Study investigates variants of adenoid cystic carcinoma

Researchers analyze variants of this aggressive malignant tumor of the salivary glands, which evolves slowly but has high mortality rates.

By Silvia Campolim

Agência FAPESP – Adenoid cystic carcinoma is considered the second most common malignant tumor of the salivary glands. It affects women three times more often than men and has a higher incidence among people aged over 60 years.

With no known predisposing factor, the tumor affects the larger, more voluminous salivary glands called the parotids in addition to very small glands found in the buccal mucosa and the upper respiratory tract (the nose, paranasal sinuses, trachea, and bronchioles).

Although it grows slowly, adenoid cystic carcinoma is very infiltrative (it disseminates through small and numerous tumor clusters) and has a tendency to invade nerves, causing great pain to patients, explains Albina Altemani, professor of the Department of Pathology at the Universidade Estadual de Campinas (Unicamp) School of Medical Sciences.

Because of these infiltrative characteristics, when the tumor grows in regions with a complex anatomical structure, such as the nose and paranasal sinuses, complete surgical resection of the tumor is much more difficult, and the possibility of tumor invasion of the intracranial nerves is increased.

According to Altemani, surgery is the first treatment for adenoid cystic carcinoma and can be followed by radiotherapy; radiotherapy without surgery is not as efficient to cure a tumor. Owing to its infiltrative growth pattern, which makes complete surgical removal difficult, the frequency of adenoid cystic carcinoma recurrence in the same location is high, and recurrent tumors require additional surgical resections.

In addition, the tumor disseminates through the blood stream (metastasis) to distant organs, such as the lungs, liver, bones, and rarely, the lymph nodes; although the cancer evolves slowly, it is frequently inoperable. The survival rate varies from 50% to 90%. The 15-year survival rate, however, is only 25%.

“The carrier often ends up dying as a result of the disease,” commented Altemani, who conducted research on the disease with FAPESP’s support.

Altemani was also the adviser for oral pathologist Ana Flávia de Mattos Costa’s doctorate on adenoid cystic carcinoma with high-grade transformation, which is a more aggressive variant of the tumor. This variant has been associated with a higher mortality rate, faster evolution and greater frequency of metastasis to the lymph nodes.

The criteria for the recognition of the aggressive variant of adenoid cystic carcinoma were only recently defined. The study by Mattos Costa indicated that adenoid cystic carcinoma can transform not only into undifferentiated or poorly differentiated carcinomas, that is, present a high-grade transformation, but can also transform into moderately differentiated adenocarcinomas and those with intracellular lumen formation, known as signet rings.

“The expression ‘signet ring’ is used because the cell acquires a light area within the cytoplasm that is similar to a ring. The signet would be the cell nucleus, which looks like a ring stone,” explains Mattos Costa.

Unlike the transformation to undifferentiated or poorly differentiated carcinomas, these other tumor variants do not seem to alter their aggressiveness. For pathologists (specialists that perform histological diagnoses of tumors), the importance of these new variants lies principally in the fact that the tumor morphology has become so modified that recognition as an adenoid cystic carcinoma is more difficult.

The study by Mattos Costa also broadens the concept of the potential transformation of the adenoid cystic carcinoma and suggests possible routes of tumor progression.

An article published by researchers of at three U.S. universities in 2007 established the morphological and immunohistochemical criteria for high-grade transformation in adenoid cystic carcinomas.

“The article sparked our attention because we had some tumors that presented these characteristics,” explained Altemani, adding that currently, this variation is believed to increase the probability of metastasis to the lymph nodes by 60%, compared to a 25% probability for conventional adenoid cystic carcinoma. Treatment of the former must be more extreme, including cervical evacuation during surgery, i.e., removal of lymph nodes in the cervical region.

Mattos Costa studied cases of adenoid cystic carcinoma based on the established criteria and identified new cases with high-grade transformation. During the study, she found that the tumors presented not only that type of high-grade transformation but also other forms that were not necessarily associated with a worse prognosis.

Costa, Altemani and colleagues published an article in Cellular Oncology with these conclusions. Later, the same group published a revision regarding high-grade transformation in all tumors of the salivary glands in Pathology Research International.

Mattos Costa’s doctoral thesis included morphological, immunohistochemical and molecular analysis of adenoid cystic carcinomas with high-grade transformation. Part of the study was conducted in Spain under the co-mentorship of Professor Mario Hermsen, a biochemist and researcher at the Institute of Otolaryngology at the University of Oviedo in Spain.

The morphological and immunohistochemical analysis, conducted under the guidance of Professor Altemani in the pathology laboratory at Unicamp, showed other forms of tumor transformation, among which was the signet ring described in the article published in Histopathology.

“We described this morphological alteration and the other forms and showed that the Ki-67 index [a marker of cellular proliferation in carcinogenic processes] increases the transformation of undifferentiated/poorly differentiated carcinoma and moderately differentiated adenocarcinoma but not of tumors with the signet ring cell alteration,” explained Mattos Costa.

During the study in Spain, she investigated the molecular and genetic characteristics of high-grade tumors with the intention of finding a molecular marker responsible for transformation in adenoid cystic carcinoma.

“However, other solid tumors are rich in genetic alterations, and it is very difficult to find a specific marker, as occurs for example, in hematological cancer, where a single genetic alteration often characterizes the disease,” she said.

The study proved, however, that the transformed area of the tumor does not always accumulate the genetic alterations of the original area, which shows that the adenoid cystic carcinoma does not necessarily follow a linear progression.

“The transformed area could evolve in parallel to a conventional area and acquire new genetic alterations. In these cases, one must take into account this process and consider the worst area inside the tumor to evaluate the prognosis and establish an approach,” commented Mattos Costa. These landmark results were submitted for publication and are under analysis.