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Diagnostic Applications of Nuclear Medicine: Head and Neck Cancer

  • Heiko SchöderEmail author
Living reference work entry

Abstract

Most head and neck cancers are squamous cell carcinomas (HNSCC) arising in the oral cavity, oropharynx, larynx, and hypopharynx. The incidence of HNSCC is rising in the industrialized world, and there is increasing recognition of the role of human papillomavirus (HPV) infection as an etiologic factor in the development of this disease. In the USA, about 48,330 new cases of head and neck cancer have been diagnosed in 2016, and approximately 9,600 patients died of the disease. CT or MRI is essential to define the extent of the primary tumor, assess lymph node size, and detect bone and bone marrow disease. [18F]FDG PET/CT imaging from the skull base to the floor of the pelvis is essential in patients with locally advanced disease and in all patients who are candidates for definitive chemoradiotherapy to define N and M staging. Interpretation of head and neck PET/CT requires expertise in head and neck anatomy and an understanding of variations of physiologic [18F]FDG uptake in normal tissues. Scan interpretation is primarily based on visual assessment, although SUV measurements may be helpful. However, SUV is related to lesion size and may be underestimated in small primary tumors. Most primary tumors originate in the palatine tonsil, base of tongue, pyriform sinus, nasopharynx, and larynx. HNSCC tends to spread locally with invasion of adjacent structures. T staging is routinely done by either CT or MRI, not PET. However, occasionally [18F]FDG PET may visualize small submucosal primary tumors that are difficult to distinguish from adjacent normal tissues with anatomic imaging studies. The presence of nodal metastases is an independent prognostic factor for survival in patients with head and neck cancer and may affect the choice of surgical or radiation therapy. Early and complete removal of neck node metastases is a prerequisite for cure. PET provides added value in the initial nodal staging. However, false-positive [18F]FDG uptake can occur in inflamed, reactive lymph nodes. False-negative [18F]FDG PET studies may occur when nodes have a small tumor burden, cystic degeneration of metastatic nodes with a small rim of viable tumor tissue, or low tracer uptake in the metastatic node. Nodal metastases in close proximity to the primary tumor may not be detectable as separate hypermetabolic focus when the primary shows very intense tracer uptake. Distant metastases are rare in patients with head and neck cancers, but the frequency increases with higher T stage and size, number of tumor-involved lymph nodes, jugular vein invasion, and in primary tumors in the hypo- and oropharynx. The most common location is the lung, followed by bone and liver. [18F]FDG PET/CT is sensitive for the detection of distant metastases. In patients treated with definitive chemoradiotherapy, [18F]FDG PET/CT should be done approximately 12 weeks after the end of therapy to assess response to treatment.

[18F]FDG PET/CT imaging is particularly useful to detect residual disease in neck lymph nodes. Clinical parameters and structural imaging cannot reliably predict the presence of residual metastatic neck disease; “planned neck dissection” was usually performed in the past after the completion of chemoradiotherapy, especially in patients with initial N2–N3 disease. Recently, in light of the high negative predictive value of posttreatment [18F]FDG PET, this approach seems no longer justified. In patients with suspected recurrence, [18F]FDG PET/CT has the highest sensitivity and specificity regardless of the primary treatment modality. However, posttherapy inflammation remains a potential source for false positive interpretation. Carcinoma of unknown primary accounts for approximately 1–2% of head and neck cancers. Occurrence of nodal metastases in neck levels I–III increases the likelihood for a primary HNSCC. However, in 5–40% of cases a primary malignancy is not identified during diagnostic evaluation, and these patients undergo extensive work-up, including panendoscopy of the upper aerodigestive tract and [18F]FDG PET/CT. The use of [18F]FDG PET/CT may reduce the number of panendoscopies. Other imaging studies are usually not needed, because it is extremely unlikely that they may identify a primary tumor that cannot be detected by [18F]FDG imaging.

In view of its unique epidemiology, tumor biology, and prognosis, nasopharyngeal carcinoma (NPC) should be considered separately. The highest incidence is noted in southern Chinese (20 times more common than in Caucasians). NPC tends to spread submucosally, in parapharyngeal tissues, along the maxillary and the mandibular nerves. Neck lymph node metastases are seen in the vast majority of patients. The lateral retropharyngeal nodes are traditionally considered first echelon nodes. The rate of distant metastases is high, involving bone, lung, and liver. Local disease extent is best defined by MRI, in particular disease involvement of the skull base and intracranial spread. Neck lymph node involvement is probably best characterized by a combination of MRI and [18F]FDG PET/CT. [18F]FDG PET/CT is useful for detection of disease outside the neck. The combination of MRI and [18F]FDG PET/CT also appears most appropriate for chemoradiotherapy response and recurrent disease assessment. Similar to other head and neck cancers, the intensity of [18F]FDG uptake in NPC primary tumors provides prognostic information. The utility of PET for delineating the gross tumor volume (GTV) in radiotherapy has been investigated. Most studies agree that the incorporation of PET in the radiotherapy planning process clearly improves target design over CT-based planning.

Keywords

Head and neck cancer in PET imaging PET imaging in head and neck cancer Squamous cell carcinomas of head and neck Radiotracers in head and neck cancer 

Glossary

Glossary of terms for chapter 10-1 (Diagnostic Applications of Nuclear Medicine: Head and Neck Cancer)

[18F]FDG

2-Deoxy-2-[18F]fluoro-d-glucose

18F-FAZA

18F-azomycin arabinoside

18F-FET

O-(2-18F-fluoroethyl)-L-tyrosine

18F-FLT

3′-Deoxy-3′-18F-fluorothymidine

18F-FMISO

18F-fluoromisonidazole, 1-fluoro-3-(2-nitroimidazol-1-yl)-propan-2-ol

5-FU

5-Fluorouracil

AJCC

American Joint Committee on Cancer

AKT

Protein kinase B

BOLD

Blood oxygen level-dependent contrast imaging, a magnetic resonance technique

CRT

Chemoradiotherapy

CT

X-ray computed tomogaphy

DCE

Dynamic contrast-enhancement, a magnetic resonance technique

DFS

Disease-free survival

DWI

Diffusion-weighted imaging, a magnetic resonance technique

E2F

Group of genes that encode for a family of transcription factors

EGFR

Epidermal growth factor receptor

GTV

Gross tumor volume

Gy

Gray unit (ionizing radiation dose in the International System of Units, corresponding to the absorption of one joule of radiation energy per kilogram of matter)

HNSCC

Squamous cells carcinomas of the head and neck

HPV

Human papilloma virus

m-TOR

Mammalian target of rapamycin

M

Metastasis status according to the AJCC/UICC TNM staging system

MEK

Mitogen-activated protein kinase

MR

Magnetic resonance

MRI

Magnetic resonance imaging

MTV

Metabolic tumor volume

N

Lymph node status according to the AJCC/UICC TNM staging system

NPC

Nasopharyngeal carcinoma

OPC

Oropharynx cancer

OS

Overall survival

p53

Tumor protein p53, also known as cellular tumor antigen p53, phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53 (TRP53)

PET

Positron emission tomography

PET/CT

Positron emission tomography/Computed tomography

PET/MRI

Positron emission tomography/Magnetic resonance imaging

PFS

Progression-free survival

PI3K

Phosphatidylinositol 3-kinase

PTEN

Gene encoding for the phosphatase and tensin homolog protein, a tumor suppressor; PTEN deletions indicate a poor prognosis

RAF

Rapidly accelerated fibrosarcoma, related to retroviral oncogenes

RAS

Oncogene regulating signaling cascades

RB

Retinoblastoma protein

ROC

Receiver operating characteristic, a statistical analysis to assess the performance of a binary classifier

RT

Radiotherapy

RTOG

Radiation Therapy Oncology Group

SUV

Standardized uptake value

T

Tumor status according to the AJCC/UICC TNM staging system

TLG

Total lesion glycolysis

UICC

Union Internationale Contre le Cancer (International Union Against Cancer)

USFNA

Ultrasound-guided fine needle aspiration

VGEF

Vascular endothelial growth factor

Epidemiology and Biology of HNSCC

In the Western world, more than 90% of head and neck cancers are squamous cell carcinomas (HNSCC). These tumors arise in the oral cavity, oropharynx, larynx, and hypopharynx (Figs. 1, 2, 3, and 4). In the United States, approximately 48,330 new cases were diagnosed in 2016 [1], and about 9,600 patients died of the disease. Only 40–50% of patients are expected to survive for 5 years. The worst prognosis is seen in patients with un-resectable advanced disease, with a 5-year survival rate of less than 10%, whereas patients presenting with tumors that are confined at the time of diagnosis (T1/2N0M0) have an excellent cure rate. Unfortunately, at the time of initial diagnosis many patients already have regional nodal metastases (~45%) or even distant metastases (Figs. 1, 2, 3, and 4). Also noteworthy is the high rate of second primary malignancies, mostly in the upper aerodigestive tract.
Fig. 1

(a) Five-year observed survival by combined AJCC stage squamous cell carcinoma of the lip, 1998–1999. (b) Five-year observed survival by “combined” AJCC stage squamous cell carcinoma of the oral cavity, 1998–1999. (From Edge S, et al. editors. AJCC cancer staging manual. 7th ed. New York: Springer; 2010, with permission of Springer Science + Business Media)

Fig. 2

Five-year observed survival by combined AJCC stage squamous cell carcinoma of the larynx, 1998–1999. (From Edge S, et al. editors. AJCC cancer staging manual. 7th ed. New York: Springer; 2010, with permission of Springer Science + Business Media)

Fig. 3

Five-year observed survival by combined AJCC stage squamous cell carcinoma of the nasopharynx, 1998–1999. (From Edge S, et al. editors. AJCC cancer staging manual. 7th ed. New York: Springer; 2010, with permission of Springer Science + Business Media)

Fig. 4

Five-year observed survival by combined AJCC stage sinonasal carcinomas (all histologies), 1998–1999. (From Edge S, et al. editors. AJCC cancer staging manual. 7th ed. New York: Springer; 2010, with permission of Springer Science + Business Media)

Traditionally, the most important risk factors for HNSCC were tobacco use and alcohol consumption, which seem to have a synergistic effect. In the past decade, a new disease entity has become more common: HNSCC of the oropharynx secondary to infection with human papilloma virus (HPV) [2]. HPV is a known cause of cervical cancer in females. Transmission to the oral cavity occurs through oral sex. In the United States, approximately 60% of patients with oropharynx cancers test positive for HPV-16. The overall incidence of HNSCC is still rising in the industrialized world because the substantial increase in HPV-positive cases (in particular males with carcinoma of the palatine tonsil and base of the tongue) exceeds the decline in HPV-negative cases. Most HPV-positive cases express the viral oncoproteins E6 and E7. E6 oncogene expression induces degradation of p53, and E7 induces inactivation of the retinoblastoma protein (RB). Under normal conditions, p53 induces cell cycle arrest in the G2 phase to allow for repair of damaged DNA; it also is a master regulator for apoptosis [3]. RB normally binds to, and inactivates, the E2F transcription factors, which control the transition from the G1 to the S phase of the cell cycle. Only under the influence of mitogen signals is this “brake” of RB on E2F released, thus permitting cell cycle progression. Binding of the viral oncoprotein E7 to RB therefore causes dis-inhibition and un-controlled cell cycle progression [3, 4]. Table 1 summarizes the epidemiologic and biologic features of HPV-positive and HPV-negative HNSCC [3, 5].
Table 1

Epidemiology of HNSCC circa 2011

Incidence

HPV-positive HNSCC

HPV-negative HNSCC

Increasing

Decreasing

Anatomical site

Oropharynx (tonsil, tongue)

All sites

Histology

Non-keratinized

Keratinized

Age

Younger; < 60 years

Older; > 60 years

Sex ratio

3:1 men

3:1 men

T stage

Tx, T1, T2

Any

N stage

Advanced, often cystic-necrotic, multilevel

Any

Risk factors

Sexual behavior

Alcohol, tobacco

Etiology

HPV virus

 

Prognosis

Favorable

Unfavorable

New approaches

De-escalation of standard therapy?, vaccination?; oral Pap smear?

Early identification of nonresponders to standard therapy > clinical trials

Adopted from Leemans, Nat Rev. Cancer 2011 [3] and Marur et al., Lancet Oncol 2010 [5]

HPV human papilloma virus, HNSCC head and neck squamous cell carcinoma

Patients with HPV-positive HNSCC have a better prognosis than patients with HPV-negative disease [6, 7]. This was initially shown in a phase II trial that employed induction chemotherapy followed by concurrent chemoradiotherapy in patients with stage III or IV HNSCC of the oropharynx or larynx. Response rates to induction chemotherapy were 82% vs. 55%, 2-year overall survival (OS) was 95% vs. 62%, and the 2-year progression-free survival (PFS) was 86% vs. 53% [7]. Similarly, in a large retrospective analysis [6] the 3-year OS was 82% for the 206 patients with HPV-positive tumors compared with 57% for the 117 patients with HPV-negative tumors. Corresponding rates for PFS were 74% and 38%, respectively. Even after adjusting for age, race, T and N stage, tobacco exposure, and treatment modality (standard fractionation vs. accelerated fractionation radiotherapy), patients with HPV-positive tumors still showed a 58% reduction in the risk of cancer death. Using a risk classification that considered HPV status, T and N stage, and smoking status, patients could be characterized as low, intermediate, or high risk. Whereas the 3-year survival was 93% in the low-risk group (HPV+ tumor and <10 pack years smoking history), it was only 46% in the high-risk group (HPV-negative, ≤ 10 pack years and T4 or >10 pack years and any TN). Collectively these data, and those reported from other groups, suggest increased sensitivity to chemo- and radiotherapy in HPV-positive tumors. The prognostic value of HPV status was again confirmed in the more recent RTOG 0522 trial [8], in which patients with p16-positive oropharynx cancer (OPC) showed better 3-year PFS and OS than those with p16-negative oropharynx cancer (73% vs. 49%, and 86% vs. 60%, respectively). By contrast, epidermal growth factor receptor (EGFR) expression of thee primary tumor did not predict patient outcome. The mounting evidence on the prognostic value of the p-16 status in oropharynx cancer has led to efforts to perform better risk stratification of patients with HPV-positive tumors. Accordingly, a new staging system has been proposed for patients with HPV-positive disease, in which even patients with the most locally advanced disease (i.e., T4 N3) will be assigned to clinical stage III, and only those with documented distant disease to stage IV, reflecting differences in OS between these groups [9]. In addition, there is growing interest in (a) developing new treatment paradigms for HNSCC that may decrease the amount and duration of standard chemoradiotherapy in low-risk patients (to maintain high cure rates but reduce potential treatment associated long-term side effects, such as dysphagia, xerostomia, feeding tube dependency, or chronic aspiration) and (b) finding more successful therapies for high-risk patients, including early participation in clinical trials [10, 11]. Patients with persistent HPV expression after completion of therapy may require closer surveillance [12]. The potential role of an HPV vaccine for men and the role of an “oral Pap smear” for early detection of oropharynx cancer are under study.

An important consideration in head and neck cancer is the concept of field cancerization. The occurrence of multiple synchronous or metachronous primary tumors in the upper aerodigestive tract was first described by Theodor Billroth more than 100 years ago. Over the past few decades knowledge has expanded, and a recent study showed that at least 35% of cases of oral and oropharynx cancers demonstrate genetic abnormalities in the surrounding (histopathologically normal) mucosa [13]. This is often addressed by the clinical term “biologically positive margins,” suggesting that local recurrence is likely even though standard histopathology shows no cancer cells at or near the surgical margins of the tumor specimen [14].

As for many other malignancies, genetic alterations and activation or inhibition of cellular signaling pathways are important for the development and progression of many HNSCC. Some signaling factors are of particular interest because they are potential targets for drug therapy, including the EGFR, vascular endothelial growth factor (VEGF), and molecules involved in regulating the PI3K–PTEN/AKT pathway as well as the RAS-RAF-MEK pathway.

Treatment Strategies

The treatment approach varies with the disease stage and site(s) of disease in the head and neck [15]. Approximately one third of patients with HNSCC present with early-stage disease. Depending on tumor location and institutional preferences, they are treated surgically or with radiotherapy, and approximately 80% are cured. Patients with locoregional advanced disease, which is surgically unresectable, and patients in whom definitive treatment is administered with an attempt at organ preservation (e.g., oropharyngeal and laryngeal carcinomas), undergo treatment with concurrent chemoradiotherapy [16, 17]. Cisplatinum is the medication with the most randomized clinical trial data to support its use as a drug enhancing the effects of radiotherapy in this setting. The larynx-preservation paradigm is supported by the results of a study that randomized 547 patients with stage III–IV supraglottic and glottic larynx cancer into three treatment arms: concurrent chemoradiotherapy, induction chemotherapy consisting of cisplatinum and 5-fluorouracil (5-FU) followed by radiotherapy, or radiotherapy alone. After a median follow-up of 3.5 years, the rates of locoregional control were 78%, 61%, and 56% for the three treatment arms, respectively. The fraction of patients who maintained an intact larynx at 2 years (and thus the ability to speak and swallow after the end of therapy) was also better with the concurrent regimen (88%, 75%, and 70% for the three treatment arms, respectively) [17]. OS rates were similar in all three groups. The utility of concurrent high-dose cisplatinum for other subsites was established in a randomized study of 295 patients with unresectable head and neck cancer [18]. Concurrent chemoradiotherapy is therefore now widely applied as the definitive treatment of choice for locoregional advanced HNSCC. If residual disease is detected after the end of therapy or during follow-up, salvage surgery (e.g., laryngectomy) may be offered.

The management of the neck when using an organ-preservation approach has remained somewhat controversial. Complete response rates in irradiated cervical lymph nodes vary between 59% and 83% and to some degree are related to nodal size, radiotherapy dose, as well as the time point when response is determined: Complete response rates are almost 100% in N1 disease, higher in N2 than in N3 disease, and better when the largest metastatic node is smaller than 3 cm [19]. In N2–N3 disease, residual cancer in neck nodes has been reported in 16–39% of patients achieving a clinical complete response (no overt residual neck mass) [19, 20, 21]. Over the past decade, locoregional control rates with concurrent chemoradiotherapy have improved. It is now widely accepted that routine neck dissection is not appropriate in this setting. Instead, fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) has emerged as a gatekeeper for the management of the neck in this setting [15] (see next section).

Newer biologic therapies in HNSCC include angiogenesis inhibitors and drugs targeting the EGFR. EGFR is over-expressed and/or activated in the majority of HNSCC relative to normal tissue, and high expression is associated with poor disease control [22, 23]. While these data suggest HNSCC as an ideal malignancy for treatment with EGFR inhibitors, the selection of appropriate patients remains challenging. In studies of anti-EGFR agents in patients with advanced HNSCC, the objective response rates were approximately 10%, depending on the specific agent [24]. Cetuximab , a chimeric IgG1 antibody against the extracellular domain of EGFR, is the most widely studied agent and has been tested in a number of clinical trials in patients with advanced disease. Cetuximab also enhances the efficacy of radiotherapy. In a randomized study of 420 patients [25], the addition of cetuximab to radiotherapy improved locoregional tumor control and OS without increasing mucositis and dysphagia when compared with radiotherapy alone. The corresponding median PFS was 24 months vs. 15 months, and the median OS was 49 months vs. 29 months. This study showed that concurrent radiotherapy plus cetuximab is a viable treatment option in locoregional advanced HNSCC. Whether this alternate regimen improves outcome vis-à-vis the standard approach with cisplatinum-based chemotherapy and concurrent radiotherapy is under investigation. Other trials investigated the role of adjuvant cetuximab in patients with recurrent or metastatic HNSCC undergoing platinum-based chemotherapy. Preliminary data showed a survival benefit over chemotherapy alone (reviewed in [26]).However, more recently published multicenter studies did not confirm this: In the RTOG trial 0522 [8], which included 981 patients, the addition of cetuximab to concurrent chemoradiotherapy with cisplatin did not improve patient outcome, with 3-year PFS rates of 61% and 59%, and 3-year OS of 73% and 76%, respectively, for those treated without vs. with the addition of cetuximab. The locoregional failure rate and rate of distant metastases were also similar between groups. Recent data have also raised concerns regarding cetuximab-associated side effects leading to lower patient compliance in chemoradiotherapy regimens [27].

Antiangiogenic therapy has mainly been studied using bevacizumab, a recombinant humanized, monoclonal IgG antibody against VEGF-A, usually in combination with chemotherapy or in combination with cetuximab. Preliminary data suggest that partial responses or disease stabilization can be achieved in more than 75% of patients [28]. Other drugs under study include various tyrosine kinase inhibitors. Recent improved understanding of relevant signaling pathways may open up new avenues for targeted drug therapies in HNSCC. For instance, down-regulation of the transforming growth factor beta receptor is frequently found, and the PI3K/PTEN/AKT/m-TOR pathway (important for increased proliferation, evasion of apoptosis, and increased survival) is frequently up-regulated. A number of drugs interfering with these tumor pathways are under study [26].

Imaging of Head and Neck Cancer

Standard imaging studies for the staging and follow-up of head and neck cancer include contrast-enhanced CT, magnetic resonance imaging (MRI), and [18F]FDG PET/CT. CT or MRI is essential for characterizing the primary tumor and in defining its extent. Bone involvement is better detected with CT, while early bone marrow disease is better detected with MRI. MRI can better define the interface between normal muscle and tumor. It is essential in staging nasopharyngeal carcinoma, and also has particular advantages for detecting intracranial tumor spread and perineural spread and for differentiating entrapped secretions in paranasal sinuses from adjacent tumor.

Lymph node staging is done equally well with either CT or MRI. Traditionally, both imaging tests have relied on the assessment of lymph node size in order to identify metastatic disease. In general, lymph nodes ≥1.5 cm in levels I and highest level II, as well as lymph nodes ≥1.0 cm in all other locations, are considered abnormal. This approach is suboptimal because metastasis can be present in normal-sized lymph nodes and enlarged nodes may not contain tumor. Depending on the chosen cut-off for lymph node size, one can achieve high sensitivity at the expense of specificity or vice versa [29]. Secondary criteria are the presence of grouped lymph nodes (usually >3 nodes in one location), heterogeneous nodal enhancement, stranding of surrounding fat indicating extracapsular spread, and demonstration of central necrosis (the most reliable criterion for nodal metastasis). Special MRI sequences, such as diffusion-weighted imaging (DWI), or newer MR contrast agents (including ultrasmall superparamagnetic iron oxide particles, or more recently various nanoparticles), may improve the characterization of nodes. However, they are not yet routinely employed and all available data are preliminary.

The vast majority of head and neck cancers show intense [18F]FDG uptake; however, uptake in salivary gland tumors may be variable (high [18F]FDG uptake in some benign tumors, low uptake in some malignant tumors). Combined PET/CT is more accurate than PET alone and has beneficial effects on patient management [30, 31]. We perform [18F]FDG PET/CT imaging from the skull base to the floor of the pelvis for appropriate N and M staging in patients with head and neck cancer. Both distant metastases and potential synchronous primaries in the aerodigestive tract are hypermetabolic and therefore easily detectable. In order to save costs and potentially radiation dose, some investigators have proposed a limited field of view scan (e.g., ending at the level of the diaphragm) for patients with head and neck cancer. We, however, believe that a different approach should be taken: Rather than using [18F]FDG PET in all patients, the test should be used in subsets of patients where imaging findings are most likely to alter management. For instance, it is essential in surgical patients with locally advanced disease. In addition, we use [18F]FDG PET/CT in all patients who are candidates for definitive chemoradiotherapy for the purpose of staging and radiotherapy planning; these scans are performed in the radiotherapy position with a mask. PET/CT is also used for response assessment in patients with advanced disease undergoing chemotherapy, concurrent chemoradiotherapy, or enrolled in experimental protocols.

Interpretation of head and neck PET/CT requires special expertise in head and neck anatomy as well as an understanding of physiologic [18F]FDG uptake in normal tissues and awareness of the many potential normal variants. Scan interpretation is primarily based on visual assessment, although standardized uptake value (SUV) numbers may be helpful in estimating biologic aggressiveness and for response assessment. SUV is related to lesion size and may be underestimated in small primary tumors. Physiologic [18F]FDG uptake is nearly always noted in lymphoid tissues (tonsils) composing “Waldeyer’s ring ,” including the pharyngeal tonsil (upper nasopharynx), symmetrical uptake in the palatine tonsils (unless the patient status is posttonsillectomy or suffers from unilateral tonsillitis or tonsillar carcinoma), and the lingual tonsil at the base of the tongue. Variable uptake is noted in the tongue and floor of the mouth muscles, and is usually more intense if the patient was moving the tongue or swallowing during the uptake phase. Asymmetrical uptake in a normal tongue can be noted after hemiglossectomy or even resection of smaller unilateral tongue lesions, leading to increased muscle activity and [18F]FDG uptake in the contralateral tongue. This is also noted after unilateral denervation, e.g., after hemimandibulectomy or due to hypoglossal nerve paralysis, where fatty atrophy and lack of [18F]FDG uptake in the denervated hemitongue is associated with relatively intense uptake in the contralateral normal tongue. Asymmetrical uptake, due to spasm, can sometimes be observed in the pterygoid or temporalis muscles. Uptake along the scalene muscles is frequently seen, either symmetrical or asymmetrical, and is easily characterized as a normal variant on fusion images. Retained mucous in paranasal sinuses shows no [18F]FDG uptake unless there is severe inflammation, infection, or tumor. Similar to MRI (but not CT), [18F]FDG PET/CT differentiates well between tumor and entrapped secretions due to sinus outflow obstruction. While mucous retention or small polyps are fairly common in the paranasal sinuses, fluid retention in mastoid air cells should prompt careful assessment of the oropharynx to identify possible reasons for obstruction of the Eustachian tube.

Normally, symmetrical [18F]FDG uptake is seen in the vocal cords and other laryngeal muscles (mild uptake is usually noted even if the patient does not vocalize during the uptake phase). Asymmetrical vocal cord uptake suggests vocal cord paralysis , usually due to damage of the ipsilateral recurrent laryngeal nerve. Secondary CT signs are sometimes helpful in confirming suspected vocal cord paralysis, including a paramedian position of the paralyzed vocal cord, tilting of the thyroid cartilage, displacement of the ipsilateral arytenoid cartilage, dilatation of the ipsilateral piriform sinus, and prominent laryngeal ventricle. Longstanding vocal cord paralysis may lead to atrophy of the posterior cricoarytenoid and thyroarytenoid muscles [32, 33]. In searching for possible reasons for vocal cord paralysis, attention should focus on the upper mediastinum as well as the lower neck to identify possible tumors or metastasis. Other reasons for vocal cord paralysis include nerve damage due to fibrosis (e.g., after radiotherapy) and chemotherapy (vinca alkaloids can cause transient vocal cord paralysis [34]). Asymmetrical or unusual focal [18F]FDG uptake can be observed in patients who received instillation of foreign material (e.g., Radiesse) for attempted medialization of a paralyzed cord. In this case the [18F]FDG uptake occurs on the treated site, likely due to foreign body reaction and inflammation. The instilled dense material is easily identified on the CT images. Large salivary glands usually show symmetrical [18F]FDG uptake (submandibular gland > parotid gland). A common cause for unilateral focal [18F]FDG uptake in parotid glands are pleomorphic adenomas (the most common benign tumor in the parotid gland), or “Warthin’s tumors” (which are entrapped normal lymphoid tissue). The submandibular gland is usually removed as part of neck dissections. Asymmetrical uptake in the contralateral remaining normal gland should not be confused with lymph node metastases. Postsurgical muscle flaps can show (physiologic) very intense [18F]FDG uptake, in particular at the flap pedicle, presumably related to hyperemia. This should not be confused with tumor recurrence. Some of the aforementioned normal findings and normal variations are described in detail in several review articles [35, 36].

Neck Metastases from an Unknown Primary Tumor

This condition, also known as carcinoma of unknown primary, accounts for 3–15% of all cancer diagnoses and for approximately 1–2% of head and neck cancers. For practical purposes this entity should be defined as the combination of no history of previous malignancy, no clinical or laboratory evidence of primary neoplasm, and a neck mass that is histologically or cytologically proven to be carcinoma. Occurrence of nodal metastases in neck levels I–III increases the likelihood of a primary HNSCC. However, in 5–40% of cases a primary malignancy is not identified during diagnostic evaluation and long-term follow-up. Provided a primary tumor cannot be identified, in many institutions these patients are treated with extensive radiotherapy fields that cover the entire pharyngeal mucosa, the larynx, and bilateral necks. This is obviously associated with considerable morbidity. Identification of a primary tumor will direct rational therapy to a single mucosal site and the ipsilateral neck (unless the primary tumor is in, or close to, the midline). Detection of the primary tumor, in general, also allows for less extensive treatment (e.g., smaller radiation fields) and may potentially improve locoregional control. Therefore, these patients undergo extensive work-up. In some cases, the “unknown primary” is already identified in a thorough clinical examination by an experienced head and neck surgeon or oncologist; all other patients should undergo panendoscopy of the upper aerodigestive tract and [18F]FDG PET/CT.

The literature is replete with studies of patients with unknown primary. Unfortunately, most study populations are very heterogeneous, and the definition of unknown primary and methods of verification vary considerably. For this chapter, we have only considered studies in which patients had at least undergone clinical examination, CT or MRI, and office endoscopy prior to PET (Table 2). The percentage of primary tumors detected is quoted as 14–37% [37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48]. When reviewing the literature, it should be noted that the sensitivity of PET is oftentimes stated incorrectly: Since all neck metastases must have an underlying primary tumor, the denominator for calculating sensitivity should be the total number of patients studied (not the much smaller number of patients in whom the primary is eventually detected by imaging and panendoscopy). Therefore, it appears overall less controversial and more meaningful to simply state the rate of primary tumors that were only detected by PET (see Table 2). Depending on the interpretation criteria, some studies report a high number of false-positive findings. It is therefore necessary to strike a reasonable balance between the wish to identify the location of the unknown primary on PET and the danger of calling every little variant suspicious. Potential reasons for false-negative PET studies include a small primary tumor (although lesions as small as 4 mm can be detected as long as there is intense [18F]FDG uptake), low metabolic activity (cystic/necrotic tumor or lymph nodes), or the primary tumor was accidentally removed at the time of neck dissection.
Table 2

[18F]FDG PET and PET/CT for the detection of unknown primary tumors in patients with neck lymph node metastases

 

N

Prior pan-endoscopy

PET or PET/CT

Total detection rate with all tests

Total PET uptake

PET detection rate for primary

PET false-positive rate %

Distant mets. with PET

Comments

Kole, Cancer 1998 [43]

14

None (was done after PET)

PET

7/14 (50%)

4/14

4/14 (25%)

N/R

N/R

Management change in 21% of pts.

Jungehülsing, ORL 2000 [42]

27

all

PET

7/27 (26%) (5 in HN)

N/R

7/27 (26%)

N/R

N/R

Management change in 29% of pts.

Johansen, Laryngoscope 2002 [41]

42

all

PET

10/42 (24%) (7 in HN)

20/42

10/42 (24%)

10/42 (24%)

N/R

 

Fogarty, 2003 [38]

21

N/R

PET

3/21 (14%) (1 path confirmed, 2 probable)

8/21

3/21 (14%)

5/8 (62%)

3/21 (14%)

PET detected more regional neck dz. in 2/21

Wong, Clin Oncol 2003 [47]

17

all

PET

N/R

8/17

5/29 (17%)

3/8 (37%)

 

Treatment plan changed in 53% of pts.

Bohuslavizki, JNM 2000 [37]

44

all

PET

22/42 (53%)

22/44 (13 in HN)

15/44 (34%) (8 HN = 18%)

5/13 (38%)

N/R

Mixed pt. population

Miller, Head Neck 2008 [44]

31

None (CT/MR, office endoscopy; panendoscopy after PET)

PET

14/31 (45%)

10/31

9/31 (29%)

1 (3%)

N/R

4 addtl. found by panendoscopy, size 0.8–5 mm

Gutzeit, Radiology 2005 (data shown for pts. with neck metastases only) [39]

18

N/R

PET/CT

6/18 (33%)

7/18

3/18 (33%)

3/16 (19%)

N/R

PET/CT slightly better than CT or PET alone

Wartski, NM Comm 2007 [46]

38

All

PET/CT

14/38 (38%)

26/38

13/38 (34%)

4/17 pts. w/further w/u (23%); addtl. 9 pts. had no further w/u

N/R

Management change in 60% of pts.

Johansen, 2008 [40]

60

41

PET or PET/CT

21/60 (35%)

30/60 (22 in HN)

18/60 (30%) total; (missed 3 HN primaries later found by panendoscopy)

12/30 (40%) total; 10/22 (45%) in HN; 1/8 pre-endoscopy; 11/22 post endoscopy

12/22 (54%) with HN primary

Management change in 25% of pts.

Roh, Oral Oncol 2009 [45]

44

None (was done after PET)

PET/CT

16/44 (36%)

19/44

14/44 (32%)

5/14 (35%)

6/44 (14%)

Subtracting tumors seen on contrast CT, PET detected 7/37 primaries (18%)

Yabuki, Eur Arch Oto 2010 48

24

all

PET

9/24 (37%)

12/24

9/24 (37%)

3/12 (25%)

N/R

 

PET/CT positron emission tomography/computed tomography, mets. metastases, path pathologically, pts. patients, dz. disease, addtl. Additional, w/u work-up, HN head and neck, N/R

In our institution, patients with unknown primary and negative results from clinical examination and office endoscopy first undergo [18F]FDG PET/CT (Fig. 5), before panendoscopy; panendoscopy is defined as naso-pharyngoscopy, direct laryngoscopy, and upper esophagoscopy (in the absence of specific symptoms or imaging findings, a bronchoscopy is no longer done routinely because the yield is exceedingly low). This approach may reduce the number of necessary panendoscopies and avoid false-positive [18F]FDG uptake after manipulation during endoscopy and biopsy (Fig. 1). Of note, other imaging studies are usually not needed, because it is extremely unlikely that they may identify a primary tumor that cannot be detected by PET. Statistically, most primary tumors originate in the ipsilateral palatine tonsil, base of the tongue, piriform sinus, nasopharynx (more commonly in East Asian populations), and larynx. Particular attention should therefore be focused during PET/CT interpretation to these sites. If the PET study is positive, biopsies should be obtained from the suggested location. If the PET study is negative, panendoscopy with biopsy sampling from suspected locations (based on the location of the lymph node and statistical considerations) should be performed. Depending on the results of these biopsies, the patient may proceed to surgery or radiation therapy.
Fig. 5

Carcinoma of unknown primary in a 46-year-old man who presented with a right neck mass from an unknown primary squamous cell carcinoma. Clinical exam and office endoscopy were negative. [18F]FDG PET was performed for localization of primary tumor. Non-contrast CT shows enlarged right neck node (a); PET/CT fusion image shows abnormal [18F]FDG uptake in right level two node and at the right base of tongue primary (b)

Primary Tumor Staging

Most HNSCC are diagnosed clinically. The primary goal of imaging studies is therefore not tumor detection, but rather to define the extent of the primary tumor, in particular with regard to structures whose involvement may alter the surgical approach (e.g., depth of soft tissue infiltration, bone invasion, orbital invasion, skull base invasion, tumor “tracking” along nerves and blood vessels).

Head and neck cancers tend to spread locally with invasion of adjacent structures. For instance, many cancers of the oral tongue tend to extend into the floor of the mouth. Staging of HNSCC is routinely done using either CT or MRI, not PET. However, occasionally [18F]FDG PET may depict small submucosal primary tumors that are difficult to distinguish from adjacent normal tissues with anatomic imaging studies. In a study of 48 patients with HNSCC (mostly tumors of the oral cavity), [18F]FDG PET detected 35 of 40 primaries known or still present at that time (88%), whereas contrast-enhanced CT of the neck identified a primary tumor only in 18 of the 35 patients (51%) with known or present primary tumors. Of the 17 primaries not detected by CT, 11 were clearly visualized with [18F]FDG PET [49]. PET/CT readers should pay attention to secondary tumor signs. For instance, cancers at the anterior floor of the mouth can cause obstruction of Wharton’s duct, through which the submandibular gland empties into the oral cavity. Ductal dilatation and enlargement of the gland, sometimes associated with increased [18F]FDG uptake, may be noted. Perineural spread can occur in various locations in the head and neck, but is particularly common with adenoid cystic carcinoma (submucosal cancers that are common in the hard palate). Therefore, PET/CT readers should also be familiar with the normal branching patterns of cranial nerves relevant for innervation of the head and neck, in particular the facial nerve and trigeminal branches V2 and V3.

Lymph Node Staging

The risk of lymph node metastases is related to the anatomic location of the primary tumor. Tumors originating in sites that are rich in lymphatics, such as the tongue and floor of mouth, metastasize earlier and more often than those in other locations, including the hard palate or upper gum. The presence of nodal metastases is an independent prognostic factor for survival in patients with head and neck cancer; it decreases OS by approximately one half [50]. These historical data were corroborated by a larger retrospective study of 3,800 patients, in which the presence of neck node metastases lowered the 5-year disease-specific survival rate by approximately 30% [51]. The prognosis worsens additionally with the number of lymph nodes involved [52], with extracapsular spread of nodal disease [53], and with metastases located in the lower neck [54, 55]. The presence and extent of nodal metastases may affect the surgical or radiotherapy approach. Early and complete removal of neck node metastases is a prerequisite for cure. Accurate nodal staging of the neck is therefore particularly important.

The clinical neck examination and anatomic imaging studies suffer from a lack of sensitivity and specificity in assessing the extent of nodal disease [29, 56]. Numerous studies have compared the accuracy of anatomic imaging modalities and [18F]FDG PET for the detection of nodal metastases in the neck [49, 57, 58, 59, 60, 61, 62] (Fig. 6). In most studies, PET had a higher sensitivity and/or specificity than CT, MRI, or ultrasound. In 124 patients with oral cavity cancer, the authors compared [18F]FDG PET and neck CT or MRI with surgical histopathology of each dissected neck level; metastatic nodes were found in 95 of 493 dissected neck levels. Overall, and for each neck level, [18F]FDG PET showed a higher accuracy then CT or MRI. The overall sensitivity, specificity, and accuracy for PET vs. CT/MR were 75% vs. 53%, 93% vs. 94%, and 89% vs. 86%, respectively [62]. However, these numbers may be somewhat optimistic, because the same authors later published data from 471 patients with oral cavity cancer, and found a suboptimal sensitivity and specificity of 73% and 58% on a per-patient basis [63]. In a meta-analysis of 35 studies comparing the diagnostic performance of [18F]FDG PET or PET/CT with that of neck CT, MRI, or ultrasound-guided fine needle aspiration (USFNA), [18F]FDG PET had a combined sensitivity and specificity in the range of 73–82% and 86–89%, compared with 74%/76% for CT, and 78%/80% for MRI. For unclear reasons, four studies comparing PET and USFNA showed a surprisingly low sensitivity of ~45% for both modalities (probably due to methodological issues or selection bias); as expected USFNA had a near perfect 96% specificity because it is based on cytology of aspirates [64].
Fig. 6

Staging studies in a 57-year-old man with base of tongue cancer. Contrast-enhanced CT of the neck shows a large enhancing mass at the left base of tongue (a), which is intensely hypermetabolic on PET/CT fusion image (b). Intense [18F]FDG uptake in lymph node metastases in the left neck level I (c, d) and level III (e, f). In addition, the staging scan showed enlarged hypermetabolic nodes in the mediastinum (g, h). Because of a potential change in management, these mediastinal nodes were biopsied: histopathology showed granulomatous disease (i.e., false-positive [18F]FDG uptake)

It is important to understand that the sensitivity and specificity of [18F]FDG PET were probably overestimated in earlier studies, when the technique had just been introduced. This is a common phenomenon applicable to any new imaging technique. In addition, CT and MRI techniques have vastly improved over the past 15 years. Readers are encouraged to review the Methods sections of published studies carefully; the most rigorous assessment would require analysis for each neck level (rather than analysis per patient or per neck), comparison with surgical histopathology of neck dissection, and at least 6–12 months of follow-up for non-dissected neck sites. Nevertheless, PET probably provides some (difficult to quantify) added value in the initial nodal staging of HNSCC.

False-positive [18F]FDG uptake can occur in inflamed, reactive lymph nodes, a common phenomenon in the “classic” (HPV-negative) patient with HNSCC, secondary to poor oral and dental hygiene. Other reasons for false-positive [18F]FDG uptake include granulomatous disease (Fig. 6) and uptake in the inflamed wall of branchial cleft cysts. The latter may be difficult to distinguish from cystic/necrotic lymph nodes, in particular since these nodal metastases often originate from small, indolent, and clinically occult primary tumors in the oropharynx [65]. Although various SUV cut-offs have been proposed, in clinical reality no single SUV number can reliably distinguish between metastatic and benign lymph nodes. Reasons for false-negative [18F]FDG PET studies may include a small tumor burden in metastatic nodes, cystic degeneration of metastatic nodes only surrounded by a small rim of viable tumor tissue, low tracer uptake in the metastatic node, and imaging artifacts. Nodal metastases in close proximity to the primary tumor may not be detectable as separate hypermetabolic focus when the primary tumor shows very intense tracer uptake.

Detection of Distant Metastases and Synchronous Second Primary Malignancies

Distant metastases are rare in patients with head and neck cancers, but the frequency increases with higher T stage and size and number of tumor-involved lymph nodes and with jugular vein invasion. The risk for distant disease also increases with nodal metastases in the lower neck or supraclavicular region, in primary tumors in the hypo- and oropharynx, and in the setting of locoregional recurrence. The most common location is the lung, followed by bone and liver (with an estimated frequency of 66%, 20%, and 10%, respectively [66]). In contrast to most squamous cell cancers, adenoid cystic and neuroendocrine carcinomas tend to metastasize early and widely, even in the absence of advanced local disease. Although the lung is the most common site of distant disease, a chest CT is insufficient for comprehensive staging if the probability for distant disease is reasonably high, because potential metastases at other sites, including bone and liver, remain undetected [67]. [18F]FDG PET/CT clearly improves the detection rates.

Patients with HNSCC have a higher propensity for synchronous (within 6 months of primary diagnosis) or metachronous (>6 month after primary diagnosis) second primaries compared with many other malignant tumors. This is likely related to synergistic effects from exposure to carcinogens in tobacco and alcohol. In a retrospective study of 1,100 patients, synchronous second primaries were noted in 7% of patients, and metachronous second primaries in another 9% of patients (at a median of 3.5 years after detection of the first head and neck cancer) [68]. However, in other analyses the reported rates for second primary malignancies in patients with HNSCC vary widely, from 7% up to 30%, probably related to selection bias [69, 70, 71, 72, 73]. Rather than recording the rate of second primaries, it may be more informative to record a standardized incidence ratio (the ratio between the number of observed to expected primary cancers in patients with prior HNSCC, using a cohort of similar age, sex, and ethnicity as standard of reference) [74]. In a recent analysis of the SEER database [74], the highest standardized incidence ratio was found for primary HNSCC in the hypopharynx, the lowest for primaries in the larynx. Patients with oral cavity or oropharynx index cancer most commonly develop a second primary at other subsites of the head and neck. Interestingly, the rate of second primaries in patients with an index tumor in the oropharynx has declined over the past decade, presumably related to the increasing number of HPV-positive tumors (which carry a better prognosis in general, and apparently also a lower risk for a second primary). Indeed, in a study of 746 patients with oropharynx primary cancer [6], the rate of second primaries at 3 years was 8.9% in total, but it was only 5.9% in patients with HPV-positive tumors compared with 14.6% in patients with HPV-negative tumors. By contrast, the 3-year rate of distant metastases overall was 10%, without significant differences in rates between patients with HPV-negative and those with HPV-positive tumors (8.7% vs. 14.6%). As discussed earlier, patients with HPV-positive tumors experience higher initial and long-term cure rates for disease in the neck, and for this reason the distribution of any recurrent disease differs in that distant metastases outside the neck are becoming relatively more common, and may present later, than in historical controls.

Based on our own experience, a second primary or distant metastases outside the neck will be detected in less than 10% of cases in the staging scan, depending on the location, size, and histology of the primary tumor, as well as presence of bulky lymphadenopathy. Similar data (8–11% prevalence) were reported by other groups [71, 72, 73]. The vast majority of second primary tumors are observed in the upper aerodigestive tract and can be identified easily and efficiently with [18F]FDG PET/CT. In a study of 350 patients, second primaries and distant metastases were detected with a sensitivity of 97% and a specificity of 93% [73]. In another study, including 589 patients, [18F]FDG PET/CT identified 56 synchronous primary tumors in 44 patients (as many as three primary tumors in some patients) and missed another nine lesions [72]. Panendoscopy is often performed as part of the initial staging in patients with locoregional advanced HNSCC. A recent study of 311 patients showed, however, that [18F]FDG PET/CT has in fact a higher sensitivity than panendoscopy, although at the expense of slightly lower specificity (100% vs. 74% and 95% vs. 99%, respectively) [71]. However, depending on reader expertise and interpretation criteria, up to 50% of suspected second primaries may be false positive in some studies. Typical sites of false-positive interpretations may include benign lymphoid hyperplasia in the nasopharynx, tonsils, and base of the tongue, as well as granulomatous nodal (Fig. 6) and lung infections. This highlights the need to temper vigilance with reason when interpreting PET scans in patients with HNSCC. Superficial, small-volume lesions in the esophagus and stomach may be missed.

In summary, PET/CT with [18F]FDG is probably the single best test for the evaluation of second primaries and distant metastases; sensitivity in the range of 90–95% has been reported [73, 75]. The specificity, and in particular positive predictive value, may vary depending on reader experience. In patients with elevated risk for distant metastases based on clinical staging parameters (e.g., ≥3 lymph node levels involved, level IV and/or bilateral neck involvement, nodal size >5 cm, CT or MR evidence of extracapsular spread, and local recurrence), whole-body PET/CT is cost-effective in the search for distant metastases [76].

Change in Patient Management

Detection of heretofore unknown lymph node metastases or distant disease may change patient management. Patients with distant disease no longer qualify for treatment with curative intent. Additional disease sites in the neck may alter the surgical or radiotherapy approach. This was convincingly demonstrated in a recent study of 71 patients with untreated HNSCC. Referring physicians formulated a management plan prior to PET, which was then adjusted based on PET findings. A change in management occurred in 33% of patients. The referring clinicians rated the impact of PET on patient management as high in 18%, medium in 15%, and low in 66% of the 71 cases. Management changes included a switch from surgery to radiotherapy, changes in the course of radiotherapy or chemotherapy, and adjustments of the radiation field. [77].

Response Assessment After (Chemo-)Radiotherapy

Structural imaging with contrast-enhanced CT or MRI and functional imaging with [18F]FDG PET/CT are now considered standard imaging tests for assessing the response to therapy in HNSCC. To determine the utility of [18F]FDG PET as an indicator of response, we shall focus on studies in which [18F]FDG PET was employed for patients treated with curative intent. Response rates at the site of primary disease are generally very high with concurrent chemoradiotherapy. Therefore, the main focus of posttherapy PET imaging is the detection of residual disease in neck lymph nodes [78, 79, 80, 81, 82, 83, 84, 85, 86] (Table 3). Of note, most studies included heterogeneous patient populations, and the treatment strategies varied. Nonsurgical definitive therapy is now usually performed with concurrent chemoradiotherapy; with this approach, a greater extent and degree of inflammation is expected than with radiotherapy alone. Chemotherapy alone is only used for induction therapy or for patients with metastatic disease. In patients undergoing chemoradiotherapy, responses should be assessed with [18F]FDG PET/CT approximately 12 weeks after the end of therapy to avoid false-negative and false-positive findings. The rate of false-positive cases declines with the length of the time interval between end of therapy and PET. A higher rate of false-negative [18F]FDG PET has been observed for scans performed less than 4–6 weeks after the end of therapy [80, 87, 88]. The majority of irradiated cells do not die instantaneously but instead can still undergo several cycles of cell division (only cells irradiated in the mid-to-late S phase show instantaneous cell cycle blockade). The subsequent fate of such cells varies: Some cells may remain dormant for a protracted time and die eventually, but some cells may recover and start dividing again [89, 90]. Indeed, experimental studies in irradiated cell cultures show a rapid decline in [18F]FDG uptake but the tracer uptake is not instantaneously abolished. Dormant cancer cells maintain their capability for glucose uptake and retention as long as their cell membrane is intact and basic metabolic processes continue. Some of these cells eventually die, whereas other cells may recover their full metabolic and proliferative potential. With increasing volume, the residual viable tumor cell nests may eventually become detectable on [18F]FDG PET images.
Table 3

Response assessment of HNSCC with PET and PET/CT (selected studies)

Author

N

Primary site

Stage

Treatment modality

Median Δt wks from end of Rx

Primary

Neck

Comments

Sen. % (PPV%)

Spec. % (NPV %)

Sen. % (PPV %)

Spec. % (NPV%)

Porceddu, Head Neck 2005 [78]

39

92% OP, La

3–4

CRT

12

N/A

N/A

83 (71)

93 (97)

 

Andrade, IJROBP 2006 [80]a

28

85% OC, OP, La

2–4

CRT

8

N/A

N/A

N/A

N/A

Combined analysis for primary and neck; PET: sen./sp./acc. 77/93/86% vs. CT: 92/47/68%; PET more accurate >8 wks after CRT

Tan, Arch Otolaryngol 2007 [81]

48

90% OP, La

4

def CRT

10

N/A

N/A

25 (15)

83 (90)

 

Nayak, Laryngoscope 2007 [82]a

43

95% OC, OP. La

4

 

ND (8–26)

N/A

N/A

87 (70)

91 (97)

 

Ong, JNM 2008 [83]a

65

89% OP, La

3–4

def. CRT

12

N/A

95 (97)

71 (38)

89 (97)

 

Yao, IJROBP 2009 [84]

188

85% OC, OP, La

1–4

128 def (96 CRT, 32 RT); 60 postop.

15

86 (32)

86 (99)

86 (70)

97 (98)

PET+ pts. have worse 3 years DFS and OS

Moeller, JCO 2009 [85]a

92

OP, La, HP

1–4

def RT or CRT

8

70 (58)

94 (96)

75 (27)

76 (96)

Only post-Rx SUV predicts outcome; PPV better in HPV- tumors

Porceddu, Head Neck 2011 [86]a

112

OP (74%), NP, La, HP

1–4

Def RT or CRT

12

  

60 (33)

98 (98)

Prospective study, PET more accurate than CT; no FN findings;

aPET/CT studies

CRT chemoradiotherapy, DFS disease-free survival, HP hypopharynx, ND not defined, N/A not available, NPC nasopharynx, NPV negative predictive value, Sen. sensitivity, OC oral cavity, OPC oropharynx, OS overall survival, PPV positive predictive value, pts. patients, Spec. specificity, RT radiotherapy, La Larynx,wks weeks

In three of the larger studies investigating the role of [18F]FDG PET for response assessment after concurrent chemoradiotherapy, [78, 79, 83] the sensitivity and specificity for detection of residual disease in neck lymph nodes were 100% and 94% [79], 83% and 93% [78], and 71% and 89%, respectively [83]. Of note, in all three studies the negative predictive value was 97%–100%. A patient example is shown in Fig. 7. False-positive lymph nodes are secondary to inflammation or granulomatous disease; false-positive uptake at other sites can occur due to inflammation, abscess formation, osteoradionecrosis, etc. Combined PET/CT reduces the fraction of false-positive cases. A prospective study of 121 patients confirmed the aforementioned observations, which largely stemmed from retrospective analyses [86]. Of the 121 patients, 62 achieved a complete response in neck nodes by CT criteria, and 50 did not. In the group of 62 patients, all PET studies were correctly negative (specificity and negative predictive value, 100%). More interestingly, of the 50 patients with residual enlarged nodes on CT, PET was correctly negative in 41 and correctly positive in two cases.
Fig. 7

Response assessment after chemoradiotherapy in a 62-year old male with primary tumor in left tonsillar fossa and left neck node metastases, staged as T3N2B. The patient was treated with concurrent chemoradiotherapy. The baseline staging scan shows the hypermetabolic left tonsillar primary, as well as metastatic neck nodes (a, b). [18F]FDG PET/CT performed 3 months after the end of treatment shows nonspecific inflammation at the base of tongue and mild nonspecific uptake in a residual level II node (c). Another hypermetabolic node in level II measured 2.6 x 2.5 cm on the staging scan (d, e). After chemoradiotherapy, a residual node measured 1.9 x 1.5 cm (f, g). Scan findings were interpreted as absence of residual viable tumor in lymph nodes. Nevertheless, because of the large extent of initial nodal metastatic disease this patient underwent left modified neck dissection. The specimen showed only necrotic tumor foci but no viable cells

The test performance of PET can probably be refined further when clinical risk parameters are considered. In a study of 92 patients with stage I–IV primary cancer in the oropharynx, larynx, or hypopharynx, who underwent definitive radio- or chemoradiotherapy, both sensitivity and specificity were higher in high-risk patients than in low-risk patients (high risk was defined as stage III–IV, N2b and N3, non-oropharyngeal primary site, smoking history, and HPV-negative status) [85]. This observation re-emphasizes a basic rationale applicable to all imaging tests: The greatest impact on disease detection and patient management is generally observed in patients with intermediate pretest probability.

It needs to be emphasized that the true value of posttherapy [18F]FDG PET in patients treated with current radio- or chemoradiotherapy protocols is the negative predictive value in the range of 95–100% (Fig. 7). This means that many patients who might otherwise proceed to biopsy or “planned neck dissection” can in fact be observed with clinical follow-up and periodic imaging studies. While the positive predictive value of PET after chemoradiotherapy is relatively low, most scans will in fact be negative when interpreted properly. However, true prolonged intense [18F]FDG uptake after definitive therapy indicates a poor treatment outcome or treatment-related complications: A study in patients with larynx cancer treated with intensity-modulated radiation therapy [91] showed an inverse relationship between the intensity of (persistent) [18F]FDG uptake at 12 months after treatment and quality of life, as well as the ability to speak and swallow solid foods. In other words, persistently high [18F]FDG uptake indicates either persistent disease or persistent treatment-induced structural and functional damage to the larynx.

Suggested PET Interpretation Criteria for Response Assessment

In general, focal and asymmetric [18F]FDG with intensity greater than that in surrounding normal tissues (in particular muscle) and blood vessels should be considered suspicious for residual disease. On PET/CT, such abnormalities should fuse to the site of the primary disease or lymph nodes (rather than blood vessels, fat tissue, skeletal muscle, etc.). By contrast, diffuse (nonfocal) [18F]FDG uptake within the radiation field is usually an indicator of postradiation inflammation. With concurrent chemoradiotherapy, high-grade toxic effects are observed in up to 80% of patients, including grade 3 or 4 mucositis in 41% and laryngeal toxicity in 14% of patients [17]. This has obvious implications for imaging studies: Laryngeal edema and treatment-induced infiltrative changes in perilaryngeal soft tissues are commonly observed on posttreatment CT, along with nonspecific contrast enhancement patterns. Likewise, increased laryngeal or oropharyngeal [18F]FDG uptake may be observed for a prolonged period after chemoradiotherapy. In most cases, this will be of mild-to-moderate intensity and diffuse throughout the larynx or along the oropharynx walls. Again, focal uptake should raise the suspicion of ulceration or persistent disease. In view of the relatively high response rates, persistent disease is uncommon, and this should be considered when interpreting PET scans in this setting. SUV numbers cannot differentiate reliably between residual cancer and inflammation. In clinical practice, scans are usually interpreted as positive or negative, or using a five-point scale (positive, probably positive, equivocal, probably negative, negative), considering focality, intensity, and pattern of residual [18F]FDG uptake in relation to findings on the pretherapy scan.

Impact on Patient Management

Because clinical parameters and structural imaging cannot reliably predict the presence of residual metastatic neck disease, “planned neck dissection” was usually performed in the past after the completion of chemoradiotherapy, especially in patients with initial N2–N3 disease. Historically, the risk for residual cancer in such nodes exceeded 20%. In light of the high negative predictive value of posttreatment [18F]FDG PET, this approach seems no longer justified [92, 93]. In one of the previously cited studies, [83] “planned neck dissection” would have been considered in 51 patients owing to the presence of residual enlarged lymph nodes, but disease was in fact only present in seven of them. Implementing a treatment strategy based on posttherapy PET/CT findings could have reduced the number of planned neck dissections by 75% (from 51 to 13) while missing disease in 2% (two of 84 heminecks). Based on our experience over the past decade, we have proposed a clinical algorithm for the management of patients with HNSCC after chemoradiotherapy (Fig. 8). A dedicated neck CT with intravenous contrast and [18F]FDG PET/CT (potentially in one imaging session) should be performed about 10–12 weeks after the end of therapy, unless clinical management requires imaging at an earlier time. This time point strikes a balance between the clinical wish for early yet accurate response assessment and the surgeon’s wish not to perform a neck dissection in tissues that have developed extensive fibrosis and scar tissue as the result of chemoradiotherapy. Management of patients with residual enlarged nodes and negative PET findings should be individualized according to the following considerations (Fig 9): Since response rates are high and PET has a high negative predictive value, “planned neck dissection” is unnecessary in the majority of cases. Nevertheless, close follow-up of these patients is required. Only if close clinical follow-up cannot be guaranteed, or if there are extenuating circumstances that indicate a higher likelihood for local recurrence (e.g., extranodal tumor extension), may a neck dissection be indicated. The rationale for this data-driven approach should be discussed with the patient.
Fig. 8

Suggested algorithm for management of HNSCC patients after chemoradiotherapy. This algorithm is based on our experience at MSKCC; PET/CT is obtained approximately 10–12 weeks after the end of therapy. (Modified from Schoeder et al. J Nucl Med. 2009;50 suppl 1:74S–88S; reprinted by permission of the Society of Nuclear Medicine)

Fig. 9

Nasopharyngeal carcinoma in a 34-year-old female presented with left neck mass. Clinical exam and MRI showed nasopharyngeal mass and left neck nodes. MRI T2-weighted fat suppressed image shows the high signal (white) mass in the left posterolateral nasopharynx (a). Staging [18F]FDG PET/CT shows the mass as well as an adjacent retropharyngeal metastatic node (b, c). After induction chemotherapy, there is mild nonspecific residual [18F]FDG uptake in the nasopharynx (d, e). The patient subsequently underwent concurrent chemoradiotherapy. (Note the different position of the head for the two scans; the second PET/CT (d, e) was obtained in the radiotherapy mask and with intravenous contrast)

Imaging During Chemoradiotherapy or After Induction Chemotherapy

The potential clinical utility of PET for early response assessment during chemo- or combined chemoradiotherapy has not been studied systematically in HNSCC. Data from other malignancies [94, 95] suggest that a significant decline in [18F]FDG uptake between baseline and interim PET after a few cycles of chemo- or chemoradiotherapy may indicate a better prognosis and high likelihood of achieving a complete response. Few studies have attempted to address this question in HNSCC [96, 97, 98, 99, 100], often including patients with a variety of primary sites (all sites, pharynx only, or focused on oral cavity tumors). One of the earlier studies used coincidence camera imaging and noted an early and significant decline in [18F]FDG uptake in 47 patients with locally advanced disease after one cycle of chemotherapy or 24 Gy of radiotherapy. When dichotomized by the median SUV, individuals with lower 18F-FDG uptake showed a better rate of locoregional control. However, a closer analysis of this study reveals that similar prognostic information could also be derived from the baseline scan alone [96]. Recent studies confirmed that persistent high [18F]FDG uptake on interim PET is associated with worse patient outcome; similarly, a greater and faster decline in SUV or metabolic tumor volume (MTV) may indicate better prognosis after completion of therapy [100]. On the contrary, persistent [18F]FDG uptake and slow decline in SUV or MTV have a low positive predictive value (as low as 30% in one recent study) [101], i.e., even many patients with slow decline in [18F]FDG uptake under therapy may achieve reasonable outcome once the full course of therapy is completed. Currently, the exact role, most meaningful time point, and optimal interpretation criteria for interim PET in patients with HNSCC remain unclear. It is also unclear how interim PET findings might alter patient management (good local control rates with current concurrent chemoradiotherapy, lack of an established alternate therapy). One meaningful approach would be a prospective study investigating the potential utility of treatment de-escalation in low-risk (usually p-16 positive) patients who show rapid response on interim [18F]FDG PET scan.

There are limited data on the role of PET imaging for assessing the response to induction chemotherapy, prior to subsequent concurrent chemoradiotherapy. This is a topic of persistent interest among medical oncologists. Proponents of this approach believe that it may improve clinical outcome (lower rate of distant metastases and better survival) in locoregional advanced HNSCC. However, two recently completed randomized clinical trials (DeCIDE and Paradigm) were not able to prove this hypothesis. Induction chemotherapy did not improve outcome in nonselected patients [102, 103]. If induction chemotherapy is to play a role in the management of head and neck cancer, future studies will need to focus on high-risk patients, using tumor biologic parameters and imaging studies. For instance, if a patient showed very little or no metabolic response after induction chemotherapy, this might indicate a low likelihood for cure with subsequent chemoradiotherapy; perhaps such patients would benefit from immediate salvage surgery after induction therapy, or should be enrolled in more aggressive chemoradiotherapy and posttreatment surveillance protocols. Conversely, patients with good response to induction therapy may perhaps benefit from de-escalation of standard chemoradiotherapy by applying lower radiation doses (e.g., ongoing clinical trial such as NCT01706939).

Imaging After Surgery Prior to Adjuvant Therapy

A few studies [104, 105, 106] investigated the role of [18F]FDG PET/CT early after surgical resection and prior to planned adjuvant radiotherapy . Usually these scans are performed relatively early after surgery in order not to delay necessary adjuvant radiotherapy. While early postsurgical imaging is associated with a higher risk for false-positive [18F]FDG findings, these studies nevertheless detected residual [18F]FDG-avid disease in 13–30% of patients, leading to changes in management, such as adjustment of radiation field or dose and abandonment of adjuvant radiotherapy or a switch to palliative chemotherapy, in 15%–30%. Patients with positive surgical margins, perineural spread of disease, or extracapsular extension of nodal disease in the surgical specimen may particularly benefit from preradiotherapy PET/CT. Because of the low positive predictive value of [18F]FDG PET in this setting, all suspicious findings should be confirmed by biopsy before changing patient management.

Recurrent Disease

The early detection of recurrent head and neck cancer is important in determining the ability to perform salvage surgery, which can improve the clinical outcome of these patients. For instance, patients with recurrent early-stage HNSCC who undergo salvage surgery have a 70% 2-year relapse-free survival, whereas those with recurrent advanced-stage HNSCC undergoing salvage surgery have a 22% 2-year recurrence-free survival [107]. It is therefore critical to detect potential recurrences early in the course of events. An imaging modality used for this purpose should have a high sensitivity for the detection of disease, but at the same time not yield too many false-positive findings.

CT and MRI, which rely on structural changes, are notoriously unreliable in this setting because of treatment-related alterations of tissue planes, nonspecific contrast enhancement, etc. However, the PET/CT interpretation may also be complicated because postsurgical changes can involve distortions of the normal anatomy related to resection and surgical reconstruction, involving various soft tissue flaps, bone grafts, bone plates, surgical obturators, etc.

It is now clearly established that [18F]FDG PET/CT has a high sensitivity and specificity for the detection of recurrent HNSCC, regardless of the primary treatment modality used [108, 109, 110, 111, 112, 113, 114, 115]. In a retrospective study of 143 patients with HNSCC at any site, including 72 patients in whom recurrent disease was ultimately proven, Wong et al. [111] found a sensitivity of 96% for [18F]FDG PET. The specificity varied with the anatomic subsite in the neck that was studied and tended to be lower at sites that showed posttreatment inflammation, whereas it was highest in the nontreated neck or outside the neck (where false-positive uptake would be less likely). This was also confirmed in other studies [109].

As a rule, clinically detectable recurrent disease is extremely unlikely in the setting of an entirely negative PET scan. With adequate patient preparation and combined PET/CT, certain sources of nontumor-related [18F]FDG uptake can be eliminated or at least correctly identified (e.g., laryngeal muscle uptake, radioactive saliva in the throat or vallecula epiglottica, nonspecific [18F]FDG uptake in brown fat tissue of the neck or scalene muscles), but posttherapy inflammation remains a potential source for false-positive interpretation. Accordingly, the sensitivity for the detection of recurrent head and neck cancer is very high, but specificity in the treated (after surgery or radiotherapy) area is lower than elsewhere in the neck or at remote sites, such as lung or bone [109, 111] (Table 4). Since the negative predictive value of [18F]FDG PET/CT is very high, these patients in general do not require any further evaluation. By contrast, the positive predictive value is lower, depending on the location and time interval since treatment, so that sites of [18F]FDG uptake require careful assessment and histologic confirmation before embarking on therapy. If biopsies from the site of [18F]FDG uptake are negative for recurrent disease, close clinical follow-up may be sufficient. Potential reasons for false-positive [18F]FDG uptake include inflammation, infection, and radionecrosis.
Table 4

[18F]FDG PET for detection of recurrent disease

 

N

Sites

RD

CT/MR

PET

Remarks

Sen.

Spec.

Acc.

Sen.

Spec.

Acc.

%

%

%

%

%

%

Lonneux, Laryngoscope 2000 [110]

44

All

26

73

50

64

96

61

81

All pts.; early + late PET

25

38

33

100

25

50

<12 weeks after all therapy

90

60

75

96

90

94

>12 weeks after all therapy

Lapela, Eur J Cancer 2000 [108]

56

All

37

59/91

100/78

81/84

84/95

93/84

88/90

Sensitive vs. specific reading

Wong, J Clin Oncol 2002 [111]

143

All

72

   

96

72

 

For all findings

97

79

 

Local rec. at primary site

92

95

 

Regional disease elsewhere in neck

94

96

 

Distant disease

Kunkel, Cancer 2003 [109]

97

Oral cavity

49

   

83

81

 

For all findings

87

67

 

Local recurrence

87

99

 

Nodal metastases

71

93

 

Distant metastases, 2nd primary

Kubota, EJNM 2004 [112]

36

All

15

75

30

46

87

78

81

PET better than CT/MRI

Salaun, Head Neck 2007 [115]

30

All

9

   

100

95

97

PET/CT

Abgral, JNM 2009 [113]

91

All

30

   

100

85

90

PET/CT, summary analysis for primary site, lymph nodes and distant sites

Acc. accuracy, pts. patients, rec. recurrence, RD number of patients with proven locoregional or distant recurrence in each study, Sen. sensitivity, Spec. specificity

SUV numbers or other quantitative and semiquantitative parameters cannot reliably distinguish between recurrence and inflammation or infection. For instance, Lapela et al. [108] reported a wide overlap in SUVs for disease recurrence (range 2.1–36.9) vs. nontumor-related [18F]FDG accumulation (range 1.5–9.3). Using ROC analysis, Wong et al. [111] suggested an SUV of 3.2 to distinguish between recurrent disease and benign conditions, providing a sensitivity of 92% and specificity of 70%. If the SUV decreases in serial scans, malignancy is unlikely and no further intervention is needed. If a high SUV persist or rises further, repeat biopsy may be required, unless there is another obvious explanation, such as infection, fistula, or radionecrosis. However, it should be noted that SUV numbers are affected by [18F]FDG uptake time and technical parameters. Therefore, SUV should be used judiciously: While it may sometimes aid in study interpretation, it is not a surrogate for clinical experience. Indeed, visual interpretation by an experienced reader appears as at least as accurate as SUV-based assessment [111].

Imaging studies should not be ordered “routinely,” i.e., in the absence of clinical signs or symptoms and without abnormalities on clinical examination. However, there may be a small subgroup of patients at high risk for locoregional recurrence, in whom PET/CT at predefined time intervals may be appropriate, even in the absence of clear abnormalities on the clinical examination: In a prospective study of 44 patients with stage III or IV HNSCC and high risk for recurrence, [18F]FDG PET was performed at 2 and 10 months, thereafter as considered necessary by the treating physician [116]. During the first year of follow-up, PET detected recurrent disease with a sensitivity of 100% and specificity of 93%. Notably, five of the 16 recurrences were only detected with PET. One of the clinically meaningful parameters for risk stratification is the patient’s HPV status, since patients with HPV-negative oropharynx tumors are at higher risk for recurrence after completion of chemoradiotherapy, even when reaching a complete clinical and metabolic response [117]. Efforts to study the role of surveillance imaging should therefore be focused on this group of patients.

Prognostic Value of [18F]FDG PET

Several studies have shown that [18F]FDG PET alone can assess the aggressiveness and proliferation rate of HNSCC [118, 119, 120]. The intensity of [18F]FDG uptake at the primary site or neck node metastases correlates with prognosis in patients both with primary and recurrent disease, and regardless of the treatment modality used [63, 77, 109, 111, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132], [133, 134, 135, 136] (Table 5). In patients with recurrent disease, clinical PET interpretation and SUV are independent prognostic markers for relapse-free survival and OS [109, 111]. More recently, the volume of [18F]FDG-avid disease (MTV) and the combination of SUV and MTV (expressed as total lesion glycolysis) have also been suggested as a prognostic indicator (Table 5). Although high [18F]FDG uptake and a large MTV thus indicate a poor prognosis, no uniform cut-off values have been established. In fact, while most studies confirm that patients with higher SUV, MTV, or total lesion glycolysis have a worse outcome, the cut-off values, methods for separation of prognostic groups (e.g., by median or by lowest p-value), as well as the clinical end points (e.g., 2-year vs. 5-year outcome; local control, disease-free survival or OS) vary remarkably. It also remains to be seen how this important information can be integrated into treatment or follow-up algorithms. For instance, in conjunction with other prognostic markers, a high tumor or nodal SUV or MTV might prompt consideration of induction chemotherapy prior to concurrent chemoradiotherapy or surgery, as well as consideration of postoperative chemoradiotherapy instead of radiotherapy alone, or shorter follow-up intervals.
Table 5

Prognostic value of [18F]FDG PET in multivariate analysis

Author

N

Measured site

Treatment

Outcome

SUV cut-off

MTV or TLG cut-off

Comments

Allal, JCO 2002 [121]

63

All sites

Radical RT

3 years LC and DFS

5.5

See their subsequent study in 2004

Halfpenny, Brit J Cancer 2002 [131]

73

All sites

Surgery ± RT or RT alone

2 years OS

10.0

 

Wong, JCO 2002 [111]

143

All sites

Post surgery or (C)RT

3 years RFS and OS

Best outcome for SUV < 2.0; worst for SUV > 6.0

Recurrent disease

Kunkel, Cancer 2003 [109]

97

Oral SCC

Post surgery

3 years OS

Best outcome for SUV < 2.0; worst for SUV > 4.0

Recurrent disease

Allal, IJROBP 2004 [122]

120

All sites

47 Surgery, 73 (C)RT

4 years LC and DFS

4.8

 

Kim, JNM 2007 [126]

52

Oropharynx

Surgery + RT or CRT

3 years DFS

6.0

Surg. pts. with high SUV did better than CRT pts. with high CRT; unclear

Scott, JNM 2008 [77]

71

All sites

Surgery or RT

1 years DFS

6.5

 

Machtay, Head Neck 2009 [129]

60

All sites

RT or CRT

2 years DFS

9.0

 

Suzuki, Oral Oncol 2009 [130]

24

Oral cavity

Surgery

3 years OS and freedom from distant mets.

12.0

 

Liao, IJROBP 2009 [128]

109

Oral cavity

Surgery

5 years local control

19.3

Tm depth > 12 mm also prognostic

Liao, IJROBP 2009 [132]

120

Neck nodes form oral cavity primary

Surgery and neck dissection

Neck control; freedom from distant mets., DSS and DFS

5.7

Extracapsular nodal spread also prognostic

Chung, CCR 2009 [124]

82

77% nasopharynx, 16% oropharynx, rest hypopharynx

CRT (90%), RT alone (10%)

“Short-term DFS” (f/u 12–64 months, mean 34 months)

MTV 40 ml

SUV per se not predictive

La, IJROBP 2009 [127]

85

All sites

CRT

2 years LC, DFS, OS

Median MTV 11.4 ml; no cut-off provided

Outcome stratified by volume; worst outcome for highest MTV

Farrag, NM Commun 2010 [125]

43

All sites

RT (27) or CRT (16)

2 years OS

8.1

Mid treatment SUV also prognostic

Lim, JNM 2012 [135]

176

Oropharynx

CRT

LTFS, DM, OS

Median MTV 9.7 ml

MTV and TLG predict OS; doubling of SUV increases hazard for death by 1.8

Chan, NM Comm 2011 [133]

196

Nasopharynx

CRT

DFS, OS

Best cut-off for TLG 330

Lower OS when TLG > 330

Chang, JNM 2012 [134]

102

Nasopharynx

RT/CRT

DFS, OS

Median TLG 65

Lower DFS when TLG > median; hazard ratio 3.5

Rasmussen, Head Neck 2015 [136]

287

All sites

RT/CRT

DFS, OS

13.0 (median)

SUV and GTV (based on PET and CT) > median carry higher risk; SUV and GTV interactive

CRT chemoradiotherapy, DFS disease-free survival, DM development of distant metastases, f/u follow-up, GTV gross tumor volume, LC local control, LTFS local tumor-free survival, mets. metastases, MTV metabolic tumor volume, RFS recurrence-free survival, OS overall survival, RT radiotherapy, SUV standardized uptake value

Nasopharyngeal Cancer

In view of its unique epidemiology, tumor biology, and prognosis, nasopharyngeal carcinoma (NPC) should be considered separately from other head and neck squamous cell carcinomas. This tumor shows a distinct racial and geographical distribution. The highest incidence is noted in southern Chinese, in whom it is more than 20 times more common than among Caucasian people [137]. Of note, the risk for NPC persists in individuals who have emigrated to other parts of the world.

NPC tends to spread submucosally with early infiltration of parapharyngeal tissues. The tumor can spread in all dimensions; intracranial spread can occur along the maxillary nerve, following initial invasion of the pterygopalatine fossa and along the mandibular nerve via the foramen ovale. Neck lymph node metastases, also including level V nodes, are seen in the vast majority of patients. The lateral retropharyngeal nodes are traditionally considered first echelon nodes, but can be bypassed in up to 30% of cases. The rate of distant metastases is higher than for HNSCC, involving bone, lung, and liver.

Standard imaging tests for staging NPC include brain and neck MRI and, at a minimum, [18F]FDG PET/CT. Local disease extent is best defined by MRI, in particular disease involvement of the skull base and intracranial spread. Neck lymph node involvement is probably best characterized by a combination of MRI and [18F]FDG PET/CT (Fig. 9); small retropharyngeal nodes may be detected better with MRI. [18F]FDG PET/CT appears sufficient as the single imaging test for the detection of distant disease outside the neck [138, 139]. A bone scan is no longer part of the staging studies. Although liver involvement can be determined with contrast CT or ultrasound, these additional studies do not appear necessary; instead, it may be advisable to simply perform the CT of the PET/CT at diagnostic dose settings and with intravenous contrast material. With modern treatment techniques, including intensity-modulated radiotherapy, proton beam therapy, and concurrent chemoradiotherapy, the majority of patients can be cured. However, accurate staging and early detection of recurrence are prerequisites to reach this goal. The combination of MRI and [18F]FDG PET/CT also appears most appropriate for response assessment, although it may be possible in many situations to employ PET/CT as the only imaging test for this purpose [140]; outside the nasopharynx (where MR performs better than CT), it may be appropriate to perform the CT component of the PET/CT as a true diagnostic study (rather than low dose CT) with intravenous contrast material. Recurrent disease is best detected by the combination of MRI and [18F]FDG PET/CT [141, 142, 143]. In a study of 63 patients with treated NPC, the accuracy for detecting local recurrence was 75% with MRI and 73% with [18F]FDG PET/CT; however, importantly, the combination of both tests increased the accuracy to 95% [141]. Nevertheless, occasionally both imaging tests may have difficulties in differentiating between posttreatment inflammation, early fibrosis, and recurrent disease. Radiotherapy-related treatment complications include temporal lobe necrosis, cranial nerve palsy, and osteoradionecrosis of the skull base (with or without superimposed infection). Of note, the latter may show contrast enhancement on MRI as well as [18F]FDG uptake on PET scan. Similar to other head and neck cancers, the intensity of [18F]FDG uptake, as well as the volume of [18F]FDG-avid disease, in NPC primary tumors provides prognostic information [144]. [134].

Radiotracers Other than [18F]FDG for Imaging of HNSCC

A number of non-[18F]FDG radiotracers have been explored for imaging of head and neck cancers, with potential applications for the study of cancer biology, staging and radiotherapy planning, and response assessment. Imaging with amino acid tracers does not appear to provide any advantage over [18F]FDG. The intense uptake in salivary glands interferes with the detection of metastatic neck nodes [145]. Although initially proposed as more specific than [18F]FDG, false-positive amino acid uptake does occur in inflamed lymph nodes as well. Another amino acid tracer, 18F-fluoroethyl-tyrosine (18F-FET), showed inferior sensitivity compared with [18F]FDG [146, 147]. Similarly, imaging with [11C]choline was not superior to [18F]FDG PET/CT for response assessment in the head and neck [148]. Several groups are focusing on developing and refining imaging techniques for hypoxia in HNSCC. Hypoxic tumors are resistant to radio- and chemotherapy. It is conceivable that the poor prognosis of patients with hypoxic primary HNSCC or nodal metastases could be improved with modern aggressive treatment strategies. Radiotracers under investigation for hypoxia imaging in the head and neck include 18F-fluoromisonidazole (18F-MISO), 18F-fluoroazomycin (18F-FAZA), and 64/60Cu-ATSM [149, 150, 151]. Ongoing clinical trials are investigating the prognostic value of tumor hypoxia as imaged by PET, and how the hypoxia PET signal can be used for dose escalation in patients with hypoxic tumors (NCT01212354, NCT02352792), or for dose de-escalation in patients with early resolution of hypoxia during chemoradiotherapy (NCT00606294), in an effort at biology-driven modern radiotherapy. Tumor cell proliferation can be imaged with 18F-fluorothymidine (18F-FLT) [152]. 18F-FLT, in general, is not a diagnostic radiotracer; in most disease sites it shows less uptake than [18F]FDG, and false-positive uptake in inflamed lymph nodes can occur [153]. It is conceivable that tumors with high FLT uptake benefit from more intense therapy. However, predominantly 18F-FLT may be a good imaging test for response assessment [154]. Based on limited data from recent studies, 18F-FLT uptake in HNSCC declines earlier and faster than [18F]FDG uptake does and such early decline is associated with better patient outcome [155, 156]. Finally, a number of radiotracers for imaging EGFR and the response to EGFR inhibitors, as well as angiogenesis and the response to angiogenesis inhibitors (both of potential clinical interest in head and neck cancer), are under study and in early clinical investigations.

PET for Radiotherapy Planning

[18F]FDG PET/CT is now an established and essential imaging technique for the staging and planning of patients undergoing definitive (chemo-)radiotherapy (mostly for tumors of the oropharynx, nasopharynx, and larynx) or for postsurgical irradiation. The utility of PET for delineating the gross tumor volume (GTV) has been investigated. Most studies agree that the incorporation of PET in the planning process clearly improves target design over CT-based planning. In the single study of head and neck cancer patients in which data were correlated with histopathology (of laryngectomy specimens), presurgical PET was more accurate than CT or MRI in outlining the presumed tumor margins [157]. Nevertheless, in clinical practice, the combination of contrast enhanced CT or MRI and PET is usually applied for treatment planning. Of note, simple physical exam remains necessary and in case of small superficial primary tumors, may be more accurate than any imaging [158]. Several other studies have shown the incorporation of PET in treatment planning improves interobserver agreement. Often the PET-derived GTV is smaller than CT-based volumes, whereas simultaneously tumor extension was shown outside the CT-based GTV. Considerable time and effort have been spent in trying to define a mathematically and biologically correct approach when outlining tumor margins on PET. For instance, [18F]FDG-avid volumes may appear larger or smaller depending on the window setting at the display. To improve objectivity, a number of segmentation algorithms have been proposed; unfortunately all have limitations in daily practice [159]. Therefore, most clinicians rely on visual assessment (and ideally close cooperation between radiation oncologist and nuclear medicine physician) for outlining PET-based tumor volumes. Beyond these clinical applications, there is growing interest in defining a “biologic” target volume. It is hoped that this will help in identifying patients with better or worse prognosis in whom radiotherapy could be escalated (dose, time, fractionation) or de-escalated. Dose escalation to highly metabolically active subvolumes has been proposed by several authors, and was shown to be technically feasible [160, 161]. Modeling studies suggest that hypermetabolic tumors may require 10–30% more dose than tumors with lower [18F]FDG uptake [162]. This concept is supported by studies showing that a majority of recurrences originate within the site of the original [18F]FDG-avid tumor volumes, and recurrence becomes more likely with increasing tumor avidity [163, 164]. In addition to [18F]FDG, other radiotracers, such as hypoxia imaging agents [149, 165, 166], some amino acids, and proliferation markers are of growing interest in radiation oncology [167].

Emerging Role for PET/MRI

PET/MRI is an emerging imaging technology. It has been applied in head and neck cancer and, depending on the primary tumor site and clinical question, may serve as a surrogate for PET/CT for staging purposes, detection of recurrence, and possibly also response assessment. Various imaging protocols have been proposed and generally attempt to strike a balance between acceptable imaging time and the number and type of MRI sequences that can be acquired in a reasonable time and are clinically necessary. Imaging times are generally longer with PET/MRI than with PET/CT, increasing the likelihood for patient motion [168]. Readers of PET/MRI need to be familiar with a number of technique-specific artifacts, including artifacts in the attenuation map, in order to avoid misinterpretation of imaging findings. There is currently no evidence that PET/MRI is broadly superior to PET/CT for imaging of head and neck cancer. Of course, MRI per se provides better information than does CT for certain clinical questions (e.g., skull base invasion, perineural spread of disease), and in these scenarios combined PET/MRI is likely to offer the most clinical benefit. The role of special MRI techniques, such as dynamic contrast-enhanced (DCE) imaging, diffusion-weighted imaging (DWI) and blood oxygen level-dependent (BOLD) imaging, is under investigation. These techniques may provide valuable (and in some instances prognostic [169, 170]) information as part of an MRI-only protocol, but when obtained as part of an PET/MRI protocol this may be redundant with the information that is already derived from the PET component of the integrated scan, such as pattern, intensity, and volume of radiotracer uptake. In practice, PET/MRI will be applied most appropriately for selected patients with head and neck cancer and for specific clinical questions (Figs. 6, 7, 8, and 9).

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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of Radiology, Molecular Imaging and Therapy ServiceMemorial Sloan Kettering Cancer CenterNew YorkUSA

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