The dangers of diagnosing cystic neck masses as benign in the era of HPV-associated oropharyngeal cancer

This case illustrates the diagnostic challenges faced in differentiating cystic nodal metastases from branchial cleft cysts, in the context of the increasing prevalence of HPV-related oropharyngeal SCC in Australia over the past two decades.1

HPV-related oropharyngeal SCC differs from traditional head and neck cancer in both its aetiology and clinical features; and because it is a relatively new clinical condition, GPs, radiologists and pathologists often do not recognise it as a potential diagnosis. Unlike traditional head and neck cancer, it occurs in a younger population who are frequently non-smokers and not heavy drinkers. Clinically, it most frequently presents with a neck mass, and often primary lesions are not easily discernible, as they are commonly small and in clinically difficult areas to examine, such as the base of the tongue or tonsil.

The natural disease pattern of oropharyngeal SCC is to metastasise to the cervical lymph nodes. In the setting of HPV-related cancer, these nodal metastases are frequently cystic in morphology and, as previously indicated, are frequently the first mode of presentation.2 Given the differing clinical features of HPV-related oropharyngeal cancer compared with non-HPV-associated oropharyngeal cancer, it is not uncommon for these nodal metastases to be misdiagnosed as branchial cleft cysts, as described in this case report. The proportion of metastatic SCCs in cysts initially presumed to be of branchial cleft origin has been reported to range from 11% to 21%.3,4

Misdiagnosis can negatively affect patient prognosis as it delays treatment, allows for further disease progression and increases the potential for metastatic spread. Alternatively, proceeding to excisional biopsy of a cystic mass suspected to be a branchial cleft cyst without adequate investigation for an occult primary can lead to tumour spillage into the surrounding tissues.

Differences in the demographics between branchial cleft cysts and cystic nodal metastases may aid clinicians in accurate diagnosis. While branchial cleft cysts may occur at any age, they most commonly present in early adulthood in the second and third decade of life.5 The reported mean age for cervical cystic masses histologically confirmed as branchial cleft cysts ranges from 32 to 37 years.6,7 In contrast, cystic nodal metastases present later, with a reported mean age ranging from 53 to 57.8 years.6,7 Particular attention must be paid to cervical cysts in patients over 40 years of age, as 44% of cystic masses in this patient population are reported to be malignant in origin.8 The most commonly represented lesions associated with cystic metastases are HPV-related head and neck cancer and thyroid papillary carcinoma.9

CT is a mainstay in the diagnosis and staging of head and neck cancer and plays an important role in differentiating benign lesions of the neck from malignant cystic lymphadenopathy. On contrast-enhanced CT, there is homogeneous attenuation throughout the substance of branchial cleft cysts.6 Features suggestive of malignancy include the presence of septations, heterogeneous attenuation and extracapsular spread.6,7 Significant overlap between the radiological features of benign and malignant cysts is, however, present. Repeated local infection involving a branchial cleft cyst may confer a radiological appearance similar to that of nodal metastasis of an SCC.7 In one study, 31% of cystic nodal metastases were reported as benign in appearance, while 38% of branchial cleft cysts had aggressive features mimicking nodal metastases.6 Evidently, isolated use of CT in evaluating a cystic neck mass confers a high degree of misdiagnosis.

FNAB cytology is the current standard of care in diagnostic workup of solid masses of the neck and is reported to have an overall sensitivity of 92% and a positive predictive value of 100% for head and neck carcinomas.10 Unfortunately, this has not been the common experience with cystic lesions, for which its role remains controversial. Reported sensitivities range from 33% to 55%,11 with a false-negative rate of up to 50%.2 The aspirate of cystic metastatic nodes may be difficult to interpret as a result of hypocellularity from the dilutional effect of the cyst fluid.2 There is commonly an associated inflammatory reaction within the cystic nodes, resulting in large quantities of degenerating epithelial cells, inflammatory cells and cellular debris within the aspirate. These cytological features overlap considerably with those of branchial cleft cysts12 and can lead to misdiagnosis.

Despite these limitations, FNAB still retains some relevance in the diagnosis of cystic lesions. Further, with the emergence of molecular analysis techniques, the detection of HPV DNA and thyroglobulin within fine needle aspirates may facilitate the pathological diagnosis of malignant cystic lymphadenopathy and detection of occult primary tumours. The presence of HPV DNA or thyroglobulin in aspirates is strongly correlated with HPV-related oropharyngeal SCC and thyroid cancer, respectively.13,14 Although these tests are primarily used for research purposes at present, their utility may expand to the clinical setting in future to help to differentiate benign and malignant cystic neck lesions.

Differentiating cystic nodal metastases from branchial cleft cysts is an important, albeit sometimes difficult, diagnostic challenge. With the growing prevalence of HPV-related oropharyngeal SCC in Australia, we conclude that metastatic lymphadenopathy should be considered as the primary provisional diagnosis in the adult population with cystic neck masses until proven otherwise. We encourage caution in the interpretation of neck masses as benign by isolated use of either CT or FNAB. Clinicians should use these modalities in conjunction with each other and, if necessary, include referral for an ear, nose and throat specialist opinion to increase diagnostic accuracy.