Imaging Approach for Cervical Lymph Node Metastases from Unknown Primary Tumor

Published Online:https://doi.org/10.1148/rg.220071

Abstract

Neck swelling due to lymph node (LN) metastasis is one of the initial symptoms of head and neck cancer, and in some cases, the primary tumor is not clinically evident. The purpose of imaging for LN metastasis from an unknown primary site is to identify the primary tumor or detect its absence, which leads to the correct diagnosis and optimal treatment. The authors discuss diagnostic imaging approaches for identifying the primary tumor in cases of unknown primary cervical LN metastases. The distribution and characteristics of LN metastases may help locate the primary site. Unknown primary LN metastasis often occurs at nodal levels II and III, and in recent reports, these were mostly related to human papillomavirus (HPV)–positive squamous cell carcinoma of the oropharynx. Another characteristic imaging finding suggestive of metastasis from HPV-associated oropharyngeal cancer is a cystic change in LN metastases. Other characteristic imaging findings such as calcification may help predict the histologic type and locate the primary site. In cases of LN metastases at nodal levels IV and VB, a primary lesion located outside the head and neck region must also be considered. One clue for detecting the primary lesion at imaging is the disruption of anatomic structures, which can help in identifying small mucosal lesions or submucosal tumors at each subsite. Additionally, fluorine 18 fluorodeoxyglucose PET/CT may help identify a primary tumor. These imaging approaches for identifying primary tumors enable prompt identification of the primary site and assist clinicians in making the correct diagnosis.

© RSNA, 2023

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Introduction

Nodal metastasis is frequently found in 37%–49% of head and neck malignancy cases (1). Although most of the primary tumors are detected with careful physical examination, endoscopy, and imaging, the primary site may not be clinically evident at treatment onset, and the nodal metastasis is subsequently diagnosed as occult cancer (24). Human papillomavirus (HPV) has emerged as an important biomarker of oropharyngeal squamous cell carcinoma (SCC), which is also positive in 60%–90% of cancers with a tumor of an unknown primary site (57). In 2017, the eighth edition of the AJCC Cancer Staging Manual included a new dedicated section for occult primary tumors of the head and neck, which considers virus-related cancers (810). Further, the T0 category for the oral cavity, skin, larynx, HPV-negative oropharynx, and hypopharynx was eliminated and used for HPV-related, Epstein-Barr virus (EBV)–related, and occult primary cancers instead (9). Even if the primary tumor is not identified, cases with lymph node (LN) metastases that are HPV or EBV positive will be diagnosed as HPV-mediated (p16-positive) oropharyngeal or nasopharyngeal cancer and treated with cancer-specific methods (11). Because of a positive correlation between HPV infection and p16 expression in oropharyngeal carcinoma cells, p16-expression status at immunohistochemical analysis is highly useful as a surrogate marker for HPV infection (12).

The purpose of imaging for LN metastasis from an unknown primary site is to assess a new neck mass (likely malignant) and simultaneously determine a probable primary tumor site to enable biopsy. In some cases, the radiologist’s role is also to evaluate a primary tumor and determine its location after a nodal mass has been aspirated and confirmed to be cancerous when the primary tumor is not evident at initial clinical evaluation. In rare cases, primary site identification is not possible even after endoscopy and biopsies. Hence, imaging-based detection of a primary tumor or determination of its absence will lead to an accurate diagnosis of cancer and appropriate treatment. Therefore, it is crucial for radiologists to be able to approximate the primary site of LN metastases based on the imaging findings and detect a primary tumor in the suspected area. In this article, we focus on a diagnostic imaging approach to identify the primary tumor for cervical LN metastases.

Epidemiology of Cervical LN Metastases from Unknown Primary Site

Cervical LN metastasis from an unknown primary site is more likely to occur in patients with few subjective primary tumor symptoms, primary sites that are difficult to identify at examination, and LN metastases that are likely large despite a small primary tumor. SCC accounts for 65%–76% of cases, making it the most common histologic type of cervical LN metastasis from an unknown primary site, followed by undifferentiated carcinoma and adenocarcinoma (13,14).

Teaching Point The most common primary sites for SCC cervical LN metastasis from an unknown primary tumor are reported to be the oropharynx (palatine tonsil, 45%; base of the tongue, 44%), hypopharynx, and nasopharynx (15). The frequency of unknown primary SCC has recently shown an increasing trend, and 60%–90% of unknown primary SCCs are p16 positive, which is strongly suggestive of a primary site in the palatine or lingual tonsils
(5,6,16). For histologic types other than SCC, the possible primary sites in the head and neck region are the thyroid gland and salivary glands. Primary sites outside the head and neck region may include the lung, breast, uterine cervix, and stomach (14,17).

Diagnostic Workup of Unknown Primary Carcinoma

LN metastasis is suspected in adults with a cervical mass that lasts more than 2 weeks and forms in the absence of physical evidence of infection (3) (Fig 1). If metastatic LNs are suspected, the head, face, ears, and oral cavity are evaluated clinically. Furthermore, fiberoptic examination of the oral cavity, pharynx, larynx, and sinonasal cavity, including areas not visible at clinical inspection, should also be performed. Recently, head and neck narrow band imaging has been introduced as a novel optical digital method of image-enhanced endoscopy in combination with an electronic laryngoscope. Narrow band imaging of the head and neck mucosa can now help identify superficial mucosal lesions, which are missed at regular white light endoscopy. These superficial mucosal lesions are identified owing to their distinct neoangiogenic pattern of vasculature (18). Fine-needle aspiration or core needle biopsy of a neck mass is necessary to establish the histologic diagnosis. It is recommended to use p16 testing for cervical LNs with carcinoma of an unknown primary site, especially for LN metastasis at nodal levels II or III, while EBV testing is used for p16-negative metastases, which indicate nasopharyngeal cancer (3,11).

Diagnosis and management algorithm for unknown primary tumors in the head                     and neck. Fiberoptic examination of the oral cavity, pharynx, larynx, and                     sinonasal cavity is performed if an LN metastasis is suspected. Fine-needle                     aspiration (FNA) or core needle biopsy (CNB) of neck masses is necessary to                     establish a histologic diagnosis. Contrast-enhanced CT or MRI should be                     performed in patients with suspected cervical LN metastasis. FDG PET/CT may be                     helpful in patients whose primary tumor cannot be identified at CT and MRI.                     Patients with no primary tumor identified at the time of initial treatment will                     be managed as an occult primary tumor. *p16 and EBV testing is                     recommended for all cervical LNs with carcinoma of an unknown primary site.                     **Even if the primary tumor is not identified, a histologically                     confirmed SCC is classified according to the AJCC Cancer Staging Manual (8th                     edition) (8). The diagnosis in patients with p16-positive or EBV-positive LN                     metastases is HPV-mediated oropharyngeal or nasopharyngeal cancer,                     respectively.

Figure 1. Diagnosis and management algorithm for unknown primary tumors in the head and neck. Fiberoptic examination of the oral cavity, pharynx, larynx, and sinonasal cavity is performed if an LN metastasis is suspected. Fine-needle aspiration (FNA) or core needle biopsy (CNB) of neck masses is necessary to establish a histologic diagnosis. Contrast-enhanced CT or MRI should be performed in patients with suspected cervical LN metastasis. FDG PET/CT may be helpful in patients whose primary tumor cannot be identified at CT and MRI. Patients with no primary tumor identified at the time of initial treatment will be managed as an occult primary tumor. *p16 and EBV testing is recommended for all cervical LNs with carcinoma of an unknown primary site. **Even if the primary tumor is not identified, a histologically confirmed SCC is classified according to the AJCC Cancer Staging Manual (8th edition) (8). The diagnosis in patients with p16-positive or EBV-positive LN metastases is HPV-mediated oropharyngeal or nasopharyngeal cancer, respectively.

CT or MRI with contrast medium is usually the first-line imaging examination for patients with cervical LN metastases from an unknown primary site. CT can be used to help identify the primary site, including in the thorax and abdomen; assess the nature of the neck mass; and determine the distribution and location of the cervical disease. MRI provides excellent tissue contrast and is superior in depicting normal structures such as the mucosa, submucosal fat tissue, and muscles—particularly for evaluation of the nasopharynx and oropharynx (19). Further, MRI is less susceptible to dental artifacts than is CT. US is useful in patients with suspected primary tumors in the thyroid gland or major salivary glands (20,21). If cross-sectional CT or MRI cannot help radiologists readily identify a primary tumor, the use of fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/CT can be considered. FDG PET/CT is useful for identifying primary tumors in the palatine tonsils, base of the tongue, hypopharynx, and nasopharynx (2224). A meta-analysis by Rusthoven et al (25) showed an additional detection rate of 25% with PET/CT compared with CT and MRI.

Locating Primary Tumor on the Basis of Imaging Findings of LN Metastasis

Distribution of Cervical LN Metastases

The distribution of cervical LN metastases can be broadly divided into the following three areas, which are useful for predicting the primary site: (a) nodal levels II, III, and VA; (b) nodal levels IV and VB; and (c) other LNs, including level I, parotid LNs, and superficial lateral, facial, and occipital LNs (Fig 2, Table 1) (26).

Anatomic boundaries of the neck levels and sublevels according to the                         American Head and Neck Society classification system (26). The line of                         separation between LN levels I and II is the posterior margin of the                         submandibular gland. The line of separation between nodal levels II and III                         and level V is the posterior border of the sternocleidomastoid muscle. The                         line of separation between levels IV and V is an oblique line extending from                         the posterior border of the sternocleidomastoid muscle to the posterior                         border of the anterior scalene muscle. The posterior border of the internal                         jugular vein separates the nodes at levels IIA and IIB. The carotid arteries                         separate levels III and IV from level VI. The superior edge of the manubrium                         separates levels VI and VII. Unclassified LN groups, such as the parotid,                         facial, and occipital LNs, are defined by the specific anatomic location.                         (Reprinted, with permission, from reference 26.)

Figure 2. Anatomic boundaries of the neck levels and sublevels according to the American Head and Neck Society classification system (26). The line of separation between LN levels I and II is the posterior margin of the submandibular gland. The line of separation between nodal levels II and III and level V is the posterior border of the sternocleidomastoid muscle. The line of separation between levels IV and V is an oblique line extending from the posterior border of the sternocleidomastoid muscle to the posterior border of the anterior scalene muscle. The posterior border of the internal jugular vein separates the nodes at levels IIA and IIB. The carotid arteries separate levels III and IV from level VI. The superior edge of the manubrium separates levels VI and VII. Unclassified LN groups, such as the parotid, facial, and occipital LNs, are defined by the specific anatomic location. (Reprinted, with permission, from reference 26.)

Table 1: Primary Site Predicted from Distribution of Cervical LN Metastases

Table 1:

In patients with level II, III, or VA cervical LN metastases, oropharyngeal cancer (palatine tonsil and lingual tonsil), hypopharyngeal cancer, and nasopharyngeal cancer are more frequent. When metastatic LNs are levels IV and VB, the hypopharynx, thyroid, supraglottis, and cervical esophagus should be considered as the primary sites. However, clinicians should also consider the possibility of a primary site outside the head and neck (27). Cervical LN metastases from an unknown primary site may also be found in level I, parotid, facial, or occipital LNs. In patients with parotid and superficial LN metastases, the scalp, skin, parotid gland, and sinonasal cavity should be considered as primary sites (28,29). In patients with level I node metastases, the possibility of a primary tumor in the submandibular gland, oral cavity, and sinonasal cavity should be considered (30). Patients with facial LN metastases may have primary tumors in the skin or oral cavity, while patients with occipital LN metastases may have a primary tumor in the scalp or skin (27,31).

Knowledge related to LN metastasis distribution for each primary tumor is helpful for further tumor estimation (Table 2). Cancer of the oropharynx is the most frequent primary site of cervical LN metastasis from an unknown tumor and is often metastasized to level IIA, followed by level III (32). Bilateral LN metastasis is more frequent because of crisscross lymphatics at the base of the tongue; 29% of cancers at the base of the tongue display bilateral LN metastases (32). Metastases from the hypopharyngeal cancers are more frequently found at level III compared with oropharyngeal and laryngeal cancers. Therefore, it should be assumed that patients with prominent level III LN involvement have hypopharyngeal cancers. Nasopharyngeal cancer, which metastasizes to level IIA in 71% of cases, is more likely to metastasize to the lateral retropharyngeal LNs (69%) at levels IIB and VA compared with the other head and neck cancers (32,33). Thyroid cancer has a high frequency of metastases at levels VI, IV, and III (34). Furthermore, approximately 6% of malignant melanomas of the head and neck develop cervical LN metastases from an unknown primary tumor, with a high incidence at levels V, IV, and II and in the parotid LNs (35).

Table 2: Frequency of Cervical LN Metastasis from Each Primary Subsite

Table 2:

Characteristics of Cervical LN Metastases

Imaging findings of metastatic LNs include a spherical shape, central necrosis, cystic change, and an abnormal cluster of nodes. The findings described in the following sections may provide information on the histologic type and primary site of cervical LN metastases.

Cystic Nodal Metastasis.—Cystic nodal metastases are defined as having homogeneous fluid content without an internal complex and also having an enhancing thin smooth capsule (36,37) (Fig 3). Necrotic nodal metastases have thick or irregular walls and a heterogeneous necrotic component and are distinguished from cystic nodal metastases (37). Cystic LN metastasis may be seen in p16-positive oropharyngeal cancer and thyroid papillary carcinoma. Thirty-five percent of p16-positive oropharyngeal cancers and 10% of p16-negative oropharyngeal cancers are associated with cystic LN metastasis (37). In oropharyngeal cancer involving LN metastasis with intranodal cysts, approximately 70% of cases are reported to be p16 positive (38). Intranodal cysts with morphologically normal (<1.5 cm) LNs show a stronger correlation with p16-positive oropharyngeal cancer (38) (Fig 4). Histopathologically, a typical p16-positive cystic nodal metastasis shows homogeneous liquefaction necrosis surrounded by a thin wall formed by p16-positive tumor cells (Fig 3).

Cystic nodal metastasis from HPV-related oropharyngeal SCC (base of                         the tongue) in a 60-year-old woman who was referred to our hospital for                         evaluation of cervical LN metastasis from an unknown primary site. (A) Image                         from initial endoscopy with narrow band imaging. The primary lesion could                         not be detected. (B) Axial contrast-enhanced CT image shows a cystic LN with                         a thin smooth capsule (arrow) and homogeneous internal content at left level                         IIA. Because a cystic LN was seen at left level IIA, p16-positive                         oropharyngeal cancer was suspected. (C) Axial contrast-enhanced CT image                         shows a mass (T) arising from the left lingual tonsil (LT) and invading deep                         into the base of the tongue (arrowheads). The normal layered structure of                         the base of the tongue is obliterated by the mass, and a diagnosis of                         oropharyngeal carcinoma was made. GG = genioglossus muscle, IF =                         intermuscular fat, IM = intrinsic muscle of the tongue, SF = submucosal fat.                         (D) Photomicrograph with p16 immunohistochemical stain at low-power                         magnification shows that the cystic metastases contain homogeneous                         eosinophilic fluid (*). The fluid-filled cavities have smooth regular                         outlines that are lined with p16-positive malignant cells (arrows),                         suggesting HPV-related cancers. The lymphoid cells are depicted further                         outside (arrowheads). (E) Comparison case of normal tongue base anatomy at                         MRI. Axial T2-weighted MR image of the normal tongue base shows the                         following five layers: genioglossus muscle (GG), intermuscular fat (IF),                         intrinsic muscle of the tongue (IM), lingual tonsil (LT), and submucosal fat                         (SF).

Figure 3. Cystic nodal metastasis from HPV-related oropharyngeal SCC (base of the tongue) in a 60-year-old woman who was referred to our hospital for evaluation of cervical LN metastasis from an unknown primary site. (A) Image from initial endoscopy with narrow band imaging. The primary lesion could not be detected. (B) Axial contrast-enhanced CT image shows a cystic LN with a thin smooth capsule (arrow) and homogeneous internal content at left level IIA. Because a cystic LN was seen at left level IIA, p16-positive oropharyngeal cancer was suspected. (C) Axial contrast-enhanced CT image shows a mass (T) arising from the left lingual tonsil (LT) and invading deep into the base of the tongue (arrowheads). The normal layered structure of the base of the tongue is obliterated by the mass, and a diagnosis of oropharyngeal carcinoma was made. GG = genioglossus muscle, IF = intermuscular fat, IM = intrinsic muscle of the tongue, SF = submucosal fat. (D) Photomicrograph with p16 immunohistochemical stain at low-power magnification shows that the cystic metastases contain homogeneous eosinophilic fluid (*). The fluid-filled cavities have smooth regular outlines that are lined with p16-positive malignant cells (arrows), suggesting HPV-related cancers. The lymphoid cells are depicted further outside (arrowheads). (E) Comparison case of normal tongue base anatomy at MRI. Axial T2-weighted MR image of the normal tongue base shows the following five layers: genioglossus muscle (GG), intermuscular fat (IF), intrinsic muscle of the tongue (IM), lingual tonsil (LT), and submucosal fat (SF).

Cystic nodal metastasis from p16-positive oropharyngeal cancer (T0) in                         a 74-year-old man who was referred for evaluation of cervical LN metastasis                         from an unknown primary site. The LN biopsy results confirmed histologically                         p16-positive SCC but no primary tumor in the oropharynx. (A) Axial                         T2-weighted MR image shows the small-sized LN with an intranodal cyst with a                         smooth margin and homogeneous fluid content (arrow) at right level IIA. (B)                         Axial T2-weighted MR image shows no primary tumor in the palatine                         tonsils.

Figure 4. Cystic nodal metastasis from p16-positive oropharyngeal cancer (T0) in a 74-year-old man who was referred for evaluation of cervical LN metastasis from an unknown primary site. The LN biopsy results confirmed histologically p16-positive SCC but no primary tumor in the oropharynx. (A) Axial T2-weighted MR image shows the small-sized LN with an intranodal cyst with a smooth margin and homogeneous fluid content (arrow) at right level IIA. (B) Axial T2-weighted MR image shows no primary tumor in the palatine tonsils.

LN metastases from thyroid papillary carcinoma show cystic changes in 20%–50% of cases, while purely cystic changes are also observed in 6%–9% of cases (39,40).

Teaching Point Cystic changes in LN metastases from thyroid cancer may be caused by colloid accumulation or hemorrhage. Among metastases with cystic changes from papillary thyroid carcinoma, 27% of cases show high signal intensity on T1-weighted images, and about 10% show high attenuation on CT images
(41). Therefore, thyroid papillary carcinoma is first suspected in patients with these imaging findings (41,42) (Fig 5). Further, approximately 2% of cystic nodal metastases have been reported to be malignant melanoma (43).

Cystic nodal metastasis from thyroid papillary carcinoma in a                         65-year-old woman who was referred to our hospital for evaluation of                         possible LN metastasis from an unknown primary site. The results of a                         fine-needle aspiration of the LN were negative for malignant cells. Total                         thyroidectomy and neck dissection were performed, confirming a small                         papillary carcinoma in the right lobe of the thyroid gland. (A) Axial                         contrast-enhanced CT image shows a cystic LN metastasis (arrow) at right                         level III. (B) Axial T1-weighted MR image shows that the internal contents                         of the cystic LN are hyperintense (arrow), suggesting a colloid                         collection.

Figure 5. Cystic nodal metastasis from thyroid papillary carcinoma in a 65-year-old woman who was referred to our hospital for evaluation of possible LN metastasis from an unknown primary site. The results of a fine-needle aspiration of the LN were negative for malignant cells. Total thyroidectomy and neck dissection were performed, confirming a small papillary carcinoma in the right lobe of the thyroid gland. (A) Axial contrast-enhanced CT image shows a cystic LN metastasis (arrow) at right level III. (B) Axial T1-weighted MR image shows that the internal contents of the cystic LN are hyperintense (arrow), suggesting a colloid collection.

Branchial cleft cyst is the differential diagnosis for cystic metastasis at level IIA. Second branchial cleft cyst is the most common type (about 95% of cases) and is located along the anterior surface of the sternocleidomastoid muscle, just lateral to the carotid space and posterior to the submandibular glands (44). Although differentiation of a branchial cleft cyst from cystic metastasis may be difficult, cystic nodal metastasis is first considered for patients with no prior history of a neck mass (37).

Homogeneous LN Metastasis.—Metastatic LNs without necrosis or keratinization tend to show a homogeneous attenuation and signal intensity at CT and MRI, respectively. Because nasopharyngeal carcinoma is mostly a nonkeratinizing SCC, keratinization necrosis is less frequently observed. In the case of nodal classification, particularly N1 (unilateral LN metastasis), necrosis is observed in only 21.8% of cases but is observed in about 50% of N2 or N3 cases (45). Furthermore, several LN metastases from nasopharyngeal carcinoma may be fused and show matted LNs (46). p16-positive oropharyngeal carcinomas are also mostly nonkeratinizing SCCs, with a higher frequency of cystic change compared with that of p16-negative carcinomas, and the solid component—except for cystic degeneration—is often homogeneous (37). Apparent diffusion coefficient (ADC) values are known to be significantly low in nonkeratinizing SCC of the nasopharynx and in p16-positive SCC (Fig 6) (47,48). Potential malignant lymphoma should also be raised as a differential diagnosis in patients with homogeneous LN involvement with low ADC values and no histologic evidence of carcinoma.

Homogeneity of LN metastasis from EBV-positive nasopharyngeal                         nonkeratinizing SCC in a 64-year-old man who was referred to our hospital                         for evaluation of cervical LN metastasis from an unknown primary site. (A)                         Axial contrast-enhanced CT image shows enlarged homogeneous LNs without                         necrosis or cystic change (arrows) at level IIB bilaterally. (B) Axial ADC                         map shows that the mean ADC value for enlarged LNs is low (0.55 ×                         10−3 mm2/sec) and reflects the high attenuation of tumor cells                         (arrow). (C) Axial gadolinium-enhanced fat-suppressed T1-weighted MR image                         shows thickened mucosa of the posterior wall of the nasopharynx (T). A                         linear contrast effect (white arrowheads) reflecting the submucosal                         capillary network, called the deep mucosal white line, is depicted. Focal                         loss of the deep mucosal white line is shown (black arrowhead), and this                         finding is suggestive of nasopharyngeal cancer. The results of biopsy of the                         nasopharynx lesion confirmed SCC.

Figure 6. Homogeneity of LN metastasis from EBV-positive nasopharyngeal nonkeratinizing SCC in a 64-year-old man who was referred to our hospital for evaluation of cervical LN metastasis from an unknown primary site. (A) Axial contrast-enhanced CT image shows enlarged homogeneous LNs without necrosis or cystic change (arrows) at level IIB bilaterally. (B) Axial ADC map shows that the mean ADC value for enlarged LNs is low (0.55 × 10−3 mm2/sec) and reflects the high attenuation of tumor cells (arrow). (C) Axial gadolinium-enhanced fat-suppressed T1-weighted MR image shows thickened mucosa of the posterior wall of the nasopharynx (T). A linear contrast effect (white arrowheads) reflecting the submucosal capillary network, called the deep mucosal white line, is depicted. Focal loss of the deep mucosal white line is shown (black arrowhead), and this finding is suggestive of nasopharyngeal cancer. The results of biopsy of the nasopharynx lesion confirmed SCC.

Calcified LN Metastasis.—Calcification within the LN metastases of the head and neck is seen in thyroid cancer. Calcification can occur in both SCC and adenocarcinoma but is less frequent (49). Calcified LN metastasis has been reported to occur in 50%−69% of thyroid papillary carcinomas and in 69%−75% of thyroid medullary carcinomas at US (5052). Since LN metastases of papillary thyroid carcinoma are also associated with a high frequency of cystic changes, it is strongly suspected in patients with LNs that show calcification and cystic changes (39,40). Calcification of head and neck lesions can be detected with CT, but US is more sensitive for evaluation of small calcifications (53) (Fig 7). Less frequently, pretreatment calcified LN metastases can occur in SCC and adenocarcinoma (49), with a significantly higher frequency of calcification observed in p16-positive SCC (Fig 8) (54). Tuberculous lymphadenitis, sarcoidosis, and amyloidosis are the differentiating diagnostic conditions for lymphadenopathy with calcification (49).

Calcified LN metastasis from thyroid papillary carcinoma in a                         61-year-old woman who was referred to our hospital for evaluation of                         cervical LN metastasis from an unknown primary site. (A) Coronal                         contrast-enhanced CT image shows enlarged LNs (arrows) at levels IIA and III                         in the right neck. The enlarged LN at right level IIA shows calcification                         (arrowhead), suggesting the possibility of thyroid cancer. The results from                         a fine-needle aspiration of the LN were negative for malignant cells. (B)                         Axial CT image demonstrates that it is difficult to detect a tumor in the                         thyroid gland at CT. (C) US image shows an ill-defined mass (arrowheads) and                         microcalcification (arrow) in the right thyroid lobe. Fine-needle aspiration                         was performed to diagnose papillary carcinoma.

Figure 7. Calcified LN metastasis from thyroid papillary carcinoma in a 61-year-old woman who was referred to our hospital for evaluation of cervical LN metastasis from an unknown primary site. (A) Coronal contrast-enhanced CT image shows enlarged LNs (arrows) at levels IIA and III in the right neck. The enlarged LN at right level IIA shows calcification (arrowhead), suggesting the possibility of thyroid cancer. The results from a fine-needle aspiration of the LN were negative for malignant cells. (B) Axial CT image demonstrates that it is difficult to detect a tumor in the thyroid gland at CT. (C) US image shows an ill-defined mass (arrowheads) and microcalcification (arrow) in the right thyroid lobe. Fine-needle aspiration was performed to diagnose papillary carcinoma.

Calcified LN metastasis in a 38-year-old woman with p16-positive                         oropharyngeal cancer. The patient was referred to our hospital for                         evaluation of cervical LN metastasis from an unknown primary site. (A) Axial                         noncontrast-enhanced CT image shows enlarged left cervical LNs (arrow) at                         levels IIA and III. Faint calcifications (arrowhead) are seen at left level                         III. The results of core needle biopsy of the LN confirmed p16-positive SCC.                         (B) Axial T2-weighted MR image shows no primary tumor in the palatine                         tonsils. Cervical dissection and tonsillectomy were performed, and no tumor                         was found in the removed tonsils. The patient was diagnosed with                         p16-positive oropharyngeal cancer (T0).

Figure 8. Calcified LN metastasis in a 38-year-old woman with p16-positive oropharyngeal cancer. The patient was referred to our hospital for evaluation of cervical LN metastasis from an unknown primary site. (A) Axial noncontrast-enhanced CT image shows enlarged left cervical LNs (arrow) at levels IIA and III. Faint calcifications (arrowhead) are seen at left level III. The results of core needle biopsy of the LN confirmed p16-positive SCC. (B) Axial T2-weighted MR image shows no primary tumor in the palatine tonsils. Cervical dissection and tonsillectomy were performed, and no tumor was found in the removed tonsils. The patient was diagnosed with p16-positive oropharyngeal cancer (T0).

Hypervascular LN Metastasis.—Hypervascularized tumors, such as papillary and medullary thyroid carcinoma, neuroendocrine tumors, olfactory neuroblastoma, and renal cell carcinoma, may develop hypervascularized LN metastases (55,56) (Fig 9). Hypervascular metastases in the head and neck are common with papillary thyroid cancer. Metastasis from renal cell carcinoma may show intravenous extension (57). The hyaline-vascular variant of Castleman disease, glomus tumor, and parathyroid adenoma are the differential diagnosis for hypervascular tumor of the neck (55).

Hypervascular LN metastasis from thyroid papillary carcinoma in a                         51-year-old woman. The patient was referred to our hospital for close                         examination of a left cervical mass. (A) Coronal contrast-enhanced CT image                         shows an enlarged LN with mixed cystic and solid components at left level                         IV. The solid component is strongly contrast enhanced in the arterial phase,                         suggesting a hypervascular LN metastasis (arrowheads). Fine-needle                         aspiration of the LNs was performed, and the results confirmed papillary                         carcinoma. (B) Axial contrast-enhanced CT image shows a small nodule (arrow)                         with calcifications in the left lobe of the thyroid gland, indicating a                         possible primary lesion. Thyroidectomy and left cervical dissection were                         performed, and papillary carcinoma of the thyroid gland was                         confirmed.

Figure 9. Hypervascular LN metastasis from thyroid papillary carcinoma in a 51-year-old woman. The patient was referred to our hospital for close examination of a left cervical mass. (A) Coronal contrast-enhanced CT image shows an enlarged LN with mixed cystic and solid components at left level IV. The solid component is strongly contrast enhanced in the arterial phase, suggesting a hypervascular LN metastasis (arrowheads). Fine-needle aspiration of the LNs was performed, and the results confirmed papillary carcinoma. (B) Axial contrast-enhanced CT image shows a small nodule (arrow) with calcifications in the left lobe of the thyroid gland, indicating a possible primary lesion. Thyroidectomy and left cervical dissection were performed, and papillary carcinoma of the thyroid gland was confirmed.

Assessment of Suspected Primary Area at Imaging

Identifying Primary Site in Head and Neck Region

Oropharynx.—In patients with cervical LN metastasis (SCC) from an unknown primary tumor, oropharyngeal cancer is the most common (about 90% of cases) (6). Most cases are related to HPV infection, and the primary tumor is generally found in the palatine tonsil and the base of the tongue. HPV causes carcinoma owing to persistent tonsillar crypt infection (6). Tumors with subepithelial extension in the tonsillar crypt may not be identified with a fiberscope, and biopsy of the palatine tonsils may produce a false-negative result. These tumors tend to be occult primary tumors because the attenuation at CT and signal intensity at MRI appear similar to those of normal tonsillar tissue, making them difficult to identify.

Simple comparison between the left and right sides of the palatine tonsils can be especially useful when identifying tumors. However, it may be difficult to diagnose the presence of a tumor with certainty owing to the physiologic difference between the two sides of the palatine tonsil. Disruption of the pharyngeal constrictor muscle, which has low signal intensity on T2-weighted images, is suggestive of small tumors extending into the parapharyngeal space (Fig 10).

p16-positive oropharyngeal SCC (right palatine tonsil) in a                         42-year-old man with right cervical swelling. Previous examination with a                         fiberscope did not show any abnormalities. Results of fine-needle aspiration                         of the LN performed previously did not show any malignant cells. (A) Axial                         gadolinium-enhanced fat-suppressed T1-weighted MR image shows enlarged LNs                         (arrow) with a cystic change at right level IIA. (B) Axial T2-weighted MR                         image shows the right palatine tonsil (PT) to be mildly enlarged compared                         with the contralateral side. Deep in the palatine tonsil, the pharyngeal                         constrictor muscle (PCM) is obscured (arrows), strongly suggesting extension                         of the tumor in the palatine tonsil into the parapharyngeal space (PPS).                         Biopsies of the cervical LN and right palatine tonsil were performed, and                         the results confirmed p16-positive SCC.

Figure 10. p16-positive oropharyngeal SCC (right palatine tonsil) in a 42-year-old man with right cervical swelling. Previous examination with a fiberscope did not show any abnormalities. Results of fine-needle aspiration of the LN performed previously did not show any malignant cells. (A) Axial gadolinium-enhanced fat-suppressed T1-weighted MR image shows enlarged LNs (arrow) with a cystic change at right level IIA. (B) Axial T2-weighted MR image shows the right palatine tonsil (PT) to be mildly enlarged compared with the contralateral side. Deep in the palatine tonsil, the pharyngeal constrictor muscle (PCM) is obscured (arrows), strongly suggesting extension of the tumor in the palatine tonsil into the parapharyngeal space (PPS). Biopsies of the cervical LN and right palatine tonsil were performed, and the results confirmed p16-positive SCC.

Teaching Point Anatomically, the base of the tongue shows the following layered structure (superficial to deep): lingual tonsil, submucosal fat, intrinsic muscle of the tongue, intermuscular fat, and genioglossus muscle. These layers of the base of the tongue are clearly demonstrated on T2-weighted MR images and contrast-enhanced CT images
(Fig 3). Cancer of the base of the tongue with mostly submucosal extension can be identified by disruption of the normal layer structure at imaging. Because the posterior lingual glands show contrast enhancement at the submucosal connective tissue and may extend into the intrinsic muscle, the minor salivary glands should not be mistaken for tumors (58).

FDG PET/CT is sometimes useful for identifying oropharyngeal lesions if a primary tumor is not evident at CT or MRI. Physiologic minor uptake asymmetry is frequently seen in the tonsil, and left to right maximum standardized uptake value ratios (1st–99th percentiles) of 0.70–1.36 have been reported (59). The cutoff maximum standardized uptake value ratio for detecting the primary site is reportedly 1.6, with 62% sensitivity and 100% specificity (Fig 11) (60). Although an abnormality might still not be seen at FDG PET/CT, tonsillar cancer should not be excluded (Fig 12).

p16-positive oropharyngeal SCC in a 49-year-old man with left cervical                         swelling. The patient was referred to our hospital for evaluation of                         cervical LN metastasis from an unknown primary tumor. (A) Axial                         contrast-enhanced CT image shows the enlarged LN (arrow) with a cystic                         change at left level IIA. CT and MRI did not help identify a primary lesion                         (not shown). (B) Coronal maximum intensity projection FDG PET image shows                         slightly increased FDG uptake in the left palatine tonsil (arrow). Left                         tonsillectomy and left cervical dissection were performed, and                         histopathologic analysis results demonstrated p16-positive SCC.

Figure 11. p16-positive oropharyngeal SCC in a 49-year-old man with left cervical swelling. The patient was referred to our hospital for evaluation of cervical LN metastasis from an unknown primary tumor. (A) Axial contrast-enhanced CT image shows the enlarged LN (arrow) with a cystic change at left level IIA. CT and MRI did not help identify a primary lesion (not shown). (B) Coronal maximum intensity projection FDG PET image shows slightly increased FDG uptake in the left palatine tonsil (arrow). Left tonsillectomy and left cervical dissection were performed, and histopathologic analysis results demonstrated p16-positive SCC.

p16-positive oropharyngeal SCC in a 40-year-old man with left cervical                         swelling for 7 months. The patient was referred to our hospital for cervical                         LN metastasis from an unknown primary tumor that was not detected at                         endoscopy. (A, B) Axial contrast-enhanced CT image (A) and axial T2-weighted                         MR image (B) did not allow identification of the primary tumor in the                         oropharynx. (C) Axial FDG PET/CT image shows FDG uptake in the palatine                         tonsils but no significant left to right difference in FDG uptake. The                         patient underwent left palatine tonsillectomy, and p16-positive SCC was                         identified in the left tonsil. (D) Histopathologic photomicrograph of the                         left palatine tonsil with p16 immunohistochemical stain (low-power                         magnification) shows proliferating tumor cells replacing the submucosal                         tonsillar tissue (*). The tumor is limited in the submucosa without                         invasion of the mucosal epithelium and diffusely and strongly positive for                         p16. In patients whose primary tumor develops mainly in the submucosa, it is                         difficult to detect the tumor at imaging or endoscopy.

Figure 12. p16-positive oropharyngeal SCC in a 40-year-old man with left cervical swelling for 7 months. The patient was referred to our hospital for cervical LN metastasis from an unknown primary tumor that was not detected at endoscopy. (A, B) Axial contrast-enhanced CT image (A) and axial T2-weighted MR image (B) did not allow identification of the primary tumor in the oropharynx. (C) Axial FDG PET/CT image shows FDG uptake in the palatine tonsils but no significant left to right difference in FDG uptake. The patient underwent left palatine tonsillectomy, and p16-positive SCC was identified in the left tonsil. (D) Histopathologic photomicrograph of the left palatine tonsil with p16 immunohistochemical stain (low-power magnification) shows proliferating tumor cells replacing the submucosal tonsillar tissue (*). The tumor is limited in the submucosa without invasion of the mucosal epithelium and diffusely and strongly positive for p16. In patients whose primary tumor develops mainly in the submucosa, it is difficult to detect the tumor at imaging or endoscopy.

Hypopharynx.—In patients with cervical LN metastases (SCC), the hypopharynx should also be considered as a primary site. Narrow band imaging can depict superficial cancer and is useful in detecting the primary site in the hypopharynx (61). The hypopharynx includes the pyriform sinus, postcricoid area, and posterior pharyngeal wall. The pyriform sinus is bounded laterally by the lateral pharyngeal wall and medially by the lateral surface of the aryepiglottic fold and arytenoid and cricoid cartilages. The postcricoid area extends from the level of the arytenoid cartilage to the lower border of the cricoid cartilage.

Teaching Point Early hypopharyngeal carcinoma of the posterior cricoid and posterior wall may not be detected at endoscopic examination because these areas are collapsed anatomically
(62). The detection rate of primary tumors at CT, MRI, or both ranges from 9.3% to 23% and rises to 60% when suspicious radiologic findings lead to subsequent endoscopic biopsies (4). One of the roles of the radiologist is to indicate the suspected primary site on the image, even if it is not definitive, thereby increasing the detection rate of the primary tumor by close endoscopic observation. Contrast-enhanced CT images depict the normal layer of the pharyngeal wall, with the mucous membrane depicted as high attenuation, the submucosal fat layer depicted as low attenuation, and the constrictor muscle depicted as soft-tissue attenuation (Fig 13) (63). Focal thickening of the mucosa and disruption of the normal layers of the pharynx suggest the presence of a tumor. In some hypopharyngeal SCC cases, no abnormalities are observed on the mucosal surface at endoscopy owing to complete submucosal location. Thus, imaging is essential to identify these submucosal tumors (Fig 14) (64).

Hypopharyngeal SCC (postcricoid) in a 50-year-old man with right                         cervical swelling. No primary tumor was found in the pharynx at the initial                         office examination with a fiberscope. (A) Axial contrast-enhanced CT image                         shows an enlarged LN (arrow) with heterogeneous enhancement at right level                         III. Other enlarged LNs were seen at right levels IIA, IIB, and III (not                         shown). Irregular wall thickening and contrast enhancement on the right side                         of the postcricoid is seen. The submucosal fat of the postcricoid (SFpc) is                         obscured (arrowhead), suggesting the presence of a tumor. MM = mucous                         membrane, PCM = pharyngeal constrictor muscle, PVM = prevertebral muscle, RS                         = retropharyngeal space, SFpw = submucosal fat of the posterior wall. (B)                         Axial contrast-enhanced repeat endoscopic image shows a brownish area in the                         hypopharynx (arrowheads) at narrow band imaging. Biopsy results from this                         site in the hypopharynx confirmed SCC.

Figure 13. Hypopharyngeal SCC (postcricoid) in a 50-year-old man with right cervical swelling. No primary tumor was found in the pharynx at the initial office examination with a fiberscope. (A) Axial contrast-enhanced CT image shows an enlarged LN (arrow) with heterogeneous enhancement at right level III. Other enlarged LNs were seen at right levels IIA, IIB, and III (not shown). Irregular wall thickening and contrast enhancement on the right side of the postcricoid is seen. The submucosal fat of the postcricoid (SFpc) is obscured (arrowhead), suggesting the presence of a tumor. MM = mucous membrane, PCM = pharyngeal constrictor muscle, PVM = prevertebral muscle, RS = retropharyngeal space, SFpw = submucosal fat of the posterior wall. (B) Axial contrast-enhanced repeat endoscopic image shows a brownish area in the hypopharynx (arrowheads) at narrow band imaging. Biopsy results from this site in the hypopharynx confirmed SCC.

Hypopharyngeal SCC in a 71-year-old man with right cervical swelling.                         (A) Axial contrast-enhanced CT image shows an enlarged LN (arrow) with                         necrosis at right level IIA. No primary tumor was found in the pharynx at                         endoscopy, including at narrow band imaging. A right cervical LN dissection                         was performed, and SCC was proven histologically. (B) Axial                         contrast-enhanced CT image obtained 6 months later shows wall thickening in                         the right pyriform sinus and continuous soft-tissue attenuation (arrowheads)                         in the paraglottic space. Hypopharyngeal or laryngeal ventricle cancer was                         suspected. (C) Endoscopic image shows a submucosal tumor on the right                         pyriform sinus (arrows). Biopsy results confirmed SCC with intraepithelial                         extension. Hypopharyngeal cancer with submucosal extension into the                         paraglottic space was the diagnosis.

Figure 14. Hypopharyngeal SCC in a 71-year-old man with right cervical swelling. (A) Axial contrast-enhanced CT image shows an enlarged LN (arrow) with necrosis at right level IIA. No primary tumor was found in the pharynx at endoscopy, including at narrow band imaging. A right cervical LN dissection was performed, and SCC was proven histologically. (B) Axial contrast-enhanced CT image obtained 6 months later shows wall thickening in the right pyriform sinus and continuous soft-tissue attenuation (arrowheads) in the paraglottic space. Hypopharyngeal or laryngeal ventricle cancer was suspected. (C) Endoscopic image shows a submucosal tumor on the right pyriform sinus (arrows). Biopsy results confirmed SCC with intraepithelial extension. Hypopharyngeal cancer with submucosal extension into the paraglottic space was the diagnosis.

Nasopharynx.—The nasopharynx is also a possible primary site in patients with cervical LN metastases from an unknown primary site. Nasopharyngeal carcinoma should especially be suspected in cases of positive EBV test results in the LNs (3). Nasopharyngeal cancer commonly arises from the Rosenmüller fossa, which is the recess formed between the eustachian tube and the posterior wall of the pharynx. Endoscopic inspection may not help detect a primary tumor that lies beneath the nasopharyngeal mucosa within the Rosenmüller fossa. With its 95% accuracy rate, MRI is useful for detection of nasopharyngeal carcinoma (65).

The superficial layer of the nasopharynx is seen as a contrast-enhancing line on gadolinium-enhanced T1-weighted MR images. This is called the deep mucosal white line (Fig 6) (66). Early-stage cancers can be detected by identifying focal loss of the deep mucosal white line. When the tumor extends into deeper structures, obliteration of parapharyngeal fat and disruption of the levator veli palatini or prevertebral muscles are suggestive of nasopharyngeal carcinoma (Fig 15).

EBV-positive nasopharyngeal carcinoma in an 82-year-old man with left                         cervical swelling. The patient was referred to our hospital with cervical LN                         metastasis from an unknown primary site. The results of a needle biopsy of                         the LN performed by the patient’s previous doctor confirmed                         carcinoma. (A) Axial contrast-enhanced CT image shows relative homogeneity                         of the LN metastasis (arrow) at left level IIB. The possibility of                         nasopharyngeal carcinoma was considered. (B) Axial contrast-enhanced CT                         image shows a tumor (T) at the left Rosenmüller fossa. The border                         between the mass and the longus capitis muscle (LCaM) and levator veli                         palatine muscle (LVPM) is unclear (arrowheads). (C) Axial T2-weighted MR                         image shows a mass in the left Rosenmüller fossa, and the border                         between the mass and the longus capitis muscle (LCaM) and levator veli                         palatine muscle (LVPM) is irregular (arrowheads), suggesting tumor invasion.                         Analysis of the needle biopsy specimen of the LN obtained by the previous                         physician confirmed malignant cells positive for EBV infection. Thus, the                         diagnosis of EBV-positive nasopharyngeal carcinoma was made.

Figure 15. EBV-positive nasopharyngeal carcinoma in an 82-year-old man with left cervical swelling. The patient was referred to our hospital with cervical LN metastasis from an unknown primary site. The results of a needle biopsy of the LN performed by the patient’s previous doctor confirmed carcinoma. (A) Axial contrast-enhanced CT image shows relative homogeneity of the LN metastasis (arrow) at left level IIB. The possibility of nasopharyngeal carcinoma was considered. (B) Axial contrast-enhanced CT image shows a tumor (T) at the left Rosenmüller fossa. The border between the mass and the longus capitis muscle (LCaM) and levator veli palatine muscle (LVPM) is unclear (arrowheads). (C) Axial T2-weighted MR image shows a mass in the left Rosenmüller fossa, and the border between the mass and the longus capitis muscle (LCaM) and levator veli palatine muscle (LVPM) is irregular (arrowheads), suggesting tumor invasion. Analysis of the needle biopsy specimen of the LN obtained by the previous physician confirmed malignant cells positive for EBV infection. Thus, the diagnosis of EBV-positive nasopharyngeal carcinoma was made.

Thyroid.—Thyroid cancer should be considered in patients with LN metastases predominantly in the lower neck with calcification or cystic change. If suspected, US is generally used to examine the thyroid gland (Fig 7). Although US allows detection of thyroid nodules smaller than 5 mm, in some cases the primary tumor may be too small to be detected (67). Therefore, if thyroid cancer is diagnosed on the basis of the results of biopsy of an LN metastasis, thyroidectomy and neck dissection may be recommended even if the primary tumor cannot be detected at imaging (68,69). Thyroid cancer derived from the ectopic thyroid tissue in the thyroglossal duct or mediastinum should also be considered as a differential diagnosis if a primary tumor is not identified in the thyroid gland.

Salivary Glands.—Salivary gland cancers should be considered in patients with cervical metastases with characteristics of adenocarcinomas. Tumors derived from the submandibular gland or the lower pole of the parotid gland may be difficult to distinguish clinically from swollen LNs. At imaging, the anterior facial veins are useful indicators for distinguishing between an intrasubmandibular gland origin or submandibular LN lesions (70).

Teaching Point A primary submandibular tumor is never separated from the gland by the anterior facial vein, whereas lymphadenopathy may be separated from the gland by the vein
(Fig 16). A submandibular gland malignancy may be intraglandular, and contrast-enhanced CT or T2-weighted MR images may show isoattenuation or isointensity in both the tumor and salivary gland tissue, making it difficult to identify. In these cases, T1-weighted images may be useful because normal salivary glands show a slightly higher signal intensity than that of muscle (Fig 16). Salivary gland carcinomas also arise from sublingual and minor salivary glands around the oral and sinonasal cavities or upper airway. Further salivary gland carcinomas may also arise from heterotopic salivary tissue, which particularly metastasizes in the periparotid and upper cervical nodes (71).

Submandibular gland carcinoma in a 69-year-old man with left                         submandibular swelling for 3 years. (A) Axial contrast-enhanced CT image                         shows an enlarged LN (N) compressing the anterior facial veins (arrow)                         medially. No primary tumor could be identified at CT. (B) Coronal                         T1-weighted MR image shows a mass (arrowheads) with hypointensity compared                         with the normal submandibular gland. The mass (T) compresses the anterior                         facial veins (arrow) laterally, suggesting a submandibular gland origin.                         Adenocarcinoma ex pleomorphic adenoma was diagnosed histopathologically                         after surgery. N = enlarged LN.

Figure 16. Submandibular gland carcinoma in a 69-year-old man with left submandibular swelling for 3 years. (A) Axial contrast-enhanced CT image shows an enlarged LN (N) compressing the anterior facial veins (arrow) medially. No primary tumor could be identified at CT. (B) Coronal T1-weighted MR image shows a mass (arrowheads) with hypointensity compared with the normal submandibular gland. The mass (T) compresses the anterior facial veins (arrow) laterally, suggesting a submandibular gland origin. Adenocarcinoma ex pleomorphic adenoma was diagnosed histopathologically after surgery. N = enlarged LN.

Searching for Primary Site Outside of Head and Neck

Occasionally, neoplasms from primary sites outside of the head and neck region may metastasize to the neck. Accordingly, patients with malignant LN metastases without a primary tumor in the head and neck should be examined for a remote primary tumor. About 1% of all head and neck malignancies are accounted for by metastases from a remote primary site (72). Ellison et al (73) reported that the most frequent cancers with supraclavicular LN metastasis were lung (25%), breast (22%), uterine cervical (12%), stomach (8%), ovarian (7%), and pancreatic (6%). Most cervical LN metastases originating from outside the head and neck are histologically adenocarcinomas, typically from breast or lung cancer. Regarding SCC, the most common primary site is the uterine cervix, followed by the lung, vulva, and esophagus (73).

Cervical LN metastases in patients with p16-positive SCC are generally suspected to be p16-positive oropharyngeal cancer but could also be metastases from HPV-positive uterine cervical cancer (Fig 17). Additionally, p16 can be positive in non–HPV-related cancers, and it has been reported that 35% of lung cancers are positive for p16 (74) (Fig 18). Therefore, patients with cervical LN metastases with p16-positive SCC without a primary site in the head and neck, especially with lower neck nodal metastases, should also be examined for a primary tumor in the chest and abdomen.

HPV-positive uterine cervical cancer in a 52-year-old woman with lower                     neck swelling and metrorrhagia. (A) Axial contrast-enhanced CT image shows                     enlarged LNs with cystic changes in the supraclavicular region (arrows). Biopsy                     results confirmed p16-positive SCC in the LN. LN metastasis in only the                     supraclavicular region is uncommon with oropharyngeal cancer and raised the                     possibility of a primary tumor in the thorax and abdomen. Gynecologic cancer was                     suspected because of metrorrhagia and findings from pelvic MRI. (B) Sagittal                     T2-weighted pelvic MR image shows uterine cervical cancer (arrows). The results                     of biopsy of a tumor (T) on the cervix indicated p16-positive SCCs.

Figure 17. HPV-positive uterine cervical cancer in a 52-year-old woman with lower neck swelling and metrorrhagia. (A) Axial contrast-enhanced CT image shows enlarged LNs with cystic changes in the supraclavicular region (arrows). Biopsy results confirmed p16-positive SCC in the LN. LN metastasis in only the supraclavicular region is uncommon with oropharyngeal cancer and raised the possibility of a primary tumor in the thorax and abdomen. Gynecologic cancer was suspected because of metrorrhagia and findings from pelvic MRI. (B) Sagittal T2-weighted pelvic MR image shows uterine cervical cancer (arrows). The results of biopsy of a tumor (T) on the cervix indicated p16-positive SCCs.

Lung cancer in a 54-year-old woman with lower neck swelling. (A) Axial                     contrast-enhanced CT image shows enlarged LNs in the supraclavicular region                     (arrows). Needle biopsy results confirmed p16-positive carcinoma in the LN. The                     LN metastasis in the supraclavicular region suggested the possibility of a                     primary tumor outside the head and neck region. (B, C) Axial contrast-enhanced                     CT images of the chest show enlarged LNs in the mediastinum and left hilum                     (arrows in B) and a mass in the upper lobe of the left lung (arrow in C),                     leading to the diagnosis of lung cancer.

Figure 18. Lung cancer in a 54-year-old woman with lower neck swelling. (A) Axial contrast-enhanced CT image shows enlarged LNs in the supraclavicular region (arrows). Needle biopsy results confirmed p16-positive carcinoma in the LN. The LN metastasis in the supraclavicular region suggested the possibility of a primary tumor outside the head and neck region. (B, C) Axial contrast-enhanced CT images of the chest show enlarged LNs in the mediastinum and left hilum (arrows in B) and a mass in the upper lobe of the left lung (arrow in C), leading to the diagnosis of lung cancer.

Conclusion

Radiologists should know how to predict the primary site on the basis of the distribution and imaging findings of LN metastases. They should be familiar with local anatomy and imaging findings for detecting a primary tumor. Identifying primary tumors at imaging or detecting the absence of primary tumors assists clinicians in reaching the correct diagnosis and providing optimal treatment.

Disclosures of conflicts of interest.—The authors, editor, and reviewers have disclosed no relevant relationships.

Funding.—T.K. supported by Canon Medical Systems.

Presented as an education exhibit at the 2021 RSNA meeting.

References

  • 1. Pisani P, Airoldi M, Allais A, et al. Metastatic disease in head & neck oncology. Acta Otorhinolaryngol Ital 2020;40(suppl 1):S1–S86. Crossref, MedlineGoogle Scholar
  • 2. Pavlidis N, Pentheroudakis G. Cancer of unknown primary site. Lancet 2012;379(9824):1428–1435. Crossref, MedlineGoogle Scholar
  • 3. Maghami E, Ismaila N, Alvarez A, et al. Diagnosis and Management of Squamous Cell Carcinoma of Unknown Primary in the Head and Neck: ASCO Guideline. J Clin Oncol 2020;38(22):2570–2596. Crossref, MedlineGoogle Scholar
  • 4. Strojan P, Ferlito A, Medina JE, et al. Contemporary management of lymph node metastases from an unknown primary to the neck: I. A review of diagnostic approaches. Head Neck 2013;35(1):123–132. Crossref, MedlineGoogle Scholar
  • 5. Cheraghlou S, Torabi SJ, Husain ZA, et al. HPV status in unknown primary head and neck cancer: prognosis and treatment outcomes. Laryngoscope 2019;129(3):684–691. Crossref, MedlineGoogle Scholar
  • 6. Motz K, Qualliotine JR, Rettig E, Richmon JD, Eisele DW, Fakhry C. Changes in Unknown Primary Squamous Cell Carcinoma of the Head and Neck at Initial Presentation in the Era of Human Papillomavirus. JAMA Otolaryngol Head Neck Surg 2016;142(3):223–228. Crossref, MedlineGoogle Scholar
  • 7. Schroeder L, Pring M, Ingarfield K, et al. HPV driven squamous cell head and neck cancer of unknown primary is likely to be HPV driven squamous cell oropharyngeal cancer. Oral Oncol 2020;107:104721. Crossref, MedlineGoogle Scholar
  • 8. Lydiatt WM, Patel SG, O’Sullivan B, et al. Head and Neck cancers: major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin 2017;67(2):122–137. Crossref, MedlineGoogle Scholar
  • 9. Amin MB, Edge SB, Greene FL, Byrd DR, eds. AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017. CrossrefGoogle Scholar
  • 10. Glastonbury CM. Critical Changes in the Staging of Head and Neck Cancer. Radiol Imaging Cancer 2020;2(1):e190022. Google Scholar
  • 11. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Occult Primary. V.2.2021. https://www.nccn.org/professionals/physician_gls/pdf/occult.pdf. Accessed August 6, 2020. Google Scholar
  • 12. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363(1):24–35. Crossref, MedlineGoogle Scholar
  • 13. Haas I, Hoffmann TK, Engers R, Ganzer U. Diagnostic strategies in cervical carcinoma of an unknown primary (CUP). Eur Arch Otorhinolaryngol 2002;259(6):325–333. Crossref, MedlineGoogle Scholar
  • 14. Issing WJ, Taleban B, Tauber S. Diagnosis and management of carcinoma of unknown primary in the head and neck. Eur Arch Otorhinolaryngol 2003;260(8):436–443. Crossref, MedlineGoogle Scholar
  • 15. Cianchetti M, Mancuso AA, Amdur RJ, et al. Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Laryngoscope 2009;119(12):2348–2354. Crossref, MedlineGoogle Scholar
  • 16. Cummings MA, Ma SJ, Van Der Sloot P, Milano MT, Singh DP, Singh AK. Squamous cell carcinoma of the head and neck with unknown primary: trends and outcomes from a hospital-based registry. Ann Transl Med 2021;9(4):284. Crossref, MedlineGoogle Scholar
  • 17. Kennel T, Garrel R, Costes V, Boisselier P, Crampette L, Favier V. Head and neck carcinoma of unknown primary. Eur Ann Otorhinolaryngol Head Neck Dis 2019;136(3):185–192. Crossref, MedlineGoogle Scholar
  • 18. Di Maio P, Iocca O, De Virgilio A, et al. Narrow band imaging in head and neck unknown primary carcinoma: A systematic review and meta-analysis. Laryngoscope 2020;130(7):1692–1700. Crossref, MedlineGoogle Scholar
  • 19. King AD, Vlantis AC, Tsang RKY, et al. Magnetic resonance imaging for the detection of nasopharyngeal carcinoma. AJNR Am J Neuroradiol 2006;27(6):1288–1291. MedlineGoogle Scholar
  • 20. Nachiappan AC, Metwalli ZA, Hailey BS, Patel RA, Ostrowski ML, Wynne DM. The thyroid: review of imaging features and biopsy techniques with radiologic-pathologic correlation. RadioGraphics 2014;34(2):276–293. LinkGoogle Scholar
  • 21. Bialek EJ, Jakubowski W, Zajkowski P, Szopinski KT, Osmolski A. US of the major salivary glands: anatomy and spatial relationships, pathologic conditions, and pitfalls. RadioGraphics 2006;26(3):745–763. LinkGoogle Scholar
  • 22. Zhu L, Wang N. 18F-fluorodeoxyglucose positron emission tomography-computed tomography as a diagnostic tool in patients with cervical nodal metastases of unknown primary site: a meta-analysis. Surg Oncol 2013;22(3):190–194. Crossref, MedlineGoogle Scholar
  • 23. Goel R, Moore W, Sumer B, Khan S, Sher D, Subramaniam RM. Clinical Practice in PET/CT for the Management of Head and Neck Squamous Cell Cancer. AJR Am J Roentgenol 2017;209(2):289–303. Crossref, MedlineGoogle Scholar
  • 24. Prowse SJB, Shaw R, Ganeshan D, et al. The added value of 18F-fluorodeoxyglucose positron emission tomography computed tomography in patients with neck lymph node metastases from an unknown primary malignancy. J Laryngol Otol 2013;127(8):780–787. Crossref, MedlineGoogle Scholar
  • 25. Rusthoven KE, Koshy M, Paulino AC. The role of fluorodeoxyglucose positron emission tomography in cervical lymph node metastases from an unknown primary tumor. Cancer 2004;101(11):2641–2649. Crossref, MedlineGoogle Scholar
  • 26. Robbins KT, Shaha AR, Medina JE, et al. Consensus statement on the classification and terminology of neck dissection. Arch Otolaryngol Head Neck Surg 2008;134(5):536–538. Crossref, MedlineGoogle Scholar
  • 27. Wang Y, Ow TJ, Myers JN. Pathways for cervical metastasis in malignant neoplasms of the head and neck region. Clin Anat 2012;25(1):54–71. Crossref, MedlineGoogle Scholar
  • 28. Williamson AJ, Haywood M, Awad Z. Intraparotid lymph node metastasis from a nasal septal carcinoma: an unusual source of the unknown primary. BMJ Case Rep 2020;13(2):e232096. Crossref, MedlineGoogle Scholar
  • 29. Mesa M, Quesada JL, Piñas J. Metastasis of amelanotic melanoma of unknown origin in the parotid gland. Br J Oral Maxillofac Surg 2009;47(7):569–571. Crossref, MedlineGoogle Scholar
  • 30. Strasnick B, Moore DM, Abemayor E, Juillard G, Fu YS. Occult primary tumors. The management of isolated submandibular lymph node metastases. Arch Otolaryngol Head Neck Surg 1990;116(2):173–176. Crossref, MedlineGoogle Scholar
  • 31. Sheahan P, Colreavy M, Toner M, Timon CVI. Facial node involvement in head and neck cancer. Head Neck 2004;26(6):531–536. Crossref, MedlineGoogle Scholar
  • 32. Lindberg R. Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 1972;29(6):1446–1449. Crossref, MedlineGoogle Scholar
  • 33. Ho FC, Tham IW, Earnest A, Lee KM, Lu JJ. Patterns of regional lymph node metastasis of nasopharyngeal carcinoma: a meta-analysis of clinical evidence. BMC Cancer 2012;12(1):98. Crossref, MedlineGoogle Scholar
  • 34. Wada N, Duh QY, Sugino K, et al. Lymph node metastasis from 259 papillary thyroid microcarcinomas: frequency, pattern of occurrence and recurrence, and optimal strategy for neck dissection. Ann Surg 2003;237(3):399–407. Crossref, MedlineGoogle Scholar
  • 35. Chang AE, Karnell LH, Menck HR. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1998;83(8):1664–1678. Crossref, MedlineGoogle Scholar
  • 36. Goldenberg D, Begum S, Westra WH, et al. Cystic lymph node metastasis in patients with head and neck cancer: an HPV-associated phenomenon. Head Neck 2008;30(7):898–903. Crossref, MedlineGoogle Scholar
  • 37. Cantrell SC, Peck BW, Li G, Wei Q, Sturgis EM, Ginsberg LE. Differences in imaging characteristics of HPV-positive and HPV-Negative oropharyngeal cancers: a blinded matched-pair analysis. AJNR Am J Neuroradiol 2013;34(10):2005–2009. Crossref, MedlineGoogle Scholar
  • 38. Morani AC, Eisbruch A, Carey TE, Hauff SJ, Walline HM, Mukherji SK. Intranodal cystic changes: a potential radiologic signature/biomarker to assess the human papillomavirus status of cases with oropharyngeal malignancies. J Comput Assist Tomogr 2013;37(3):343–345. Crossref, MedlineGoogle Scholar
  • 39. Monchik JM, De Petris G, De Crea C. Occult papillary carcinoma of the thyroid presenting as a cervical cyst. Surgery 2001;129(4):429–432. Crossref, MedlineGoogle Scholar
  • 40. Levy I, Barki Y, Tovi F. Cystic metastases of the neck from occult thyroid adenocarcinoma. Am J Surg 1992;163(3):298–300. Crossref, MedlineGoogle Scholar
  • 41. Som PM, Brandwein M, Lidov M, Lawson W, Biller HF. The varied presentations of papillary thyroid carcinoma cervical nodal disease: CT and MR findings. AJNR Am J Neuroradiol 1994;15(6):1123–1128. MedlineGoogle Scholar
  • 42. Takashima S, Sone S, Takayama F, et al. Papillary thyroid carcinoma: MR diagnosis of lymph node metastasis. AJNR Am J Neuroradiol 1998;19(3):509–513. MedlineGoogle Scholar
  • 43. Ustün M, Risberg B, Davidson B, Berner A. Cystic change in metastatic lymph nodes: a common diagnostic pitfall in fine-needle aspiration cytology. Diagn Cytopathol 2002;27(6):387–392. Crossref, MedlineGoogle Scholar
  • 44. Lanham PD, Wushensky C. Second brachial cleft cyst mimic: case report. AJNR Am J Neuroradiol 2005;26(7):1862–1864. MedlineGoogle Scholar
  • 45. Liu Y, Chen S, Dong A, et al. Nodal grouping in nasopharyngeal carcinoma: prognostic significance, N classification, and a marker for the identification of candidates for induction chemotherapy. Eur Radiol 2020;30(4):2115–2124. Crossref, MedlineGoogle Scholar
  • 46. Hu Y, Lu T, Huang SH, et al. High-grade radiologic extra-nodal extension predicts distant metastasis in stage II nasopharyngeal carcinoma. Head Neck 2019;41(9):3317–3327. Crossref, MedlineGoogle Scholar
  • 47. Ichikawa Y, Sumi M, Sasaki M, Sumi T, Nakamura T. Efficacy of diffusion-weighted imaging for the differentiation between lymphomas and carcinomas of the nasopharynx and oropharynx: correlations of apparent diffusion coefficients and histologic features. AJNR Am J Neuroradiol 2012;33(4):761–766. Crossref, MedlineGoogle Scholar
  • 48. Payabvash S, Chan A, Jabehdar Maralani P, Malhotra A. Quantitative diffusion magnetic resonance imaging for prediction of human papillomavirus status in head and neck squamous-cell carcinoma: a systematic review and meta-analysis. Neuroradiol J 2019;32(4):232–240. Crossref, MedlineGoogle Scholar
  • 49. Eisenkraft BL, Som PM. The spectrum of benign and malignant etiologies of cervical node calcification. AJR Am J Roentgenol 1999;172(5):1433–1437. Crossref, MedlineGoogle Scholar
  • 50. Rosário PWS, de Faria S, Bicalho L, et al. Ultrasonographic differentiation between metastatic and benign lymph nodes in patients with papillary thyroid carcinoma. J Ultrasound Med 2005;24(10):1385–1389. Crossref, MedlineGoogle Scholar
  • 51. Gorman B, Charboneau JW, James EM, et al. Medullary thyroid carcinoma: role of high-resolution US. Radiology 1987;162(1 Pt 1):147–150. LinkGoogle Scholar
  • 52. Yun G, Kim YK, Choi SI, Kim JH. Medullary thyroid carcinoma: Application of Thyroid Imaging Reporting and Data System (TI-RADS) Classification. Endocrine 2018;61(2):285–292. Crossref, MedlineGoogle Scholar
  • 53. Li JW, Chang C, Chen M, et al. Is Ultrasonography More Sensitive Than Computed Tomography for Identifying Calcifications in Thyroid Nodules? J Ultrasound Med 2016;35(10):2183–2190. Crossref, MedlineGoogle Scholar
  • 54. Shah PH, Karagianis AG, Lester MS, Paintal AS, McComb EN. Calcified lymph nodes in the setting of head and neck squamous cell carcinoma: A predictor of HPV positivity? Clin Imaging 2022;81:136–142. Crossref, MedlineGoogle Scholar
  • 55. Karandikar A, Gummalla KM, Loke SC, Goh J, Tan TY. Approach to intensely enhancing neck nodes. Diagn Interv Radiol 2016;22(2):168–172. Crossref, MedlineGoogle Scholar
  • 56. Howell MC, Branstetter BF 4th, Snyderman CH. Patterns of regional spread for esthesioneuroblastoma. AJNR Am J Neuroradiol 2011;32(5):929–933. Crossref, MedlineGoogle Scholar
  • 57. Maralani P, Mohan S, Rassekh CH, Loevner LA. Salivary neoplasms presenting with radiologic venous invasion: an imaging pearl to diagnosing metastatic renal cell carcinoma. ORL J Otorhinolaryngol Relat Spec 2014;76(2):105–109. Crossref, MedlineGoogle Scholar
  • 58. Hiyama T, Kuno H, Sekiya K, Oda S, Kobayashi T. Imaging of malignant minor salivary gland tumors of the head and neck. RadioGraphics 2021;41(1):175–191. LinkGoogle Scholar
  • 59. Birkin E, Moore KS, Huang C, et al. Determinants of physiological uptake of 18F-fluorodeoxyglucose in palatine tonsils. Medicine (Baltimore) 2018;97(24):e11040. Crossref, MedlineGoogle Scholar
  • 60. Pencharz D, Dunn J, Connor S, et al. Palatine tonsil SUVmax on FDG PET-CT as a discriminator between benign and malignant tonsils in patients with and without head and neck squamous cell carcinoma of unknown primary. Clin Radiol 2019;74(2):165.e17–165.e23. Crossref, MedlineGoogle Scholar
  • 61. Hayashi T, Muto M, Hayashi R, et al. Usefulness of narrow-band imaging for detecting the primary tumor site in patients with primary unknown cervical lymph node metastasis. Jpn J Clin Oncol 2010;40(6):537–541. Crossref, MedlineGoogle Scholar
  • 62. Hamada K, Ishihara R, Yamasaki Y, et al. Transoral endoscopic examination of head and neck region. Dig Endosc 2018;30(4):516–521. Crossref, MedlineGoogle Scholar
  • 63. Schmalfuss IM, Mancuso AA, Tart RP. Postcricoid region and cervical esophagus: normal appearance at CT and MR imaging. Radiology 2000;214(1):237–246. LinkGoogle Scholar
  • 64. Ash L, Srinivasan A, Mukherj SK. Radiological reasoning: submucosal laryngeal mass. AJR Am J Roentgenol 2008;191(suppl 3):S18–S21. Crossref, MedlineGoogle Scholar
  • 65. King AD, Vlantis AC, Bhatia KSS, et al. Primary nasopharyngeal carcinoma: diagnostic accuracy of MR imaging versus that of endoscopy and endoscopic biopsy. Radiology 2011;258(2):531–537. LinkGoogle Scholar
  • 66. King AD, Wong LYS, Law BKH, et al. MR Imaging Criteria for the Detection of Nasopharyngeal Carcinoma: Discrimination of Early-Stage Primary Tumors from Benign Hyperplasia. AJNR Am J Neuroradiol 2018;39(3):515–523. Crossref, MedlineGoogle Scholar
  • 67. Guth S, Theune U, Aberle J, Galach A, Bamberger CM. Very high prevalence of thyroid nodules detected by high frequency (13 MHz) ultrasound examination. Eur J Clin Invest 2009;39(8):699–706. Crossref, MedlineGoogle Scholar
  • 68. Maceri DR, Babyak J, Ossakow SJ. Lateral neck mass. Sole presenting sign of metastatic thyroid cancer. Arch Otolaryngol Head Neck Surg 1986;112(1):47–49. Crossref, MedlineGoogle Scholar
  • 69. Toda S, Iwasaki H, Suganuma N, et al. Occult Thyroid Carcinoma without Malignant Thyroid Gland Findings during Preoperative Examination: Report of Three Cases. Case Rep Endocrinol 2020;2020:4249067. MedlineGoogle Scholar
  • 70. Weissman JL, Carrau RL. Anterior facial vein and submandibular gland together: predicting the histology of submandibular masses with CT or MR imaging. Radiology 1998;208(2):441–446. LinkGoogle Scholar
  • 71. Daniel E, McGuirt WF Sr. Neck masses secondary to heterotopic salivary gland tissue: a 25-year experience. Am J Otolaryngol 2005;26(2):96–100. Crossref, MedlineGoogle Scholar
  • 72. López F, Rodrigo JP, Silver CE, et al. Cervical lymph node metastases from remote primary tumor sites. Head Neck 2016;38:(suppl 1):E2374–E2385. Crossref, MedlineGoogle Scholar
  • 73. Ellison E, LaPuerta P, Martin SE. Supraclavicular masses: results of a series of 309 cases biopsied by fine needle aspiration. Head Neck 1999;21(3):239–246. Crossref, MedlineGoogle Scholar
  • 74. Zhou Y, Höti N, Ao M, et al. Expression of p16 and p53 in non-small-cell lung cancer: clinicopathological correlation and potential prognostic impact. Biomarkers Med 2019;13(9):761–771. Crossref, MedlineGoogle Scholar

Article History

Received: Mar 30 2022
Revision requested: July 15 2022
Revision received: Aug 15 2022
Accepted: Aug 17 2022
Published online: Feb 16 2023