CANCER TREATMENT REVIEWS (2005) 31, 106–114
www.elsevierhealth.com/journals/ctrv
TUMOUR REVIEW
Branchiogenic carcinoma – conceptual or true clinico-pathological entity? Barbara A. Jereczek-Fossaa,*, Chiara Casadiob, Jacek Jassemd, Felipe Luzzattob, Giuseppe Vialeb,e, Roberto Bruschinic, Fausto Chiesac, Roberto Orecchiaa,e a
Department of Radiation Oncology, European Institute of Oncology, 435 via Ripamonti, 20141 Milan, Italy b Department of Pathology, European Institute of Oncology, Milan, Italy c Department of Head and Neck Surgery of the European Institute of Oncology, Milan, Italy d Department of Oncology and Radiotherapy, Medical University of Gdansk, Poland e University of Milan, Faculty of Medicine, Milan, Italy
KEYWORDS
Summary The existence of branchiogenic carcinoma remains controversial. According to some authors, this malignancy is more conceptual than a true clinicopathologic entity. The originally proposed diagnostic criteria of branchiogenic carcinoma have been subsequently challenged. Many reports regarding primary branchiogenic carcinoma have failed to provide sufficient evidence to distinguish this entity from nodal metastases arising from unrecognized primary tumours. There is growing evidence that the majority of branchiogenic carcinomas are in fact cystic metastases from oropharyngeal carcinoma, most commonly originating in the tonsils, and not true carcinomas arising in a branchial cleft cyst. The missing link between branchial cyst and branchiogenic squamous cell carcinoma could be fulfilled by the occurence of in situ branchial cyst carcinomas, yet such cases are extremely rare. Isolated cystic neck lesions, necessitate a thorough search for a primary tumour, similarly to other occult primaries presenting with cervical metastases. The treatment of cervical cyst with dysplasia or carcinoma in situ includes complete surgical excision. The true branchiogenic carcinomas should be approached with postoperative irradiation to the half neck. A cervical metastatic cystic squamous carcinoma of unknown origin should be treated as for other cases of occult primaries, i.e. with surgery and radiotherapy. The data on the prognosis of branchiogenic carcinoma are scarce, though long-term survival has been
Branchial cyst; Branchiogenic carcinoma; Malignant branchioma; Cystic lymph node metastasis; Squamous cell head and neck carcinoma; Occult primary
* Corresponding author. Tel.: +39 02 57489607; fax: +39 02 57489036. E-mail address:
[email protected] (B.A. Jereczek-Fossa).
0305-7372/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2004.12.007
Branchiogenic carcinoma
107 reported. Further histopathologic and clinical studies are warranted in order to better understand the biology and natural history of cervical cystic lesions. The existence of true branchiogenic carcinoma remains to be verified with new clinical and molecular criteria. c 2005 Elsevier Ltd. All rights reserved.
Introduction Neck masses are frequently seen by otolaryngologists. In paediatric and young adult patients, congenital cysts comprise the majority of these lesions whereas in adult patients nodal metastases are more frequent.1 Congenital cysts include thyroglossal cysts, branchial cleft cysts and thymic cysts. Branchial cysts are usually localized in the lateral anterior neck or juxtaposed to the parotid gland and are often misdiagnosed as parotid gland tumours. They can also be found rarely in the parapharyngeal space or nasopharynx. They contain thin watery fluid and mucoid or gelatinous material, and are usually lined by squamous epithelium, though foci of ciliated respiratory or pseudostratified epithelium may also be present.1–4 Lymphoid aggregates with germinal centers are often present within the cystic wall.5 A typical branchial cyst presents as a superior cervical mass (II level) anteriorly to the jugular vein (between the tragus and the clavicle along the anteromedial border of the sternocleidomastoid muscle). In the majority of cases the lesion appears between the 2nd and 4th decade. The most common initial sign is a single cervical lump, while later symptoms may include dyspnoea, dysphagia, and abscess formation. Thyroglossal duct cysts are usually localized near the foramen caecum of the tongue and in the middle anterior neck. The cysts localized high in the neck and close to the tongue have squamous epithelium lining, whereas cysts localized near the gland contain thyroid acini. These lesions often become clinically apparent in adult life as neck swellings that move with the tongue and thyroid during swallowing. Bronchogenic cysts are usually localized in the middle mediastinum as fluid-filled extrapulmonary masses, lined by respiratory epithelium and surrounded by a parietal wall that contains muscle, cartilage, and submucous glands. Clinically they often present with mass effect and airway compression, infection, haemorrhage, and perforation. Some cases may be diagnosed incidentally on a chest X-ray.1 Rarely, lymphangioma can give rise to lateral cervical cystic lesions.6 The development of a carcinoma from epithelial remnants of embryonal branchial elements was
first reported by Volkmann in 1882 and called branchiogenic carcinoma (malignant branchioma).7 Initially branchiogenic carcinoma was a common diagnosis for many cystic carcinomas of the neck,8 but after the introduction of strict criteria (see below) the number of new cases has steadily decreased. Although there are numerous reports of branchiogenic carcinoma, several investigators still question the existence of such an entity.6,9–16 There is now growing evidence that the majority of cases labelled as branchiogenic carcinoma are indeed cystic metastases from oropharyngeal carcinoma, most commonly tonsillar carcinoma. When the primary tumour cannot be found, the hypothesis of carcinoma of unknown primary (CUP) with solitary cystic metastasis is most likely.6,9–16 The data on the incidence, aetiology, morphologic features, diagnostic criteria and management of true branchiogenic carcinoma are scarce. Due to its rarity, the current knowledge on this malignancy is mainly based on case reports and retrospective series collected over many years. In many reports the pathology was not reviewed or even not provided, thus making diagnostic verification impossible. Similarly there are few data on cystic cervical metastases, and only recently have a few retrospective series of this rare entity been published.6,17,18 References for this review were identified by a comprehensive search of MEDLINE for the years 1980–2003 (with no language restriction). References were supplemented with relevant citations from older literature and from the reference list of the retrieved papers. Papers were selected on the basis of their relevance to the topic. Data presented in abstract form or non-English language were included in some cases where they added significant information.
Pitfalls In 1950, Martin et al.19 proposed strict criteria for the diagnosis of branchiogenic carcinoma: (1) the location of the tumour along a line anterior to the sternocleidomastoid muscle between the tragus and the clavicle; (2) the histologic appearance
108 of the tumour consistent with tissue present in the branchial vestige; (3) the clinical course of the disease with no primary tumour occurring within a 5-year follow-up period after the diagnosis; (4) the histologic demonstration of a cancer developing in the wall of an epithelial-lined cyst situated in the lateral site of the neck. According to Thompson and Haffner,6 however, squamous cell carcinoma arising in the branchial cleft cyst is a hypothetical, and practically non existent entity. Doubts about the existence of this tumour were also expressed by other authors.6,9,13–16,20–28 According to Thompson and Heffner6,9 previous studies included several confounding factors such as: (1) no tonsillectomy performed (in order to exclude tonsillar primary);29–40 (2) no random biopsies performed;30,31,37,38,40 (3) no biopsy of tonsillar bed performed (in case of previous tonsillectomy);14 (4) insufficient follow-up or follow-up period not provided (to exclude later appearance of the primary tumour);30,33,34,36–38,40,41 (5) subsequent irradiation comprising potential primary;29,32–34,42 (6) the occurence of multiple recurrent, metastatic foci to other lymph nodes and distant sites;29,32,39,41 (7) the occurence of previous tumour of similar histology;35,42–44 (8) mucoepidermoid carcinoma or an atypical histologic appearance;35,36,42,44,45 (9) disease not occurring in the correct anatomic location;8,38 (10) a lack of illustrations;46 (11) extremely well differentiated tumour arising from a background of longstanding chronic inflammation and scarring.47 Although a possibility of occasional cancer development in a branchial cleft cyst cannot be ruled out,6 in a series of 136 cases of cystic neck masses (most regarded by the contributors as branchial cleft carcinomas) none was eventually accepted as true branchial cyst carcinoma.6 The revision of these cases revealed a primary lesion localized in the lingual or faucial tonsil in 64% and in nasopharyngeal tonsillar tissue in 8%.6 Other cases included laryngeal, palatal or sinus carcinoma. The primary tumour was revealed within a wide period of time ranging from the day of surgery to up to 11 years (average of 12.4 months). However, in 20% of cases the primary tumour was never found. The cases that did not originate in the Waldeyer’s tonsillar ring generally differed in histologic appearance from the tonsillar cases. Most
B.A. Jereczek-Fossa et al. were small tumours, suggesting a slower growth rate than usually expected for squamous cell carcinomas.6 Prognosis in patients bearing these tumours was much better than in those with metastatic squamous cell carcinomas of other upper airway mucosal sites.6 In many reports, given the absence of cancer in other anatomic sites, such carcinomas were considered as branchiogenic carcinomas or squamous cell carcinomas arising in a branchial cyst.6 Frequently, however, accurate head and neck evaluation or follow-up showed synchronous or metachronous existence of tonsillar tumours in patients initially diagnosed as branchiogenic carcinoma.10,48–50 In some cases other primaries including thyroid and parotid gland tumours, were found.51 Thyroid tumours are often associated with slowly growing cystic metastases in the neck. The review of Khafif et al.45, including 67 cases reported in the English literature since Martin’s publication19, confirmed the presence of branchiogenic carcinoma in 41 cases. Another literature review of 43 cases showed that the criteria of Martin had been fulfilled in only seven cases.52 Micheau et al.13 and other authors conclude arbitrarily that so called branchiogenic carcinomas are actually cystic metastases in the neck from a tonsillar primary.6,9,13–15,20–28 According to Delank et al.15 branchiogenic carcinoma does not exist and is an oncological artifact. Thompson and Heffner6 conclude that at best branchiogenic carcinoma must be a very rare entity. Several authors agree with this statement.40,52–56 Due to the rarity of this tumour, its consideration in the differential diagnosis becomes almost untenable.6,9–16
Aetiology The origin and pathogenesis of lateral cysts remain unclear. Several hypotheses have been put forward, including development from congenital embryonal remnants of the second branchial pouch,15,19,34,42,57–59 proliferation of ectopic epithelium within a lymph node,20,60,61 metamorphosis of squamous epithelium from lymphatic endothelium,62 secondary proliferation of epithelium from the tonsillar fossa12,15,59,61,63 and acquired salivary gland inclusions within lymph nodes. Some authors report a causal relationship between previous oropharyngeal inflammatory reactions like tonsillitis or odontogenic infection, and the appearance of a lateral cervical cyst.7,10,15,61,64
Branchiogenic carcinoma Recently, evaluation of the cytokeratin profile showed that lateral neck cysts arise from developmental remnants of the 2nd branchial pouch, which may remain dormant for many years.65 Further enlargement, squamous metaplasia and lymphoepithelial hyperplasia is a consequence of immunologic stimulation.65 The aetiology of malignant transition within a branchial cyst is even less clear. Postulated causative factors include head and neck irradiation44 and inflammatory reactions52, but the aetiological relationships for the latter remain to be determined. In the majority of cases the pathogenesis of cystic lymph node metastasis includes the collection of cellular debris and cystic degeneration.17 The primary in the Waldeyer’s ring often demonstrates cystic spaces, especially deep in the crypts, and cystic metastases appear to simulate the growth pattern of the primary tumour. Interestingly, there have been reports of cystic haematogenous metastases originating from the Waldeyer’s ring.17 Regauer et al.17 conclude that induction of cyst formation in lymphatic and haematogenous metastases is an intrinsic feature of keratinocytes that can be expressed and maintained in a permissive environment in the absence of lymphoid tissue.
Histology Although criteria proposed by Martin et al.19 were criticized by some authors,32,34–36,40,45,66,67 many still use them to diagnose and report branchiogenic carcinoma.8,29,33–35,38,40,41,44,45,47,54,56,66–70 Interestingly, only in 1990, some authors claimed to have encountered the first cases of true branchiogenic carcinomas.8,56 Modifications of Martin’s criteria were also proposed.45,52 The vast majority of branchiogenic carcinomas are squamous cell carcinomas,31,34,41,68,70–74 whereas mucoepidermoid carcinomas are occasional.36,42 The typical histological picture includes lymphoepithelial cyst, with transition of the inner surface epithelium into mucoepidermoid carcinoma, and its partial invasion of the cyst wall.36 According to Zimmermann et al.,7 all four criteria of Martin19 are met in only occasional cases.30–33,42,47,71 The third criterion (5-year follow-up without appearance of any tumour) was criticized as too theoretical and of limited clinical value.15,33,36,40,67 Several investigators suggest that the primary lesion can regress, remain occult or become clinically evident after a long per-
109 iod.6,9,12,33,75 Some authors hypothesize the existence of two synchronous or metachronous tumours, i.e., pharyngeal or laryngeal carcinoma and branchiogenic carcinoma.7 Cases of synchronous branchiogenic carcinoma (squamous cell carcinoma in the cyst of flat lining epithelium) and metastatic papillary thyroid carcinoma have been reported.76 Other situations included continuous spread in an ascending (cyst to tonsil) or descending (tonsil to cyst) way with the presence of parietal elements typical of a lateral cyst, and the duct connecting the cyst and pharyngeal wall (with squamous cell carcinoma of the tonsil).77 Some authors proposed the diagnosis of branchiogenic carcinoma based on histological criteria, like the absence of typical lymph node structures such as peripheral lobulation, internodular trabeculae and perinodular sinuses.29,34,36,40,41 Other authors, however, stress the possible disappearance of lymph node architecture in cystic metastases.14,15 According to Thompson and Heffner,6 the lesion can only be interpreted as a branchial cyst carcinoma if the cystic lesion is associated with a well-defined sinus tract, with a course indicating a branchiogenic developmental anomaly (based on embryologic knowledge of the development of the branchial cleft region). However, the authors did not encounter any such a case in their series of 136 cystic neck masses. Definitely, the transition of a normal into a malignant epithelium (fourth Martin’s criterion19) and demonstration of premalignant epithelial changes within lateral cervical cyst would be the most important criteria for the histopathological diagnosis of a primary branchiogenic carcinoma.7,14,17,30,32,45,67 The missing link between branchial cyst and branchiogenic squamous cell carcinoma could be fulfilled by the occurrence of in situ lesions within a lateral branchial cyst. Although only six such cases were reported,7,32,38,53,75 they do add credibility to the concept of primary branchiogenic carcinoma.7 Interestingly, Ryska and Kucera78 reported a cystic metastasis of squamous cell tonsillar carcinoma, clinically presenting as a branchiogenic cyst. They observed a transition to dysplastic areas with features of carcinoma in situ and small focal invasion of the epithelial structures into lymphoid tissue.78 Despite its known metastatic nature, the tumour fulfilled the histological criteria of branchiogenic carcinoma, thus exemplifying difficulties in an accurate differential diagnosis of branchiogenic carcinoma or cystic metastasis. It was recently demonstrated that cystic lymph node metastases resemble cystic squamous cell
110 carcinomas discovered in the upper neck6,17,18 Thompson and Heffner6 hypothesized that a tumour presenting with a small primary and cystic neck metastases is a particular subtype of squamous cell carcinoma. Typically, cystic metastases involve the jugular digastric lymphnodes6. The majority of metastatic lymph nodes originating in Waldeyer’s ring are multicystic.17 Regauer et al.,17 categorize cystic metastases as occult (with cystic lumina less than 5 mm) and clinically evident (with luminal diameters greater than 5 mm). Histologically, cystic metastasis is composed of a thin, relatively uniform wall. Thompson and Heffner6 established five criteria to define the typical histologic features of the squamous cell cystic lesion in the neck: (1) formation of a large cyst or cysts, as opposed to multiple small or comedo-like cysts; (2) predominantly a cystic lesion with only focal areas of solid growth; (3) cystic spaces lined by a squamous epithelium arranged in a ribbon-like configuration, maintaining a relatively uniform thickness and orderly polarity throughout the cyst (approximately the thickness of a normal mucosal squamous epithelium), with occasional areas of either endophytic or irregular papillary exophytic proliferations; (4) epithelium that is generally of a transitional nature, with the cells demonstrating a high nuclear-to-cytoplasmatic ratio, no appreciable degree of surface maturation, and limited (if any) keratinization, with a prominent degree of squamous pearl formation; and (5) no prominent degree of anaplasia, but instead a recapitulation of a normal tonsillar crypt epithelium, with variable mitotic activity. Cases without these five histologic characteristics, or not localized in the typical jugular digastric lymph nodes, were categorized as ‘‘atypical’’.6 In the series of Thompson and Heffner6, the lesions with atypical histologic appearance often originated from a nontonsillar primary, as opposed to those with typical histology, originating from the tonsil in 88%. Image cytometry DNA analysis of the preoperative cytological specimen is possible in 80% of patients with solitary cysts in the lateral region of the neck.79 The Swedish study showed that in about 50% of cystic metastases, DNA analysis revealed aneuploidy confirming malignancy.79 In benign cases (branchial cleft cysts) DNA diploidy was observed.79
B.A. Jereczek-Fossa et al. age indicates a greater probability of malignant degeneration.7,12,18,81 The risk of a cystic cervical lesion in a patient over 40-years old having a malignant phenotype was estimated to be about 80%.13 In the series including exclusively malignant cervical cystic lesions, the average age at presentation was 54 years.6 As in other head and neck cancer populations, the majority of patients were males.6 The average age at the diagnosis of branchiogenic carcinoma is 60 years40 and the majority of patients are males.40 Due to the rare occurence of this entity and diagnostic pitfalls, its true incidence remains unknown. Clinically, cysts can be easily misdiagnosed as a parotid swelling or odontogenic infection.82 Solitary cystic squamous cell carcinoma metastases may be also difficult to distinguish from a benign cervical cyst. According to surgical excision findings, 10–24% of the cervical cysts represent metastases from squamous cell carcinoma.18,21,51,83 In large series, the average size of neck mass was 3.9 cm (range, 1.5–13 cm).6 Cystic neck lesions are usually characterized by slow growth.6 A case of a cervical branchial cyst existing for more than 40 years prior to malignant degeneration was reported.84 In a series of 708 partial or total parotidectomies, 23 cystic lesions and 16 branchial cysts (2%) were found.85 The vast majority of cystic metastases to lymph nodes arise from squamous cell carcinomas, but cases originating from papillary thyroid carcinoma have also been reported.86–92 In a series of 123 primary squamous cell carcinomas of Waldeyer’s ring, nodal metastases were identified in 82% of cases17 of whom 39% were exclusively solid metastases, 37% exclusively cystic metastases and 25% included both cystic and solid components. Cystic metastases were more common in patients with squamous cell carcinoma of the tongue (27%), followed by palatine tonsils (21%) and nasopharynx (1.8%). Clinically evident (luminal diameter greater than 5 mm) solitary cystic metastases were found exclusively in tonsillar carcinoma. In tumours of the base of the tongue, solid metastases were found more frequently in N1 lesions, whereas cystic metastases were more common in N2b and N3 cases.17
Diagnostic procedures Incidence and natural history The average age at diagnosis of a lateral cervical cyst ranges from 20 to 40 years,12,63,80 the higher
In the case of an isolated cystic neck lesion, a search for the primary tumour should be performed as in other cases of occult primary with cervical
Branchiogenic carcinoma metastases (CUP).6 Recommended diagnostic procedures include physical examination with evaluation of the head and neck mucosa by fiber-optic endoscopy under general anaesthesia, and in case of negative endoscopy, biopsies from any suspicious site or blindly from the sites of possible origin of the primary, head and neck computerized tomography and/or magnetic resonance, a systematic tonsillectomy (ipsi- or bilateral), endoscopic evaluation of trachea, bronchi, lung and esophagus, and computerized tomography of the chest (especially in the case of lower neck lesions).12,18,83 In the majority of cases these procedures reveal an occult primary that is often localized within the Waldeyer’s ring (palatine tonsils, the base of the tongue, nasopharynx) or, less frequently, in the hypopharynx, larynx and oral cavity.17 Exclusion of an occult primary before cyst excision is particularly recommended in patients over 40 years (several authors conclude that a solitary cervical cyst in patients older than 40 years should be presumed to be carcinoma until proven otherwise).18,21 However, in up to 35–50% of patients the primary tumour remains occult (lower rates have been reported for the series managed by Ear–Nose–Throat specialists).18,83 Some authors suggest that the diagnosis of a branchiogenic carcinoma can be made provided a primary lesion is thoroughly excluded.93 However such an approach would include some CUP patients with a solitary cystic lymph node metastasis. Fine needle aspiration of the cystic lesion enables diagnosis of squamous cell carcinoma when the following cytologic criteria are fulfilled: increased nuclear/cytoplasmic ratio, irregularity of nuclear outline and nuclear hyperchromatism. The branchial cleft cysts show benign squamous cells with only mild nuclear atypia.94 Obviously, the cytologic diagnosis should be confirmed by histologic examination. Preoperative fine needle biopsy of the lateral cervical cyst can be negative in up to 42% of the cases and this might be explained by hypocellularity of the cyst fluid.18 Other authors, however, recommend this procedure due to its sensitivity in diagnosing malignancy of 73%.83 In the case of a lateral cervical mass that is suspicious for branchiogenic carcinoma, aspiration biopsy and incisional biopsy are not recommended due to the risk of false-negative results, dissemination of malignant cells and increased patient morbidity.7,11,12,50,61,66 In fact, in patients over 40-years old, the diagnosis of a branchial cyst should not be accepted even when the fine needle aspiration is not suspicious of malignancy.95 Serial sections of the excised benign cyst to rule out focal malignant lesions in the epithelium are warranted.7,96
111
Treatment Lateral cervical cysts with dysplasia or carcinoma in situ and without signs of malignant infiltration, may be managed successfully with complete surgical removal.7,82 Recently, endoscopic resection has been proposed.97,98 Clinical follow-up is recommended due to an increased risk of lateral cervical cyst recurrence,32,68,96 malignant transformation29,45,47 or second primary tumour.69,99 The risk of recurrence was assessed to be about 7%, with the latency time ranging from 3 months up to 62 years.100 Nodal metastasis underlying the cyst can also sometimes be misdiagnosed. The management of cases suspected as branchiogenic carcinoma is wide surgical excision of the tumour, preferably with ipsi-lateral radical neck dissection.101 If the diagnosis of branchiogenic carcinoma is confirmed, postoperative irradiation to the ipsi-lateral neck is recommended. A cervical metastatic cystic squamous carcinoma of unknown origin should be treated as other cases of occult primaries, i.e. with surgery and radiotherapy. The surgical treatment includes removal of the cyst with or without radical neck dissection.13 The initial surgical excision of the cystic neck mass in many patients is equivalent to the removal of all metastatic disease, since many of these lesions are solitary.6 Neck dissection (if possible conservative) should be done in multiple metastatic lesions or lesions that are larger than 3 cm.6 Adjuvant radiotherapy should include the neck and the sites of a potential primary tumour. In order to limit late radiation toxicity, more limited radiotherapy portals may be recommended. For example, treatment to just one side of the neck and any potential primary is recommended for typical cystic metastases localized in the jugular digastric nodes.6 Since the majority of cystic metastases originate in the lower part of Waldeyer’s ring, some authors suggest radiotherapy limited to one side of the neck and the oropharynx.6 Retropharyngeal nodes should also be included in the treatment portals, thus encompassing the nasopharynx.6 Careful follow-up is recommended to secure effective salvage treatment in the case of the primary tumour occurrence.15
Prognosis The data on the prognosis of the branchiogenic carcinoma are scarce. Nevertheless, a proportion of patients seem to enjoy long-term survival. Cystic
112 metastases from squamous cell carcinoma appear to have a better prognosis compared to other squamous cell carcinomas of the head and neck.14,16,102 Some authors suggest that these lesions constitute a separate category, distinct from other head and neck malignancies.16 In the series of Thompson and Heffner,6 the 5-year survival was 77%. The survival rates in patients with cystic metastases and an overt primary or with an unknown primary site seem to be similar.6,103
Conclusions Despite several decades of observational studies, branchiogenic carcinoma remains a poorly recognized entity and its true existence is questioned. Probably a proportion of cases previously classified as branchiogenic carcinoma may now be considered cervical cystic lesions, yet differential diagnosis of these two entities is difficult. Further histopathologic and clinical studies are warranted in order to better understand the biology and natural history of cervical cystic lesions. The existence of true branchiogenic carcinoma remains to be verified with new clinical and molecular criteria.
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