Definition

Tumors of neuroendocrine origin of varying differentiation and aggressiveness.

Etiology

No predisposing factors are known.

Synonyms

In addition to the degree of differentiation, they may be referred to by grade (1 to 3, with carcinoid being grade 1 and small cell being grade 3). The generic acronym “SNEC” (sinonasal neuroendocrine carcinoma) is often used. Atypical or moderately differentiated lesions are sometimes called large cell whereas the small cell type has been called “oat cell.” Small cell carcinoma has also been called small cell undifferentiated (neuroendocrine) carcinoma or poorly differentiated neuroendocrine carcinoma.4

Incidence

These lesions are rare but they may have been underdiagnosed in the past. They are more often encountered in the submucosa of the supraglottis. The first case at this site was described by Goldman in 1969.5 The atypical or moderately differentiated neuroendocrine carcinoma and small cell variants are commoner than the well-differentiated carcinoid tumors and, of the three, the small cell variant is the one that is also found in the sinonasal tract.6 Only a handful of cases of sinonasal carcinoid carcinoma have been described. Up to 2000, only around 30 small cell carcinomas had been described in the sinonasal region, but on review a number were probably sinonasal undifferentiated carcinomas (SNUCs) so the true number would have been somewhat less.7–10 By 2004 Georgiou and colleagues reported that the number of documented cases had risen to 61,11 but no series have more than 10 cases.12

Site

From the very small number of validated cases, it is impossible to generalize about the site of origin except to say that lesions have occurred in the nasal cavity, ethmoid, maxillary and, in one case, sphenoid sinuses.13–16 Specifically, they can arise on the nasal septum17 but in many other cases no site of origin can be accurately determined.2

Diagnostic Features

Clinical

(See Table 15.12.)

In the larynx these rare tumors are generally much commoner in men, occurring in the fifth to sixth decades, whereas in the nose this male predilection is not so evident and the age range is wider (26 to77 years, median 48 years). Nasal obstruction and epistaxis are the main symptoms and a smooth polypoid mass or area of granular thickening have been observed.9,10 One of the largest cohorts was reported by Babin et al in 2006,18 who considered 21 patients with neuroendocrine carcinoma presenting between 1989 and 2003 to several French hospitals. There were 12 men and 9 women, with a mean age of 55 years (range 27–79 years). The majority were T4 and three had bilateral neck nodes, the rest being N0. One patient had distant metastases at presentation. Our 7 cases comprised 5 men and 2 women, aged 32 to 70 years (mean 47.2 years). All presented with advanced disease affecting the skull base and including skin and bone metastases in 2 cases. Three presented with disease in the antroethmoid, 2 in the sphenoid, and 2 in the nasal cavity.

Some case reports describe presentation with inappropriate secretion of antidiuretic hormone associated with a neuroendocrine carcinoma in the sinonasal region.19,20

In keeping with the degrees of differentiation, cervical metastases are more common in atypical and small cell tumors, occurring in 22 to 30% at presentation with atypical tumors and 50% with small cell tumors.21,22

Clinical and pathological features of neuroendocrine carcinomas of the upper aerodigestive tract

	Carcinoid tumor	Atypical carcinoid tumor	Small cell carcinoma	Poorly differentiated, large cell neuroendocrine carcinoma (including SNUC)
Age (y)	50–60	50–60	50–60	50–60
Sex	M > F	M > F	M > F	M > F
Site	Supraglottic larynx	Supraglottic larynx	Supraglottic larynx and other sites including sinonasal tract	All sites, especially sinonasal tract
Survival, 5 y	>90%	~50%	<10%	<10%a
Atypia	None	Mild to moderate	Marked	Marked
Mitoses	None	Few, scattered	Numerous	Numerous
Necrosis	None	None to little	Abundant	Abundant
Abbreviations: F, female; M, male; SNUC, sinonasal undifferentiated carcinoma; y, year(s)

Natural History

The behavior of these tumors is predicted by their histological differentiation. Increasing locoregional and systemic metastases are associated with moderate and poorly differentiated tumors.25 Bone, lung, liver, and skin deposits have been reported.8,10

Treatment and Outcome

Surgery is the treatment of choice for well- and moderately differentiated tumors and some have advocated an elective neck dissection for moderately differentiated tumors occurring in the larynx. Their rarity in the nose and sinuses and paucity of lymphatic drainage make this strategy less relevant at this site, so neck dissection is confined to proven positive lymphadenopathy.

The choice of surgical approach, as ever, would be determined by the site and extent of the lesion, although it should be noted that these tumors can be quite vascular. Thus, anything from craniofacial to endoscopic resection has been described, through lateral rhinotomy and midfacial degloving.23,26

The outcome for the few cases of well-differentiated sinonasal carcinoid is reasonable if the tumor is completely excised, but no robust statistics are available. One of the largest series comprises 18 patients from the MD Anderson Cancer Center, 14 of whom had surgery and 12 chemotherapy resulting in 5-year survival of 64%.27 Five-year local failure was 21.4%, regional failure was 13%, and distant metastases occurred in 14%. However, the situation with atypical/moderately differentiated neoplasms is worse, certainly in the larynx, where 5-year survival is <50%, with two-thirds dead by 10 years.

With small cell carcinoma the outlook is even worse, with <5% alive at 5 years irrespective of treatment. The MD Anderson series included 7 patients, all with advanced disease, 5 of whom were treated with chemoradiotherapy and with only one long-term survivor. Consequently, chemotherapy and radiation employing protocols developed for pulmonary disease have been advocated rather than radical surgery.28

Cisplatin and etoposide seem to be the drugs of choice for all neuroendocrine tumors, be it induction,28 combined with radiotherapy,29 or for small cell carcinoma.30

In a series of 21 patients with SNECs reported by Babin et al, 52% had surgery, 66% radiotherapy, and 57% chemotherapy (usually cisplatin and etoposide).18 Forty-seven percent developed local recurrence, 23% had regional or systemic metastases, and 10 out of 21 (48%) died of disease within 4 years of diagnosis, with only one long-term survivor. Reviews by Their and Silva et al2,18 of SNEC patients show that in addition to intracranial extent of tumor, the presence of ectopic hormone syndrome increased mortality, whereas, interestingly, intrinsic size of tumor and number of mitoses did not correlate with recurrence, metastases, or survival.

In our small group of 7 SNEC cases, all patients received chemoradiotherapy and 5 subsequently underwent radical surgery including craniofacial resection and removal of the eye (1 case). Unfortunately, we have no long-term survivors, with death occurring between 3 and 48 months after treatment.

Definition

(ICD-O code 8020/3)

Sinonasal undifferentiated carcinoma (SNUC) is a rare aggressive malignancy of the sinonasal region that is generally regarded as being of neuroendocrine origin.1–4 The World Health Organization subsequently defined SNUC as a highly aggressive and clinicopathologically distinct carcinoma of uncertain histiogenesis.5

Etiology

Sinonasal undifferentiated carcinoma was originally described by Frierson in 1986, but its precise etiology is unknown.6

Synonyms

Anaplastic carcinoma.

Incidence

This tumor is increasingly diagnosed and was undoubtedly overlooked in the past. Between 1986 and 2009, 28 papers with 152 patients were published, so close to 200 cases have been reported since the condition was recognized in 1986, with numbers increasing every year.7

Site

The rapid growth of this tumor can make determination of the exact site of origin difficult as more than one area of the nose and sinuses is usually involved, often with intracranial and orbital extension at presentation. Generally the nasal cavity, ethmoid, and maxilla are affected (Table 15.13).6

Diagnostic Features

Histological Features and Differential Diagnosis

Diagnosis is often one of exclusion as the tumor is undifferentiated by definition and falls into a large group of potential tumors (Table 15.14). SNUCs are composed of medium-sized cells that grow in nests, ribbons, sheets, and wide trabeculae, with many mitoses and apoptosis. There is a high nuclear-to-cytoplasmic ratio with prominent nucleoli. Necrosis and vascular invasion are prominent features and there is both mucosal surface growth and extension into surface mucosal glands.7,17

Tumors that may be microscopically undifferentiated

• Sinonasal undifferentiated carcinoma

• Olfactory neuroblastoma

• Small cell neuroendocrine carcinoma

• Malignant melanoma

• Rhabdomyosarcoma

• Lymphomas, e.g., T/NK lymphoma

• Primitive neuroectodermal tumor

• Ewing′s sarcoma

• Nasopharyngeal carcinoma

• NK—natural killer

Source: After reference 3.

Adjunctive analyses such as immunohistochemistry, molecular biology, and electron microscopy are usually required to confirm the diagnosis. Indeed, immunohistochemistry is regarded as mandatory to confirm the diagnosis (Table 15.1)18 and specifically shows positivity to parakeratins, cytokeratin 7 and 8,19 and neuroendocrine markers such as NSE and synaptophysin but not as intensely as olfactory neuroblastoma (which is negative to cytokeratin). It is for this reason that it is now classified with other neuroendocrine tumors. Epstein-Barr virus status and melanocytic and lymphoid antigens should not be present to differentiate the tumor from NPC, melanoma, and lymphomas.1,9,20 The other important differentiation is from basaloid squamous carcinoma and adenoid cystic carcinoma (solid variant). In our entire cohort of nearly 1,000 malignant sinonasal tumors, apart from the 24 proven SNUCs, there is an additional group of 20 patients who, prior to the immunohistochemistry available from the early 1980s, were diagnosed as having anaplastic forms. It is quite possible that these were also SNUCs but we have excluded them from this discussion and they demonstrate the difficulties of estimating accurate incidence.

It has also been suggested recently that some SNUCs may be part of an unusual group of aggressive midline carcinomas characterized by genetic translocations that involve the gene nuclear protein in testis (NUT), a novel gene on chromosome 15.21 These tumors often involve the upper aerodigestive tract in younger people and appear undifferentiated, although may have some focal squamous differentiation. This may explain some of the debate whether SNUCs are of epidermoid or neuroendocrine origin.

Natural History

In addition to the usually large tumor mass at presentation, cervical lymphadenopathy is reported at between 10% and 30%.2,10–13,22 While distant metastases are uncommon at diagnosis, subsequent spread can occur and the cerebrospinal fluid may be seeded, leading to “drop metastases.”23 Time to metastasis ranges from 2 to 30 months.24

Treatment and Outcome

All permutations of surgery, radiotherapy, and chemotherapy have been used for this aggressive tumor. However, two broad strategies have been adopted. If the tumor is resectable, a craniofacial resection followed by radiotherapy has been employed with some success16,25,26 and has been our approach in the past 20 years. Endoscopic excision has also been described, either alone or combined with craniotomy plus chemoradiotherapy27 in a small number of patients7 with at least comparable results. Overall and disease-free survival of 57% with a mean follow-up of 32.3 months was reported. This would be in keeping with our own experience but our numbers are too small to undergo robust statistical analysis. However, the majority of patients who present with advanced disease are now managed by chemoradiotherapy after biopsy, usually using cisplatin-based regimes, with surgery reserved for residual or recurrent disease.12,16 It could be argued that this is one tumor for which endoscopic debulking as opposed to oncological resection is an acceptable approach.

A case can also be made for irradiation of the N0 neck.26 Intensity-modulated radiotherapy and/or proton beam therapy may offer some benefit in the future but this is essentially speculative. High-dose chemotherapy combined with autologous marrow transplantation has also been advocated but lack of numbers precludes comment.28

In a meta-analysis of the literature up to 2009, results are often compromised by relatively short follow-up which has ranged from 1 to 195 months (mean 23.2 months, median 14 months).29 However, overall the tumor has a poor prognosis with 5-year disease-free survival less than 25% despite dramatic initial responses. Twenty-two percent were reported as alive with disease and 52.6% dead of disease. Lin et al13 reviewed 19 patients treated over 13 years in a single institution who at 2 years had local and regional control rates of 83% and regional control of 50%. However, at 5 years, overall survival was 22%. Indeed, one study suggested a median survival of 4 months, others less than a year.1,22 Death occurs from extensive local disease and distant metastases to liver, bone, brain, and elsewhere. However, in our own series there are several long-term survivors (Table 15.13) and Rosenthal and colleagues, who reviewed 72 individuals with neuroendocrine tumors of which 16 were SNUCs, suggested that survival may be improving, either due to better histological differentiation from small cell carcinoma or/and the addition of chemotherapy.15 The difficulty remains that with small numbers treated with a range of therapeutic options it has been difficult to prove that one strategy was superior to another. However, the meta-analysis by Reiersen in 200929 comparing similarly staged disease (irrespective of the system of staging) demonstrated that the best patient survival was obtained with combined surgery, radiotherapy, and chemotherapy.