Hypopharyngeal squamous cell carcinoma and laryngeal neuroendocrine carcinoma colliding in the aryepiglottic fold: a case report



A collision tumor consists of 2 different histologically distinct and topographically independent tumors merging in the same mass. In the head and neck region they are rare, with only 4 cases reported in the larynx.

Case report

A 60-year-old heavy smoker complained of a left submandibular lesion in October 2014. The lesion was excised and showed a poorly differentiated carcinoma, suggestive for adenocarcinoma. After a positron emission tomography-computed tomography scan showed increased metabolic activity in the left laterocervical region and right vocal cord, the patient underwent endoscopic biopsy of the lesion of the left piriform sinus, which was positive for moderately differentiated squamous cell carcinoma (SCC). He was then submitted to circular pharyngolaryngectomy, reconstruction with a radial forearm free flap, and bilateral neck dissection. The histopathologic examination showed an in situ and microinvasive SCC of the left pyriform sinus colliding with a high-grade, non-small-cell neuroendocrine carcinoma of the larynx.


To our knowledge, this is the first case described of laryngeal collision tumor comprising a neuroendocrine component. The choice of treatment of this kind of lesion is difficult because of the presence of 2 different histologies and of the controversial prognostic correlation of non-small-cell neuroendocrine neoplasms of the head and neck region.

Tumori 2017; 103(Suppl. 1): e1 - e4

Article Type: CASE REPORT



Roberta Marangoni, Simone Mauramati, Giulia Bertino, Antonio Occhini, Marco Benazzo, Patrizia Morbini

Article History


Financial support: No financial support was received for this submission.
Conflict of interest: None of the authors has conflict of interest with this submission.

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Collision tumors are neoplasms in which 2 different histologically distinct and topographically independent tumors merge in the same mass. They can be found in every part of the body, including different subsites of the head and neck region, where they are very rare (1). The most common site in this region is the thyroid. Other reported subsites are the tonsil, the skin of the face and the scalp, and the nasal cavity (1, 2).

We report a patient with a collision tumor of the larynx, in which a squamous cell carcinoma (SCC) merged with a neuroendocrine tumor. While SCC is the most commonly represented malignant tumor the larynx (95%), the incidence of neuroendocrine tumors (NET) at this site is only about 0.5%. Literature reports of collision tumors of the larynx are extremely rare, with only 4 cases described. To our knowledge, this is the first case of a laryngeal collision tumor comprising a neuroendocrine component.

Case report

A 60-year-old male smoker came to our attention with the diagnosis of left submandibular metastasis of a poorly differentiated adenocarcinoma. Computed tomography (CT) scan showed a 20 × 11 mm lesion of the right false vocal cord, bilateral lymphadenopathies, and contrast enhancement in the left pyriform sinus, where NBI fiber endoscopy documented a pathologic vascular pattern (Fig. 1). A biopsy from this area was positive for moderately differentiated SCC. Gross examination of the circular pharyngolaryngectomy surgical sample showed a 3 × 2.5 cm lardaceous submucosal mass in the right glottis and a 2 × 2.5 cm keratotic mucosal thickening of the left pyriform sinus.

(A, B) Laryngeal endoscopy shows a bulging lesion of the left aryepiglottic fold and a superficial vegetation extending from the left aryepiglottic fold to the anterior and medial wall of the apex of the left pyriform sinus (arrow). (C, D) Computed tomography scan reveals a contrast-enhancing 20 × 11 mm lesion of the right false vocal cord extending laterally to the paralaryngeal fat (arrow) and a second area of contrast enhancement in the contralateral aryepiglottic fold and anterior wall of the apex of the pyriform sinus (arrows).

Histopathologic examination (Fig. 2) showed an in situ and microinvasive SCC of the left pyriform sinus, extending to the homolateral aryepiglottic fold, and a poorly differentiated carcinoma, infiltrating the right paraglottic space from the anterior commissure to the right arytenoid, and extending to the infraglottic region. The immunophenotype and cell morphology prompted the diagnosis of high-grade, non-small-cell neuroendocrine carcinoma (NEC), with diffuse lymphatic invasion and pagetoid spread along the basal layer of the surrounding and distant mucosa, including the left aryepiglottic fold and pyriform sinus, where immunohistochemical stains showed abundant neoplastic neuroendocrine cell nest at the deepest front of the otherwise classic SCC. Metastases found in 3 right (Levels IIa and IV) and 4 left (Level II) laterocervical lymph nodes, with extranodal involvement and measuring up to 1.9 cm, showed uniform morphologic features and immunophenotype typical of poorly differentiated NEC; SCC markers (p40) were not expressed. Revision of the previous lymphadenectomy sample confirmed the diagnosis of metastatic NEC.

Light micrographs show the poorly differentiated neuroendocrine carcinoma in the right vocal cord, characterized by solid growth with necrosis (A), intermediate-sized cells with pseudorosette formation (B), and high proliferative index with ki67 immunostain (B, inset); the tumor cells were positive for cytokeratin 7 and 8, synaptophysin (C), CD56/n-CAM, and chromogranin A, and negative for p40, high molecular weight cytokeratins and TTF1. (D) Intraepithelial squamous cell carcinoma of the left aryepiglottic fold with a parabasal nest of nonsquamous neoplastic cells (arrow). These cells were positive for synaptophysin (E) and negative for p40 (F).

The patient was discharged on postoperative day 35, in good general condition with normal oral feeding after reconstruction with a radial forearm free flap. Adjuvant chemotherapy with cisplatin and etoposide was given from February to April 2016. In June, he was readmitted to our department for occipital headache and paralysis of the left VII and XII cranial nerves. A total body CT scan showed metastatic disease in the brain occipital lobe, lungs, and liver. The patient died of metastatic disease 9 months after surgery.


Collision tumors are extremely rare in the larynx, as in other head and neck areas: from a literature search on the PubMed database, we retrieved 4 cases, as summarized in Table I. Coca-Pelaz et al (2) recently published a review of laryngeal collision tumors, including cases in which 1 of the 2 tumors originated in adjacent organs such as the thyroid, and collided with the one grown in the larynx, and found only 3 cases in which both neoplasms developed in the laryngeal/hypopharyngeal region. We were able to find one further published case (3). Squamous cell carcinoma was present in all 4 tumors, admixed with an adenoid cystic carcinoma of the hypopharynx (4), a laryngeal melanoma (5), a malignant chondrosarcoma (3), and a benign pleomorphic adenoma (6).

Summary of 4 cases found in the literature search and current case

Authors Sex/age, y Presentation Histology Treatment
Biopsy Surgery
RT = radiotherapy; SCC = squamous cell carcinoma.
Medina-Banegas et al (3) M/45 Laryngeal dyspnea Malignant chondral tumor Chondrosarcoma/SCC Total laryngectomy
Kufeld et al (4) M/47 NA NA Adenoid cystic carcinoma/SCC Hemipharyngolaryngectomy, neck dissection, RT
Sirikanjanapong et al (5) M/53 Hoarseness Mucosal melanoma Melanoma/SCC Total laryngectomy, neck dissection, RT
Chau et al (6) M/66 Dyspnea Salivary gland epithelial tumor Pleomorphic adenoma/SCC Total laryngectomy
Present case M/60 Laterocervical mass SCC High-grade neuroendocrine tumor/SCC Hemipharyngolaryngectomy, neck dissection, RT

While there are no previously reported laryngeal collision tumors involving a neuroendocrine component, a 2010 review by Aggarwal et al (7) collected a total of 17 published cases in which the same laryngeal mass showed features of small cell NEC and SCC (combined tumor). In 2010, Davies-Husband et al (8) reported the first case of laryngeal atypical carcinoid combined with a SCC.

Our case was better defined as a collision rather than a combined tumor because it satisfied the criteria proposed by some authors who tried to define this entity (2), in that it was composed of 2 distinct primary tumors originating in adjacent organs (right larynx and left hypopharynx) with separated tumor areas of each histologic pattern and no intermediate or transitional morphology (as can be found in combined tumors). In light of these considerations, we can assume that this is the first reported case of hypopharyngolaryngeal collision tumor between a neuroendocrine carcinoma and an SCC.

Among the hypotheses proposed to explain the development of collision tumors, an independent origin of the 2 components as a consequence of exposure to common risk factors (tobacco smoke) (1, 2) seems the most likely in our case, due to the patient’s smoking habit. The treatment of laryngeal collision and combined tumors should be tailored on the most aggressive histology found in the tumor, since that seems to affect the prognosis. However, as previously reported, a preoperative bioptic diagnosis of collision tumors is difficult to achieve, due to the limitations of biopsy sampling, often leading to inadequate treatment of the most aggressive component. Moreover, in our case, the initial misdiagnosis of a laterocervical metastasis as an adenocarcinoma, on the basis of a partial immunohistochemical characterization (CK7+, p40-,p16-, TTF1-), delayed the treatment by prompting a search for a possible pulmonary primary. Neuroendocrine morphology on conventional light microscopy can be confused with a more common one when the expression of neuroendocrine markers is not investigated (9). The presentation of a head and neck NET, in absence of a carcinoid syndrome, is not different from that of more common tumors at the same location. The rarity of laryngeal NET and their complex diagnostic classification complicates the definition of a standardized approach to treatment: to date, 700 cases have been reported (9). The updated WHO classification of head and neck cancers (2017) (10) divides NET into those of epithelial origin and of neural origin (paragangliomas). The former are then subdivided into well-differentiated, moderately differentiated, and poorly differentiated neuroendocrine carcinoma, and small cell undifferentiated carcinoma, finally discarding the previous carcinoid terminology. The classification recognized that large cell neuroendocrine tumors with high degree of cellular atypia and invasiveness, previously grouped with atypical carcinoids, are actually high-grade aggressive tumors similar to large cell neuroendocrine carcinomas of the lung or neuroendocrine carcinomas of the gut, and need to be classified separately, to ensure a more aggressive therapy (9). Our case exemplifies how the appropriate treatment choice for laryngeal tumors including a neuroendocrine component requires a precise histologic definition of both components: according to the former WHO classification for laryngeal NETs, which considered large cell neuroendocrine tumors as moderately differentiated (grade II), the surgical approach followed by adjuvant chemoradiotherapy (even if some authors suggest that it is ineffective on atypical carcinoid) was the adequate treatment for both SCC and neuroendocrine components. On the other hand, if we recognize the neuroendocrine tumor as a high-grade tumor (grade III), the treatment of choice should be chemoradiotherapy, since surgery does not seem to improve local tumor control and the loss of voice and function is not justifiable in face of other treatment modalities that may offer better primary tumor control. In fact, as observed in our case, the prognosis of high-grade NET is poor (the 2- and 5-year survival rates are 16% and 5%, respectively), because of rapid growth and high metastatic potential (50% of the patients present with positive regional lymph nodes and about 60%-90% develop distant metastases), and for this reason chemoradiotherapy is considered the standard treatment, even if the right timing for chemotherapy (neoadjuvant, concurrent, or adjuvant) is still debated.

The appropriate treatment of rare instances of collision and combined tumors is based on the awareness of the possibility of their occurrence, both from the clinical and histologic point of view, and on the correct classification of all components and of their biological behavior. As far as laryngeal NET are concerned, an updated classification that better correlates cell morphology with tumor aggressiveness will help to make adequate therapy decisions, both as individual entities and as components of combined and collision tumors.


Financial support: No financial support was received for this submission.
Conflict of interest: None of the authors has conflict of interest with this submission.
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  •  Department of Otorhinolaryngology, Foundation IRCCS Policlinico San Matteo, University of Pavia, Pavia - Italy
  •  Department of Molecular Medicine, Unit of Pathology, University of Pavia, Foundation IRCCS Policlinico San Matteo, Pavia - Italy

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