The focus of this month’s blog post is a discussion of malignant peripheral nerve sheath tumors (MPNSTs), which represent one of the few potentially life-threatening complications of neurofibromatosis type 1. Because these tumors, which occur in about 10% of people with NF1, are not responsive to any known mode of treatment when they have spread through the body, early diagnosis and surgical treatment are currently important for a better outcome. Clinical trials are underway to identify more effective approaches to early detection and treatment.

Symptoms and Clinical Features

MPNSTs occur mostly in teens and young adults with NF1. These tumors usually arise from pre-existing plexiform or nodular neurofibromas and do not originate from cutaneous neurofibromas (i.e., the small tumors on the skin). Atypical neurofibromas (technically called “atypical neurofibromatous neoplasm of uncertain biological potential,” or ANNUBP), which have distinctive clinical and pathological features, may be a precursor to the development of an MPNST and appear as homogenous nodules by magnetic resonance imaging (MRI); if superficial, these nodules have a firm consistency when palpated, though not all firm nodules are atypical neurofibromas.

The development of MPNSTs from tumors such as plexiform neurofibromas occurs by the progressive accumulation of genetic changes that are characteristic of cancer. Cancer cells are fueled by an accumulation of genetic changes that drive altered cells to divide rapidly and spread throughout the body. The genetic changes in MPNSTs make these tumors difficult to control.

Because MPNSTs are very challenging to treat, early diagnosis is critical. MPNSTs can be hard to recognize, and the diagnosis is often late because individuals are either not aware the tumors are there or do not recognize changes in neurofibromas that should be investigated. The following are indications that a tumor requires medical evaluation:

• Persistent, unexplained pain. Most neurofibromas are not painful, so occurrence of pain, which is often attributed to other causes, is a sign the tumor should be medically checked. The pain tends to be severe, persistent, and may wake the person from sleep. Sometimes a neurofibroma may become painful if it is bumped or subject to pressure. This typically resolves quickly. The pain of MPNST does not require such stimuli and is persistent.
• Rapid growth of a tumor. Although neurofibromas may grow, the sudden growth of a tumor or growth that is significantly out of proportion to other neurofibromas should be evaluated.
• Change in the consistency of a tumor from soft to hard. Most neurofibromas are soft and spongy, although firm nodular neurofibromas under the skin are not worrisome. However, if a tumor that was previously soft develops a component with a hard, firm consistency, it requires evaluation.

The Use of Imaging in Diagnosis

If a malignancy is suspected based on clinical features, an MRI is usually performed. While MRI will not diagnose a malignancy, it can indicate areas of a tumor where cells have deteriorated that are characteristic of a malignancy. Based on these results, a positron emission tomography (PET) scan with radiographic computed tomography (PET-CT) or magnetic resonance imaging (PET-MRI) may be performed to determine the tumor’s uptake of radioactive tracer material. Malignant tumors take up more of the radioactive material on the scan, indicating a possible malignancy. Either a needle or surgical biopsy then needs to be performed for pathological confirmation of a malignancy.

There are emerging technologies that may facilitate early diagnosis of MPNST. Whole-body MRI might detect nodular neurofibromas at the greatest risk of malignant change, though the possibility of false positive (or false negative) results needs to be considered. Another involves the identification of tumor DNA in the bloodstream. Some cells in a tumor may die, and DNA from these dead cells can be detected in the bloodstream; if the tumor is malignant, the damaged DNA from the malignancy can be identified in the bloodstream, indicating the possible presence of the malignancy. This would, in turn, trigger additional studies, such as imaging to find the malignant tumor.

Management and Treatment

Treatment of MPNSTs usually involves surgery to resect the tumor, if possible. Sometimes radiation therapy will be used to help shrink the tumor; we tend to avoid radiation treatment in NF1 patients because of concern that it could trigger malignancy, but sometimes it is necessary if a malignant tumor has already occurred. For metastatic tumors, the only possible treatment is chemotherapy. However, tumors continue to acquire rapid genetic changes that often cause them to develop resistance to chemotherapy and other traditional cancer treatments after a period of time.

Current NF clinical trials are evaluating chemotherapy as well as other therapeutics targeting genetic changes in the tumor. Also, immunotherapy, which trains the individual’s immune system to attack tumors, is an important new area of potential treatment, though it has not yet been tested extensively on MPNSTs.

In conclusion, because MPNSTs are difficult to treat, early detection is critically important. Individuals with NF1 should report instances of chronic pain or rapidly growing tumors. Clinical trials are focused on finding better indicators of tumors that have the potential to become malignant to facilitate early detection and treatment.