Association of cystic neck metastases and human papillomavirus-positive oropharyngeal squamous cell carcinoma.
A 54-year-old male presented with a 4.3 X 3.5 X 2.2-cm, right upper neck mass, located just inferior to the angle of the mandible. The patient had no other symptoms and was a nonsmoker. Direct laryngoscopy and nasopharyngoscopy revealed no visible mucosal abnormalities of the upper aerodigestive tract. A fine-needle aspiration was performed, which yielded cyst contents and occasional squamous epithelial cells. The patient underwent excisional biopsy of the right neck mass, with a clinical diagnosis of branchial cleft cyst. The lymph node was largely replaced by a ribbon-like proliferation of predominantly nonkeratinizing squamous epithelium with prominent cystic architecture (Figure 1, A). The epithelium consisted of small, poorly differentiated, basaloid cells with high nuclear to cytoplasmic ratios and with little surface maturation (Figure 1, B). Given these findings, a diagnosis of metastatic nonkeratinizing squamous cell carcinoma with cystic change was rendered. Subsequent ipsilateral tonsillectomy revealed a small, nonkeratinizing squamous cell carcinoma (Figure 1, C).
Human papillomavirus (HPV) is an important cause of a subset of head and neck squamous cell carcinomas. Infection with HPV is required for the development of uterine cervix squamous cell carcinoma. Its etiologic role in nonanogenital squamous cell carcinomas has been less clear until recently. During the past decade, several studies have demonstrated a causal role of HPV infection with some squamous cell carcinomas of the oropharynx. The palatine tonsils and base of tongue (lingual tonsil) are preferentially affected. Most recent studies from the United States, using in situ hybridization and polymerase chain reaction methodologies, demonstrate that approximately 65% of oropharyngeal squamous cell carcinomas can be attributed to HPV infection. (1-2) Human papillomavirus type 16 accounts for 90% to 95% of these [HPV.sup.+] oropharyngeal squamous cell carcinomas. (3)
Human papillomavirus-associated head and neck cancer demonstrates unique clinicopathologic features compared with conventional squamous cell carcinomas of the oral cavity and oropharynx. (3) Patients with [HPV.sup.+] oropharyngeal squamous cell carcinoma tend to be younger, are less likely to have significant exposure to tobacco and alcohol, are more responsive to chemoradiation therapy, and, therefore, have improved clinical outcomes. Human papillomavirus-positive oropharyngeal squamous cell carcinomas are also distinguished by characteristic and reproducible histopathologic features. Similar to oropharyngeal cancer, in general, they often produce cystic cervical lymph node metastases that may precede recognition of a primary tumor. This combination of findings often results in misdiagnosis as branchial cleft cysts or as carcinoma arising in a branchial cleft cyst.
The purpose of this overview is to summarize the current concept of carcinomas arising in branchial cleft cysts (so-called, branchiogenic carcinoma), indicating that most, if not all, represent cystic metastases from oropharyngeal squamous cell carcinoma primaries. In addition, a brief review of HPV-related oropharyngeal squamous carcinoma, with particular attention to its unique clinicopathologic features, will be presented.
[FIGURE 1 OMITTED]
BRANCHIOGENIC CARCINOMA VERSUS OROPHARYNGEAL CARCINOMA WITH CYSTIC METASTASES
Developmental defects of the second branchial cleft are a common cause of lateral neck masses. The branchial apparatus appears about the fourth week of gestation and consists of 6 paired mesodermal arches separated externally by 5 paired ectodermal clefts and internally by 5 paired endodermal pouches. (4) Shortly after appearance of the branchial apparatus, the second arch proliferates and extends caudally toward the epicardial ridge. Fusion with the epicardial ridge results in an ectoderm-lined cavity, the cervical sinus of His, which encloses the second, third, and fourth branchial clefts. Failure of this structure to develop or involute properly results in most branchial anomalies, the most common of which are related to the second branchial cleft (90%-95%). Most of these (75%) are cysts characterized by a uniform, smooth, unilocular space lined by stratified squamous epithelium (90%), respiratory epithelium (8%), or a combination and are typically surrounded by a variable amount of lymphoid stroma.
Approximately 11% to 21% of lateral neck cysts that are presumed to be branchial cleft cysts turn out to be cystic metastases of squamous cell carcinomas after histopathologic analysis. (5-7) Because some of these patients do not have a known primary tumor, the possibility of a carcinoma arising from the lining of a branchial cleft cyst is often entertained. Dr von Volkman (8) first proposed the concept of carcinoma arising in a branchial cleft cyst in 1882 and coined the term branchiogenic carcinoma. Although some authors embraced this concept, others were not as willing as reflected by the R. A. Willis comment, "Branchiogenic carcinoma should be neither tolerated as a clinical diagnosis nor as a histologic finding on surgical material." (9) Willis and others argued that a thorough search for a primary carcinoma must be performed before accepting this hypothesis. Martin et al (9) published a study in 1950 in which 250 patients with alleged branchiogenic carcinomas were systematically reviewed. Of these cases, the authors concluded that only 3 (1.2%) represented possible examples of carcinoma arising in a branchial cleft cyst, with the remainder representing metastatic cystic squamous cell carcinomas. Given these findings, they proposed strict criteria for making a tentative diagnosis of branchiogenic carcinoma (Table 1).
Based on a review of the literature, it can be reasonably concluded that, if they exist at all, branchiogenic carcinomas are exceedingly rare. Two of the largest of such studies failed to identify a single case meeting these criteria among 440 patients, (10-11) most eventually proving to be cystic lymph node metastases from a primary squamous cell carcinoma in the head and neck region. In fact, most are shown to be cystic metastases from squamous cell carcinomas arising in Waldeyer tonsillar ring. (12-13) Specifically, palatine tonsil (tonsillar crypt) and lingual tonsil squamous cell carcinomas are notorious for producing cystic metastases that are often solitary. Palatine tonsil primaries are also well known to result in early metastases, even when the primary tumor is small and often clinically undetectable. (13)
Squamous cell carcinomas arising in other sites, such as the esophagus, hypopharynx, nasopharynx, and larynx can produce cystic neck metastases, but they generally do not have the histologic features characteristic of most oropharyngeal cystic squamous cell carcinoma metastases. (13) Oropharyngeal cystic metastases can be unilocular but typically are composed of multiple variably sized cysts (Figure 2, A). The cystic spaces are associated with variable amounts of intracystic papillary growths as well as endophytic proliferations within the underlying lymph node stroma. Tonsillar squamous cell carcinomas and their metastases are typically composed of a uniform, ribbonlike proliferation (Figure 2, B) of predominantly nonkeratinizing, squamous epithelium, with a transitional (Figure 2, C) or basaloid (Figure 2, D) appearance. The cells have high nuclear to cytoplasmic ratios with little appreciable surface maturation and typically do not show diffuse, marked cytologic anaplasia. Although most are predominantly nonkeratinizing, foci of abrupt keratinization are present in many tumors (Figure 2, D). These histologic features essentially recapitulate the tonsillar surface and crypt epithelium from which these carcinomas originate.
[FIGURE 2 OMITTED]
Patients who present initially with cystic squamous cell carcinoma involving cervical lymph nodes should undergo imaging studies as well as endoscopy to search for a primary tumor. If the metastasis has the morphology described above, the primary tumor will almost always be located in the palatine or lingual tonsil region. If no obvious primary tumor is identified, biopsies from the base of the tongue, nasopharynx, and pyriform sinus (hypopharynx) should be taken. In addition, diagnostic tonsillectomy on the ipsilateral side should be performed. Some authors even recommend bilateral tonsillectomies because up to 10% of cases will have contralateral or bilateral tonsillar squamous cell carcinomas; however, this is not standard practice in many institutions. (14) The tonsillectomy specimens should be thinly sectioned, and if no lesion is grossly identified (as is often the case), the entire specimen should be submitted for histologic evaluation. In recent years, it has become clear that the epidemiology and pathogenesis of this subset of head and neck cancer is changing.
HPV AND OROPHARYNGEAL SQUAMOUS CELL CARCINOMA
In the United States, between 1973 and 2001, the incidence of oral (mobile) tongue, base of tongue, and palatine tonsil squamous cell carcinoma increased significantly in patients between 20 and 44 years of age (annual percentage changes of +2.1, +1.7, and +3.9, respectively) according to data from the Surveillance, Epidemiology, and End Results database (US National Cancer Institute, Bethesda, Maryland). (15) In contrast, the incidence of squamous cell carcinoma at other oral and head and neck sites either decreased or remained stable. Although oral/ oropharyngeal squamous cell carcinoma in adults 55 years and older is strongly associated with tobacco or alcohol use, the risk factors in this younger cohort are less certain. It is likely that some other factor is playing a role in its carcinogenesis, especially in nonsmokers and nondrinkers.
High-risk HPV (especially HPV16) has emerged as an important cause for a subset of head and neck squamous cell carcinomas, especially for tumors arising in the oropharynx. Around two-thirds (20%-90% in different studies) of oropharyngeal squamous cell carcinomas in the United States harbor HPV DNA. (1-2) Several studies have shown that, in these tumors, HPV DNA is present in high copy numbers, is frequently integrated, is transcriptionally active, and is localized to nuclei in both primary and metastatic tumor cells. (16) This indicates tumor specificity and supports the vital role of the virus in carcinogenesis.
Human papillomavirus-positive squamous cell carcinomas have been shown to have genetic alterations indicative of HPV oncoprotein function that are distinct from those present in [HPV.sup.-] tumors. (3) As with many human cancers, both [HPV.sup.+] and [HPV.sup.-] oral cancers demonstrate alterations of the p53 and pRB tumor suppressor pathways, but the alterations occur via different mechanisms in these 2 groups. Specifically, p16 tumor suppressor protein is paradoxically over-expressed in virtually all [HPV.sup.+] tumors. (3) This results from up regulation, which occurs in response to E7 viral oncoprotein-mediated functional inactivation of pRB. Therefore, similar to HPV-related uterine cervix cancers, p16 immunohistochemistry can be used as a surrogate marker for high-risk HPV positivity in these tumors. In contrast, in [HPV.sup.-] tumor alterations of the pRB pathway more frequently result from p16 mutations and alterations of cyclin D1. Although most tobacco- and alcohol-related head and neck squamous cell carcinomas manifest TP53 mutations, [HPV.sup.+] carcinomas usually have wild-type TP53. Dysregulation of p53 is mediated, instead, by E6 viral oncoprotein-mediated degradation.
Epidemiologic studies also support the association of HPV infection with an increased risk for oropharyngeal squamous cell carcinoma. Analogous to uterine cervix squamous cell carcinoma, several epidemiologic studies have demonstrated a link between oropharyngeal HPV infection, [HPV.sup.+] squamous cell carcinoma, and certain sexual behaviors. (17) Young age at first intercourse, increasing number of lifetime sexual partners, personal history of genital warts, and ever having performed oral sex have been associated with oral cancer in men. (18-20) In women, increasing number of lifetime sexual partners is associated with oral cancer risk. Certain sex behaviors also impart increased risk of HPV-related oral carcinoma, including practices involving oral-genital and oral-anal contact. (19-20)
The incidence of HPV-related head and neck squamous cell carcinoma is increasing. Using the SEER database, Chaturvedi et al (21) showed that, compared with HPV-unrelated oral squamous cell carcinoma, HPV-related oral squamous cell carcinoma incidence rates increased significantly from 1973 to 2004 in the United States (annual percentage change +0.8; P < .001). This increase was noted to be most prominent for younger individuals, similar to the findings of others, and particularly among men. In fact, it is currently estimated that 15% to 20% of new cases of head and neck squamous cell carcinoma in the United States are HPV-related. (3)
Human papillomavirus-related oropharyngeal squamous cell carcinomas are associated with unique demographic, histopathologic, molecular, and behavioral characteristics (Table 2). Patients with [HPV.sup.+] tumors tend to be younger (by approximately 5 years) and are much less likely to have tobacco or alcohol exposure compared with patients with [HPV.sup.-] tumors. (3) Human papillomavirus-positive tumors have a marked predilection for the palatine and lingual tonsils, where they account for about two-thirds of carcinomas arising at these sites in the United States.
Human papillomavirus-positive tumors have a characteristic morphologic appearance and tend to be non-keratinizing with basaloid morphology and are more frequently poorly differentiated (Figure 3, A). (20,22) Although HPV-related oropharyngeal squamous cell carcinomas are predominantly nonkeratinizing and basaloid, they often have foci of abrupt keratinization and, occasionally, have broad areas of such keratinization (Figure 3, B through D). However, they are never of the conventional keratinizing squamous cell carcinoma type and will still have the characteristic basaloid morphology in the nonkeratinized areas. Although most of these carcinomas have this basaloid morphology, they are not usually true basaloid squamous cell carcinomas as described by Wain et al. (23) However, some true basaloid squamous cell carcinomas of the oropharynx have been shown to be [HPV.sup.+]. (24) Another characteristic is that they tend to produce cystic lymph node metastases to cervical lymph nodes.
[FIGURE 3 OMITTED]
About one-half of [HPV.sup.+] oropharyngeal carcinomas result in cystic nodal metastases. (25) In fact, recent investigations have shown that most cystic cervical node metastases are from [HPV.sup.+] palatine or lingual tonsil primaries. Goldenberg et al (25) evaluated 100 consecutive patients who underwent neck dissection at a single institution between 2002 and 2004 and identified cystic metastases in 20 of them. Among these 20 patients, 17 (85%) had primary tumors located in the palatine/lingual tonsil and 3 (15%) had unknown primaries. Using in situ hybridization, 13 (84%) of these patients were found to have [HPV.sup.+] tumors, in contrast to none of the 21 patients with solid metastases. In addition, 2 of the 3 patients (67%) with unknown primaries were [HPV.sup.+] in the metastatic tumors, suggesting a likely origin from the oropharynx. The authors concluded that cystic nodal metastases are strongly associated with [HPV.sup.+] palatine/lingual tonsil squamous cell carcinoma, a finding that reflects my own practice.
The morphologic features described for cystic metastases from [HPV.sup.+] oropharyngeal squamous cell carcinoma are very similar to those described for "branchiogenic carcinoma." (13) In my own practice, when confronted with cystic nodal metastases with this characteristic, moderately poor differentiation, nonkeratinizing, or "basaloid" morphology, I suggest that the primary tumor is likely to be found in the palatine tonsil or base of tongue (lingual tonsil). In situ hybridization/polymerase chain reaction for high-risk HPV (Figure 3, C) or p16 immunohistochemistry (Figure 3, D) can also be useful in identifying HPV-related cancers.
Pathologists will likely be asked more frequently to test head and neck squamous cell carcinomas for HPV status. This primarily is a result of several studies showing that patients with [HPV.sup.+] tumors, especially nonsmokers, have improved responses to chemoradiation therapy and improved outcomes. (3,21,26) Most of these earlier studies were retrospective, and not all authors have found a survival advantage for HPV-related carcinomas. However, a recent prospective study from the group at Johns Hopkins investigated the association of HPV status with a standardized treatment protocol, evaluating response and survival among patients with laryngeal and oropharyngeal squamous cell carcinomas. (26) In this study 40% (38 of 95) of patients were [HPV.sup.+], all of whom had oropharyngeal cancers; in fact, 63% of oropharyngeal cancers were [HPV.sup.+]. Patients with [HPV.sup.+] tumors had significantly higher response rates following induction chemotherapy as well as following chemoradiation treatment. In addition, they had significantly improved overall and progression-free survival, with a 61% lower risk of death and a 62% lower risk of progression compared patients with [HPV.sup.-] tumors. The reasons for the improved therapy response are uncertain but may be related to having an intact apoptic mechanism with the presence of wild-type TP53.
In summary, HPV-related oropharyngeal squamous cell carcinoma is a unique subgroup of head and neck squamous cell carcinoma that can be considered a distinctive clinicopathologic entity. It differs from [HPV.sup.-] squamous cell carcinoma in patient demographics, risk factors, molecular alterations, tumor histopathology, and behavior (Table 2). These patients tend to be younger, with less cumulative tobacco exposure, and with tumors arising in the palatine or lingual tonsil, which have a nonkeratinizing, often poorly differentiated, morphology. They respond better to chemotherapy and radiation and have improved survival compared with patients with [HPV.sup.-] tumors. In addition, they often present initially with cystic neck metastases that masquerade clinically as branchial cleft cysts.
Recognition of this unique subset of head and neck cancer is important for several reasons. First, in patients who present initially with cystic neck metastases, the pathologist should suggest the likely primary site as the palatine tonsil or base of tongue, recognizing that "branchiogenic carcinomas" are essentially nonexistent. This will allow for the proper and most efficacious therapy to be delivered because HPV-related tumors have different treatment responses and outcomes. Because of the differing response to therapy and improved prognosis, these patients are increasingly being offered organ-preserving therapeutic regimens as first-line therapy at some institutions in contrast to those patients with HPV-unrelated tumors. Therefore, it is quite certain that the pathologists' role in defining [HPV.sup.+] oropharyngeal squamous cell carcinomas will become increasingly more important.
(1.) Hammerstedt L, Lindquiest D, Dahlstrand H, et al. Human papillomavirus as a risk factor for the increase of tonsillar cancer. Int J Cancer. 2006;119(11): 2620-2623.
(2.) Gillison ML, D'Souza G, Westra W, et al. Distinct risk factor profiles for human papillomavirus type 16-positive and Human papillomavirus type-16 negative head and neck cancers. J Natl Cancer Inst. 2008;100(6):407-420.
(3.) Fakhry C, Gillison ML. Clinical implications of human papillomavirus in head and neck cancers. J Clin Oncol. 2006;24(17):2606-2611.
(4.) Benson MT, Dalen K, Mancuso AA, Kerr HH, Cacciarelli AA, Mafee MF. Congenital anomalies of the branchial apparatus: embryology and pathologic anatomy. Radiographics. 1992;12(5):943-960.
(5.) Flanagan PM, Roland NJ, Jones AS. Cervical lymph node metastases presenting with features of branchial cysts. J Laryngol Otol. 1994;108(12):1068-1071.
(6.) Cinberg JZ, Silver CE, Molnar JJ, Vogl SE. Cervical cysts: cancer until proven otherwise? Laryngoscope. 1982;92(1):27-30.
(7.) Granstrom G, Edstrom S. The relationship between cervical cysts and tonsillar carcinoma in adults. J Oral Maxillofac Surg. 1989;47(1):16-20.
(8.) Von Volkmann R. Das tiefe branchiogene halskarcinom. Zentralbl Chir. 1882;9:49-63.
(9.) Willis RA. Pathology of Tumors. 2nd ed, St. Louis, MO: CV Mosby Co; 1953. Quoted by: Martin H, Morfit HM, Ehrlich H. The case for branchiogenic cancer (malignant branchioma). Ann Surg. 1950;132(5):867-887.
(10.) Neel HB, Pemberton J. Lateral cervical cysts and fistulas. Surgery. 1945; 18:267-286.
(11.) Gourin CG, Johnson JT. Incidence of unsuspected metastases in lateral cervical cysts. Laryngoscope. 2000;110(10, pt 1):1637-1641.
(12.) Regauer S, Mannweiler S, Anderhuber W, et al. Cystic lymph node metastases of squamous carcinoma of Waldeyer's ring origin. Br J Cancer. 1999; 79(9-10):1437-1442.
(13.) Thompson LDR, Heffner DK. The clinical importance of cystic squamous cell carcinomas in the neck: a study of 136 cases. Cancer. 1998;82(5):944-956.
(14.) Kock WM, Bhatti N, Williams MF, Eisele DW. Oncologic rationale for bilateral tonsillectomy in head and neck squamous cell carcinoma of unknown primary source. Otolaryngol Head Neck Surg. 2001;124(3):331-333.
(15.) Shiboski CH, Schmidt BL, Jordon RCK. Tongue and tonsil carcinoma: increasing trends in the U.S. population ages 20-44 years. Cancer. 2005;103(9): 1843-1849.
(16.) Gillison ML, Chaturvedi AK, Lowy DR. HPV prophylactic vaccines and the potential prevention of noncervical cancers in both men and women. Cancer. 2008;113(suppl 10):3036-3046.
(17.) Gillison ML. Current topics in the epidemiology of oral cavity and oropharyngeal cancers. Head Neck. 2007;29(8):779-792.
(18.) Schwartz SM, Daling JR, Doody DR, et al. Oral cancer risk in relation to sexual history and evidence of Human papillomavirus infection. J Natl Cancer Inst. 1998;90(21):1626-1636.
(19.) Smith EM, Ritchie JM, Summersgil KF, et al. Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. Int J Cancer. 2004;108(5):766-772.
(20.) D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356(19):1944 1956.
(21.) Chaturvedi AK, Engels EA, Anderson WF, et al. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008;26(4):612-619.
(22.) El-Mofty SK, Lu DW. Prevalence of human papillomavirus type 16 DNA in squamous cell carcinoma of the palatine tonsil, and not the oral cavity, in young adults: a distinct clinicopathologic and molecular disease entity. Am J Surg Pathol. 2003;27(11):1463-1470.
(23.) Wain SL, Kier R, Vollmer RT, Bossen EH. Basaloid-squamous carcinoma of the tongue, hypopharynx, and larynx: report of 10 cases. Hum Pathol. 1086; 17(11):1158-1166.
(24.) Begum S, Westra WH. Basaloid squamous cell carcinoma of the head and neck is a mixed variant that can be further resolved by HPV status. Am J Surg Pathol. 2008;32(7):1044-1050.
(25.) 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.
(26.) Fachry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100(4):261-269.
Jonathan B. McHugh, MD
Accepted for publication June 3, 2009.
From the Department of Pathology, University of Michigan Health Systems, Ann Arbor.
The author has no relevant financial interest in the products or companies described in this article.
Presented at New Frontiers in Pathology: An update for Practicing Pathologists meeting, University of Michigan, Ann Arbor, Michigan, September 20, 2008.
Reprints: Jonathan B. McHugh, MD, Department of Pathology, University of Michigan, 1500 E Medical Center Dr, Rm 2G332, Ann Arbor, MI 48109 (e-mail: email@example.com).
Table 1. The Martin et al9 Criteria for the Tentative Diagnosis of Branchiogenic Carcinoma 1. Occurrence along the anterior sternocleidomastoid muscle from anywhere anterior to the tragus down to the clavicle. 2. Histopathology consistent with an origin from a tissue known to be present within branchial cysts. 3. Demonstration of carcinoma arising in association with a benign, epithelial-lined cyst (ie, transition from healthy to in situ to invasive carcinoma). 4. At least 5 y of clinical follow-up, including periodic examinations without identification of a primary tumor. Table 2. Clinicopathologic Differences of Human Papillomavirus-Positive (HPV+) and Human Papillomavirus-Negative (HPV-) Oral and Oropharyngeal Squamous Cell Carcinomas HPV+ HPV- Younger Older Nonsmoker History of tobacco/alcohol use High-risk sex behaviors With or without sex risk factors Wild-type TP53 TP53 mutated Nonkeratinizing "basaloid" Conventional squamous cell morphology morphology Moderate to poorly differentiated Well to moderately differentiated Cystic metastases Solid metastases Improved outcome Worse outcome
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|Author:||McHugh, Jonathan B.|
|Publication:||Archives of Pathology & Laboratory Medicine|
|Article Type:||Case study|
|Date:||Nov 1, 2009|
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