Adenoid Cystic Carcinoma of the Head and Neck
Cecilia Tran, M.D.
October 28, 2004

Good morning. Today I will be reviewing adenoid cystic carcinoma (ACC) of the head and neck, and I will also be presenting the results of a basic science research project that I did this summer at M.D. Anderson.

It took almost 100 years for the full nature of adenoid cystic carcinoma to be appreciated. This tumor was first described in the French literature by three Frenchmen, Robin, Loraine, and LaBulin. They published two articles in 1853 and 1854 about this unusual sinus tumor. In 1859, Bilroth noted its tendency to recur and was the first to coin the term “cylindroma” for its characteristic pathologic appearance. In 1930s, Spies was the first to name the tumor adenoid cystic carcinoma and to identify the malignant nature of the disease and, finally, in 1974, Dr. John Connelly and Dr. Digman published an article in the Archives of Otolaryngology describing adenoid cystic as one of the most biologically destructive and unpredictable tumors of the head and neck and even today, in 2004, 30 years later, it still remains an extremely difficult disease to treat.

Adenoid cystic carcinoma arises from mucus secreting glands, structures derived from the foregut. The salivary glands are the most common site of origin in the head and neck. ACC accounts for approximately 10% of all non-squamous carcinomas in the head and neck. It represents 10% of all neoplasms of the salivary glands. It represents 5% of parotid tumors and approximately 25% of minor salivary gland tumors. It is the most common malignant tumor of the minor salivary glands and the submandibular and sublingual glands. ACC is slightly more common among women. Approximately 90% of patients are between 30-70 years of age. There have been no strong environmental risks factors that have been identified. There have been several significant allelic losses noted in ACC. It has been found that polysomy of both chromosomes 3 and 17 occur during the development of salivary gland tumors, and the frequency of polysomy is higher in ACC when compared to pleomorphic adenoma.

This picture shows an ACC in the oral cavity arising from the palate. Lesions on the palate usually present either as a submucosal mass or an ulcerative lesion. ACC usually presents in the head and neck as a painless mass enlarging slowly. About half of the patients will have facial pain. Patients such as the one in our VA case report today may complain of numbness or tingling in the distribution of the branches of the trigeminal nerve, which may indicate perineural spread. FNA is often used in diagnosis of salivary gland neoplasms. FNA of ACC will show these small cells with bland nuclear features forming a pseudoglandular space, which will contain a homogenous metochromatically staining hyaline globule; however, it is important to remember that on FNA it is difficult to distinguish between pleomorphic adenoma and ACC. Other diagnoses in the differential include mucoepidermoid carcinoma and polymorphous low-grade adenocarcinoma.

Histologically, ACC can be categorized into three growth patterns based on tumor architecture: cribriform, tubular, and solid. Most of these tumors have a mixed architecture of more than one pattern, and it is then categorized according to the more predominant histologic subtype. The tumor is graded as grade 1 if it is cribriform or tubular. A grade 2 tumor is 1%-30% solid, and a grade 3 tumor is greater than 30% solid. The cribriform pattern, which you see here, is the most common subtype. It has the classic Swiss cheese appearance in which the cells are arranged in nests separated by these round or oval spaces. It is believed that this characteristic stromal appearance of cribriform ACC results from the ability of the cells to synthesize, secrete, and degrade basement numbering proteins. The tubular pattern has a more glandular architecture and has the best prognosis, and on this slide you can see the difference between the cribriform pattern on the left and the tubular pattern on the right. The solid or basaloid pattern shows sheets of cells with few or no luminal spaces. Studies have found that a solid growth pattern is associated with a worse prognosis, more advanced stage, and development of distant metastasis. Adenoid cystic carcinoma is distinct in these three different histologic patterns and in its paradoxical clinical behavior.

Clinically, this tumor is paradoxical in many ways. On the one hand, it has several seemingly positive characteristics such as slow tumor growth and high five-year survival rates; however, while tumor growth may be slow, its clinical course is relentless. It presents insidiously and is generally advanced when diagnosed. Second, operative intervention is usually feasible, but there are frequent multiple local recurrences. Third, spread to regional lymph nodes is uncommon, but distant spread to the lungs and bones occurs frequently. Fourth, five-year survival rates are optimistically high, but 10-20 year survival rates are very low. The distant metastasis can cause death as long as 10-20 years after initial treatment. Another clinical characteristic is perineural spread. ACC is well known for the tendency to perineural spread even with early stage tumors. It can insidiously and widely disseminate through submucosal tissue planes around the primary site and extend through major and minor nerves. This neurotropic tendency has been reported to occur in anywhere from 20% to 80% of patients. It is more frequent in advanced, recurrent, and high-grade tumors. The most commonly involved nerves are the facial nerves and the maxillary and mandibular branches of the trigeminal nerve. Previous theories held that tumor emboli spread through perineural lymphatics. It has been found now that malignant cells directly invade through the path of least resistance in the perineural and endoneural spaces. Dr. Hutchinson and Dr. Hannah proposed that neural cell adhesion molecules may have a role in the pathogenesis of perineural spread of malignant tumors, including ACC and squamous cell carcinoma. This slide demonstrates perineural spread with the nerve that is surrounded by malignant epithelial cells. In contrast to perineural spread, lymphatic spread of ACC is common. The incidence of lymph node metastasis from ACC either detected at presentation or developing later in the course of the disease ranges from 10%-30% in different studies. Metastasis to regional lymphatics is more common among tumors that originate from the parotid gland or in those with a solid histologic pattern. It is associated with poor outcomes. After systemic metastasis, it is difficult to estimate the true incidence because it depends on the length of follow-up of any particular group of reported patients. Although distant metastasis occurs most frequently in the first five years after diagnosis, the risk of developing them continues for up to 20 years or longer. Recently, Dr. Spiro reviewed 196 patients with ACC who received definitive treatment at Memorial Sloan Kettering Hospital between 1939 and 1986. With a minimum follow-up of ten years, the incidence of distant metastasis was 38% for all patients and 70% for those who died of disease. The incidence of distant metastasis correlated highly with the stage of disease on presentation. Approximately two-thirds of patients with distant metastasis had associated local or regional recurrence. The lung was the most common site of distant metastasis at 90%, either alone or in combination with other sites. After development of distant metastasis, patients had survival ranging from one to 16 years. Fifty-four percent survived less than three years and only 10% with distant metastasis survived more than ten years. Again, the reported prognosis of patients with ACC depends on the length and type of follow-up. Many studies report overall survival rather than recurrence rate or disease-free survival. This is misleading because there is prolonged survival in many patients with recurrent or residual disease. Despite local aggressive therapy, 60% of patients will develop recurrent disease. Approximately half of these recurrences are clinically evident within two years of initial treatment. Also, unlike the survival curves of patients with squamous cell carcinoma, survival curves of patients with ACC do not show a plateau at five years, and survival can decline even after 20 years. In a review of the outcomes of 400 patients with adenoid cystic carcinoma, Dr. Connelly and Dr. Kassler reported that, at ten years, roughly one-third of patients were free of disease, one-third had passed away with disease, and one-third were alive with disease. They commented that if patient follow-up were longer, those who were free of disease would develop recurrences and those who are alive with disease might end up dying from ACC, and they projected that at 30 year follow-up, 80% of these patients would have passed away with this disease. In light of this data, how do we care for these patients?

I would like to focus on the conclusions of two papers published recently from M.D. Anderson. Dr. Fordis, Dr. el-Naggar, and Dr. Goepfert published a retrospective review in 1999. They reviewed 160 patients treated at M.D. Anderson for adenoid cystic carcinoma during a 20-year period between 1977 and 1996. One hundred and forty patients received a consistent treatment of surgery and postoperative radiation therapy. This combined treatment yielded an 85% local regional freedom from relapse. Fifty-nine of 160 patients had treatment failure. Eleven had local failure only, two had local regional failure, 35 had distant metastasis as the only site of failure, and 11 had both distant failure and either local or regional failure. This is a figure from their study and it depicts disease specific survival. At five years it was 89%, but you can see the prolonged course of the disease. Disease specific survival at ten years was 67%, and at 15 years it was close to 50%. Three factors were found to have a significant correlation with increased treatment failure: perineural invasion of major nerves, positive margins at surgery, and solid histologic patterns. The most common sites of treatment related morbidity were the skin and subcutaneous tissue and the ear. In this paper, the authors speculated that two populations of ACC may exist: one group with aggressive tumor and another group saddled with indolent disease with sporadic recurrences and survival measured in decades. They did look for a bimodal survival distribution within their study cohort and they did not find one. But this paper helps demonstrate that the combination of surgery and postoperative radiation has enabled improved local regional control of disease.

A study by Dr. Garden and Dr. Weber in 1995 also reinforced this combined approach. This study contends that local control is possible in a significant number of patients with positive margins when treated with surgery and postoperative radiation therapy. They studied 198 patients between the ages of 13-82 with adenoid cystic carcinoma of the head and neck treated at M.D. Anderson between 1962 and 1991. These patients received postoperative radiation therapy for known or suspected microscopic residual disease following surgery. In patients with positive margins, there was a trend toward better local control with increasing radiation dose. The crude control rate was 40% for doses of less than 56 Gy and the control rate was 88% for doses of greater than 56 Gy. This study recommended a radiation dose of 60 Gy to the tumor bed, supplemented 66 Gy if there were positive margins and, like the previous study conclusions, poor prognostic factors included perineural invasion of a major named nerve and microscopic positive margins. In this study, 83 patients had microscopic positive margins. Fifty-five were noted to have close, up to 5 and less than 5 mm, or uncertain margin. One hundred thirty-six patients had perineural spread with 55 having invasion of a major named nerve. Again in this study, a median dose of 60 Gy was delivered to the tumor bed. All surviving patients had a minimum of two year follow-up. Twenty three patients had local recurrences. It was found that 15 of the 83 patients with microscopic positive margins developed local recurrence compared to five of 55 with close or uncertain margins. Only three of the 60 patients with negative margins recurred locally and out of 136 patients with perineural spread, 13 recurred locally. In patients with invasion of a major named nerve, ten of the 55 had crude failure. This graph is from their report and depicts the differences among the groups. Thirty-four patients had both positive margins and a named nerve involved. The ten-year local control rate was 70%. This compared to 83% when only one of these adverse features was present and when neither factor was present, neither nerve involvement nor positive margins, 93% of patients had local control at ten years. Yet, despite this effective local therapy, failure due to distant metastatic disease remains a major problem in these patients. Distant metastasis was the most common type of disease recurrence, developing in 74 patients. Sixty-two of these 74 patients were disease free at the primary site.

One of our patients at the VA demonstrated the impact of distant metastasis as well as the prolonged clinical course. Our patient is a 74-year-old male who initially presented to the VA with epistaxis and headache. Subsequent biopsy and imaging revealed that he had adenoid cystic carcinoma of the nasopharynx with perineural invasion. He initially began treatment with radiation and completed a course in July of 1996. He was subsequently diagnosed with metastasis and underwent a right middle lobe lung resection in June of 1997. He then went on to develop a cranial nerve VI palsy, progressive skull base disease, and loss of vision. He began chemotherapy in September of 1997, but subsequently expired after being placed in hospice care.

In terms of chemotherapy, there is no single regimen that is considered the treatment of choice. Results are conflicting because most studies report a small number of patients, include different histologic types treated with different drug combinations, and group the previously untreated patients with those with recurrent disease. A further complicating factor in chemotherapy decisions is that many patients with asymptomatic and indolent disease feel better and enjoy a better quality of life without chemotherapy.

Many factors have been shown to influence the survival and outcome of patients with ACC. Tumor stage is considered the most reliable indicator of overall outcome. It has been found to be more significant than grade in predicting the outcome of treatment. There is a strong correlation between the site of origin and prognosis. Adenoid cystic carcinoma of the nasal cavity and paranasal sinuses has a worse prognosis than any other area of the head and neck. Histologic pattern is significant. The three patterns may exhibit different biologic behaviors and different outcomes, yet none of these parameters has been proven to be an unequivocal predictor of disease activity. The biologic behavior of this tumor is still not understood due to its highly variable natural history. Clinical parameters do not consistently predict outcomes for these patients.

Many labs today are attempting to characterize some of the genetic basis for the development of this cancer and define molecular markers associated with aggressive behavior. Such markers could be used to further refine the classification of tumors and to help plan optimal treatment strategies, particularly adjuvant therapy. Molecular genetics may eventually be able to predict patient outcome for this tumor. Patients with p53 positive tumors have been found to have worse prognoses than those with p53 negative tumors; and flow cytometry of samples of submandibular gland adenoid cystic carcinoma show that anaploid carcinoma demonstrated a higher frequency of solid histology, lymph node metastasis, and advanced clinical stage when compared with diploid carcinoma. Other markers that have been studied in adenoid cystic carcinoma include c-kit, c-erb-b2, and intercellular adhesion molecule 1. Many other additional markers have been studied; however, no one has previously published data on NFκB. Eighteen years ago, the first paper describing NFκB was published. NFκB regulates target genes in various cells and is critical in cell proliferation and differentiation. The most common form of NFκB is a heterodimer of a 50K Dalton protein and a 65K Dalton protein. It mediates their immune response controlling the expression of inflammatory cytokines, chemokines, immune receptors, and cell adhesion molecules. It drives cell proliferation and differentiation activating transcription of genes such as c-myc, cyclin B, TNF, and IL1. The molecular mechanism of action has been extensively studied. NFκB is maintained in a saddle cytoplasm bound to an inhibitor, and the rate limiting step in the activation of NFκB is believed to be its release from the inhibitor IκB molecules. During cell activation, signals are generated that result in the assembly of the IκB kinase complex. This kinase phosphorylates the inhibitor. The phosphorylated IκB is then ubiquitylated and degraded, freeing the NFκB molecule to dimerize and translocate to the nucleus, and there it can activate transcription and gene expression of genes such as TNF and IL1. This picture is from the San Diego Biotechnology Journal in 2001, which declared that NFκB was the new molecule of the millennium. Defects in the NFκB pathway have been shown to contribute to the growth of cancers such as tumors of the prostate, breast, and thyroid. A recent study found that there was defective IκB and constituative activation of NFκB in Hodgkin’s disease. NFκB has been shown to be activated in many other human tumors, but its expression had not yet been studied in adenoid cystic carcinoma or salivary gland neoplasms in general.

I would now like to present some data from my research project at M.D. Anderson this summer. We hypothesized that NFκB was actively involved in malignant transformation and progression of adenoid cystic carcinoma of the head and neck. Our goal was to correlate the effects of NFκB expression with stage, histologic grade of the tumors, and other clinical and pathologic parameters. This project consisted of three components. First, we analyzed 50 tissue samples for NFκB protein expression by immunohistochemistry. These 50 tissue samples were all from surgical specimens of the head and neck. These patients had adenoid cystic carcinoma of the head or neck and were diagnosed and treated during the past ten years. Second, we also analyzed these samples for histologic grade and KI-67 expression. Third, case records of these patients were reviewed retrospectively for clinical findings. Follow-up information was difficult to verify and was not included in the study. Clinical information was collected, including age and gender of the patient, primary tumor site, presence of nodal metastasis, and clinical stage. For immunohistochemistry, the tissue sections were incubated with primary mouse monoclonal antibody directed against NFκB and then with goat anti-mouse immunoglobulins. For the negative control, we used adjacent normal tissue. We selected representative areas of each tissue section and examined cells in at least four fields at 200 x magnification. All of the slides from these 50 specimens were evaluated and scored independently by three investigators: Dr. El-Naggar, Professor of Head and Neck Pathology, Dr. Mao, who is the head of my lab, and myself. We classified the staining as either nuclear or cytoplasmic and graded the intensity as either 1+, 2+, or 3+. Second, we also assigned all 50 tissue samples a histologic grade. Again, as I mentioned earlier, ACC has three grades: grade 1 being cribriform or tubular, grade 2 being less than 30%, and grade 3 being more than 30% solid. We also wanted to examine proliferative activity, so we analyzed all 50 tissue samples for KI-67 expression. We performed immunohistochemistry using sections of tonsil tissue as a positive external control. Representative areas of each tissue section were selected and cells were counted in at least four fields at 400 x magnification. KI-67 is a nuclear antigen expressed in all phases of the cell cycle and is commonly used to estimate the growth fraction of tumors. A KI-67 value of more than 4% has been reported in the Wordgard article to be the single most significant indicator of a short term clinical course of adenoid cystic carcinoma. A total of 50 patients were identified and included in our study. Patients included 27 men and 23 women. The mean age of the patients was 51 years, with ages ranging from 16-71 years. Thirty-five of the patients or 70% were early stage 1 or 2. Fifteen of the samples were advanced stage, stages 3 or 4. Fifty-eight percent were in the minor salivary glands and 42% were in the major salivary glands. The three most common tumor primary sites in our study were the palate at 24%, the submandibular gland at 22%, and the sublingual gland at 14%. We graded 58% of the samples as grade 1, 22% as grade 2, and 20% grade 3. KI-67 expression was detected in 100% of the cases. KI-67 expression ranged from 1%-60% with a mean of 7% and a median of 13%. What we found is that 49 of the 50 samples demonstrated significantly increased staining for NFκB expression. The one specimen that did not stain consisted entirely of myoepithelium. Twenty-two percent demonstrated cytoplasmic staining, and 76% had nuclear staining. We scored 14% as 1+, 56% as 2+, and 6% as 3+. This is a slide from a tumor of the right palate in a 47-year-old male. This is a stage 2, grade 1 tumor and, if you increase the magnification, you can see the clarity and intensity of the nuclear staining in this tumor. We graded this as 2+ nuclear staining. This shows our negative control. This normal tissue did not stain at all for NFκB. Both the nucleus and the cytoplasm did not stain. This is an example of our cytoplasmic staining. We graded this as 2+ cytoplasmic staining, and again here you can see the characteristic Swiss cheese appearance of cribriform adenoid cystic carcinoma. This is another example of cytoplasmic staining, and you can see how the nuclei do not stain at all; but there is strong cytoplasmic staining. This is a slide from a tumor of the palate in a 49-year-old woman. This is a stage 2, grade 3 tumor, and we rated this as 2+ nuclear staining and 2+ cytoplasmic staining. So, previous publications suggest that the molecular mechanism of NFκB bound to an inhibitor in the cytoplasm and then traveling into the nucleus to activate gene expression. We wanted to understand why different specimens of adenoid cystic carcinoma stained differently. Is it significant that some tumors show a clear nuclear location of NFκB while other tumors from different patients show a cytoplasmic location? We found that tumors of stage 3 and 4 were more commonly found to have nuclear localization of NFκB. This table shows that we had 35 early stage tumors, 11 of which had no nuclear staining. In contrast, of the 15 late stage tumors, 14 of them had nuclear staining, either 1, 2, or 3+. By Pi grade analysis, the P value on this was 0.129. On further analysis of our data, we found an even stronger association with nuclear localization when we included early stage tumors in younger patients. A subset of six patients in our study had stage 1 or 2 tumors and were diagnosed before the age of 36. Five of these six had nuclear staining of NFκB. When we included these young stage 1 and stage 2 patients with the advanced stage 3 and stage 4 tumors, we found a stronger association with nuclear NFκB expression and the P value is still 0.088. Twenty-one patients had stage 3 or 4 tumors or were less than 40 with an early stage and of these 21 tumors, 19 of them had nuclear staining of NFκB. In our data, we found no statistical correlation between NFκB nuclear expression and KI-67 expression or histologic grade. There was also no association between NFκB expression and gender, age, or tumor site.

In conclusion, in our study, 98% of the samples showed high positivity for NFκB whether it was cytoplasmic or nuclear. The one specimen from the patient that did not stain consisted of myoepithelium without any ductal cells present. Adenoid cystic carcinoma is one of several salivary gland neoplasms that characteristically displays dual myoepithelial and ductal epithelial differentiation. Interestingly, the myoepithelium did not stain for NFκB and so it appears that this NFκB expression is restricted by cell type. So, we can speculate that alterations in NFκB expression may correlate with tumors arising from ductal cells, but perhaps not those arising independently from myoepithelium.

I worked on a second project this summer as well at M.D. Anderson studying FIT expression in adenoid cystic carcinoma and basically found similar results with different expression of FIT in the two different histologic cell types. Altered expression of NFκB has been observed in many human tumors, but there have not yet been any known studies published in the salivary glands. This is the first report of NFκB expression in adenoid cystic carcinoma. The intensity of the nuclear staining suggests that NFκB is actively involved in regulating adenoid cystic carcinoma and shows promise as a prognostic marker and possible therapeutic target in these patients. Patients with nuclear NFκB localization may have more aggressive disease and then be candidates for more novel therapeutic regimens. Further studies involving cell lines have now been started at M.D. Anderson in Dr. Meyers’ lab.

In conclusion, Dr. Connelly’s words from 1974 still hold true today. Adenoid cystic carcinoma accounts for approximately 10% of all salivary gland neoplasms. It is distinct in its three histologic patterns and its tendency for perineural spread. Current treatment includes surgery and postoperative radiation therapy, and our data now suggests that NFκB may be actively involved in tumor genesis.

Case Presentation

CR was a 74-year-old otherwise healthy male, who presented to the VA clinic with epistaxis. He also complained of left otalgia, worsening headaches, and left hearing loss. He denied other head and neck complaints. On physical examination, he had left serous otitis media. He also had decreased sensation in the distribution of V2 and V3. Endoscopy revealed a mass in the left nasopharynx that was smooth and submucosal. Imaging confirmed this mass and showed involvement of the left petrous apex and pterygopalatine fossa. He then underwent direct laryngoscopy and biopsy of this nasopharyngeal mass in the operating room.

He was diagnosed with adenoid cystic carcinoma of the nasopharynx with perineural invasion in June 1996. He received 36 XRT treatments that were completed in July 1996.

In June 1997, the patient was found to have a right lung mass. He underwent resection of the right middle lobe, with the diagnosis of metastatic adenoid cystic carcinoma. In August 1997, he developed a right sixth cranial nerve palsy. Progressive skull base disease was noted that involved the cavernous sinus, superior orbital fissure, the clivus, and encasing the internal carotid artery. He then lost all vision in the right eye. He received several courses of chemotherapy from September through December 1997. He started hospice care in December 1997 and expired shortly thereafter.

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