Among the rarest of the rare malignancies, parathyroid carcinoma poses myriad diagnostic and treatment challenges. Owing to its extreme rarity, very little is known about the mechanisms driving parathyroid carcinoma, let alone how to target them; and survival rates have not budged in decades. However, researchers at The University of Texas MD Anderson Cancer Center are working to change this.
“This is an exciting time to be treating patients with this disease, because we are finally gaining the ability to combine an earlier diagnosis, more precise surgery, a better discernment of aggressive tumors, and the potential for targeted therapy,” said Nancy Perrier, M.D., a professor in the Department of Surgical Oncology and chief of the Section of Surgical Endocrinology. “Historically, parathyroid carcinoma was an unusual diagnosis with few therapeutic options other than the management of high serum calcium levels. But now we have something more to offer.”
Parathyroid carcinoma occurs in approximately one out of every 2 million people; it has no predilection for men or women. Because parathyroid carcinoma can be clinically indistinguishable from benign causes of hyperparathyroidism, the cancer often remains unidentified until after it has metastasized and the opportunity to effectively treat it has passed.
“Some of these tumors are smoldering—they recur locally and persistently, and they do so over several decades. Others are very locally aggressive, and others metastasize,” Dr. Perrier said.
Parathyroid tumors account for most cases of primary hyperparathyroidism. Worldwide, 85%–95% of these cases are attributable to benign adenomas; fewer than 3% are attributable to parathyroid carcinomas. Unsurprisingly, primary hyperparathyroidism is the initial clinical presentation of parathyroid carcinoma, with symptoms of hypercalcemia predominating. These symptoms may include fatigue, weakness, confusion, bone pain, and pathologic fracture.
According to Dr. Perrier, any patient who presents with symptoms of hypercalcemia should be given a thorough diagnostic workup. Such a workup includes laboratory assessments of serum calcium and parathyroid hormone levels, neck ultrasonography to assess local disease, and both functional and anatomical imaging. In some cases, nuclear medicine imaging techniques such as sestamibi/single-photon emission computed tomography (CT) or positron emission tomography are used to assess the primary tumor and for systemic evaluation.
“Parathyroid cancer is very rare, and it’s hard to know what to look for,” said Naifa Busaidy, M.D., an associate professor in the Department of Endocrine Neoplasia and Hormonal Disorders. However, some signs should increase the index of suspicion for parathyroid carcinoma. The effects of hypercalcemia may be more pronounced in patients with parathyroid carcinoma than in those with benign disease and include serum calcium levels higher than 13 mg/dL or parathyroid hormone levels more than 2 times the upper limit of the normal range. Also, evidence of bone involvement (e.g., subperiosteal bone resorption, “salt and pepper” skull, or osteitis fibrosa cystica) is more common with carcinoma. A neck mass that is palpable (rare in cases of benign disease) or that on ultrasonography is cystic or larger than would be expected in the case of benign disease also should increase one’s suspicion of carcinoma.
However, there is no test or set of characteristics to definitively differentiate parathyroid carcinoma from benign disease preoperatively. The only definitive marker of parathyroid carcinoma, metastatic disease, is seldom seen at the initial presentation. And fine-needle aspiration is strongly discouraged because cytological features alone do not differentiate benign from malignant parathyroid cells.
Rather, the diagnosis is usually made intraoperatively, when the parathyroid surgeon finds that the mass is larger, firmer, grayer, and more attached to surrounding structures than would be expected in the case of benign disease. Pathological analysis of the surgical specimen is performed to identify architectural features of malignancy, especially invasion into adjacent tissues and vessels. However, parathyroid carcinoma does not have a specific set of markers to distinguish it from benign disease, and a tumor may have only one or two pathological features indicative of malignancy. Thus, many cases cannot be definitively classified as malignant and are considered parathyroid neoplasms of uncertain malignant potential.
According to Michelle Williams, M.D., an associate professor in the Department of Pathology, caution is used before making a diagnosis of parathyroid carcinoma to ensure that the sampled tissue isn’t a more common condition with atypical features, such as fibrosis from a previous procedure.
Cytology alone is insufficient to differentiate parathyroid carcinoma from benign disease. Unlike many other types of cancer cells, most parathyroid carcinoma cells show only subtle morphological changes compared with normal cells. “In some cancers, such as squamous carcinoma, the cells themselves look ugly,” Dr. Williams said. “But in parathyroid carcinoma, the cells more closely resemble normal cells, which is why it can be difficult to figure out what the biology is by cytology alone.”
Ancillary tests used to help strengthen the case for or against a diagnosis of parathyroid carcinoma include staining cells for parafibromin and Ki-67 expression. Compared with normal parathyroid cells, parathyroid carcinoma cells tend to have loss of parafibromin expression and higher levels of Ki-67 expression. Although neither test alone is conclusive, Dr. Williams said, “These tests help us characterize what the cells are doing in borderline cases.”
Assessing for mutations in CDC73 (formerly called HRPT2), the gene for parafibromin, also may be informative. Patients with mutations in this gene may have hereditary syndromes associated with parathyroid carcinoma. Used in combination with abnormal pathological findings, a positive result on genetic testing for CDC73 mutations would support a diagnosis of parathyroid carcinoma.
Few treatment options
Surgery is currently the only definitive treatment for parathyroid carcinoma. Performed early in the disease process, when the cancer is localized, en bloc resection to completely remove all tumor cells offers a chance at a cure.
“Having a suspicion about the tumor preoperatively is important because it allows planning for the initial operation to be appropriate,” Dr. Perrier said. Whereas only about a third of the patients who are diagnosed before or during surgery—and thus undergo en bloc resection—have a recurrence, more than half of those who are diagnosed after surgery—who do not undergo en bloc resection—have a recurrence.
“Often, it’s only after the patient has a recurrence that carcinoma is diagnosed,”
Dr. Perrier said. “At that point, local recurrence in proximity to vital structures often makes surgical treatment less effective, and essentially, we’ve missed our window of opportunity to provide localized tumor control.”
Prophylactic, large, lateral neck dissections are unnecessary, Dr. Perrier said, because parathyroid carcinoma doesn’t kill by multiple recurrences of nodal disease; rather, death is usually caused by the debilitating effects of severe hypercalcemia.
“The right thing to do is to remove the tumor in continuity with anything else it might be attached to, without disrupting the tumor capsule and leaving microscopic disease behind,” Dr. Perrier said. “What’s not needed is aggressive lymph node dissection and surrounding prophylactic surgery. That doesn’t seem to affect survival.”
Fifty percent of parathyroid carcinoma patients have recurrent disease within 5 years after the initial oncological resection. While many recurrences are locoregional, 30%–40% involve distant metastases in the lung(s), liver, and/or bone(s), which require multiple surgeries to control the tumor burden. “Because of the high rate of recurrence, we know that surgery alone is not enough in every case. But we don’t have any adjuvant therapy to control the metastatic disease,” said Angelica Silva, M.D., a postdoctoral fellow in the Department of Surgical Oncology.
Cytotoxic chemotherapy regimens have no effect on parathyroid carcinoma, and the risks of postoperative radiation therapy often outweigh the treatment’s benefits.
“In the past, we thought that giving local radiation would help, but that comes with too many side effects,” Dr. Silva said, “and it does nothing for improving survival because it doesn’t influence metastatic disease.”
Because of the disease’s propensity to recur, parathyroid carcinoma patients must be monitored for life after their disease has been resected. The followup for patients with parathyroid carcinoma is the same as that for patients with hyperparathyroidism. Serum calcium and parathyroid hormone levels are assessed regularly; a sudden increase in either level would prompt additional investigation with imaging studies. How - ever, there is no established algorithm for follow-up imaging, and whether one imaging modality is better than another for detecting recurrent local or distant metastatic disease is unknown. Typically, however, cervical ultrasonography is performed to assess for local recurrence; if no disease is found in the neck, then a CT study of the lungs, the most common site of metastasis, is performed. Abdominal imaging may be performed if the CT study reveals the lungs to be disease-free.
Historically, parathyroid carcinoma was an unusual diagnosis with few therapeutic options…. But now we have something more to offer.
The main challenge in treating patients with unresectable or recurrent disease is managing their profound hypercalcemia. According to Dr. Perrier, these patients’ hypercalcemia eventually manifests as fatigue, arthralgia, cloudy thinking, and changes in mood, memory, and concentration. Bisphosphonates are given to protect bone against the risk of fracture, and calcimimetics are given to keep serum calcium levels down. However, Dr. Perrier said, these agents do not affect the parathyroid hormone level, and their effects are not durable.
Finding some answers
Investigating parathyroid carcinoma has not been easy. Studies of the disease have been largely limited to case reports, case series, and small, single-institution retrospective analyses.
MD Anderson sees about 12 parathyroid carcinoma patients per year—the largest experience in the country, if not the world, according to Dr. Perrier. Recognizing this, Dr. Silva, who was training in Chile at the time, reached out to Dr. Perrier in 2014 to explore the possibility of working together to find new and effective treatments for parathyroid carcinoma. In 2015, she completed her training and came to MD Anderson to focus solely on para - thyroid carcinoma. Since her arrival, she has worked with Dr. Perrier and others to initiate programs aimed at better understanding and treating the disease.
Dr. Silva has established an international consortium to facilitate the study of parathyroid carcinoma. In addition to MD Anderson and other U.S. institutions, the consortium includes groups based in the United Kingdom, Australia, Spain, and the Netherlands and continues to grow. “It’s an uncommon disease, but it’s also potentially lethal. We need to find a specific treatment to control this disease, and a collaborative effort is needed,” Dr. Silva said. The main objective of the consortium is to share knowledge and discoveries about the disease, along with cell and tumor samples. “Different groups have worked on this very rare disease, but we need to put together all the information,” Dr. Silva said. “This is the first time we’ve tried to create a big picture of the disease, from making the diagnosis to finding options for controlling it.”
One main component of MD Anderson’s push to understand more about parathyroid carcinoma is an institutional review of all parathyroid carcinomas. This includes obtaining parafibromin stains, looking at molecular changes, and investigating new immunohistochemical parameters to identify the disease and predict its trajectory more easily.
“We are trying to approach this disease from all directions—not only in terms of diagnosis but also in terms of predictive and prognostic markers,” Dr. Williams said. “We want to see if any of those help predict which patients have mere atypia versus carcinoma and which are likely to develop advanced disease.”
Dr. Silva is investigating several antibodies that could be used in histo - pathology to clarify whether a patient’s disease is a benign adenoma or parathyroid carcinoma. Whereas most previous reports have used only one or two antibodies, Dr. Silva intends to develop a panel of markers for differentiating the diseases.
“With these biomarkers, we hope to improve the sensitivity and specificity of our diagnosis when we first encounter the patient,” Dr. Silva said, “and this will help us provide earlier, more effective treatment.”
Genomic profiling, too, plays an increasingly large role in determining how to best approach parathyroid carcinoma. At MD Anderson, all parathyroid cancers archived between 1986 and 2015 are being subjected to genomic profiling, which should identify genes the tumors commonly express and help reveal the pathways underlying the disease. Tissues are also being banked to look at additional genes and underlying changes that may point to causes of the disease or that can be used to help guide treatment.
“Currently, we don’t know what genes these tumors have in common,” Dr. Perrier said. “Once we have those data and can perform computational analysis, we can design a panel on a platform for genomic profiling and tailor treatment according to the results.”
Creating new therapies may not be necessary. “We already have targeted therapies, such as vaccines and antibodies, that were created for other kinds of tumors,” Dr. Silva said.
The whole-genome exon sequencing data should be available soon, Dr. Perrier said, meaning that before long her team may have something other than surgery to offer parathyroid carcinoma patients. In the meantime, patients may be eligible for clinical trials on the basis of their individual tumor’s characteristics (see “A Patient’s Perspective,” below).
In a pilot program of immunogenic profiling that was recently initiated by Dr. Silva and her colleagues, 45 parathyroid tumors will be analyzed to investigate the differences in the tumor environment according to the presence or absence of tumor-infiltrating lymphocytes and programmed death ligand 1 expression on parathyroid tumors.
“We need to look at the tumor’s mutational status,” Dr. Busaidy said. “We’re also working with the immunotherapy group here and looking at tumors’ immune signatures to see if they’re likely to respond to immunotherapy or if they need priming before they’ll respond. And we have a few patients with parathyroid carcinoma who have responded to antiangiogenic therapy, so that is something else we’re looking into.”
Adding to the improvements in parathyroid carcinoma treatment and research that may result from the initiatives at MD Anderson, the American Joint Committee on Cancer will soon offer staging guidelines for parathyroid carcinoma.
“The new staging guidelines mean that there will be a patient-based registry, and we will be able to accumulate information and develop survival curves to predict and better understand who we need to treat more aggressively and when,” Dr. Perrier said. “Up to now, we’ve only been able to attempt this at individual institutions because we haven’t had a collective effort of looking at clusters of tumors and because of their rarity.”
Despite the vast amount of work required to move forward in parathyroid carcinoma, the outlook is generally positive.
“It takes an effort to look at a rare disease like this to figure out how we can improve the diagnosis and treatment,” Dr. Williams said. “Working together, we can certainly make strides.”
Asare EA, Sturgeon C, Winchester DJ, et al. Parathyroid carcinoma: an update on treatment outcomes and prognostic factors from the National Cancer Data Base (NCDB). Ann Surg Oncol. 2015;22:3990–3995.
For more information, call Dr. Naifa Busaidy at 713-792-2841, Dr. Nancy Perrier at 713-794-1345, Dr. Angelica Silva at 713-745-0377, or Dr. Michelle Williams at 713-794-1765.
Bryan Tutt contributed to this article.
OncoLog, August 2016, Volume 61, Number 8
A Patient’s Perspective
Jennifer Jordan of Seattle had a parathyroid tumor removed in 2013. A pathological examination of the tumor revealed it to be carcinoma, and when the cancer recurred 18 months later, Ms. Jordan’s doctors referred her to MD Anderson. “I have great doctors at home, but they sent me here because this type of cancer is so rare,” Ms. Jordan said.
At MD Anderson, Dr. Perrier removed the recurrent parathyroid carcinoma; Jean-Nicolas Vauthey, M.D., a professor in and chief of the Hepato-Pancreato-Biliary Section in the Department of Surgical Oncology, removed several metastatic lesions from Ms. Jordan’s liver; and Ara Vaporciyan, M.D., a professor in and chair of the Department of Thoracic and Cardiovascular Surgery, removed a tumor from her upper chest.
Genomic analysis of tissue from one of the liver lesions revealed mutations in two genes that affect the phosphatidylinositol 3-kinase/mammalian target of rapamycin (mTOR) signaling pathway. So when the disease recurred again in her neck and liver, Ms. Jordan signed up for a clinical trial (No. 2011-0953) in which she received everolimus, which inhibits mTOR, plus vandetanib, which inhibits vascular endothelial growth factor receptor 2.
“We thought this trial might work because everolimus attacks one of the tumor drivers and vandetanib starves the tumor of its blood supply,” Dr. Busaidy said. “We’ve had some patients with parathyroid carcinoma who were treated with an antiangiogenic drug similar to vandetanib, and it controlled their calcium levels.”
Clinical trials that enroll patients on the basis of their tumors’ molecular and genetic characteristics rather than their tumors’ locations often are the only trials available to patients with rare cancers like parathyroid carcinoma. “I was the only patient in the trial with parathyroid cancer,” Ms. Jordan said.
Ms. Jordan was treated in the trial for 5 months. During this time, her calcium levels normalized and her disease remained stable. Since her neck and liver tumors were neither growing nor shrinking, Ms. Jordan had the choice of remaining in the trial and taking the drug combination indefinitely or undergoing surgery to remove the tumors. “I decided to just go ahead and get the cancer out of me,” she said.
As this article was being written, Ms. Jordan was preparing to undergo a procedure to ablate the liver tumor and surgery to remove the neck tumor. “After the surgery, we’ll take it one day at a time and see how I do,” she said. “If my tumors come back after my surgery, I may go back on the trial. It did at least stabilize the disease, so it feels good to know that there’s something there for me.”
“Ms. Jordan is one of a kind,” Dr. Perrier said. “Her internal strength and level-headed optimism are an inspiration to us.”
“She’s a real pioneer—always willing to push the boundaries and try something new,” Dr. Busaidy said. “And that’s how we’ll find a cure.”