Introduction
Many patients with squamous cell carcinoma of the head and neck (SCCHN) present with metastasis to the cervical lymph nodes. Metastatic carcinoma in the neck without an identifiable primary cancer is defined as a squamous cell carcinoma of the head and neck of unknown primary origin (SCCHNUP). Patients with isolated supraclavicular metastatic carcinoma usually have a primary source from the skin or infraclavicular sites of origin (stomach, breast, lung, esophagus, and ovary) and are thus not the focus of this chapter. Retrospective studies suggest that SCCHNUP is a relatively rare disease, affecting between 1% and 3% of new cases of SSCHN. However, as the incidence of human papillomavirus (HPV)–associated oropharyngeal cancer, which is known to metastasize to the lymph nodes with low-volume primary disease, continues to rise, SCCHNUP will likely increase in incidence as well. Since these patients provide a particularly challenging diagnostic problem to the head and neck surgeon, a systematic approach including a thorough physical examination, appropriate imaging, and surgical evaluation is necessary to identify the site of the primary cancer.
Patients who present with SCCHNUP can be treated with either surgery followed by adjuvant treatment or primary nonsurgical therapy. The identification of the primary cancer can help better define the targeted areas for radiation therapy and provide more accurate staging and prognostic information for these patients. A diagnostic regimen that includes transoral surgery (TOS) of the base of the tongue (BOT) has demonstrated a diagnostic ability of approximately 90% of the primary cancers that otherwise would go undetected by contemporary diagnostic tools. This chapter delineates the evaluation and management of patients with squamous cell carcinoma metastatic to the neck from an unknown primary cancer and provides new insights into the application of transoral robotic technologies for the diagnosis and treatment of patients with SCCHN of unknown primary origin.
Key Operative Learning Points
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Initial evaluation of a SCCHNUP patient should include a thorough history and physical examination, positron-emission tomography (PET) scan, molecular testing of the fine- needle aspiration biopsy (FNA) specimen, and examination under anesthesia (EUA) with palatine tonsillectomies.
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Transoral robotic surgery (TORS) of the BOT can be safely undertaken if these methods fail to identify the primary cancer and has shown a success rate in almost 90% in those cases.
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Care must be taken to remove all of the lingual tonsillar tissue, including the lymphoid areas within the glosso-tonsillar sulcus, since these occult tumors can be only a few millimeters in size.
Preoperative Period
History
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The most common presenting symptom in Squaous cell carcinoma unknown primary (SCCUP) is a painless mass in the neck. Nearly 40% of patients come to medical attention with a single enlarged lymph node, which is most commonly located in level 2, suggesting an occult primary cancer location in the oropharynx.
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Lymphadenopathy in level 3, without involvement of level 2, suggests a primary site in the supraglottic larynx or hypopharynx.
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Patients with SCCHN are traditionally heavy tobacco and/or alcohol abusers. Recently, however, a larger number of patients who report never having been smokers, or who have stopped smoking in the distant past, and have a minimal history of alcohol intake are presenting with SCCHN. These patients often have a cancer that is related to the HPV, an etiologic factor contributing to the development of their cancer. Taking a thorough history on risk factor exposure that includes not only current alcohol and tobacco consumption but also questions regarding remote history of tobacco consumption or high-risk sexual behaviors is important, since these factors may also contribute to the diagnosis of an HPV-related malignancy.
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Female patients should be asked about their gynecological history, with a specific focus on abnormal Pap smears.
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It is also important to ascertain whether these patients have complaints of hoarseness, dysphagia, odynophagia, weight loss, or otalgia, all of which may point to the site of the primary cancer.
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A dermatologic history may also be relevant, and patients should be questioned about prior skin surgery or head and neck cutaneous squamous cell carcinoma.
Physical Examination
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A thorough examination of the head and neck is warranted in all patients who present with occult nodal metastasis.
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The physical examination should include palpation of the neck to determine whether the lymph nodes are fixed to the skin or underlying structures or if they are freely mobile. Palpation should also include examination of the thyroid and tracheal regions, as well as the nodal lymphatic basins of levels I through VI.
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Many cases of SCCHNUP are initially diagnosed by excision of a mass in the neck, which is ultimately confirmed to be SCCHN. In these cases, the physical examination can be challenging, since postsurgical scarring and induration can negatively impact palpation and examination of the residual cervical lymph nodes.
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An examination of the oral cavity and oropharynx should be performed, ideally with indirect mirror-laryngoscopy to examine the BOT and tonsillar fossae. Bimanual palpation of the BOT and tonsillar fossae is also required.
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The physical examination should also include a careful evaluation of the cutaneous structures of the head and neck, since previously treated primary malignancies of the skin can present with isolated metastatic SCC. Physical stigmata of prior skin resections, such as scars or white spots from liquid nitrogen–induced cryoablation, should also be documented.
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Once this portion of the physical examination is concluded, these patients should all be subjected to flexible fiberoptic nasopharyngolaryngoscopy. This provides a better view of the BOT, tonsil fossae, glottis, hypopharynx, and supraglottic structures. It is important to evaluate vocal fold mobility and to look for areas of salivary pooling or submucosal masses in the postcricoid area. The nasopharynx should also be examined to exclude the possibility of an occult nasopharyngeal carcinoma.
Imaging
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Computed tomography (CT) and/or magnetic resonance imaging (MRI) with contrast is generally considered to be the first-line imaging for patients with SCCHNUP.
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If the CT and MRI do not identify the primary cancer, a PET with integrated CT (PET/CT) may be useful. If a PET/CT scan is performed, it should be done before panendoscopy, since the PET can potentially guide the surgeon, and the biopsies or surgical interventions may in fact induce FDG avidity on the PET/CT scan, thus resulting in a false positive. With addition of PET and fusion PET/CT images, a recent meta-analysis of patients with unknown primary cancer demonstrated an improved detection rate of 37.5% by adding PET/CT to the standard evaluation, with a sensitivity and specificity of 84% overall.
Indications
Patients who present with a diagnosis of SCCHNUP are candidates for this procedure. The diagnosis of SCCHNUP should be established on the basis of pathologic evaluation of enlarged cervical lymph node(s).
Contraindications
There are no contraindications to surgery based on anatomic factors. However, patients who have significant medical comorbidities that may preclude the administration of general anesthesia may not be candidates for surgery. Those patients who have a demonstrable primary cancer that appears deeply invasive on preoperative imaging do not require robotic surgery to identify the primary cancer.
Preoperative Preparation
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Even with an extensive investigation and a thorough physical examination, a primary cancer may not be found. New diagnostic procedures can potentially aid in the identification of the primary cancer or at least suggest a subsite from which the primary cancer could have arisen.
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The majority of primary cancers that are identified among patients with SCCHNUP are located within the oropharynx.
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Furthermore, recent studies suggest that a large percentage (up to 70%) of SCC of the oropharynx are HPV related, and only a small percentage of cancers from nonoropharyngeal sites in the head and neck are HPV related. Therefore, detection of HPV within tissue biopsies from the lymph node strongly suggests the oropharynx as the primary source. Immunohistochemical analysis of p16 is a valuable biomarker and can identify those cancers that are associated with HPV infection. HPV in situ hybridization also provides confirmatory data that validate HPV etiology.
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Detection of HPV or Epstein-Barr virus (EBV) in the FNA from a metastatic lymph node may be useful and can provide prognostic information. EBV is also a sensitive marker for nasopharyngeal carcinoma, and positivity on lymph node aspirates for EBV strongly suggests a primary nasopharyngeal source. It should be noted that nasopharyngeal carcinoma typically metastasizes to the posterior neck (level 5), and isolated level 5 nodal metastases in a patient should raise the index of suspicion for an occult primary in the nasopharynx. However, despite the relatively high frequency of HPV and EBV positive cancers of the oropharynx and nasopharynx, respectively, a negative result does not necessary exclude the oropharynx or nasopharynx as the source of the primary cancer.
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Care must also be taken in relying solely on these biomarkers, as cutaneous malignancies have been shown to be p16 positive, and nasopharyngeal cancers have demonstrated HPV positivity.
Operative Period
Patients in whom the unknown primary cancer remains occult despite having an extensive evaluation, including PET/CT scan, tonsillectomy, and directed biopsies of the nasopharynx/BOT, may benefit from a robotic BOT resection to identify the primary cancer. In prior series, the lingual tonsillectomy has demonstrated an approximately 90% success rate in finding the primary tumor when the standard methods have failed. This method is especially useful when HPV positivity has been demonstrated in the metastatic node. The overall goal of the robotic BOT resection procedure is to use an en bloc resection approach under high magnification to remove all lingual tonsil tissue from the inferior portion of Waldeyer’s ring as a method of identifying the primary cancer.
Anesthesia
General anesthesia. A small (6-0) regular endotracheal tube can be used intraorally with the tube taped to the contralateral side of the mouth from the mass in the neck. If robotic surgery is being considered after a prior EUA and directed biopsies, nasotracheal intubation can also be considered to further optimize surgical space for TORS but is not a requirement for TORS.
Positioning
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The table should be turned 180 degrees and the upper and lower teeth protected with a nasal splint that is bisected and molded to the teeth.
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A 2-0 silk suture is then placed in the midline of the tongue, which is a half mattress to allow for traction to be placed on the tongue.
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Both arms are then tucked for the patient ( Fig. 61.1 ).
Fig. 61.1
Depiction of the placement of robotic instruments in the transoral robotic surgery approach for base of tongue resection. The patient’s mouth is retracted using a Dingman retractor with a flat blade. The da Vinci robot is then docked with instruments in the patient’s mouth.
Perioperative Antibiotic Prophylaxis
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Clean contaminated surgery
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Antibiotics are administered during induction of anesthesia and continued for 24 hours.
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Choices
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Clindamycin
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Amoxicillin-clavulanate
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Cephalosporin and metronidazole
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Monitoring
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The surgeon and surgical team including anesthesia need to work together to monitor the patient during robotic surgery. For example, attention should be directed to ensure that robotic instrumentation is not clashing with mouth retractors or each other or causing trauma to the patient. In addition, care must be taken to avoid inadvertent extubation during the procedure from manipulation of the endotracheal tube by the surgeon or the assistant.
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Particular attention is required to ensure that the height of the operating room table is not changed during the procedure. The robotic instruments are docked in the oral cavity in a fixed position. Relative movement of the patient to the instrument position (up-toward and down-away from the instruments in a sudden fashion) can cause inadvertent damage to the oral cavity or pharyngeal tissues.
Instruments and Equipment to Have Available
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Operating headlight
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Tooth guard
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Dingman, Crowe Davis, or Feyh-Kastenbauer (FK) retractor with various size flat tongue retractor blades
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da Vinci Robotic System (Intuitive Surgical)
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5-mm spatula tip monopolar cautery
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5-mm Maryland dissector
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2-0 silk suture
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The patient’s mouth is opened using a mouth gag with the flat retractor blade. It should be noted that the exposure obtained should demonstrate the circumvallate papillae and the lateral pharyngeal walls ( Fig. 61.2 ). Once this exposure is obtained, the mouth gag is then suspended from a Mayo stand.
