Conclusion

Cancer in the head and neck commonly presents as a cervical lymph node metastasis. A thorough, systematic evaluation will allow the primary site to be identified in most cases. When no primary site is found, endoscopic examination under anesthesia with biopsy, radiography, and other ancillary tests are used to help identify the primary site. A high-resolution imaging study such as CT or MRI is often of value in the identification of primary site among patients without any abnormal history or physical findings other than the neck mass. The selection of biopsy sites should be based, in part, on suspicious areas on imaging studies and the location of the metastatic lymph nodes.

If a primary site is not discovered despite an extensive evaluation, and if an infraclavicular primary site is not suspected, treatment is directed at the cervical disease and potential primary sites. Limited and early neck disease is often treated with a single therapeutic modality, either radiotherapy or cervical lymphadenectomy. Prophylactic treatment to potential primary sites is often not delivered in these cases of limited disease when surgical management is used. Survival is primarily determined by the extent of the cervical metastasis, with 5-year survivals averaging better than 50% among patients with the most limited cervical disease.

REFERENCES

Zitsch III and Smith—CHAPTER 62

1. Richard JM, Micheau C. Malignant cervical adenopathies from carcinomas of unknown origin. Tumori 1977;63:249-258

2. Barrie JR, Knapper WH, Strong EW. Cervical nodal metastases of unknown origin. Am J Surg 1970;120:466-470

3. Mendenhall WM, Mancuso AA, Parsons JT, et al. Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Head Neck 1998;20:739-744

4. Walter MA, Menarguez-Palanca J, Peiper SC. Epstein-Barr virus detection in neck metastases by polymerase chain reaction. Laryngoscope 1992;102:481-485

5. Righi PD, Sofferman RA. Screening unilateral tonsillectomy in the unknown primary. Laryngoscope 1995;105:548-550

6. Davidson BJ, Spiro RH, Patel S, et al. Cervical metastases of occult origin: the impact of combined modality therapy. Am J Surg 1994;168:395-399

7. Templer J, Perry MC, Davis WE. Metastatic cervical adenocarcinoma from an unknown primary tumor: treatment dilemma. Arch Otolaryngol 1981;107:45-47

8. Strasnick B, Moore DM, Abeymayor E, et al. Occult primary tumors: the management of isolated submandibular lymph node metastases. Arch Otolaryngol Head Neck Surg 1990;116: 173-176

9. Gluckman JL, Robbins KT, Fried MP. Cervical metastatic squamous cell carcinoma of unknown or occult primary source. Head Neck 1990;12:440-443

10. Fu KK. Neck node management from unknown primary. Front Radiat Ther Oncol 1994;28:66-78

11. Pearson GR, Weiland LH, Neel HB III, et al. Application of Epstein-Barr virus serology to the diagnosis of North American nasopharyngeal carcinoma. Cancer 1983;51:260-268

12. Harwick RD. Cervical metastases from an occult primary site. Semin Surg Oncol 1991;7:2-8

13. Macdonald MR, Freeman JL, Hui MF, et al. Role of Epstein-Barr virus in fine-needle aspirates of metastatic neck nodes in the diagnosis ofnasopharyngeal carcinoma. Head Neck 1995;17:487-493

14. Robbins KT, Cole R, Marvel J, et al. The violated neck: cervical node biopsy prior to definitive treatment. Otolaryngol Head Neck Surg 1986;94:605-610

15. Ellis ER, Mendenhall WM, Rao PV, et al. Incisional or exci-sional neck node biopsy before definitive radiotherapy, alone or followed by neck dissection. Head Neck 1991;13:177-183

16. Colletier PJ, Garden AS, Morrison WH, et al. Postoperative radiation for squamous cell carcinoma metastatic to cervical lymph nodes from an unknown primary site: outcomes and patterns of failure. Head Neck 1998;20:674-681

17. Righi PD, Sofferman RA. Screening unilateral tonsillectomy in the unknown primary. Laryngoscope 1995;105:548-550

18. Jesse RH, Perez CA, Fletcher GH. Cervical node metastasis: unknown primary cancer. Cancer 1973;31:854-859

19. Davidson BJ, Spiro RH, Patel S, et al. Cervical metastases of occult origin: the impact of combined modality therapy. Am J Surg 1994;168:395-399

20. Harper CS, Mendenhall WM, Parsons JT, et al. Cancer in the neck nodes with unknown primary site: role of mucosal radiotherapy. Head Neck 1990;12:463-469

21. Maulard C, Housset M, Brunel P, et al. Postoperative radiation therapy for cervical lymph node metastases from an occult squamous cell carcinoma. Laryngoscope 1992;102:884-890

22. Bataini JP, Rodriguez J, Jaulerry C, et al. Treatment of metastatic neck nodes secondary to an occult epidermoid carcinoma of the head and neck. Laryngoscope 1987;97: 1080-1084

23. De Braud F, Heilbrun LK, Ahmed K, et al. Metastatic squa-mous cell carcinoma of an unknown primary localized to the neck—advantages of an aggressive treatment. Cancer 1989; 64:510-515

24. Jeremic B, Zivic DJ, Matovic M, Marinkovic J. Cisplatin and 5-fluorouracil as induction chemotherapy followed by radiation therapy in metastatic squamous cell carcinoma of an unknown primary tumor localized in the neck. A phase II study. J Chemother 1993;5:262-265

25. Wang RC, Goepfert H, Barber A, Wolf PF. Squamous cell carcinoma metastatic to the neck from an unknown primary site. In: Larson DL, Ballantyne AJ, Guillamondegu OM, eds. Cancer in the Neck: Evaluation and Treatment. New York: Macmillan;1986:183-192

26. Talmi YP, Wolf GT, Hazuka M, Krause CJ. Unknown primary of the head and neck. J Laryngol Otol 1996;110: 353-356

Patients with cancer of the upper aerodigestive tract (UADT) commonly present to their primary caregivers with a mass in the neck. It is important that an appropriate evaluation be undertaken to include a search for the primary tumor from which the cervical metastasis developed. It is the inability to find the source that has led to the concept of the unknown primary. However, the meaning of unknown primary has a great deal to do with the extent of the treating physician's ability to search for this often elusive lesion. The staging of the tumor is TX when complete evaluation has not been accomplished. This is changed to TO if a complete evaluation has not revealed the primary tumor.1 Frequently, surgical excision of a neck mass is carried out to secure a diagnosis after a course or two of antibiotics has failed to cause resolution without consideration of a neoplastic cause for the mass. Several deleterious effects can arise from this course of treatment if the disease process proves to be malignant. Violation of the fascial planes of the deep neck may give a decreased rate of control in the neck when compared to formal neck dissection, especially if radiotherapy is not employed. Perhaps more distressing is the potential for the primary lesion to go undiagnosed until local symptoms prompt further investigation. It was this very situation that prompted warnings from Martin as early as 1961 when he wrote, "exci-sional or incisional lymph node biopsy should be used only as a last resort and then preferably by the surgeon who accepts responsibility for the treatment himself if the diagnosis eventually proves to be cancer."2

The pivotal question that lies at the heart of this subject is: How should the head and neck surgeon approach a patient with a neck mass? This process begins with establishing a diagnosis. The evaluation includes a physical examination, a careful history, radiologic studies, histologic studies, and often examination under anesthesia.

A thorough history and physical examination includes specific questioning regarding exposure to potentially carcinogenic agents such as ethanol and tobacco products. A complete exam is carried out to visualize all visible surfaces of the UADT possible during an office examination. This exploration includes an exam with a flexible fiberoptic nasopharyngoscope to evaluate otherwise difficult to visualize areas such as the fossae of Rosen-mueller and the pyriform sinuses. A modified Valsalva maneuver may be performed with the fiberoptic laryngoscope in place to maximally expose the hypopharynx.

In most patients in whom the cervical mass is suspected to be malignant, the primary site will be apparent on physical exam in the office setting. When the primary is not visible, additional effort is necessarily spent to search for the source of the neck metastasis. Identification of the primary site at the time treatment has begun has been shown to improve ultimate rates of disease control.3 Several tools are available to help with this search.

Histologic evaluation of the neck mass is best first approached with fine needle aspiration biopsy (FNAB). This technique has been shown to be both sensitive and specific for detecting many of the common histologic entities responsible for head and neck neoplasms.4 Accuracy approaching 100% has been described in diagnosing squamous cell carcinoma (SCC).4 This technique is easily carried out in the office and for this reason the histology of the cervical disease is usually known by the time the patient is evaluated under anesthesia. It is our practice to attempt histologic diagnosis in patients with a neck mass on the day of their first presentation. In most cases involving neoplasm, SCC will be the histologic class of cancer. There are other entities that can present as masses in the neck. These include tumors of thyroid or salivary gland origin, lymphoma, benign masses, and rare tumors such as sarcoma. If FNAB does not suggest carcinoma, open biopsy may be required to make a diagnosis. The remainder of this discussion focuses on SCC presumed to be metastatic to the neck.

A new dimension was added to this diagnostic scheme during the 1970s with the advent of computed tomographic (CT) scanning. This modality has continued to evolve with advancements in computer software and now is capable of providing the clinician with images with quite good resolution. This three-dimensional imaging technique, as well as the techniques of magnetic resonance imaging (MRI) and positron emission tomography (PET) scanning, extends the evaluation beyond that accomplished through physical inspection of mucosal sur-faces.5'6 As early as 1983, Muraki et al.7 were convinced that CT evaluation "should be used as part of the routine evaluation of patients with this clinical problem (unknown primary)." This group was able to find a primary site in four cases among 17 patients who had been previously evaluated with a negative endoscopic examination under anesthesia. We routinely obtain a CT for all patients with a neck mass thought to be neoplastic in origin. The information gained from contrast-enhanced CT scan from skull base to clavicles often provides crucial information beyond that gained by physical examination, especially for patients with short or bulky necks with difficult physical examinations. Continuous refinement of additional imaging techniques has given rise to new modalities such as MRI and PET scanning that hold future promise in helping to find an unknown primary. Great effort is now under way to explore physiochemically based imaging that can differentiate normal and malignant tissue.

In contrast to CT and MRI, PET scanning capitalizes on the different physiochemical properties of tumor and nontumor cells.8 Imaging is possible because tumor cells have been shown to have increased glycolysis (compared with normal cells) as monitored by PET using 18F-labeled 2-deoxy-D-glucose. Work done by Braams et al. has shown this modality to have approximately 30% sensitivity for detecting an unknown primary as we have defined above.8 It is still difficult to recommend PET scanning as the standard of care in the search for an unknown primary because of its low sensitivity.

MRI scanning has allowed greater resolution for evaluating soft tissue structures than does CT. As a result, MRI is most useful when there is question of whether a soft tissue structure is fluid trapped in a paranasal sinus or a solid anatomically abnormal tissue mass as often presents a dilemma when evaluating anomalies of the paranasal sinuses. Additionally, resolution afforded by MRI is unsurpassed when evaluating intracranial structures for metastatic involvement because MRI is able to show subtle differences between similar soft tissues that are not discernible with CT.

Molecular genetics has received attention as a potential tool in the evaluation of patients with a cervical metastasis. This approach has found greatest application through the association between Epstein-Barr virus (EBV) and nasopharyngeal carcinoma. Macdonald et al.9 have identified a clear association between polymerase chain reaction (PCR)-amplified sequences of EBV in FNAB samples of cervical metastatic disease and presence of nasopharyngeal carcinoma. This test is limited by the fact that a positive result only proves exposure to EBV. Many more patients have been exposed to EBV than actually have nasopharyngeal carcinoma. Until specificity can be improved, this assay will have an unacceptably high false-positive rate. It does, however, hold promise as an interesting diagnostic tool.

An extension of physical examination is endoscopy under anesthesia. The combination of laryngoscopy, bronchoscopy, esophagoscopy, nasopharyngoscopy with biopsies directed at any mucosal abnormalities is needed. In the absence of identifiable tumor, directed biopsies to likely sites of occult disease such as base of tongue, pyriform sinus, larynx, and tonsils are needed to reveal an occult primary. Questions have arisen as to whether it is necessary to remove the entire tonsil as a means of biopsy.

Tonsillectomy has been advocated by many as a part of the search for a primary of the UADT. Lapeyre and collegues showed that 26% of 87 patients with cervical metastases of unknown primary proved to have a lesion of origin in the tonsil. The author asserts that this intervention (tonsillectomy) saved this 26% of his group of patients from the morbidity of receiving radiation to the larynx and nasopharynx and further supports this intervention by demonstrating significant cases of appearance of a previously unknown primary tumors of the tonsil in formerly radiated fields. They also state that "tonsillectomy never induced specific complications" (in his group of patients).10 Mendenhall et al.11 showed similar rates of discovery (35%) in their series of patients (n = 34) undergoing ton-sillectomy in search of a primary. They point out that their patients received tonsillectomies only when physical exam or radiographic studies indicated the tonsil as a primary site. Righi and Sofferman12 echo this experience in their group of 19 patients, 32% of whom proved to have occult primary tumors in their tonsils.

We agree that tonsillectomy, although not completely without complications, is worthwhile for patients not at increased risk of bleeding. Moreover, we believe that removing the entire tonsil will demonstrate lesions that can be overlooked by noncomprehensive tonsil biopsies. A strong argument for bilateral tonsillectomy exists in avoiding a confusing physical examination secondary to oropharyngeal asymmetry for future examiners. This procedure is likely to demonstrate a site of primary in a significant number of patients. The capacity to narrow treatment fields when a primary tumor is found helps decrease morbidity. Patients with a tonsil primary that has been treated appropriately have significantly better prognoses than do patients whose primaries remain unknown.3'7 For these reasons, it is our practice to perform bilateral tonsillectomy as part of our routine directed biopsies in the search for an occult primary.

We believe that only after an extensive search that reveals no primary lesion can a neck metastasis be said to have no primary and therefore be staged as T0 rather than TX.1 Several theories exist to explain this phenomenon. The simplest proposes that a primary tumor does exist and is not found. Others propose that a primary lesion did exist but was eliminated by the immunologic defense mechanisms. Still other investigators suggest that epithelial cells lining a congenital cyst can convert to malignant cells that present as cervical carcinoma without an apparent primary source. Although there is no definite patho-physiologic mechanism to explain the occult primary there is a general consensus that epithelial malignancy does not arise de novo in the neck.

The standard of care at our institutions for patients in whom the primary remains occult is most often neck dissection performed at the diagnostic endoscopy with biopsies directed at high-risk sites as outlined above, followed by radiotherapy. If no primary is found at endoscopy, it is safe to assume that the primary (if present) is a T1 at most and, as such, is amenable to treatment with radiation as a single modality. The field of the radiation is designed to encompass all potential mucosal sites of the primary tumor, usually including naso-, oro-, and hypopharynx as well as larynx and both sides of the neck. There is controversy concerning several aspects of this routine.

Coster et al.13 take issue with the assertion that all patients with unknown primary sites should receive radiation after neck dissection. They make the point that some of these patients will have disease originating from below the clavicles and that irradiation of wide mucosal fields will only increase the morbidity for these people. They also state that approximately one-half of the tumors eventually identified as potential head and neck primaries present more than 5 years after the original and must be considered second primaries. As such, these patients would not benefit from prior radiotherapy, and they would have one less treatment option if a new lesion is diagnosed in the field of previous radiation. This group does agree that N2 or higher disease and histologic evidence of extracapsular spread or lymphoep-ithelioma are indications for postoperative radiotherapy both to the neck and to potential sites of the primary tumor.13 The experience of Mohit-Tabatabai and colleagues14 mirrors these findings. These workers found 8 of 35 patients treated with radiation had primaries arise at a later date in field (although it is not clear how far out from treatment). The numbers of patients in these studies are too small to propose definite conclusions. However, we feel that the decision to withhold radiation in the face of unknown primary disease can only be made with a much greater experience and should not be routinely advised on the basis of the available data.

There is strong support for bilateral technique (as opposed to treating only the neck with obvious neoplastic disease) when using radiotherapy to treat cervical metastases from an unknown primary. Reddy and Marks15 demonstrated significantly lower rates of subclinical metastasis in the contralateral neck (higher rates of control) when both sides of the neck were irradiated. Our groups support this practice not only because it promises better locoregional control, but also because it does not add significant morbidity as compared with an ipsilateral technique.

The potential to improve management of patients with an unknown primary SCC metastatic to the neck through administration of adjuvant chemotherapy is attractive. However, there are currently no strong data to support the use of chemotherapy in this setting. Khansur et al.16 prospectively showed a 53% response rate in patients with occult primary disease and cervical metastasis treated with a combination of cisplatinum and 5-fluorouracil (5-FU). Similarly, DeBraud et al.17 showed that the addition of either of these agents to a regimen of surgery and XRT seemed to improve outcome. Tabatabai and his group14 also support the idea that adjuvant chemotherapy holds much promise in improving survival in patients with cervical SCC of unknown primary. No survival advantage has been demonstrated with any of these regimens and further study is needed before acceptable regimens can be adopted. At this time, the role of chemotherapy is limited to palliative treatment, as an adjuvant to radiotherapy in the treatment of nasopharyngeal cancer, and as part of controlled clinical trials. The use of chemotherapy in other situations is strongly discouraged.

It is common for practitioners in a tertiary referral center to see patients with neck metastasis from an unknown primary who have already received treatment. Most commonly the patient has undergone open biopsy of the neck mass and it is at this point that the histologic diagnosis is made. Mack et al.18 have claimed that there is no detriment to outcome in patients with cervical disease diagnosed by open biopsy whose primary tumor has remained occult after an extensive search as outlined above as long as radiotherapy is given as the next step in treatment after the biopsy. Others support this idea.19-22 Many times, there has not been significant search for a site of primary, and it is then incumbent on the treating physician to undertake this search. There is often concern that the scar resulting from the incisional biopsy may be seeded with tumor. It is our practice to excise this scar if it can be included in an incision for the definitive neck dissection and to have it remain attached to the neck dissection specimen. Parsons et al.20 have discussed the management dilemma of patients diagnosed with cervical carcinoma of unknown primary by open biopsy. They point out that the initial biopsy and possible hematoma have the potential to spread tumor cells outside of the normal fascial planes in a manner that is impossible to predict. They believe that an operation to eradicate these malignant cells is difficult to design and that in this situation radiation therapy should be the next step in treatment. These investigators suggest that radiotherapy to both sides of the neck is preferred, in the belief that open biopsy of the neck can alter patterns of lymph flow significantly enough to change normal patterns of metastasis.

Appropriate management of the majority of patients with SCC metastatic to the neck from an unknown primary (T0, N+) results in control of locoregional disease. Outcome has been shown to be linked to several identifiable factors. Survival decreases as tumor stage increases. Extracapsular spread in cervical metastatic nodal disease portends a worse outcome both in terms of local control and overall survival. It is prudent to follow these patients frequently, as they are likely to demonstrate a mucosal neoplasm over time. Some have advocated the practice of close observation with fiberoptic endoscopy in an office setting during the course of radiotherapy. These clinicians believe that radiation tumoritis will often make the primary site visually obvious and allow a planned excision. It is hoped that work in areas such as adjuvant chemotherapy will hold promise for improved outcomes, especially with advanced-stage tumors, in the near future.

REFERENCES

Arnold and Hoffman—CHAPTER 63

1. American Joint Committee on Cancer. Cancer Staging Man- 3. Marcal-Vega VA, Cardenes H, Perez CA, et al. Cervical metas-ual. 5th Ed. Philadelphia: Lippincott-Raven; 1997 tases from unknown primaries: radiotherapeutic management

2. Martin H. Untimely lymph node biopsy. Am J Surg 1961; and appearance of subsequent primaries. Int J Radiat Oncol 102:17-18 Biol Phys 1990;19:919-928

4. Shaha A, Webber C, and Marti J. Fine-needle aspiration in the diagnosis of cervical lymphadenopathy. Am J Surg 1986;152: 420-423

5. Mancuso AA, Hanafee WN. Elusive head and neck carcinomas beneath intact mucosa. Laryngoscope 1983;93:133-139

6. Schaefer SD, Merkel M, Diehl J, Maravilla K, Anderson R. Computed tomographic assessment of squamous cell carcinoma of oral and pharyngeal cavities. Arch Otolaryngol 1982; 108:688-692

7. Muraki AS, Mancuso AA, Harnsberger HR. Metastatic cervical adenopathy from tumors of unknown origin: the role of CT. Radiology 1984;152:749-753

8. Braams JW, Pruim J, Kole AC, et al. Detection of unknown primary head and neck tumors by positron emission tomography. Int J OralMaxillofac Surg 1997;26:112-115

9. Macdonald MR, Freeman JL, Hui MF, et al. Role of Epstein-Barr Virus in fine-needle aspirates of metastatic neck nodes in the diagnosis of nasopharyngeal carcinoma. Head Neck 1995; 487-493

10. Lapeyre M, Malissard L, Peiffert D, et al. Cervical lymph node metastasis from an unknown primary: is a tonsillectomy necessary? Int J Radiat Oncol Biol Phys 1997;39:291-296

11. Mendenhall WM, Mancuso AA, Parsons JT, Stringer SP, Cas-sisi NJ. Head Neck 1998;20:739-744

12. Righi PD, Sofferman RA. Screening unilateral tonsillectomy in the unknown primary. Laryngoscope 1995;105:548-550

13. Coster JR, Foote RL, Olsen KD, Jack SM, Schaid DJ, DeSanto LW. Cervical nodal metastasis of squamous cell carcinoma of unknown origin: indications for withholding radiation therapy. Int J Radiat Oncol Biol Phys 1992;23:741-749

14. Mohit-Tabatabai MA, Dasmahapatra KS, Rush Jr. BF, Ohan-ian M. Management of squamous cell carcinoma of unknown origin in cervical lymph nodes. Am Surg 1986;52(3):152-154

15. Reddy SP, Marks JE. Metastatic carcinoma in the cervical lymph nodes from an unknown primary site: results of bilateral neck plus mucosal radiation vs. ipsilateral neck irradiation. Int J Radiat Oncol Biol Phys 1997;37:797-802

16. Khansur T, Allred C, Little D, Anand V. Cisplatin and 5-Fluorouracil for metastatic squamous cell carcinoma from unknown primary. Cancer Invest 1995;13(3):263-266

17. DeBraud F, Heilburn LK, Ahmed K, et al. Metastatic squamous cell carcinoma with unknown primary localized to the neck. Cancer 1989;64:510-515

18. Mack Y, Parsons JT, Mendenhall WM, Stringer SP, Cassisi NJ, Million RR. Squamous cell carcinoma of the head and neck: management after excisional biopsy of a solitary metastatic neck node. Int J Radiat Oncol Biol Phys 1993;25:619-622

19. Ellis ER, Mendenhall WM, Rao PV, et al. Incisional or exci-sional neck-node biopsy before definitive radiotherapy, alone or followed by neck dissection. Head Neck 1991;13:177-183

20. Parsons JT, Million RR, Cassisi NJ. The influence of excisional or incisional biopsy of metastatic neck nodes on the management of head and neck cancer. Int J Radiat Oncol Biol Phys 1985;11:1447-1454

21. Robbins KT, Cole R, Marvel J, Fields R, Wolf P, Goepfert H. The violated neck: cervical node biopsy prior to definitive treatment. Otolaryngol Head Neck Surg 1986;94:605-610

22. Wang RC, Goepfert H, Barber AE, Wolf P. Unknown primary squamous cell carcinoma metastatic to the neck. Arch Otol Head Neck Surg 1990;116:1388-1393

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