinoma is a genetically defined neoplasm caused by chromosomal rearrangement of the gene encoding NUT at 15q13 Approximately two-thirds have a translocation t(15;19) (q13;p13.1) involving NUT and BRD4, resulting in a BRD4-NUT fusion oncogene [43, 55] Less common tumors have a different rearrangement involving NUT, of which t(9;15)(q34.2;q13) with BRD3-NUT fusion gene is the most common variant [55] There is no significant Pediatric Cancer in the Head and Neck 207 Molecular diagnostic features and cytogenetics: NUT midline carcinoma can be diagnosed by conventional cytogenetics with characteristic t(15;19) Since the discovery of NUT rearrangement and its partner genes, reverse transcriptase (RT)-PCR and fluorescence in situ hybridization (FISH) have been used for the diagnoses but are largely replaced by NUT immunohistochemistry (see above) Nonetheless, they remain the gold standard for confirming the diagnosis Fig 7.2 NUT midline carcinoma The tumor is typically composed of poorly differentiated, uniform round, oval, or spindle-shaped tumor cells (right half of the picture) with occasional abrupt squamous differentiation with minimal keratinization (left half of the picture) association between translocation type (BRD4-NUT, BRD3-NUT, or NUT variant) and outcome, although some studies suggest that NUT-variant cancers may be associated with longer survival [44, 46] Gross and microscopic features: The histology of NUT midline carcinoma mimics many tumors arising in these locations Most tumors have poorly differentiated carcinoma morphology with uniform round, oval, or spindle-shaped tumor cells arranged in sheets, islands, or ribbons, with or without desmoplastic stroma The tumor cells often have high nuclear-to-cytoplasm ratios with inconspicuous cytoplasm, dense chromatin, and absent nucleoli Occasional cases show abrupt squamous differentiation with minimal keratinization (Fig 7.2) Sometimes neuroendocrine structures mimic neuroblastoma or Ewing’s sarcoma/primitive neuroectodermal tumor (PNET) Apparent chondroid differentiation has been described [47] The tumor often shows brisk mitoses, apoptosis, and focal necrosis NUT midline carcinoma is often confused with similar, poorly differentiated carcinoma features, such as poorly differentiated SCC, Ewing’s sarcoma/PNET, nasopharyngeal carcinoma, and pancreatoblastoma [51, 56] Immunohistochemistry and other special stains: Immunohistochemical staining with a monoclonal antibody against NUT has been proven highly sensitive and specific for the diagnosis of NUT midline carcinoma [57] In addition, the tumors express cytokeratin and p63, in keeping with squamous cell differentiation [56] Occasionally, there is negative staining for keratins including a pan-keratin cocktail, Cam5.2, and/or AE1/AE3 [58] The tumor is in general negative for sarcoma, melanoma, and lymphoma markers Prognostic features: All NUT midline carcinomas show aggressive behavior with early locoregional invasion and distant metastases They are often initially responsive to chemotherapy and radiation but invariably recur and not respond to subsequent therapeutic interventions The overall survival at and years after diagnosis has been 30 and 19 %, respectively, and the average survival is less than year [46] Esthesioneuroblastoma (Olfactory Neuroblastoma) Definition: Esthesioneuroblastoma, also called olfactory neuroblastoma, is a malignant neuroendocrine tumor arising from the olfactory mucosa of sinonasal tract and frequently invading into the orbits and skull base Clinical features and epidemiology: Esthesioneuroblastoma is an uncommon tumor, accounting for approximately 3–6 % of all sinonasal malignancy [59, 60] It usually occurs in adults between the ages of 40 and 70 years (mean 53) [61] but is rare in children; only 10 % of reported cases in English literature are in the pediatric population [62] Most pediatric patients are adolescents, with slight male predominance (1.5:1) Patients usually present with a nasopharyngeal polypoid mass that may cause unilateral nasal obstruction, local swelling, facial pain, and recurrent epistaxis The tumor may protrude into the orbit and cause proptosis, ophthalmoplegia, and even visual loss, or extend via the cribriform plate into the cranium The resultant frontal lobe lesion mimics a brain tumor [63, 64] Occasional patients may present with Cushing syndrome or hyponatremia due to ectopic ACTH or ADH production [6, 65, 66] Pediatric esthesioneuroblastoma seems to have a more aggressive presentation than in adults [67] There is no evidence of EBV infection [68] Imaging features: Esthesioneuroblastoma and its imaging characteristics have been well described in the adult literature Because these are rare tumors in the pediatric population, there is paucity of literature focusing on imaging of this tumor in children Typically, esthesioneuroblastoma demonstrates a large aggressive-appearing nasal mass with common extension into the paranasal sinuses and erosion of the cribriform plate and orbital wall, with 208 Z Yu et al Fig 7.3 (a) Esthesioneuroblastoma Coronal T1W postcontrast MRI image in an adult patient demonstrates the common appearance of esthesioneuroblastoma, with a large nasal mass extending into the ethmoid sinuses and causing erosion of the cribriform plate, with orbital and intracranial extension Image courtesy of Dr Nicholas Weisman, Yale New Haven Hospital (b, c) 14-year-old girl with left nasal esthesioneuroblastoma (b) Non-contrast-enhanced T1W axial MRI shows that the tumor is isointense to muscle and infiltrates the left maxillary sinus (c) Axial T2W MRI shows the tumor to be slightly hyperintense to muscle Mucoperiosteal thickening of both maxillary sinuses is present Images courtesy of Dr Beth McCarville, St Jude Children’s Research Hospital, Memphis, TN (d) Esthesioneuroblastoma The tumor is located in the subepithelial region of the nasal mucosa It is composed of nests of primitive small round blue cells invested by fibrovascular stroma (e) Esthesioneuroblastoma The tumor cells show strong expression of synaptophysin demonstrated by immunohistochemical stain intracranial and/or orbital extension (Fig 7.3a) On CT, they are usually homogenous, enhancing masses which cause bone remodeling As mentioned, they can involve the nasal cavity and the paranasal sinuses On MRI, esthesioneuroblastoma has intermediate signal on T1 and T2 (Fig 7.3a–c) and enhances with gadolinium In tumors with intracranial extension, peripheral cysts can be present at the margins of the intracranial mass and are helpful in suggesting the diagnosis of esthesioneuroblastoma [69] Erosion of the paranasal sinuses is common In contrast to neuroblastoma in other locations, metaiodobenzylguanidine (MIBG) scans have been shown to be negative in a series of patients with esthesioneuroblastoma [67] Gross and microscopic features: Esthesioneuroblastoma is a small round blue cell tumor that resembles neuroblastoma arising from adrenal gland or sympathetic chain Grossly, tumors form a red-gray, highly vascularized, polypoid mass, commonly located in the roof of the nasal fossa Sizes range from