Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Squamous Cell Carcinoma: Evaluation of Unknown Primary Many different types of tumors metastasize to the neck. These include squamous cell carcinomas, adenocarcinomas, undifferentiated carcinomas, melanomas, and lymphomas. After complete workup, those with an unidentified primary site usually range from 3-9%. By far the most common type of metastasis to the neck is squamous cell carcinoma. It is interesting that these head and neck squamous cell carcinomas are characterized by low risk of distant metastasis; thus, priority is given to local regional control, as noted by our treatment strategies and radiation or neck dissection. Today I plan to focus on squamous cell carcinoma. History. Dr. Hayes Martin, pictured here, was one of the first authors to publish articles on this topic. In 1944, with Dr. Morfit, he published a landmark article in which he described his workup on his patients over several decades. Drs. Stewart and Everson in the 50s and 60s proposed the spontaneous regression theory as the reason why we could not identify the primary tumor. Dr. Jesse from M.D. Anderson started formulating early treatment strategies and Dr. McComb, from New Yorker, came down to be Chief of Head and Neck Surgery here at M.D. Anderson and was the first Hayes Martin lecturer. His topic for that lecture was the same as mine today. Of note, within the department, Dr. Angela Atkins gave an exc ellent Grand Rounds in the late 90s in which she described our treatment strategies and included bilateral tonsillectomy as part of our standard workup. So what are the theories for not being able to detect these tumors? There have been multiple theories proposed in the literature, but there is no real support for any one of these in particular. The theories proposed include spontaneous regression of the primary tumor, and immune modulated destruction. Some have postulated that there are probably faster proliferation rates in the lymph nodes or that the metastases somehow have a negative biofeedback on the primary lesion. Also, there have been theories on epithelial arrests or branchiogenic cysts as being the only site of these tumors. If we look at the anatomy, as seen here, the most frequent nodal regions involved are levels II and III. Unilateral involvement is most common, with bilateral adenopathy only presenting in 10% of the cases. Understanding the lymphatics gives us a great deal of information on where the primary can be. There are the superficial cervical lymphatics as well as the deep cervical lymphatics. Superficially, we have the submental nodes that generally drain the chin and mid-lower lip, as well as the tip of the tongue and anterior part of the nose; the submandibular glands, which are responsible for the parotid and much of the oral cavity; and the rest—the facial, preauricular, postauricular, and superficial cervical nodes—draining their local regions. It is also important to know the deep cervical lymphatics. There are two main drainage pathways. There is the jugular vein pathway and the spinal accessory pathway. Knowing these gives us insight as to where the primary may can be. Pictured here are the upper jugular digastric nodes. These are the most often involved lymph nodes in unknown primaries of head and neck. The lymphatics pictured here often drain the submandibular triangle, the parotid, as well as several mucosal sites of the pharynx and larynx. Moving on down, the middle jugular omohyoid nodes are responsible for draining the submental triangle, the oral cavity, hypopharynx, and larynx. The lower jugular nodes often drain areas of the subglottis, glottis, hypopharynx, and thyroid. These have rich anastomosis and often coalesce into supraclavicular nodes. Supraclavicular nodes should heighten the awareness of the surgeon because they are typically metastasized from below the clavicles. So, whenever we see these supraclavicular nodes, a different workup should be considered. The importance should be looking for metastasis below the clavicles, as stated, as well as using bronchoscopy and esophagoscopy to try to find the primary tumor. The spinal accessory nerve pathway has upper and lower posterior nodal groups. These are also significant: if these are involved, one should think about the nasopharynx, the retropharyngeal lymph nodes, as well as the scalp. So, where are these primary tumors located? In literature from the 40s, the tonsils and nasopharynx were listed as the most likely sites; in the 60s, the piriform sinus; in the 70s, the supraglottis and the piriform sinus. It was in 1998 that Dr. Mendenhall, from the University of Florida, published his review of 130 patients. He noted that over 83% of them were located in the tonsillar fossa or base of tongue. He attributed the lower incidence of occult tumor in the nasopharynx, hypopharynx, and supraglottic larynx to two things. Number one, better fiberoptic equipment, so that we can diagnose these in the clinic prior to panendoscopy. Second, advances in technology, including CT scanning and MRI, help us detect these unknown primaries. What is the gold standard with regards to current workup? Well, the credo of otolaryngology is, “No head and neck mass should undergo biopsy prior to a complete history and physical.” This actually began with Hayes Martin, who was the first to set forth the rule that, at all costs, you should not try to obtain an excisional biopsy of this neck mass prior to trying to diagnose it and work it up with a good history and physical. At last resort, if you need to perform an excisional biopsy of the lymph nodes, the surgeon performing it should be able to take care of the neck as well as the subsequent discovery of the primary tumor. So, as otolaryngologists, what do we do? A thorough history and physical exam and a fiberoptic exam in clinic. Routinely we get CT scans of the neck, chest x-ray to look for pulmonary primary, standard labs, and the gold standard, panendoscopy with directed biopsy. I will review each of these modalities that have contributed to finding these primary cancers. CT scans have a detection rate of 15-20%. Dr. Muraki, from the University of Utah, published his work on CT scans, which he found very useful for detecting submucosal tumors. Using direct laryngoscopy, sometimes the tumors can be underneath the mucosa and would be missed by visual inspection. Dr. Muraki found it beneficial to use CT scans in detecting this type of malignancy. Also, CT scans have been used for contralateral cervical metastasis in patients with difficult necks to examine. With regards to MRI of the head and neck, there are really no good, specific studies that look only at MRI for evaluating unknown primary squamous cell. There are typically just “how I do it” reports in the literature. Again, Dr. Mendenhall in 1998 said he uses MRI with cases of equivocal findings. Dr. Gluckman, in 1990, said he does not routinely use MRIs, whereas Dr. Robbins, who was at San Diego at the time, recommended MRIs prior to panendoscopy; and Dr. Fried, from Harvard, recommends that areas not directly assessed by palpation or endoscopy are the sites that are useful for MRI. An example of a location like this would be a deep lobe of the parotid. So, what is our standard? It is surgical endoscopy with directed biopsy. Our endoscopy should include the nasopharynx, oral cavity, oropharynx, hypopharynx, larynx, the esophagus, and the tracheobronchial tree. The esophagus and tracheobronchial tree are especially important, as stated earlier, with supraclavicular mets. Biopsies should be directed to the nasopharynx, base of tongue, tonsil, and piriform sinus. There have been studies out of Hopkins that state that biopsies will reveal about a 17% yield. Dr. Mendenhall actually attributed a 24% yield to his directed biopsies. So, when we look at our patient under endoscopy, it is under white light as well as using the naked eye. This is exc ellent for finding structural changes in the anatomy. But in many of these tumors, it is at the molecular and cellular level that these changes will be seen. There is interesting research using laser-induced fluorescence being done in Thailand. In a study in 1999, Dr. Kulapaditharom used a helium cadmium laser and, with this, he evaluated 13 patients. Using the type of device shown here, he found 5/13 unknown primaries. Using standard white light endoscopy, three malignancies were missed. Every malignancy that was picked up by white light endoscopy was also picked up by laser fluorescence, so this appears to be very promising. This slide illustrated what laser fluorescence typically looks like. Here is a vocal cord lesion and what it looks like under fluorescence. You can see that it gives a good idea of extent. Kulapaditharom as well, in 2001, published a follow-up article in which he used a type of fluorescence to evaluate 56 patients with unknown primaries. Here we see what it would look like just under standard endoscopy, as well as when using the fluorescence, where we can see the cancer is lighting up. This would help guide our biopsies and, hopefully, provide a more positive return. He formulated asensitivity of 92% and a specificity of 78%. Dr. Kulapaditharom would be the first to tell you that white light endoscopy will never be replaced by this type of new technology, because it aids so much with regard to anatomic detail and in giving us a gross assessment of what is going on. Tonsillectomy. Dr. McQuone, in 1998, recommended bilateral tonsillectomies. In his study, over 25% of the tumors were found in the tonsils. Of these 25%, using just biopsy of the tonsil bed had a high false negative rate. Based just on tonsil biopsy, he only discovered 12% of the 25%. Also, he noted that if you do a unilateral tonsillectomy, it is difficult to follow the asymmetric tonsillar beds postoperatively in the clinic. Dr. Koch, in 2001 from Hopkins, had a follow-up study in which he again recommended bilateral tonsillectomy. His main reason for this was that he found an incidence of 10% contralateral spread. So the neck disease would, say, be on the right, but the actual squamous cell carcinoma would be in the left tonsil. In his study, he actually had a 34% incidence of tonsillar squamous cell carcinoma and 12% were only found on biopsy of the tonsils. Based on these two studies, other literature has recommended bilateral tonsillectomies when evaluating patients for unknown primary. A hot topic in today’s literature is the use of PET scanners. So, what is the role of PET scanning with regard to squamous cell carcinoma of unknown primary? What PET scan does is a metabolic study; it detects increased metabolism. It detects glucose utilization, and these tumors have a high tumor uptake to background ratio. You can see here an example of a positive PET scan. It has been shown in many articles that PET scan is exc ellent for seeing the avid uptake of FDG in the cervical metastasis of squamous cell carcinoma. So, with squamous cell carcinoma in the neck lymph nodes, we can rest assured that PET scan is going to pick it up. Now, the question remains, can the PET scan pick up the unknown primary? Dr. Schechter, from M.D. Anderson, published a review article on the M.D. Anderson experience and she describes the standard uses of PET scan. She recommends PET scanning for measuring response to therapy, post radiation therapy to evaluate for tumor eradication, as well for detecting recurrent or residual disease. There have been some articles that suggest that if the patient is not healthy enough to undergo panendoscopy, you might try a trial of PET scanning to find an unknown primary that you could biopsy in clinic. What are the limitations of PET scans? The resolution of PET scanning is approximately 5mm-7mm. Areas that are difficult to detect are the supraglottic regions and Waldeyer’s ring because the physiologic uptake of FDG is variable in tonsils, adenoids, salivary glands, and muscles of head and neck. So, these would be the limitations of PET scanning. What does the literature have to say on PET scanning with regard to unknown primaries? A study from Cologne, Germany looked at 27 patients with unknown primaries. No false positives were found and it had a 26% detection rate. This article recommended PET scan after defined conventional diagnostic workup, but before other diagnostic approaches such as EBV, MRI, colonoscopy, etc. are performed. But this study was limited in that it looked at types of malignancies other than squamous cell carcinoma, including adenocarcinoma. Dr. Regelinkfrom Amsterdam looked at 50 patients and discovered 32% of primary tumors. He also noted that in four patients, PET scan was the sole modality to pick up these tumors, as well in six distant metastases that PET scan was the only modality to pick up. He stated no false-negatives and only two false-positives. Thus, he recommended PET scans as a screening tool to help guide our directed biopsies. This slide shows the neck metastasis as well as the unknown primary lighting up. The bottom picture shows a distant metastasis. Again, the drawback to this study for us is that it did not specifically look at squamous cell carcinoma. He included all tumor types and, again, the behavior of these different types of tumors is unlike that of squamous cell carcinoma. So, are there studies that look specifically at squamous cell carcinoma? Dr. Greven, from Wake Forest, looked at 13 patients. Standard workup, as mentioned earlier, found 3/13 primaries. PET scan only found 1/13, so had a high false-positive rate and two false-negatives. She recommends further study with regard to PET scanning. Another non-advocate for PET scanning is Dr. Nieder from Munich, Germany. He reviewed the literature with regard to the use of PET scanning for unknown primary squamous cell carcinoma. Based on his literature review, he could not advocate that PET scanning have a primary role in squamous cell carcinoma of unknown primary. In 2001, Dr. Schechter, from M.D. Anderson, reviewed the literature as well and come to similar conclusions. In 2003, Dr. Stoeckli, from Zurich, Switzerland, focused on 18 patients, specifically looking at metastatic squamous cell carcinoma undergoing defined clinical radiographic and endoscopic evaluation in parallel with PET scans. As stated earlier, all cervical mets of squamous cell carcinoma were identified using PETs. He also found that there was one false-positive and three false-negatives in 18 patients. Overall, all primaries found with PET scanning were also detected by standard workup, thus indicating that there is no additional benefit to using PET scans for unknown primary. In 2003, Fogarty, from Australia, evaluated 21 patients and found eight potential spots with PET scan. Pathologically, only one of these eight was definitively diagnosed as squamous cell primary. Of note, though, in these 21 patients he did find three distant metastases below the diaphragm. He concluded that PET scan does not necessarily significantly add to the detection of occult primary in a patient that has already been comprehensively evaluated, but he did note that there might some benefits for detecting unsuspected distant metastases. Our standpoint, overall, is that PET scan may not be the standard of care for evaluating unknown primaries of squamous cell carcinoma, but, in the future might have a role in detecting distant metastases. What are the molecular studies being done to try to find these unknown primaries? In 1995, Dr. McDonald had FNA samples of neck metastasis in 23 patients. He had six samples of nasopharyngeal carcinoma, five squamous cell carcinomas, and 12 controls, which included normal lymph nodes as well as other types of malignancies. He used PCR to try to detect EBV DNA. Interestingly, in the 5/5 patients who had nasopharyngeal carcinoma, he detected 5/5 positive EBV DNAs. He detected EBV DNA in two patients with a squamous cell carcinoma. Later on, one of these two patients developed nasopharyngeal carcinoma. None of the controls, including normal tissue and other malignancy types, were EBV positive. Here we see his PCR amplification and the electromicrographs of the EBV. Dr. Lee did a follow-up study in the year 2000 in which 30 FNA samples were taken from neck masses: 10 from nasopharyngeal carcinoma, 19 from squamous cell, and one from diffuse lymphoma. At the top of the slide is the FNA of nasopharyngeal carcinoma, and below is the in situ hybridization of the EBR-1 target. This study noted that every patient with neck metastasis from nasopharyngeal carcinoma had positive signal EBVR-1. None of the nodes from the 20 other cancer patients or non-cancer patients were EBVR signal positive. So, this is interesting with regard to Epstein-Barr virus. Human papilloma virus has been studied extensively in head and neck cancer. Gillison, in the year 2000, had 253 tissues of head and neck cancer. She used PCR to try to detect human papilloma virus and found a 25% incidence of human papilloma virus. In particular, human papilloma virus 16 was 90% positive. She attributed a positive prognosis when they were human papilloma virus positive. There have been two faculty members and many others who have published articles on human papilloma virus. These include Dr. Stewart in 1994, in the Archives of OtolaryngologyHead and Neck Surgery, in which he found a 46% positive rate of human papilloma virus in laryngeal and hypopharynx cancers and noted decreased survival. Dr. Brissett, in 2003 in Clinical Cancer Research found a 46% incidence of human papilloma virus in tonsillar squamous cell carcinoma. Still, much research has to be done in human papilloma virus. Some physicians use toluidine blue staining, especially in the oral cavity, to help define the lesion. Here we see what it looks like before and after staining. This stains DNA as well as RNA, and anaplastic and dysplastic cells take up this staining more readily than normal tissues. Moving on to the molecular identification, Dr. Califano from Hopkins, in 1999, looked at microsatellite analysis of metastatic tumors and compared them to histologically benign surveillance biopsies. Of note, it is very interesting that 55% or 10/18 patients had at least one histopathologic benign mucosal biopsy demonstrate the exact same genetic alteration as a cervical lymph node met. Also of note, each of the three patients in his study that relapsed genetic changes identical to those in the benign mucosal biopsy specimens and in the metastatic lymph nodes. Pictured here are the tumor and the benign biopsy. Below you see a normal pathology slide of the biopsy, but molecularly you can see it has the same changes as the metastasis. This is an interesting area of research, and much work will undoubtedly be done to see where this cancer biology takes us. For now, Dr. Califano thinks that this might help us with regard to telling the physician areas which required future surveillance as well as how to direct our portals for radiation therapy. The management of squamous cell carcinoma of unknown primary is very controversial. There are basically four modalities to treat it: radiation therapy alone, neck dissection alone, neck dissection followed by postop XRT, or radiation therapy first and then a planned neck dissection. The literature is abundant, with articles supporting each one of these methods. There are also controversies as to the extent of radiation therapy needed and the extent of the neck dissection required. In short, this is a Grand Rounds topic within itself, so I will only briefly touch on the points and try to provide a good summary of management and treatment. Radiotherapy alone has been shown equal to surgery alone in early stages of nodal disease such as N 1. Typically, radiation therapy is also used in nonoperative patients. The portals are directed either unilaterally, bilaterally, or directed based on neck involvement. Neck dissection can be used with N 1 disease, with no evidence of extracapsular spread or any history of incisional or excisional biopsy. Neck dissection and postoperative radiation therapy have been reported in the literature, as you can see from this slide. Collitier and Goepfert in 1999 published the M.D. Anderson experience from 1968 to 1992. In their 136 patients, they noted 12 relapses. Of the patients who relapsed, 12 out of 12 had extracapsular spread noted on their pathology and 9 of 12 were noted to have multiple nodes. Thus, from this study and other studies, they concluded that extracapsular spread and multiple lymph nodes have a worse prognosis with regard to regional control and disease specific survival. There are many critics who state that you should not perform radiotherapy first because there has been a reported 44% incidence with poor survival, high postoperative morbidity compared to surgery followed by radiation therapy. The counter argument is that radiation therapy is often used for patients with larger, advanced, inoperable neck disease. Dr. Mendenhall, in 1998, was not opposed to performing planned neck dissection following radiation therapy. Chemotherapy has been investigated with regard to more advanced disease. DeBraud had advocated it for N 3 stage tumors of the neck. Research is ongoing with platinum-based chemotherapy preceding radiotherapy in N 3 disease. A good summary article came out at M.D. Anderson in 1998. Their conclusions were that for N 1 and N 2 stages of the neck, surgical therapy alone or radiotherapy covering all possible primary sites. They also recommended combined modalities in patients with extracapsular invasion, multiple lymph node metastases, and residual disease. Regardless of what your institution uses, meticulous documentation is key for allowing future generations to study management outcomes. . Again, prognosis and survival have been directly correlated with nodal stage and extracapsular spread. Discovery of the primary tumor has been reported to be approximately 30% eventually finding the primary tumor in follow-up. Overall survival from this type of cancer is 20%-55%. Neck control can be expected in 85% of the patients with N 1 disease versus 60% in N 3 disease; distant metastases, 25% in N 1 and a 50% chance of N 3 disease. The lung, liver, and bone are the most common sites of distant metastases. So, where do I see the future of research into unknown primaries? I think there will be extensive research and further refinement of imaging studies such as PET scanning. I also believe that the molecular and cellular studies will further help define cancer biology and help guide therapy. Regardless of treatment modality, or ongoing research, institutions should focus on meticulous documentation on their practice strategies. That way, future generations can look retrospectively at their outcomes. . In summary, there are a couple of points I would like everybody to take home today. Full history and physical, as stated by Hayes Martin, cannot be overemphasized. FNA is the gold standard for evaluating the type of neck metastasis as well as imaging. CT of the neck with contrast helps evaluate the neck. Secondarily, panendoscopy with directed biopsy remains a gold standard. Based on literature review, bilateral tonsillectomy is a safe practice as well. PET scanning, based on my review of the literature, cannot be strongly advocated in locating unknown primaries, specifically in squamous cell carcinoma. PET scanning may be useful in detecting distant metastases. Again, future research in PET scanning is ongoing. But overall, the future is bright with regard to finding these unknown primaries. Case Presentation RB is a 57-year-old man referred to the Michael E. DeBakey VA Hospital ENT clinic by his PCP for a 2-month history of a gradually enlarging, painless right-sided neck mass. He denies any otalgia, hemoptysis, dysphagia, odynophagia, hoarseness, fever, night sweats or weight loss. His medical history is significant for diabetes, hypertension and he has smoked two packs per day for 20 years. He has no family history of cancer except for his 38-year-old son who was recently diagnosed with lung cancer, type unknown. He is married with two children and served in the Army in the late sixties. Examination of the head and neck reveals absence of any mucosal lesions in the upper aerodigestive tract by visual inspection, bimanual palpation, and fiberoptic examination of the nasal cavity, nasopharynx, hypopharynx, and larynx. There is no serous otitis media, trismus, parapharygneal space fullness, or cranial nerve abnormalities. Palpation of the neck shows normal parotid, submandibular, and thyroid glands. There is a 4.0cm x 5.0cm firm, nonpulsatile right level II mass that is freely mobile from the sternocleidomastoid muscle and the carotid sheath structures. CT Neck Scan from an outside hospital revealed lobulated right level II mass suggestive of lymph nodes. No other LAD was detected. CT Chest and Abdomen reveal no evidence for primary neoplasm or metastatic disease within the thorax, abdomen and pelvis. Fine needle aspiration biopsy was performed and reveals metastatic poorly differentiated squamous cell carcinoma. The patient was taken to the operating room for panendoscopy, bilateral tonsillectomy, and directed biopsies of pyriform sinus, base of tongue, glossopharyngeal fold, and nasopharynx. Pathology was negative for malignancy. The patient subsequently underwent a right modified radical neck dissection, with preservation of the internal jugular vein, spinal accessory nerve, level I, and the sternal portion of the sternocleidomastoid muscle. Pathology revealed metastatic poorly differentiated squamous cell carcinoma in four out of twenty lymph nodes with focal extranodal extension. Patient underwent full course of radiation therapy and at 3-month follow up has no evidence of disease. Bibliography: Barrie JR, Knapper WH, Strong EW. Cervical nodal metastases of unknown origin. Am J Surg 1970;120:466-470. Califano J, Westra WH, Koch W, et al. Unknown primary head and neck squamous cell carcinoma: molecular identification of the site of origin. J Natl Cancer Ins 1999;91:599-604. 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