Unknown primary in head and neck of squamous cell origin

Squamous cell carcinoma of unknown primary (SCCUP) of the head and neck is defined as clinically palpable nodes in the neck region without any evidence of the primary site on routine clinical workup which includes the history, physical examination, flexible optic endoscopy of the upper aerodigestive tract, and radiographic investigation with ultrasound, CT and/or MRI. This constitutes approximately 5% of all head and neck cancers. The pathophysiology behind why primary malignancies cannot be determined is understood; reasons which have been postulated include regression of the primary tumor tissue, small size with a slow growth rate, or histologic and/or genetic differences between the primary tumor and metastasis, and obscure anatomical locations. Nearly 80%–85% of metastatic nodes in neck region arise from tumors in the head and neck, with almost 85%–90% of the primary sites of disease detected in the oropharynx (common sites being palatine tonsils or base of tongue). Other potential primary sites of HNCUP include the vertex of the scalp, nasal vestibule, oral cavity, nasopharynx, hypopharynx, and larynx with extension into the distal esophagus (Tables 2.16.1.1 and 2.16.1.2).

FDG PET/CT in CUPHN

Imaging forms the fulcrum of diagnosis and staging in CUPHN, especially with the combination of anatomical and metabolic imaging with FDG PET/CT, detection of occult primaries and further targeting biopsies for better tissue characterisation has changed the management approach. Kwee et al. published a meta-analysis of 11 studies published between 2005 and 2007, comprising 433 patients who underwent FDG PET/CT. The primary tumor detection rate, pooled sensitivity, and specificity of FDG-PET/CT/were 37%, 84% and 84%, respectively; whereas the false positive rate (15%) was highest for oropharyngeal tumors. However, the variability of study population, timing of PET/CT studies and panendoscopy, and HPV status have a significant impact on the results. Patients with negative physical examination and office endoscopy should directly undergo FDG PET/CT. Sokoya et al studied 190 patients with CUPHN, who underwent panendoscopy after FDG PET/CT. The authors adopted this approach based on the fact that the sensitivity of PET/CT in detecting the primary site in CUPHN of squamous cell origin is 73.1% (NPV 68.9%), which implied that a significant portion of primary sites were undetected. In this cohort, PET/CT scan identified primary sites in 87 patients, who were initially designated as CUPHN, based on clinical examination studies. After panendoscopy, primary sites were identified in 32 of 103 patients (31%) with negative PET/CT scans. An added advantage of ¹⁸F FDG PET/CT is its ability to detect malignancies outside the head and neck region, such as distant metastases or synchronous or metachronous primaries at other sites. However, whole body FDG PET/CT had low specificity and a high false positive rate when it comes to primary site in tonsil, which has been extensively reported in literature. The high false-positive rate in the tonsils is due to physiologic uptake in the normal lymphoid tissue; or inflammation or tonsillitis, which is commonly seen. Other causes of false positive FDG accumulation can occur in conditions like sarcoidosis, granulomatous disease, or in benign tumors, which can hamper the specificity. False negatives can arise due to limited resolution of PET/CT scanner to detect subcentimeter sized primaries (less than 5 mm in modern PET/CT scanners). Also, uncommon histologies like mucinous, adenoid cystic or rhabdoid have low grade FDG uptake (Figs. 2.16.1.1–2.16.1.3).

Extracervical CUP

Extra cervical carcinoma of unknown primary commonly tends to be of adenocarcinomatous etiology although it can be of squamous cell type too. Rarely it can be of neuroendocrine origin also. It is defined as the presence of metastatic nodes, disseminated solid organ metastases and/or disseminated abdominopelvic deposits of carcinomatous cell histology (squamous, adeno or neuroendocrine) without any evidence of primary cancer on standard diagnostic workup. In only less than 30% of cases the site of primary in identified ante mortem. Post mortem examinations reveal a primary site in 60%–80% cases most often in the lung (27%), pancreas (24%) and hepatobiliary tree (8%). Current era has seen the development of tailored and specific chemotherapeutic regimens for solid tumors. Thus failure to identify the primary lesion leads to an even poorer prognosis in a cohort with already bad prognosis. Hence establishment of the site of the primary tumor is of paramount importance here to ensure timely and effective treatment and more importantly avoidance of ineffective, expensive and potentially toxic treatments.

PET/CT for extracervical CUP

Standard diagnostic workup tends to be heterogeneous and comprises multitude of invasive and non invasive tests which can be applied. FDG PET/CT has shown promising results in this regard. It proves to be the most valuable the earlier in the course of workup it is applied as it provides pivotal evidence of the site of primary, the guide to targeted biopsy and obviates the need for further invasive diagnostic procedures. Burglin et al did a systematic review and meta-analysis of 20 studies including 1492 patients and assessed the utility of FDG PET/CT for detection of the primary tumor in adults with extra-cervical metastases from cancer of unknown primary. Although there was heterogeneity in workup and studies in general, but still FDG PET/CT had a detection rate of 40.93% and their study suggested that upfront application of FDG PET/CT does has a role in CUP as it obviates the need for further invasive diagnostic procedures. A review by Seve et al provided similar results in patients of CUP with extra-cervical metastases, FDG PET/CT revealed tumor site in 41% patients here (range 24%–63%). A large prospective randomized study is the need of the hour to confirm the potential benefit of using FDG PET/CT up front in extra cervical CUP. Majority of the retrospective studies have not compared PET/CT findings with conventional imaging. This would bring down the diagnostic yield of PET/CT for primary sites like lungs, which are diagnosed even on a chest radiograph or CT scan of thorax. As far as the data on neuroendocrine neoplasm (NEN) of unknown primary is concerned, the NCCN guidelines state that Gallium-68-labeled peptide (Ga-68 DOTA) PET/CT should be performed in cases where CT or MRI have failed to identify the site of primary. However the UK and European guidelines differ on this regard and advocate the use of Ga68 DOTA PET/CT in all cases of NEN of unknown primary and also recommend that this modality replaces the traditional somatostatin receptor scintigraphy (SRS). Naswa et al carried out a prospective study using Ga-68 DOTANOC PET/CT to localize primary tumor in 72 patients and found that it had sensitivity of 78%. Another prospective study was conducted by Prasad et al in 59 patients with NEN of unknown primary, Ga68 DOTANOC PET/CT was able to localize the primary in 59% of patients.

Future directions

The main diagnostic challenge for PET/CT in CUP lies in minimizing the number of false negatives results. It is also well known that FDG is not a specific marker of malignancies since uptake is seen in inflammatory tissue also. To overcome these drawbacks PET tracers reflecting more specific biologic tumor characteristics are under development and clinical investigation. Since the receptor expression on different tumor types has been identified in recent times, the choice of investigation for detection of primary sites has become more focused. Advanced immunohistochemistry and molecular markers provide us with valuable clues to which metabolic pathway to focus on, and we now have molecular imaging radiotracers targeting specific receptors, illustrated in Table 2.16.1.3. These receptors also provide suitable targets for planning radionuclide therapy, based on the principle of Theranostics.

Clinical diagnosis overview

Routinely, all the palpable cervical lymph nodes are considered positive for regional metastasis in oral cancer. The site, number, shape, size, tenderness, consistency, and fixity to underlying structures are the criteria commonly used during a clinical examination of the cervical lymph nodes. Even though palpation has the advantage of being easy and inexpensive to perform and repeat, it is generally accepted to be inaccurate. Therefore, appropriate investigations should be carried out which have high accuracy for the N0 neck.

Conventional methods such as ultrasound (USG), computed tomography (CT), magnetic resonance imaging (MRI) which provides morphological and anatomical assessment are commonly used and some novel methods like diffusion-weighted imaging of MRI, positron emission tomography (PET), or PET/CT and MRI are sometimes added for staging (Fig. 2.16.2.4).

Grayscale USG

Grayscale USG is the commonest method for evaluating superficial LNs. High-frequency linear array USG transducers are typically used for evaluating superficial LNs (i.e., neck, inguinal region, or the axillary fossa). It evaluates the nodes for Size and morphologic criteria (Table 2.16.2.1). The absence of a fatty hilum and cortical hypertrophy in an LN is regarded as the most specific predictive factor for metastasis. Moghaddam et al. noted an echogenic hilum of cervical LN in 81% of benign LNs and 55% of malignant ones, thus spotting the absence of hilum as a marker for LN involvement in USG. Besides hilum, some other specific signs within LNs can be displayed by the USG, such as necrosis and microcalcifications.

Color doppler

Color Doppler is useful in distinguishing non-metastatic nodes from the metastatic node based on the vascularity of lymph nodes (Table 2.16.2.1).

Computed tomography (CT)

CT has now become the most important and routinely used modality for pretreatment staging and evaluation of cancer patients. As a structural imaging method, the CT diagnostic criteria for metastatic LNs mainly depend on location, size, and morphologic criteria (Table 2.16.2.1 and Fig. 2.16.2.5).

Among them, size is still the most common criterion with a wide variable range from 5 to 15 mm. A short-axis diameter of more than 1 cm is usually accepted as a threshold for malignancy in most studies. However, the diagnostic sensitivity of this standard is obviously weakened by a high false-negative ratio, viz. 16%–74% metastatic LNs with normal size. Hence, it is difficult to choose an appropriate cutoff to balance the sensitivity and specificity at the same time.

Magnetic resonance imaging (MRI)

Thoracic and axillary lymph nodes and their metastases

Thoracic lymph nodes are separated into two types:

Diaphragmatic lymph nodes – situated on the thoracic surface of the diaphragm as summarized in Table 2.16.2.7.

Clinical significance

Patterns of lymphadenopathy in thoracic malignancies

Various cancers like lung, breast, lymphoma, esophageal, and malignant mesothelioma have different lymphatic drainage pathways in the thorax that are useful in the staging. Computed tomography (CT) is the primary modality for imaging malignancy in the chest for staging, sampling, planning treatment, evaluating the response, and estimating prognosis.

Size criteria

The majority of CT studies record the short-axis diameter (SAD) of a lymph node, as this is the most reproducible measurement and are generally considered enlarged in more than 10 mm SAD; while hilar and periesophageal nodes can be considered enlarged beyond 7 mm SAD and diaphragmatic nodes beyond 5 mm in short-axis diameter. No size criteria are available for retrocrural, internal mammary, and other parietal nodes, and hence, detection of these nodes should be considered abnormal.

Limitations of size criteria

Nodal size cannot be used reliably to indicate metastatic involvement. In patients with lung cancer, about 13% of nodes measuring less than 1 cm were metastatic while one-third of nodes 2–4 cm in diameter were hyperplastic and did not contain metastases as per McLoud et al. Here, FDG PET has an increasing role in the detection of diseased lymph nodes that appear normal at CT alone; pathologic confirmation of mediastinal nodal involvement should be undertaken when there is increased uptake in mediastinal lymph nodes.

Lung cancer

The lung’s lymphatic supply comprises the parenchymal and pleural network. The parenchymal lymphatics are situated in the interlobular septa and broncho vascular bundles which drain sequentially into the intralobular, interlobular, lobar, and finally, the hilar nodes and the hilar nodes drain into the mediastinal nodes (Figs. 2.16.2.13 and 2.16.2.14) whereas the pleural lymphatics drain into hilar node while anastomosing with the parenchymal lymphatics. Most lung parenchymal tumors drain to the hilar nodes before reaching the mediastinum. However, mediastinal metastases may occur by directly bypassing the hilar nodes. Direct connection may exist with the thoracic duct, enabling systemic nodal metastases without mediastinal node involvement. Table 2.16.2.9 illustrates predilection for regional node involvement as per lobar tumor. In a patient with lung cancer, the nodal status determines surgical resectability. AJCC eighth edition has classified the nodal staging as illustrated in Table 2.16.2.10.

Lymphoma

They are divided into Hodgkin and non-Hodgkin disease. There is frequent involvement of the anterior mediastinal and paratracheal regions and a tendency for contiguous spread to subcarinal, peridiaphragmatic, periesophageal, and internal mammary nodes nodal groups in decreasing order of frequency (Fig. 2.16.2.15). In most patients, two or more nodal groups are involved at the initial presentation. Involvement of the posterior mediastinal lymph nodes is associated with pleural, retrocrural, and retroperitoneal disease. Isolated hilar involvement is rare and should suggest an alternative diagnosis.

Lymph node involvement is demonstrated by enlargement of a node detected clinically or by imaging when alternative pathology may reasonably be ruled out. Imaging criteria include demonstration of fluorodeoxyglucose (FDG) avidity on FDG positron emission tomography (FDG-PET) or unexplained node enlargement on CT. Suspicious nodes should always be biopsied if treatment decisions are based on their involvement. preferably with an excisional biopsy; fine needle aspirations are strongly discouraged because of the potential for false negatives or misdiagnosis because of loss of lymph node architecture. Core needle biopsy may be able to provide adequate material for diagnosis, particularly of a secondary site. Non-Hodgkin lymphoma is a more heterogeneous group of diseases. However, It is difficult to differentiate Hodgkin disease from non-Hodgkin lymphoma on the basis of nodal distribution alone.

Therapy planning in lymphoma

High-grade tumor and large bulky mediastinal adenopathy (greater than 10 cm in transverse diameter or greater than one-third of the thoracic diameter) is associated with an increased risk of relapse and therefore, requires both chemotherapy and radiation therapy. An accurate description of the extent of the disease is important for radiation therapy planning. After treatment, diseased lymph nodes may show irregular or eggshell calcifications at CT. Recurrent disease is common in the pericardial and internal mammary lymph nodes, as these are usually not included in the radiation field. Lymph node calcification before treatment is unusual.

Esophageal carcinoma

The esophagus is divided into cervical and thoracic portions each having its separate nodal drainage. The lymphatics of the upper two-thirds of the esophagus drain the cervical and mediastinal nodes. The lymphatics of the lower one-third drain toward the abdomen as illustrated in Table 2.16.2.11 and Fig. 2.16.2.17. The N stage of the disease is determined by the number of regional LNs involved by the tumor as shown in Table 2.16.2.12 and Fig. 2.16.2.16. Also, not all nodal stations used by the IASLC for lung cancer are considered regional LNs for esophageal cancer staging. Endoluminal ultrasound has improved accuracy in the assessment of local lymph node metastases when compared with CT (80% compared with 51%).

Malignant pleural mesothelioma

They are aggressive neoplasms related to asbestos exposure, arising from mesothelium lining pleura, pericardium, and peritoneum with nodal staging as described in Table 2.16.2.13.

The anterior pleural and diaphragm lymphatics in the upper and middle thorax drain into the internal mammary lymph nodes and while in the lower thorax they drain into peridiaphragmatic lymph nodes. The posterior pleural lymphatics drain into the extrapleural lymph nodes, which lie in the paraspinal fat. The posterior diaphragm lymphatics drain into the posterior mediastinal nodes, paraaortic lymph nodes, nodes along the celiac axis, and gastrohepatic ligament.

The regional lymph nodes (Fig. 2.16.2.18) include the following:

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