Differential diagnosis of small round blue cell tumors.
Head and neck malignancies are a part of the differential diagnosis of head and neck masses seen in the pediatric age group. It is critical to make prompt diagnosis and employ proper treatment. We will review the most common malignant pathologies as well as their specific clinical presentations and management. Centers that are able to provide multidisciplinary care for pediatric patients with head and neck pathology can help achieve the best outcomes.
- pediatric tumor
- neck mass
- pediatric cancer
- head and neck cancer
Head and neck malignancies are rare within the pediatric population and represent 12% of all pediatric cancers according to the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database . While epithelial tumors are more common in adults, childhood tumors are more frequently derived from mesenchymal and endothelial cells. Genetic conditions, previous chemotherapy, or exposure to ionizing radiation predispose this population to both primary and secondary malignancies, but the cumulative environmental carcinogen exposures (e.g. cigarette smoke inhalation, ultraviolet radiation) are much less common given the patients’ younger ages .
The most common pediatric head and neck cancers include lymphoma (Hodgkin and non-Hodgkin), rhabdomyosarcoma, thyroid carcinoma, nasopharyngeal carcinoma, and salivary gland malignancies (Figure 1). While other malignancies such as neuroblastoma, neuroendocrine tumors, various soft-tissue sarcomas, cutaneous tumors, and metastases infrequently manifest within the head and neck region, a complete and thorough discussion of these cancers is outside the scope of this review and are covered elsewhere throughout literature. The primary aim of this review is to highlight the more common head and neck childhood malignancies and present a focused examination of the etiology, presentation, workup, and treatment of these conditions.
Lymphoma is the third most common pediatric malignancy - following leukemia and brain tumors - and the most common head and neck cancer in children and adolescents . The broad differential diagnosis for small round blue cell tumors, like lymphoma is shown in Table 1. The treatment of childhood lymphoma has experienced significant improvements in recent decades and is now associated with cure rates approaching 80 to 90% [4, 5]. Lymphoma is divided into two groups: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). HL is further subdivided into two clinical subtypes by the World Health Organization (WHO) classification which includes classic Hodgkin lymphoma (CHL), which accounts for approximately 95% of HL cases within the United States, and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Overall, HL is less common in developed countries with distribution patterns that vary widely according to geography and ethnicity. HL is characterized by a bimodal distribution with a peak in adolescence between 15 and 40 years of age and another in adulthood beyond 60 years of age. Recently, HL has been shown to cluster within certain families with associations to specific HLA loci, thus suggesting vertical transmission of susceptible genotypes . Pediatric HL exhibits a 2:1 male predominance with as many as 40 to 50% of cases linked to the Epstein Barr virus (EBV) infection as well as the pathognomonic Reed-Sternberg cell morphology [7, 8, 9]. Four subtypes of HL have been characterized: nodular sclerosis, mixed cellularity, lymphocyte predominant, and lymphocyte depleted, which account for roughly 50%, 30%, 15%, and less than 10% of the cases, respectively . The Ann Arbor staging system is used to stratify these tumors based on the extent of disease and whether organs on one or both sides of the diaphragm are involved (Table 2).
|I||Involvement of a single lymph node region (cervical, axillary, inguinal, mediastinal) or lymphoid structure (spleen, thymus, or Waldeyer’s ring) (I); or extralymphatic site in the absence of involved nodes (I-E)|
|II||Two or more sites on the same side of the diaphragm (II) including:|
|III||Involvement of regional lymph nodes or lymphoid structures on both sides of the diaphragm (III):|
|IV||Diffuse or disseminated involvement (IV) of:|
In contrast to HL, the incidence of pediatric NHL is lower in younger children and increases with age. Pediatric NHL is more frequently associated with higher grades and extranodal involvement when compared to cases of adult NHL. Average survival rates are greater than 80%, regardless of histologic subtype, of which there are several . The most common pediatric NHL subtype is Burkitt lymphoma (BL) which accounts for 50 to 60% of childhood cases, followed by T-cell lymphoblastic lymphoma (1520%), anaplastic large cell lymphoma (1015%), diffuse large B-cell lymphoma (510%), followed by other rare subtypes . BL, a highly aggressive tumor, is derived from the classic t(8;14) cytogenetic translocation of the
Lymphomas of the head and neck can present insidiously, but are typically discovered as a “rubbery,” enlarged cervical or supraclavicular lymph node on physical examination. The majority of HL patients present with asymptomatic cervical adenopathy with or without the constitutional “B” symptoms including fever, night sweats, chills and weight loss which are also incorporated into the HL Ann Arbor staging system. While adult NHL is characterized by nodal disease, pediatric NHL has a predisposition for extranodal involvement with the most common head and neck extranodal localizations involving the larynx, sinonasal cavities, salivary glands and orbit. Lymphoma is present within Waldeyer’s ring in approximately 44% of cases especially in NHL patients [7, 22]. Oguz et al. conducted a retrospective study of 457 pediatric patients with lymphadenopathy and demonstrated that chronic lymphadenopathy (greater than 4 weeks in duration), generalized and supraclavicular involvement, and lymph nodes measuring greater than 3 cm were findings most commonly associated with malignancy among 111 patients with confirmed disease . Other causes for concern include persistent lymphadenopathy despite antibiosis, nodal firmness, immobility, fixation to underlying tissues, and progressive nodal enlargement .
Otolaryngologists and other surgeons primarily serve diagnostic roles via lymph node biopsy As the initial differential diagnosis for pediatric cervical adenopathy is broad and widely varied, a detailed history and physical examination is critical to stratify the likelihood of malignancy against other processes such as infection, hypersensitivity reactions, granulomatous diseases, and rheumatic or lymphoproliferative disorders as these patients may present prior to evaluation by other clinicians. Prior to surgery, management and workup should include an array of laboratory testing which includes complete blood count (CBC) with differential and peripheral blood smear, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, lactate dehydrogenase (LDH), as well as a serum ferritin, copper and alkaline phosphatase levels. Bone marrow biopsy and lumbar puncture (LP) are also routinely performed. Imaging should include chest radiograph and ultrasound (US) with computed tomography and magnetic resonance imaging (MRI) reserved for more suspicious or concerning presentations. Ultrasound is often the imaging mainstay given its accessibility without the need for sedation or radiation exposure (Table 3); however, CT continues to play an integral role in surveillance because of simplicity and rapidity. F-fluorodeoxyglucose positron emission tomography (FDG-PET) has demonstrated improved sensitivity and specificity in accurately diagnosing lymphoma compared to conventional imaging modalities [24, 25] (Figure 2).
|Size||Shape||Borders||Hilar fat, Cortex||Vascular flowa||Chronicity||Additional Characteristics|
|Benign||Typically <2 cm||Long axis to short axis ratio ≥ 2:1;|
Oval or reniform
|Typically blurred, regular||Echogenic, hypoechoic||Hilar (radiating from center), avascular|
Low vascular resistance
|Reactive||Variable||Long axis to short axis ratio ≥ 1:1||Blurred, regular||Echogenic, hypoechoic||Hilar flow, avascular|
Low vascular resistance
|Typically acute (0–2 weeks) or subacute (2–6 weeks)||Calcifications possible|
|Malignant||Typically >2 cm||Long axis to short axis ratio < 2:1|
|Typically sharp, irregular. Matting indicates malignancyb||Hypoechogenic, hypoechoic||Peripheral flow (cortical), mixed flow|
Elevated vascular resistance
|Chronic, >6 weeks suggests malignancy||Necrosis (cystic or coagulation), calcifications, reticular internal pattern|
Following imaging, biopsy is needed to obtain a sufficient amount of tissue for frozen and permanent histopathologic analysis along with flow cytometry and immunohistochemistry as indicated. These specimens should be sent fresh rather than in formalin to provide a viable sample responsive to flow cytometry. Following diagnosis, staging of disease typically requires bone marrow biopsy and lumbar puncture to assess extent of bone marrow involvement and to determine whether malignant cells are present in the CSF, respectively. Diagnosis based on fine needle aspiration biopsy (FNAB) has remained controversial and challenging as it results in a dearth of cellularity from sclerosis, decreased detection of clonal populations, and a lack of diagnostic Reed-Sternberg cells . As such, excisional biopsy remains the gold standard in the primary diagnosis of pediatric lymphoma.
Treatment of pediatric lymphoma is non-surgical and includes multi-agent chemotherapy with or without radiotherapy (RT) as the first line. With respect to the treatment of HL, various combinations of chemotherapeutic agents have been utilized with 3- and 8-year event-free survival (EFS) approximating 90% and greater than 80%, respectively, while overall survival (OS) has been demonstrated to range from 80 to 90% [27, 28]. Some regimens include MOPP (mechlorethamine, vincristine, procarbazine, prednisone), COPP (cyclophosphamide, vincristine, procarbazine, prednisone), and ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) , each uniquely selected based upon the subtype of HL and the side-effect profiles. RT is also commonly added in combination with chemotherapy. With NHL, a large number of chemotherapeutic combinations are possible, as outlined by Kahn et al.: ABV (doxorubicin, bleomycin, and vinblastine), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) COPDAC (cyclophosphamide, vincristine, prednisone, and dacarbazine), and COPP . In contrast to HL, RT is infrequently used to treat NHL. Additionally, if high-grade NHL is present, intrathecal chemotherapy may be indicated. Post-operative surveillance examinations and imaging are obtained at regular intervals to monitor for evidence of disease recurrence (Figure 3).
Rhabdomyosarcoma (RMS), a malignant tumor of mesenchymal origin, is the most common pediatric soft tissue sarcoma affecting approximately 250 children per year within the United States . It accounts for 4.5% of all childhood malignancies and is the third most common extracranial pediatric solid tumor following Wilms’ tumor (nephroblastoma) and neuroblastoma. RMS of childhood is characterized by a bimodal distribution and presents between the ages of 2 and 6 and again between 10 and 18 years of age . Although this tumor may arise throughout the body given its mesenchymal nature, the head and neck is the most commonly involved, comprising 35% of all cases [32, 33, 34]. Of the cases involving the head and neck, nearly 75% arise within the orbit or parameningeal regions (e.g. nasopharynx, nasal cavity, paranasal sinuses, infratemporal fossa, pterygopalatine fossae, and middle ear) (Figure 4). The remainder originates primarily in the oral cavity, cheek, parotid region and soft tissues of the neck, which are commonly referred to as non-orbital or non-parameningeal lesions [35, 36]. Although most tumors occur sporadically, some RMS cases are associated with familial syndromes such as Li Fraumeni and neurofibromatosis type I [31, 37, 38]. The tumor typically presents as a painless, asymptomatic mass in the majority of cases but may cause compressive symptoms and cranial neuropathies secondary to mass effect in more advanced disease.
RMS histology classically appears as a small round blue cell tumor of childhood and is classified alongside similar appearing neoplasms including lymphoma, neuroblastoma, Wilms’ tumor, Ewing’s sarcoma and peripheral neuroectodermal tumors. There are two main histologic subtypes of RMS: embryonal (ERMS) and alveolar (ARMS). ERMS is the more common subtype and comprises approximately 75% of cases with a preponderance for younger patients. In contrast, the ARMS subtype—appearing histologically similar to pulmonary parenchyma—represents approximately 25% of cases and is more prevalent among older children and adolescents with the majority occurring in children greater than 10 years of age. Compared to ERMS, the ARMS subtype is associated with an unfavorable prognosis. A review of the SEER database performed by Ognjanovic et al. analyzed the incidence and survival rates for pediatric and adolescent RMS between 1975 and 2005 with five-year overall survival rates ranging from 40.1–47.8% and 60.9–73.4% for the ARMS and ERMS types, respectively . Similar findings were reported by Pappo et al. with five-year survival rates of 97% for non-orbital, non-parameningeal embryonal cases versus 67% for ARMS subtypes . With respect to head and neck tumors, the ERMS subtype occurs more frequently and may be further classified into the botryoid and spindle-cell variants with botryoid histology demonstrating a more favorable prognosis .
Patients with suspected RMS should undergo a thorough workup including a complete head and neck physical exam along with laboratory testing, imaging and pathologic confirmation prior to treatment. Evaluation for metastatic disease often includes a lumbar puncture for cerebrospinal fluid analysis. Imaging studies of the primary tumor site often involve CT - which is useful for the evaluation of osseous erosion - and MRI for further characterization of the primary tumor and the surrounding anatomy. This is especially beneficial in determining whether the tumor may be safely resected with primary surgery or if neoadjuvant treatment is required to decrease the morbidity. FDG-PET imaging has so far seen limited use in the pediatric population. However, several studies have suggested an increased utility in evaluating the presence of lymphadenopathy, occult disease, response to treatment, and detection of recurrence compared to standard imaging alone [40, 41, 42, 43]. Biopsy is required for definitive diagnosis and may often be achieved via fine needle aspiration or open biopsy while taking care to obtain an adequate amount of tissue for accurate histopathologic analysis. Although lymph node involvement in pediatric head and neck RMS is uncommon, determining the presence of locoregional and metastatic lymph node involvement is critical in establishing pre-treatment staging and, in cases of suspected disease, pathologic evaluation should be undertaken which will further influence radiotherapy fields. In an analysis of regional lymph node disease in 898 patients within the pivotal Intergroup Rhabdomyosarcoma Study IV, Rodeberg and colleagues demonstrated that the presence of nodal disease is an independently poor prognostic indicator for both failure-free and overall survival, further underlining the need to establish the extent of disease prior to treatment .
In an effort to design effective and tailored treatment regimens for these patients, the Intergroup Rhabdomyosarcoma Study and its subsequent iterations (IRS I-IV) established a staging and grouping system to aid in directing treatment strategy based upon tumor location, disease extent, and completeness of surgical resection [45, 46, 47, 48]. Within this classification scheme, the pre-operative “stage” is based upon pre-operative standard TNM staging guidelines whereas the post-operative clinical “group” refers to the extent of disease and completeness of surgical resection prior to adjuvant therapy. Group I reflects complete resection with negative pathologic margins. Group II consists of patients with complete gross resection but microscopically positive residual disease (close or positive margins, presence of regional nodal disease, or both). Group III includes patients with gross residual disease following incomplete resection or unresectable disease. Group IV reflects those with distant metastatic disease other than first echelon nodal metastases. An overview of the IRS pre-treatment staging (Tables 4 and 5) and post-treatment grouping classification (Table 6) is provided.
|I||Orbit||T1 or T2||a or b||N0, N1, or Nx||M0|
|Head and neck (excluding parameningeal)||a or b||N0, N1, or Nx|
|Genitourinary (non-bladder/non-prostate)||a or b||N0, N1, or Nx|
|II||Bladder/prostate||T1 or T2||a||N0 or Nx||M0|
|Extremity||a||N0 or Nx|
|Head and neck (parameningeal)||a||N0 or Nx|
|Other (includes trunk, retroperitoneum, etc.)||a||N0 or Nx|
|III||Bladder/Prostate||T1 or T2||a||N1||M0|
|Extremity||b||N0, N1, or Nx|
|Head and neck (parameningeal)||b||N0, N1, or Nx|
|Other (includes trunk, retroperitoneum, etc.)||b||N0, N1, or Nx|
|IV||All||T1 or T2||a or b||N0 or Nx||M1|
|T1||Confined to anatomic site of origin|
|a||<5 cm in diameter|
|b||≥5 cm in diameter|
|T2||Extension and/or fixation to surrounding tissue|
|a||<5 cm in diameter|
|b||≥5 cm in diameter|
|N0||Not clinically involved|
|Nx||Clinical status unknown|
|M0||No distant metastases|
|M1||Distant metastases present|
|Group 1||Localized disease, complete resection, no microscopic residual disease|
|A||Confined to site of origin, complete resection|
|B||Infiltrating beyond site of origin, complete resection|
|Group 2||Gross total resection|
|A||Gross resection with microscopic residual disease|
|B||Regional disease with spread to regional lymph nodes, complete resection without residual microscopic disease|
|C||Regional disease with spread to regional lymph nodes, gross total resection, but evidence of microscopic residual disease|
|Group 3||Incomplete resection or biopsy with gross residual disease remaining|
|Group 4||Distant metastases present irrespective of surgical approach to tumor|
Chemotherapy and radiation have remained the mainstay of multimodal treatment for childhood RMS. Recently, there has been an increasing trend towards primary surgical resection in localized tumors involving the head and neck . The success of surgical treatment is often dependent on the specific location of tumor [35, 36, 50, 51]. Orbital RMS, associated with a favorable prognosis, is rarely associated with meningeal extension and is treated with primary chemotherapy and radiation with surgery reserved for salvage cases . On the other hand, parameningeal lesions are more challenging to remove and are often categorized as IRS Group III tumors because they are not typically amenable to complete surgical resection. Given its anatomic location in close proximity to vital neurovascular structures, parameningeal RMS is associated with an increased likelihood of cranial neuropathies, cranial base erosion, and intracranial extension . As primary surgical resection with wide margins is often infeasible for these tumors, chemotherapy with or without radiation is the preferred treatment modalities. (Figures 4 and 5). Reilly et al. conducted a retrospective chart review of 17 children diagnosed with head and neck RMS over an 18-year period and found that the majority presented with cranial neuropathies, thus reflecting the aggressive nature of this disease upon symptom onset with 5 of 17 (29.4%) patients demonstrating advanced metastatic disease at first referral. Within their series, 4 of 4 patients with non-parameningeal disease underwent primary surgical resection but tumor-free margins were unobtainable and adjuvant chemotherapy with radiation was ultimately required. All patients with parameningeal disease underwent multimodal treatment . However, Daya et al. also demonstrated that many children may avoid radiation therapy without compromising survival in cases of completely resected RMS .
In general, pediatric RMS necessitates systemic treatment in the form of chemotherapy with local control achieved with surgery and/or radiation. The treatment approach must nonetheless be carefully tailored for each individual patient according to tumor location and the potential morbidities associated with each modality. Although primary surgical resection may be possible in select non-parameningeal tumors, the decision for adjuvant therapy is ultimately determined by margin status.
4. Thyroid carcinoma
Thyroid carcinoma represents approximately 21% of all pediatric head and neck malignancies with an annual reported incidence of 0.54 per 100,000 persons within the United States [55, 56]. In contrast to adults, thyroid nodules are less likely to be palpable in children (2% vs. 35%) and carry a much higher likelihood of malignancy with a risk of 1 in 4 in pediatric patients compared to less than 1 in 10 for adults . The majority of thyroid cancers are differentiated with papillary thyroid cancer (PTC) accounting for greater than 90% of cases . Less common variants include follicular thyroid cancer (FTC) and medullary thyroid cancer (MTC) while anaplastic and poorly differentiated subtypes are even rarer . MTC is more common among younger children (ages 0–4) and declines with increasing age while the incidence of PTC increases as one approaches adolescence and adulthood . A significant number of patients present with regional lymph node involvement (60–80%) and distant metastatic disease may occur in up to 20% of children with the lungs most commonly involved . Despite the frequency of advanced disease at initial presentation, several case series have demonstrated an excellent prognosis with greater than 95% long-term survival for papillary and follicular variants [58, 60, 61, 62]. Notably, previous radiation exposure and treatment of other childhood malignancies increases the risk for developing pediatric thyroid cancer with an 18-fold greater risk of thyroid cancer compared to the general population, thus highlighting the importance of close follow up and frequent surveillance among this cohort [63, 64, 65].
The diagnosis of suspected pediatric thyroid cancer involves a focused history and physical examination with particular attention to previous radiation exposure and treatment of prior childhood malignancies, such as lymphoma. Patients typically present with an asymptomatic thyroid nodule or mass following incidental discovery on surveillance imaging studies. US and FNAB of the most suspicious thyroid nodules should be completed along with histocytologic analysis. A review of 89 pediatric patients by Buryk et al. examined patients with thyroid nodules ≥0.8 cm and demonstrated that larger-sized nodules, palpable nodules, and palpable lymphadenopathy were significant predictors of malignancy . Sonographic characteristics associated with malignant nodules include larger size, solid parenchyma, taller-than-wide shape, microcalcifications, irregular margins, and abnormal-appearing lymph nodes [67, 68, 69]. Richman et al. also found significantly increased rates of cancer in patients with solitary nodules compared to those with multiple nodules (29.4% vs. 14.2%,
Surgical resection is the primary treatment modality for childhood thyroid cancer with options including total thyroidectomy and lobectomy with isthmusectomy. The American Thyroid Association (ATA) guidelines utilize the American Joint Committee on Cancer (AJCC) pTMN staging system to stratify patients into low, intermediate, and high-risk groups. Total thyroidectomy is the preferred surgical method for PTC given an increased likelihood of bilateral and multifocal disease in these tumors  (Table 7). The extent of resection nonetheless remains a source of controversy. Nice et al. performed a retrospective review of 3861 patients less than 21 years old with primary PTC nodule greater than 1 cm in diameter and found no significant difference between total thyroidectomy compared to partial thyroidectomy (e.g. sublobar resection, lobectomy, or lobectomy with isthmusectomy) on both univariate and multivariate analyses, with both groups demonstrating 96% 15-year overall survival (OS) . In contrast, Bargen et al. found that, while there were no significant increase in surgical complications, patients receiving less than total thyroidectomy were at an increased risk for requiring revision surgery (
|ATA risk level||Definitiona||Initial post-operative stagingb||Surveillance for pediatric patients with no evidence of disease|
|Low||Disease grossly confined to the thyroid with N0/Nx disease|
Disease grossly confined to the thyroid with N0/Nx disease (microscopic metastases to a small number of central neck lymph nodes)
|Tgc||US at 6 months postoperatively, then annually x 5 years|
Tgc on LT4 every 3–6 months x 2 years, then annually
|Intermediate||Extensive N1a or minimal N1b disease||TSH-stimulated Tgc and diagnostic 123I scan||US at 6 months postoperatively, every 6–12 months x 5 years, then less frequently|
Tgc on LT4 every 3–6 months x 3 years, then annually
Consider TSH-stimulated Tgc ± diagnostic 123I scan in 1–2 years in patients previously treated with 131I
|High||Regionally extensive disease (extensive N1b)|
Locally invasive disease (T4 tumors), with or without distant metastasis
|TSH-stimulated Tgc and diagnostic 123I scan||US at 6 months postoperatively, every 6–12 months x 5 years, then less frequently|
Tgc on LT4 every 3–6 months x 3 years, then annually
Consider TSH-stimulated Tgc ± diagnostic 123I scan in 1–2 years in patients previously treated with 131I
MTC is a unique variant of thyroid carcinoma. Most pediatric cases are inherited in an autosomal-dominant fashion although sporadic cases are possible. Pediatric MTC patients commonly present with bilateral and multifocal thyroid nodules, with metastatic disease common at the time of diagnosis. Parafollicular C-cell hyperplasia results in an excess production of calcitonin and carcinoembryonic antigen (CEA). Mutations in the
Following total thyroidectomy, hormone replacement is necessary. Together with RAI therapy, it may reduce the risk of tumor recurrence. Long-term surveillance includes serum thyroglobulin levels, thyroid US, and radioiodine-123 (123I) diagnostic whole-body scans. Radioiodine-131 (131I) may be used for ablation of residual thyroid tissue and is indicated in select pediatric patients with distant metastases or residual disease not amenable to surgical resection [71, 84, 85]. Complications of RAI are dose-dependent and include pulmonary fibrosis, infertility, and the development of secondary cancers, thus highlighting the importance of careful patient selection as well as follow-up .
5. Nasopharyngeal carcinoma
Nasopharyngeal carcinoma (NPC) is a rare pediatric malignancy. Overall, NPC accounts for less than 1% of all childhood cancers and represents approximately 20–50% of nasopharyngeal tumors [87, 88]. Globally, the incidence of pediatric NPC is highest throughout southeast Asia, southern China, and the Mediterranean. In the United States, childhood NPC is more commonly diagnosed in the southern states. The age distribution is bimodal with the first peak in adolescence followed by mid-adulthood (ages 40–60) while the distribution in endemic regions (e.g. Southeastern Asia and China) is unimodal without a pediatric peak . In all regions, the etiology and pathogenesis of NPC is closely related to Epstein–Barr virus (EBV) infection with children sharing a closer association with EBV than adults [88, 90].
The WHO separates three distinct histopathologic subtypes of NPC: Type I (keratinizing squamous cell carcinoma), Type II (non-keratinizing epidermoid carcinoma), and Type III (undifferentiated carcinoma) (Table 8) [88, 91]. Type I is characterized by the production of keratin, is commonly associated with alcohol and tobacco exposure and, as such, is less common in the pediatric population. Type I NPC may be found in those with EBV infections in endemic areas. Type II and III commonly demonstrate lymphoid, plasmoid, and eosinophilic cell infiltration. Type III, also referred to as lymphoepithelioma or Schminke tumor, is the most common histopathologic subtype in pediatric patients and may be found in as many as 90% of patients with a high rate of distant metastases .
|I||Keratinizing squamous cell carcinoma|
|III||Undifferentiated carcinoma (Lymphoepithelioma or Schminke tumor)|
Childhood NPC most commonly presents a painless neck mass, which may be appreciated in 70–90% of patients at the time of first diagnosis. Nasal obstruction, epistaxis, and Eustachian tube dysfunction with resultant conductive hearing loss and serous otitis media may occur from tumor mass effect . In more advanced disease, trismus, headache, facial pain, diplopia with vision changes, and other cranial nerve palsies may be present secondary to skull base involvement [88, 93, 94]. Patients with systemic disease may present with paraneoplastic syndromes such as syndrome of inappropriate antidiuretic hormone (SIADH) or dermatomyositis . Evaluation involves a thorough clinical examination with contrast-enhanced CT and MRI with particular attention to skull base structures. Recommended laboratory testing includes a CBC, serum chemistry, lactic acid dehydrogenase (LDH) level, and liver function panel. More specifically, elevated LDH levels carry prognostic significance with higher values shown to correlate with decreased OS, disease-free survival (DFS), and distant metastasis-free survival (DMFS) [96, 97]. Bone marrow biopsy and CSF cytologic analysis is indicated in cases of distant metastases or when skull base extension is suspected while biopsy of the primary tumor is required for accurate tissue diagnosis.
Given the rarity of pediatric NPCs, treatment strategies have been tailored from established adult guidelines. As these tumors are rarely amenable to surgical resection, the standard of care for locoregional NPC involves a combination of high-dose radiotherapy (RT) to the primary nasopharyngeal tumor bed and the surrounding nodal basin with lower doses targeted at surrounding tissues and uninvolved lymph nodes. Due to high rates of locoregional and distant failure in patients presenting with advanced disease, chemotherapeutic regimens have recently been incorporated into treatment schemas. With combined RT and chemotherapy, survival rates ranging from 60 to 70% have been reported with some studies documenting as high as 90% [89, 90, 94, 98, 99]. In patients with early-stage T1 or T2 disease, single modality RT may be utilized. In locally advanced cases, dual modality treatment has been shown to result in improved OS compared to RT alone. A meta-analysis by Langendijk et al. demonstrated that concurrent chemotherapy was associated with a pooled hazard ratio (HR) of 0.48 (95% CI, 0.32–0.72) which corresponded to a 20% improvement in five-year OS compared to RT alone while neoadjuvant chemotherapy was associated with improved locoregional control with a decreased rate of distant metastases . Similar results have been documented throughout the literature [101, 102, 103, 104, 105]. Despite these advances, many patients continue to present with locoregional or systemic recurrence with most relapses occurring within the first two years (median 8 months) following treatment [98, 106, 107]. The short interval between therapy completion and distant metastases may be a result of occult disease at the time of presentation. Notably, T and N classification, total irradiation dose, presence of metastatic disease at diagnosis, and delay in time to RT have all been demonstrated as prognostic factors in locoregional control of NPC [93, 105, 106, 107, 108, 109, 110].
6. Salivary gland malignancy
Pediatric salivary gland malignancies are rare and comprise approximately 3% of head and neck cancers in the pediatric population and 5% of salivary gland malignancies overall . In contrast to adults, the majority of salivary gland neoplasms in children are malignant in nature (40–60%) and most are epithelial in origin. The parotid gland is the most common site and mucoepidermoid carcinoma (MEC) represents the vast majority of salivary gland malignancies. Less common histologic subtypes include acinic cell carcinoma (24–40%) and adenoid cystic carcinoma (15–26%) . Several series have evaluated treatment outcomes associated with these tumors and demonstrate surgical resection as the mainstay of treatment followed by adjuvant RT in select instances [112, 113, 114, 115, 116, 117, 118, 119]. A retrospective study by Ribeiro and colleagues reviewed outcomes associated with the treatment of 38 pediatric patients with salivary gland neoplasms, 27 (71.1%) of whom presented with malignant tumors . MEC was the most frequent pathology occurring in 17 of 27 (69.3%) cases followed by 3 patients with adenoid cystic carcinoma; the remaining seven patients had a diverse range of rare malignancies. The parotid gland was the most common primary site followed by minor salivary glands and submandibular gland with 74.1%, 22.2%, and 7.4% of the cases, respectively. All were treated with surgical resection while 10 patients underwent concurrent neck dissection; however, only 6 were found to have pathologically positive lymph node disease. RT was administered to a total of 10 patients (neoadjuvant in 2 patients, adjuvant in 8 patients) and chemotherapy in 3 individuals. Overall, five and ten-year survival rates were both 81.6% with tumor differentiation found to be a significant prognostic factor in those with MEC with a five-year OS of 100% in low-grade histology compared to 50% for intermediate and high-grade histology (
While MEC is the most common adult and childhood malignant salivary gland tumor, it has also been reported to occur more frequently in patients previously treated with RT and/or chemotherapy regimens for both cancerous and benign pathology [122, 123, 124]. A literature review by Verma et al. assessed the characteristics and treatment outcomes of 58 patients selected from 23 studies with treatment-related MEC and showed a significantly shorter latent time to the development of MEC from initial treatment in those treated with chemotherapy with or without RT compared to RT alone (7.9 years vs. 27.2 years) . The primary MEC treatment modality was surgery alone in the majority of patients (64.9%) or in combination with radiation (29.8%) while the remaining patients received surgery plus chemotherapy, or underwent RT alone. Survival was similar to those documented in previous studies with two and five-year OS rates of 98.0% and 93.4%, respectively. Despite favorable survival, the potential for the development of secondary malignancy underscores the importance of continued surveillance in these patients for not only salivary gland cancers but other solid tumor malignancies (Table 1).
Clinically, most salivary gland neoplasms present as asymptomatic masses and are rarely associated with cranial neuropathies; the presence of facial nerve weakness or other cranial nerve deficits should heighten the suspicion for malignant potential [111, 112, 125, 126]. US remains the first-line imaging modality and has been shown to be useful in combination with FNAB in establishing a timely diagnosis, specifically in parotid tumors . While CT is useful for further imaging characterization, MRI is superior in demonstrating soft-tissue enhancement which is particularly beneficial in evaluating the status of the facial nerve, lingual nerve, and other surrounding neurovascular structures . Open biopsy should be avoided given the potential for injury to the facial nerve, especially in children with parotid tumors, and possibility for tumor seeding [129, 130]. Treatment consists of local excision with tumor-free margins of the affected salivary gland. In the case of partial or total parotidectomy, careful attention to preserving facial nerve function is recommended as the critical neurovascular structures are smaller in pediatric patients. The same principles hold true in cases of submandibular gland malignancy where the marginal mandibular and lingual nerve should be preserved [112, 131]. A review of the SEER database from 1973 to 2006 by Sultan et al. identified a total of 263 children and adolescents with salivary gland carcinoma and, in comparison to adults, found that disease is more often localized (50%) with regional lymph node metastases being less common (11% vs. 31%) . The need for neck dissection in children is poorly understood as the majority of tumors are low-grade without occult nodal disease. As a result, several authors have suggested that neck dissection be performed in cases of clinically evident nodal involvement and high-grade histology which may altogether avoid the need for adjuvant therapy in the absence of positive margins or pathologically positive nodal disease [116, 125, 132, 133].
Sarcomas account for 14% of primary head and neck malignancies in children and adolescents. Osteosarcoma remains the most common subtype consisting of approximately 0.5% of the cases and Ewing sarcoma is the second most common cancer of bone . Osteosarcoma most frequently involves the long bones of the extremities (e.g. distal femur, proximal tibia, proximal humerus) but may occur in the mandible or maxilla which are the most commonly involved head and neck subsites [134, 135, 136, 137, 138, 139]. In general, childhood mandibular and maxillary tumors are benign and are discovered incidentally during routine dental examinations or non-related imaging studies [140, 141]. Head and neck osteosarcoma is also associated with a better prognosis when compared to their long bone counterparts with three and five-year survival rate at approximately 65% [142, 143, 144]. Patients tend to present during adolescence with a painless mandibular mass, but pain, edema, loose dentition, paresthesias, diplopia, or cranial nerve palsies are especially suspicious for malignancy [134, 135, 144].
Management and treatment protocols are primarily based upon large trials or meta-analyses focused on osteosarcoma of the limbs and trunk . In addition to laboratory studies, imaging commonly involves a combination of plain radiographs, CT, MRI, and 99 m technetium methylene disphosphonate bone scans [146, 147, 148]. The classic “sunburst” finding in addition to a “fluffy” or spiculated osseous appearance suggests the presence of an aggressive periosteal reaction along with osteolytic or osteoblastic bony destruction associated with malignancy. Lesions are sampled for histologic determination of subtype which includes the osteoblastic, chondroblastic, and fibroblastic high-grade forms with tumor grade carrying prognostic significance [137, 149, 150, 151, 152]. Estimating survival rates for pediatric head and neck osteosarcoma is difficult as studies tend to group adult and pediatric patients together. Despite this, surgical resection appears to play an important role with negative surgical margins being the most important prognostic factor [142, 143, 153, 154, 155, 156, 157]. Similar to other surgically resected tumors, adjuvant RT and chemotherapy are reserved for use in cases with incompletely resected disease or in the setting of positive surgical margins. In the case of unresectable disease, RT and chemotherapy either as single or multi-modal therapy may be indicated, though RT should be approached with particular care as some studies attribute RT as a causative intervention for OS. Other less common sarcomas exist (e.g., fibrosarcoma, synovial cell sarcoma, chondrosarcoma, liposarcoma), although a complete discussion of the management of these entities is outside the scope of this review. Nonetheless, surgical resection remains the mainstay of treatment in many of these diagnoses and leads to a successful outcome when complete resection with tumor-free margins is obtained (Figure 6).
Pediatric head and neck malignancies represent a minority of childhood tumors. Although the relative rarity of these tumors largely prevents initiation of high-volume trials, experiences from adult cases and in pediatric case reports stipulate that multimodal therapy is often indicated based upon the specific histopathology, stage, and anatomic sites involved. In select instances, primary surgical management with or without free tissue transfer and microvascular reconstruction may also be indicated. While adjuvant therapy including post-operative radiation may improve long-term survival rates, careful consideration must be given to the potential for the development of deleterious side effects in young children including secondary malignancies later in life.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest
The authors declare no relevant conflicts of interest.