Adult Sinonasal Tumors
Gabriel Calzada, M.D.
August 24, 2006

Paranasal disease and malignancies have showed dramatic improvement in survival, starting off in 1950s at 20% to the most current literature, which cites 60% to 80% survivals.  The advancement is closely tied to the development and use of endoscopy, which allows better visualization of the interior of the nose and improved pathology.  In addition, refinements in imaging, high-resolution MRI, has allowed both improved evaluation of the extent of disease and better surgical planning.  The remaining challenge in this disease is the critical structure associated with paranasal sinuses, a subject that we will discuss later. 

The histology of the nose is very interesting.  Its pseudostratified ciliated columnar epithelium, otherwise known as ciliated epithelium or respiratory epithelium, contains mucus glands and serous glands.  In addition to this, there is a specialized olfactory epithelium at the roof of the nose.  The histology is varied in this part of the body, which lends itself to the diverse pathology that presents itself here.  The cells are so uniquely different and the pathology is so uniquely different, that each entity behaves in a different clinical manner and should be addressed differently.

The maxillary sinuses and ethmoid sinuses are first seen at 70th fetal day.  At birth, they are several millimeters in size and facial growth and sinus growth proceed together, and do not reach adult size until about 15 years of age.  The anatomy is very complex, and pictured here is the inferotemporal fossa.  This has several fissures, the infraorbital fissure, as well as pterygomaxillary fissure.  These fissures can act as conduits for malignancies to spread.  In addition to this fossa, there is also the pterygopalatine fossa that has several foramina, such as the foramen ovale and Vidian’s canal.  Again, these may act as conduits for tumors of the nasal cavity to spread to the orbit, the cranial base, as well as the neck.  Surgically, the anatomy of the sinuses is very important.  Pictured here in the middle, the cribriform plate tends to lie a little lower than the fovea ethmoidalis, which is lateral to the insertion of the middle turbinates.  Also, it slopes away at a 30-degree angle from anterior to posterior, which must be taken into consideration when operating in this area.  Pictured here to the left of the screen is the maxillary nerve.  The innervation of the nodes is very intricate, including the second branch of the trigeminal nerve as well as the ophthalmic branch.  These can act as conduits as well, especially for acinic cell carcinoma, which is a common pathology in this area and which tends to have perineural invasion and spread.

The anterior nose has the same lymphatic drainage as the external nose.  These tend to spread to the submental or level I area.  The posterior nose tends to drain to the retropharyngeal nodes as well as the lateral pharyngeal nodes, which eventually drain into the level II.  This information is also important when looking for regional metastasis.

Early symptoms are very unusual in these patients, in that they mimic conditions that are commonly seen  in by otolaryngologists.  Episodes of sinusitis, epistaxis, and complaints of nasal obstructions are early complaints.  As astute clinicians, we should look for unilateral symptoms or diseases that are not responding to our medical management, which should provide some insight as to possible malignancy involving the nasal sinuses.  It is normally the late symptoms that bring patients to our attention.  Symptoms of proptosis, diplopia, vision changes, and cheek swelling are all changes of advanced invasive disease, and often these are what bring the patient to see us; and, by that time, the tumor is usually quite advanced. 

The etiology of paranasal disease and malignancies is unknown, but there have been numerous epidemiological studies that indicate that occupational exposures predispose these sinus cancers: metal ducts, aerosols, nickel compounds seen in battery manufacturer, and individuals who work in chromium factories.  Italy’s literature is abundant with boot and shoe industry workers developing adenocarcinoma.  In France, there are reports of these tumors in textile workers and all other collaborative European studies show that leather and wood dust tend to lead to adenocarcinoma.  In a 2000 study from Mexico City, Calderon reported that outdoor pollution had a correlation with these malignancies, but more studies are needed to further define this relationship.  Epidemiologically, sinonasal cancer is very rare, only about 1% of all tumors in the human body.  For head and neck surgeons, it is approximately 3% of the clinical practice.  It tends to have a male predominance in later age.  Some reports indicate that this male predominance is due to the industrial exposure, these occupations traditionally being male-dominated.

As to the differential diagnosis, for malignant processes we begin with the malignant epithelial tumors.  As you see, there is squamous cell, adenocarcinoma, and adenoid cystic – and the list goes on and on.  The most common, by far, is squamous cell carcinoma, followed by adenocarcinoma.  Malignant nonepithelial tumors include the sarcomas as well as lymphomas, and with malignant disease, one must consider metastatic disease.  The most common metastasis to the nose is from renal cell carcinoma.  In addition, adenocarcinomas can be metastasized to the nose from the lung, breast, and ovary.

In 1933, Ohngren published the beginning of a staging system, where he described the Ohngren line, a line that is drawn from the angle of mandible to the medial canthus.  Ohngren indicated that tumors that presented above this line, both superiorly and posteriorly, tended to have a worse prognosis.  This classification system, although useful, was difficult to reproduce, and Sisson, in 1963 made refinements.  Throughout the 1970s, classification schemes were abundant, but currently the American Joint Committee on Cancer Staging System is the gold standard used for reporting in most professional papers.  T1 tumors of the nose and nasal cavity, and ethmoid sinuses, are tumors restricted to any one sub-site, with or without bony invasion.  T2s are tumors invading two sub-sites, single region or extending to involve adjacent regions of the nasal ethmoid complex.  T3 tumors begin to have bony involvement, invading the medial wall of the floor of the orbit, cribriform or palate.  T4-A tumors involve the anterior orbital contents, nose, and cheeks, with extension into the anterior cranial fossa.  Lastly, the largest tumors, the T4-B, involve the orbital apex, dura, middle cranial fossa, as well as the clivus.

Clinically, our goal should be to establish the diagnosis, determine the extent of disease, the size of the tumor, and what is involved.  Lastly, develop a plan for treatment.  History and physical exam are of utmost important, looking for paresthesias and determining if there is any neural involvement.  Anytime that malignancy is suspected, imaging is key.  CT scans are excellent for determining bony erosion and extent of invasion.  If there is a question of neural involvement, MRI is excellent for determining perineural spread, involvement of the dura, or involvement intracranially.  Lastly, confirm diagnosis via biopsy.  Most often biopsy is performed after imaging rule out encephaloceles or other vascular issues.  Lastly, since imaging with PET scan has yet to be formally accepted as relevant in paranasal disease, it is not recommended as a first line.  PET scan has been used to evaluate for residual tumor, recurrent tumor, and radiated treated fields.  Angiography is not initially used, but can be used for vascular tumors to determine extent and vascularity as well as to allow for embolization prior to any surgical interventions.

Most of these tumors spread through local spread to direct extension, and this is often what brings patients to the physician.  The most difficult area is sphenoid involvement, as pictured here, which is problematic in that these often have involvement of optic nerve, cavernous sinus, and pituitary fossa early on, which makes treatment very difficult.  Cervical metastasis, as I previously stated, is through the retropharyngeal, lateral pharyngeal nodes, and upper jugular lymph nodes.  It is relatively uncommon, most often seen is maxillary tumors and particularly in squamous cell carcinoma.  It is so rare, occurring in only about 10% in these tumors, that elective treatment of the neck is generally not recommended.  Distant metastasis is rare, but tends to happen with ethmoid sinus tumors, in particular adenocarcinomas, and most common sites of spread, as pictured here, is to the lungs as well as bones.

In discussing sinonasal pathology, I will cover several of the more common pathologies.  On this pictogram, we see the most common pathology is squamous cell carcinoma, encompassing over 50% of these tumors, followed by adenocarcinoma.  Sinonasal undifferentiated carcinoma, often abbreviated as  SNUC tumors, was first described as a distinct clinical entity by Levine in 1987.  Using light microscopy, he could differentiate it from other tumors, such as esthesioneuroblastoma.  Also, immunohistochemistry can help differentiate sinonasal undifferentiated carcinoma, which, in terms of clinical behavior, are rapidly progressive and have a very poor prognosis, with a median survival of 18 months.  Given the size of tumor that these SNUC represent, they present with very few symptoms.  The pathology is usually pleomorphic cells, arranged in sheaths with a high nuclear cytoplasmic ratio.  Shinokuma, in 2000, published work showing that 80% of his patients had EBV positive proteins, but the role of Epstein-Barr virus has yet to be determined in these tumors.  The ideal treatment is unknown at this time, although there are some European advocates for preoperative treatment with chemotherapy.

About 3% to 15% of these paranasal sinus malignancies are adenoid cystic carcinoma.  It is occurs most frequently in women, and in the fifth and sixth decades.  There are three classic pathology types: cribriform, tubular, and solid.  Cribriform histologically looks like sheath.  Tubular tends to have the best prognosis, with the solid variance having the worst prognosis, and with cribriform being somewhere in between.  The clinical behavior of adenoid cystic carcinoma is much different from SNUC tumors.  These are usually slow growing, locally aggressive, and relentless.  They tend to find the nerves, attach to nerves, and tend to spread along the innervation of the nerves.  For these reasons, the standard treatment for adenoid cystic carcinomas has been surgery with postoperative radiation therapy.  Michigan recently published their work in which they reviewed their experience with adenoid cystic carcinoma of the paranasal sinuses and found that a 73% 5-year survival with surgery and postoperative radiation, versus 50% survival at 5 years with just radiation.  Lastly Konno, in 1998, published a large study in which patient with these tumors were followed for 20 to 30 years.  He found that, unlike squamous cell carcinoma that plateaus at 5 years, adenoid cystic carcinoma has high recurrence rates up to 20 to 30 years.  So the 5-year survival rates may be misleading in this disease.

Adenocarcinoma is the second most common malignancy in this area.  It is most often in the ethmoids, has a male predominance, and is often seen in industrial workers, particularly wood workers in Europe.  Papillary, as seen here, is the most common pathologic type.  Sessile has the best prognosis and alveolar has the poorest.  Papillary, often found in wood workers, generally has a better prognosis as well.  Treatment is controversial, but the literature indicates that craniofacial resection is the key.  Stoll, from Bordeaux, France, published the largest study of 76 patients. Fifty percent of these patients underwent resection and, of these, 60% received radiation therapy.  He achieved local control at 5 years of 80% and a local recurrence rate of 23%.  Lastly, recent literature from the Netherlands has shown that they can debride endoscopically and place topical chemotherapeutic agents.  They report similar 5-year results to the Bordeaux studies.  These multiple treatment modalities show that further studies are needed to determine the optimal treatment for adenocarcinoma of the paranasal sinuses.
Melanoma is rarely seen, comprising only about 3% of these paranasal sinus malignancies,  On endoscopic examination, they are seen as fleshy, pigmented lesions.  Often the pigments can be varied, and some can be amelanotic.  They are often in the nasal cavity, as opposed to the sinuses, and the long-term survival is dismal with the average survival being 21 months.  Lund published the largest series in the literature and described various types of resection and chemotherapy, but found no survival difference between the treatment modalities.  He also found no correlation between age presentation, extent of disease, treatment method.  Much more work must be done if we are going to make advancements with regards to melanoma.
Olfactory neuroblastoma or esthesioneuroblastoma are neural crest in origin, and they arise from an olfactory epithelium.  Often they are in the cribriform area, presenting in about 7% to 10% of patients with paranasal disease, presenting equally among men and women, and, interestingly, having a bimodal distribution.  These esthesioneuroblastomas present most often either in 20s or in the 50s.  Classically, it is described as rosette patterns of round cells with fibrillary material.  Histologic grade has been shown to have influence on biologic behavior.  Well-differentiated tumors have shown better outcomes and better survivals, in the work by Silva in 1991 from MD Anderson, and supported in later work by Girod in 2001.  The treatment is craniofacial resection.  If we are able to remove these tumors en bloc, they generally tend to do better.

There are also other pathologies, including the sarcomas, which are of many types including rhabdomyosarcoma, fibrosarcoma, and osteogenic sarcoma.  The Intergroup Rhabdomyosarcoma Study Group has shown benefits in survival with the use of chemotherapy and radiation, which tend to be the accepted treatment modalities for these sarcomas.  Also, there are lymphomas, which sometimes need special stains to obtain diagnosis.  Extranodal non-Hodgkin’s lymphoma is very unusual.  The studies are difficult to compare since they employ different classification schemes, different treatment modalities, and incorporate different sites.  This makes it difficult to draw conclusions.  There have also been descriptions of lethal midline granulomas, midline lesions causing destruction of the face, which are now thought to be nondiagnosed lymphomas.  Again, these lymphomas need combination of chemotherapy and radiation treatments.

The most common entities are squamous cell carcinoma.  The lateral nasal wall is the most common site of involvement, but SCC can also present in the sinuses.  Regional lymph node metastasis is more common with squamous cell than most other paranasal sinus malignancies, occurring in about about 10% to 20%.  Local recurrence rates are quite high, as high as 30% to 40%.  This high rate may be due to underestimation of the sites of disease.  In those patients with the worst outcomes, morbidity comes from local recurrence, not necessarily regional metastasis.  The physician must focus on obtaining good margins and treating with postoperative radiation if there are any doubts.  These squamous cell carcinomas of the nose tend to be well-differentiated, most of them having keratin pearls.  Studies have shown that the degree of differentiation does not affect prognosis.

For the treatment of early lesions, surgery, if the tumor is excised en bloc with good margins, and, if there is no evidence of perineural spread, then surgery is usually sufficient.  If there are any questions about the margins or perineural invasion, the addition of radiation is indicated.  There has been some literature reporting the use of radiation therapy alone for early disease, but this is not necessarily recommended since radiation of this side of the body has significant morbidity, with possible osteoradionecrosis and vision loss as well as damage to the spinal cord.  Combined modality generally tends to be the gold standard: surgery with postoperative radiation therapy.  Also, the use of chemotherapy is now being added with the goal of better local control and improvement in survival.  Studies are ongoing, but there is currently no solid study that shows long-term effect of chemotherapy.  Chemotherapy does have a role in palliation for large tumors that are nonresectable.

As I stated previously, if there is nodal disease of the neck with squamous cell carcinoma, a neck dissection is generally indicated.  Postoperative radiation to the neck may be added.  Indications include:  if there are more than 3 lymph nodes involved, or if the lymph node size is greater than 3 cm or there is evidence of extracapsular spread.  Lastly, radiation may be used for palliation, especially since there tumors sometimes present late resulting in few treatment options.  Radiation may be helpful with relieving some of the patient’s symptoms of compression as well as for pain.

Surgery of the paranasal sinuses is truly a collaborative effort, often involving a neurosurgeon, head and neck surgeon, plastic reconstructive surgeon, as well as orthodontists for obturators.

Discussion of the surgery of the paranasal sinuses may be divided into two areas:  the various surgical approaches and a decision on how much surgery should you performed and how to get the tumor out en bloc.

Let us begin with surgical approaches.  Endoscopes have really come to age in the last 15 years or so, and the literature contains studies that advocate endoscopic sinus surgery in the treatment of these diseases.  Stammberger as well as Dale Rice have published articles.  This remains difficult, since advanced disease does not lend itself to endoscopic removal.  In 2000, Goffar, from Belgium, published a series of 66 patients.  He removed these lesions endoscopically and had a local recurrence rate of 20% and a 5-year survival of 64%, with the adenocarcinoma having the best results.
I would recommend that endoscopic surgery for malignancies should be done at centers that have experience with advanced endoscopic techniques. 

Lateral rhinotomy is the standard for the transfacial approaches to the sinuses.  The incision is pictured here, and provides an excellent view of the nasal cavity, excellent views of the ethmoids as well as sphenoids, and provides good views for attempting to remove these tumors en bloc.  Transoral and transpalatal approachs have been described.  These have been used primarily for low lying tumors and tumors of the nasopharynx.  Other surgical approaches include midfacial degloving, traditionally used for benign disease of the paranasal sinuses.  The advantages of this approach include the fact that there are no external incisions and it allows great views on both sides of the lower nose.  So, this is excellent for bilateral tumors of medial maxilla.  The disadvantage of midfacial degloving is that the superior view, especially of the cribriform plate, is limited and almost impossible.  For tumors involving the cribriform plate, such as esthesioneuroblastomas, the treatment is craniofacial resection, done with the neurosurgeons.  Bicoronal flaps are raised and these pericranial flaps can be elevated for reconstruction.  When you retract the frontal lobes, you get an excellent view of the anterior cranial fossa allowing for resection of these tumors en bloc. 

The goal should be to resect the tumor en bloc and obtain negative margins, but to do the patient no harm and to try to limit morbidity.  Medial maxillectomy can often be performed.  These are the bony cuts that you would see with the medial maxillectomy, which is excellent for tumors involving the medial maxilla as well as some of the lateral nasal wall.  There is also the inferior maxillectomy and infrastructure maxillectomy, which are useful for tumors involving the hard palate and nasopharynx, but very limited for tumors involving the paranasal sinuses as well as the cribriform plate.  Total maxillectomy with lateral rhinotomy incision, with the extension via Weber-Ferguson incision, provides excellent exposure, especially in the ethmoids and sphenoids area.  Lastly, large craniofacial resections have been described.  The craniofacial resection, with adjuvant therapy or radiation therapy, has improved survival.  In the 1950s, survival from these tumors was approximately 20%; now, with these combined resections and adjuvant therapy, it is as high as 60% to 80%.  The extent of resection does not limit its complications.  Complications are much higher, of course, with these craniofacial resections, due to the larger nature of resection.  The reported incidence of morbidity and even mortality with these anterior craniofacial resections has ranged between 30% and 63%, so it remains a risky procedure.

Future progress will probably be made in the area of adjuvant therapy; both radiation and chemotherapy.  Radiation therapy has improved and more precise doses of radiation therapy can now be provided to specific areas of paranasal sinuses.  Radiation may be given with a curative intent as well as for adjuvant therapy to surgery.  Single modality has poor control rates and much more morbidity, and, when given at effective doses, can have complications, such as blindness, destruction of the brain as well as the spinal cord.   Chemotherapy has been advocated with the goal of providing better local control and improving 5-year survival.  Chemotherapy has different sequences.  The literature is abundant with different administration modalities for chemotherapy.  It can be given as a neoadjuvant therapy, before treatment with surgery; concomitant, meaning at the same time as radiation therapy or surgery, or sequentially. Reviewing the literature, the most promising current data is with the use of cisplatin and 5-FU.  Lastly, chemotherapy should be advocated for advanced tumors that may are surgically unresectable.

In summary, progress has been made in the prognosis of these tumors of the paranasal sinuses, especially over the past 40 years.  Progress will continue to be made with the adjuvant therapies that I have discussed.  The most effective way of treating these diseases is to catch it earlier.  Otolaryngologists using endoscopes and imaging can identify these pathologies earlier, which will provide better treatment options.  Again, local control is a difficult problem, with recurrence likely to at the primary site, as opposed to distant metastasis.  Overall, complete surgical removal of the tumor with postoperative radiation remains the mainstay of treatment.  In the future, the use of chemotherapy and radiation therapy should show substantial benefit for advanced tumors.

Case Presentation:

HS is a 79-year-old male who presented with a four-month history of right sided eye swelling.  He denied having epistaxis, odynophagia, otalgia, hemoptysis, unexplained weight loss, or difficulty breathing.

Past medical history is significant for coronary artery disease and hypertension.  Patient was blind in his right eye status post an arterial emboli in the 1960s.   Patient’s past surgical history included coronary artery bypass, aortic valve replacement, and a squamous cell carcinoma excision from his nasal dorsum with a split thickness skin graft reconstruction.  Social history revealed no significant use of tobacco products or alcohol abuse.  He had no previous exposure to industrial waste products.

Physical exam revealed a thin appearing man.   Eye exam revealed right periorbital edema with crusting over the right medial canthus.  Extraocular movements were intact, and pupils were equally round and reactive to light.  External nasal exam showed a well healed split thickness skin graft over the nasal dorsum.  Intranasal exam revealed an erosive mass located along the ethmoid area.  The patient was found to have paraesthesia along the ophthalmic branch of the trigeminal nerve distribution. The remainder of his cranial nerves and his head and neck exam were unremarkable. 

Preoperative chest x-ray, cell blood count, electrolytes, and liver function tests were normal.  A CT scan of the sinuses showed 2.6x2.1 cm right ethmoid mass with extension to the right orbital region and into the right frontal sinus, with no definite intracranial extension.   CT neck and chest were negative for metastatic disease.  MRI revealed an infiltrative lesion measuring 2.3 cm with some violation of the orbital rim with minimal intracranial extension.    There was abnormal enhancement along the ophthalmic branch of the trigeminal nerves.  Biopsies revealed poorly differentiated squamous cell carcinoma. 

The patient has since undergone orbital exenteration and a total ethmoidectcomy with a pericranial flap and split thickness skin graft reconstruction.  The patient is scheduled for postoperative radiation therapy.   

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