Gynecology’s deadly surprise: Cancers are frequently missed prior to routine procedures

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As they reach for surgical tools, gynecologists vastly underestimate the probability that their patients have undiagnosed uterine cancers, a study by Yale University researchers found.

Their paper, published in Obstetrics & Gynecology last month, is immediately relevant in the clinic, because a suspicion that cancer may be present dictates the choice of surgical techniques employed in gynecological procedures that are performed in about 650,000 women every year in the United States.

The newly calculated prevalence rates, based on analysis of data from 26,444 cases in the 2014-2015 American College of Surgeons National Surgical Quality Improvement Program, are staggering:

  • One in 20 women over age 55 were subjected to surgery for benign indications, but were later found to have malignancies in the main body of the uterus. Nearly one in 10 women over age 55 who underwent total abdominal hysterectomies had hidden corpus uteri cancer.

  • Overall, prevalence of cancers undetected at the initiation of hysterectomies was almost as high as one in 70. For women who underwent total laparoscopic or laparoscopic-assisted vaginal hysterectomies, the estimated prevalence rose to nearly one in 50.

An earlier estimate by FDA places the risk of spreading previously undetected uterine sarcomas at one in 350 for women undergoing hysterectomy or myomectomy for uterine fibroids. Sarcomas, which account for about 3 to 7 percent of all uterine cancers, are just one category of malignancies commonly missed by gynecologists. The new study by Yale researchers looks at prevalence of all malignancies—not just sarcomas—thereby taking the controversy to a new level.

When all uterine cancers are taken into account, deadly surprises can be up to one in 70, in contrast to FDA’s estimate that focused on missed sarcomas and the 1 in 10,000 frequency of leiomyosarcoma cited by gynecologists for decades.

Over the past four years, public discussion of these undiagnosed malignancies revolved around power morcellators, devices that pulverize uterine tissue in the abdominal cavity. These new data are relevant to all gynecological surgical devices.

“We were surprised that the prevalence of occult cancer was higher than some prior estimates,” Cary Gross, a co-author of the study, professor of medicine and epidemiology, and director of the National Clinician Scholars Program at Yale, and the senior author of the study, said to The Cancer Letter. “At the end of the day, we may end up with a helpful clinical guide that suggests which women would benefit from further evaluation to rule out occult malignancy before making decisions about how to operate.”

Gynecologic oncology experts contacted by The Cancer Letter said the Yale study points to an urgent need for more rigorous preoperative workup and risk stratification for patients undergoing hysterectomies and myomectomies—and raises questions about morcellation remaining a reasonable option.

FDA had come down hard on power morcellation, making it almost non-existent in the U.S. In November 2014, FDA issued a guidance that severely limited the use of power morcellators, electrical devices resembling glue guns, except for the long cylinder of spinning blades that protrudes from the main body. It was designed for the purpose of slicing fibroids and uterine tissue into easily removable fragments.

Prior to FDA guidance, power morcellation was the standard of care, with 50,000 to 100,000 women undergoing the procedure every year in the U.S.

Gynecologists’ reliance on the procedure was the subject a four-year investigation at The Cancer Letter that resulted in a series of stories, “How Medical Devices Do Harm.”

As power morcellation became less common, some gynecologists who prefer minimally-invasive procedures switched to performing something called “manual morcellation,” using other tools at their disposal—scalpels, laparoscopic devices, and robots instead of electromechanical morcellators to tear uterine tissue into strips.

There are no published studies to indicate how often these procedures are performed. Since manual procedures do not necessarily involve high-risk devices that require FDA clearance or approval, the agency has limited purview over what essentially amounts to clinical judgment by individual surgeons.

From manual morcellation to 30 “Skittle-sized” mets

According to court documents and patient records, in one such case, Alivia Greenfield, of Forreston, Ill., underwent manual morcellation. Her gynecologist, Joseph Ehle, raised her uterus to skin level and used a scalpel to slice it into 26 strips.

The website of Monroe Clinic, where he practices, describes Ehle as “skilled in minimally invasive surgery.” Greenfield had been a patient at the clinic for over a decade. It was where she had delivered both her daughters.

Medical records that Greenfield made available to The Cancer Letter show that Ehle, who practices in Freeport, Ill., performed an ultrasound and an endometrial biopsy prior to her laparoscopic supracervical hysterectomy.

“I obviously knew that something was not normal on you [sic] ultrasound,” Ehle wrote months later in a thread in Greenfield’s patient portal. “The part of you [sic] ultrasound was fluid filled area behind the normal part of your uterus.”

The preoperative endometrial biopsy came back as “early benign simple (cystic) endometrial hyperplasia; no evidence for atypicality, dysplasia or malignancy.”

Greenfield underwent morcellation on July 22, 2015. During surgery, Ehle noticed a discoloration in the uterine tissue. He sent a frozen section specimen—an intraoperative sample—to a pathologist at the clinic. The results returned as “Spindle Cell Neoplasm: Further diagnosis pending additional studies,” which is usually interpreted as inconclusive, experts say.

Ehle went on with the manual morcellation, completing it. “The report, as I understood it from the pathologist at the time of frozen specimen, was benign,” Ehle said in an email to The Cancer Letter. “It wasn’t until weeks later I understood it to be inconclusive.”

James Caya, the Monroe Clinic pathologist who evaluated Greenfield’s frozen section specimen, did not respond to questions from The Cancer Letter.

In a lawsuit filed against the clinic, Greenfield alleges that manual morcellation ended up spreading her previously undetected endometrial stromal sarcoma. She was 37 at the time.

Two months later, Greenfield sought care at the Carbone Cancer Center at the University of Wisconsin School of Medicine and Public Health. There, in a follow-up surgery, David Kushner, director of the Division of Gynecologic Oncology, removed about 30 endometrial stromal sarcoma implants from her abdominal cavity, records show.

“He ultimately found that I had sarcoma spread throughout my abdominal cavity,” Greenfield said to The Cancer Letter. “I believe it was 30 new sarcoma implants—it’s described as ‘Skittle-sized’—I went into surgery thinking it was, again, a very routine surgery to have my ovary removed, and I woke with a massive incision and exploratory surgery, and a big unknown.”

Greenfield’s husband, Joshua, said he’ll never forget the day he authorized Kushner to remove the sarcomatous implants Kushner had found without waking Alivia up:

“You know that it has spread, but you really don’t know what all this means, and a couple of hours now of surgery, just sitting there in the waiting room, and you think about it, and make some deals with God, and think about your kids.”

Kushner’s assessment and treatment plan for Greenfield reads: “Alivia has low grade endometrial sarcoma. At the time of surgery, cancer deposits were removed from her abdomen. While we did remove all visible cancer, microscopic disease could remain. Alivia does have a 90-100 percent chance that her cancer will return.”

Nearly three years later, Greenfield has no evidence of disease.

Alivia Greenfield and husband, Joshua Greenfield. Alivia’s undetected cancer was disseminated by manual morcellation, her lawsuit states. A video interview is posted here.

When Greenfield asked Ehle, the physician who performed the manual morcellation, to expound on his therapeutic rationale, he responded:

“Had I known the outcome, I would have done things differently. I have been doing this for 15 years and I have never had a patient with this type of tumor. I knew the ultrasound was not normal looking, but I honestly thought that the fluid in the tube explained the appearance on the US, this is why I proceeded with the case the way I did. I clearly took more comfort in that then [sic] I should have in retrospect.

“I have done this procedure very successfully on numerous close friends and even a not immediate family member. That is not me just being defensive with you, it is a true statement.”

In a statement to The Cancer Letter, Ehle’s attorney, Samuel Lieb, said Greenfield received the standard of care in gynecology:

“The care that she was provided in 2015 was at all times within the standard of care and, as your proposed article seems to be alluding to, there are always new therapies and protocols to respond to medical problems that have existed since the modern medical age.”

Greenfield’s attorney, Gregory Barrett, said the lawsuit was voluntarily withdrawn without prejudice on Oct. 16, 2017.

“This is a common procedural strategy that allows a plaintiff to reinstate the case when circumstances are ready to do so,” he said to The Cancer Letter. “It is anticipated that the Greenfield case will be reinstated in the immediate future; probably in the next 60 days or so. At that point, the case will pick up right from where it left off.”

The case of another patient, Nancy Curtis, of Missoula, Mont., who underwent power morcellation on Sept. 12, 2013, raises questions about how much workup should be performed before surgery.

According to court filings and materials in her medical records that were made available to The Cancer Letter by her husband, Ray Curtis, an ultrasound was performed, but no further preoperative workup was done.

She died Dec. 19, 2015 from metastatic endometrial adenocarcinoma. Curtis was 53.

The clinical scenarios: How much workup is enough?

Greenfield’s and Curtis’s stories point to the myriad of clinical scenarios that gynecologists face when—first—they screen for uterine cancers and—second—they choose a surgical procedure for a benign indication that may, in fact, turn out to be malignant.

Broadly speaking, there are three surgical procedures that may result in dissemination and upstaging of an occult uterine malignancy, surgeons say:

  • Power morcellation, which can be avoided, especially when it is unclear whether tissue indicated for a benign hysterectomy is truly devoid of cancer,

  • Manual morcellation, which is also avoidable, because other procedures are available for hysterectomies, and

  • Morcellation or removal of fibroids as part of a uterus-sparing myomectomy. These procedures involves cutting into potentially malignant tissue, which may be unavoidable, especially in younger women who would like to preserve childbearing ability.

“Upstaging would only be done by morcellation, manual or power,” said Stephen Rubin, chief of the Division of Gynecologic Oncology, professor in the Department of Surgical Oncology, and the Paul Grotzinger and Wilbur Raab Chair in Surgical Oncology at Fox Chase Cancer Center. “You’re right to think of it as two separate issues. One is the prevalence of undiagnosed cancer, and the second is, are these cancers being spread by an inappropriate surgical procedure?”

A conversation with Rubin appears here.

Over 80 percent of black women and nearly 70 percent of white women develop fibroids at least once in their lifetime. Many women with occult leiomyosarcomas—one of the most aggressive forms of uterine cancer and one of the most likely to be missed in preoperative workup—disseminated by power morcellation die within two years of the procedure.

Amy Reed, the anesthesiologist who, with her husband Hooman Noorchashm, launched a successful campaign against power morcellation, died from metastatic leiomyosarcoma three years and seven months after her initial surgery. She was 44 (The Cancer Letter, May 26, 2017).

Reacting to the Yale study and a letter from Rep. Brian Fitzpatrick (R-PA), officials at the Centers for Disease Control and Prevention are considering launching a review of whether gynecologists are sufficiently thorough in evaluating patients in the preoperative setting, according to insiders with knowledge of the agency’s plans (The Cancer Letter, May 4).

CDC has the authority to set screening guidelines—for instance, by recommending that gynecologists perform biopsies on women undergoing myomectomies to preserve fertility. The agency may do so if it determines that gynecologists aren’t evaluating patients as rigorously as oncologists in a setting where there is a high risk of encountering unsuspected malignancies.

The take-home message from the Yale study is clear: all patients must be properly assessed for a gynecologic cancer prior to undergoing surgery, said Ronald Alvarez, the Betty and Lonnie S. Burnett Professor of Obstetrics and Gynecology, and chair of the Department of Obstetrics and Gynecology at Vanderbilt University Medical Center.

“While those percentages seem somewhat high, the biggest issue to me is what type of preoperative evaluation are patients having to rule out a potential cancer,” Alvarez said to The Cancer Letter. “I think that it probably represents a failure in our health care system. My guess would be that if everybody had the appropriate evaluation, the actual number of people that had occult cancer would be a much smaller percentage.”

A conversation with Alvarez appears here.

As clinicians adjust to alternative surgical options for specimen removal, it is essential that patients receive rigorous preoperative workup, said Vrunda Desai, lead author of the study, assistant professor of obstetrics, gynecology, and reproductive sciences at Yale University School of Medicine.

“We hope that our study increases the awareness and discussion of occult cancer risk in the thousands of women undergoing hysterectomy and myomectomy annually,” Desai said to The Cancer Letter. “Morcellation of a specimen allows for the dissemination of cancer. Having an informed conversation with patients preoperatively is essential to this process.”

A conversation with Desai appears here.

Larger study, similar results

The same group of Yale researchers recently completed a second, much larger, study, “Occult Uterine Cancer in Presumed Benign Hysterectomies: A Population-Based Study” that analyzed data from 233,979 women who underwent a hysterectomy between 2003 and 2013. An abstract has been published in Obstetrics & Gynecology, also known as The Green Journal.

Drawing from the New York Statewide Planning and Research Cooperative System database, the researchers got similar results: the overall prevalence of occult uterine cancer was one in 100. Up to 1.96 percent of women who underwent total abdominal hysterectomy had undetected uterine cancers. The prevalence rate jumped to 8.64 percent for women with postmenopausal bleeding.

All women undergoing hysterectomies or myomectomies need to receive thorough preoperative workup, especially older women at high risk, said Robert Mannel, director of the Stephenson Cancer Center at the University of Oklahoma, a group chair of NRG Oncology, and the chair of the Protocol Development Committee for Gynecologic Cancers in the NCI National Clinical Trials Network.

“I think the takeaway that I got from reading this article was very similar to what the author stated and that is, in a postmenopausal woman, you better really make sure that you are very thorough in your evaluation and particularly, if somebody has abnormal uterine bleeding, you really want to make sure,” Mannel said to The Cancer Letter. “You might need more than just an endometrial biopsy or an ultrasound. That individual may need diagnostic hysteroscopy, something that can be even more sensitive at picking up occult malignancies.”

A conversation with Mannel appears here.

CDC eyes a role in setting guidelines

CDC’s new director, Robert Redfield, has signaled that he is interested in convening an advisory panel of surgeons from different specialties to discuss how other fields in medicine preoperatively evaluate tumors and other masses that may contain occult malignancies.

In other fields—breast cancer, for example—all solid tumors are presumed to be potentially malignant, and workup is done to rule out that possibility, even though the vast majority of suspicious findings turn out to be benign.

Should gynecologists adopt the same presumption of malignancy?

“The biological and emotional issues are different, but we can learn from one another,” said Joanne Mortimer, director of Women’s Cancer Programs, vice chair and professor in the Department of Medical Oncology & Therapeutics Research, Baum Family Professor in Women’s Cancers, associate director for education and training, and a breast oncologist at City of Hope Comprehensive Cancer Center.

“We do absolutely biopsy everything in the breast world. That’s pretty much true,” Mortimer said to The Cancer Letter. “The reason is, in breast cancer, you want to know everything, and where it is, and whether you need to do a mastectomy, and also, because we learned that breast cancer is frequently systemic at a much earlier stage, even when it’s very small, than uterine cancer.

“That said, the biology is so different—not that there aren’t ugly uterine cancers—in how we manage it. The GYNs have one operation for uterine cancer. We may do a lumpectomy, a skin-sparing mastectomy, a nipple-sparing mastectomy. There are so many different approaches depending on patient preference.”

Olive: GYNs don’t really biopsy

Gynecologists do not perform as many biopsies as other specialties, said David Olive, president of the Wisconsin Fertility Institute, formerly a professor and chief of reproductive endocrinology at Yale University, and an outspoken proponent of morcellation.

“It’s true, here’s the reason why. In all other specialties, a mass is unusual, and there is a high risk of malignancy,” Olive said to The Cancer Letter. “In obstetrics and gynecology, when we’re talking about fibroids in particular, fibroids occur in somewhere between 70 and 80 percent of all women at some point in their lifespan. We obviously can’t biopsy every fibroid, and plus, there are multiple fibroids that occur in many patients.

“We can’t even biopsy every fibroid in every patient in those that are going to surgery. It would be ridiculous in terms of medical cost, it would be ridiculous in terms of the amount of intervention, and, we don’t have good evidence about whether or not it itself might spread cancer, if in fact we were able to biopsy it.”

A conversation with Olive appears here.

Gynecologic oncology experts interviewed by The Cancer Letter echoed Olive’s concerns about core needle biopsies for fibroids, but urged gynecologists to follow current guidelines.

“The most difficult cancer to detect preoperatively may be leiomyosarcomas of the uterus,” Vanderbilt’s Alvarez said. “Consultation with a gynecologic oncologist when diagnostic tests suggest or confirm a gynecologic malignancy is always wise.”

Olive co-founded the Wisconsin Fertility Institute with his wife, Elizabeth Pritts, who is a “national leader in the use of robotic surgery for gynecologic disorders,” according to the institute’s website. In the power morcellation debate, Pritts is known for challenging FDA’s risk estimates for sarcomas and leiomyosarcomas (The Cancer Letter, July 25, 2014).

In a recent review, FDA said its updated estimate is generally consistent with the numbers from 2014. A separate review of data by the Agency for Healthcare Research and Quality—published on the same day as the FDA report—said the risk of unexpected leiomyosarcoma ranged from less than 1 in 10,000 to as high as 13 of 10,000 (The Cancer Letter, Dec. 15, 2017).

Pritts and Olive were co-authors of an April 9 editorial, “FDA report a disservice to fibroids patients,” published in Contemporary OB/GYN. William Parker, a professor of obstetrics, gynecology, and reproductive sciences at UC San Diego Health, is the lead signatory on the statement.

Parker, formerly the director of minimally-invasive gynecologic surgery at UCLA Medical Center, didn’t respond to an email from The Cancer Letter. The American College of Obstetricians and Gynecologists also didn’t respond to an email.

“There is no consensus on how frequently sarcomas occur,” Olive said. “And even with sarcoma, if you look at the AHRQ study, they didn’t find statistical significance—there was a trend and a suggestion that it might be, but there’s no statistical evidence right now that confirms that things get worse if you morcellate a sarcoma.”

A 2014 retrospective analysis published in the journal Cancer concluded that women with uterine leiomyosarcoma who underwent morcellation of presumed leiomyoma had worse outcomes and experienced significantly shortened median recurrence-free survival (10.8 months vs. 39.6 months).

The study, conducted by Harvard researchers from the Center of Sarcoma and Bone Oncology at Dana-Farber Cancer Institute, compared the outcomes of 19 women who underwent morcellation to 39 women who had total abdominal hysterectomy.

Oncologists and pathologists with access to a patient’s medical history tend to be biased, Olive said.

“Frequently, oncologists who do repeat surgery down the road in a patient who has had morcellation for hysterectomy and found to have some type of uterine cancer—or the pathologist examining the specimen—they frequently know the history of the patient and the fact that they had morcellation,” Olive said. “Their bias is that morcellation is what caused the problem.”

Olive said bias in oncology is the reason why there is widespread belief that morcellation causes upstaging of uterine cancers.

“There is no suggestion that morcellation of any other cancer within the uterus causes any upstaging or worsening of prognosis,” Olive said. “Now, if you ask most people, they’d say, ‘Yeah, there’s a chance that it could get worse,’ and I wouldn’t disagree with that point of view, but the evidence doesn’t necessarily support it yet. There still could be a chance of that.”

Noorchashm, the cardiothoracic surgeon whose wife, Reed, died from sarcomatosis, disagrees.

“From a surgical perspective, the notion that morcellating a cancer does not lead to catastrophic local regional spread that could cause premature or unnecessary death, is simply absurd,” Noorchashm said to The Cancer Letter. “Also, the suggestion that uterine tumors cannot be biopsied efficiently is puzzling. Every breast mass is biopsied, and these are not any less frequent than uterine tumors.

“The Desai study is not simply uncovering the prevalence of occult cancer. For the authors to classify these cancers as occult, in a setting where biopsy guidelines are absent to lax, is a misrepresentation. These are missed cancers, not occult ones.”

Olive said there is no evidence that morcellation worsens outcomes for patients with endometrial cancer: “And for all the others, they’ve been unable to find any evidence for endometrial cancer, for endometrial stromal sarcoma, that anything becomes worse with morcellation.”

“Fragmentation of the specimen” makes diagnosis a mystery

Alas, Alivia Greenfield’s prognosis did worsen after morcellation.

In her final pathology report, Paul Weisman, an assistant professor in the Department of Pathology and Laboratory Medicine at the University of Wisconsin School of Medicine and Public Health, wrote:

“Although the most usual scenario would be that the tumor in the peritoneum is metastatic from a known primary endometrial tumor, the possibility of spilling and secondary implantation in the peritoneum secondary to morcellation of the uterus performed as a treatment of an endometrial stromal tumor cannot be excluded as ‘recurrence’ occurred in a very short period of time.

“The original tumor in the uterus could not strictly be classified as endometrial nodule or low-grade sarcoma as evaluation of margins could not be performed due to fragmentation of the specimen.

“I would favor that the endometriotic foci are entrapped within the tumor, and the morphology of the tumor in both locations (uterus and extrauterine) is very similar.”

Greenfield’s gynecologist at the time, Ehle, at Monroe Clinic, likely followed the standard of care by recommending morcellation when the first preoperative biopsy was diagnosed as hyperplasia without atypia.

“I think it depends on what type of hyperplasia there is,” Olive said. “If it’s hyperplasia with atypia, then my guess is some do morcellate and some don’t. If it’s not with atypia, then my guess is most will probably do it, if they still have electromechanical morcellators around.”

As for Greenfield’s intraoperative frozen section, “Spindle Cell Neoplasm: Further diagnosis pending additional studies” is usually interpreted as “inconclusive,” which means, “Be careful, I don’t know whether this is benign or malignant.”

“That’s how I would interpret it,” Olive said. “At that point, what you do is probably end your procedure as fast as you can, unless you have an oncologist in the vicinity who can stage the patient. You cannot assume that it’s benign if it’s inconclusive.

“If you’re in the midst of morcellating and something looks suspicious, I think I would probably change my plans and switch to a total abdominal hysterectomy at that point.”

Gynecologists would not have to worry about biopsies or inconclusive pathology if morcellation is taken off the table as a therapeutic option, Fox Chase’s Rubin said.

“I think the better idea is don’t morcellate the damn thing. That would solve the problem,” Rubin said. “Yes, remove it all.”

The Green Journal papers show that the standard of care in gynecology needs to change, Yale’s Gross said: “In the larger picture, yes—we need to first develop evidence that demonstrates whether new medical or surgical devices are effective. And then disseminate them into practice.

“We’ve been doing things backwards for 50 years and it’s not working so well—disseminating new devices first and then not really carefully assessing how they impact patients unless a problem arises.

“Although further studies are needed to build upon our findings, at the very least our study suggests that it is imperative to conduct definitive studies—and our study is not the definitive study—to determine the prevalence of occult cancer across clinically relevant sub-groups.

“Our hope is that this study will add momentum to the idea that we need to be constantly assessing medical practice—including the way we perform hysterectomies—so that we can build a body of evidence that will allow women to choose the type of surgery according to their values and preferences. And without data, that’s pretty hard to do.”

Women are being harmed by the standard of care in gynecology, and that needs to change, Greenfield said.

“The minimally-invasive gynecology specialty needs to take a hard look at itself and make decisions that are in the best interest of women,” Greenfield said. “Also, women should absolutely have information about risks and prevalence rates that are readily available.

“We should be more informed about what they’re actually doing to us, so that we can make our own choices as well.”

Clarification: This story has been updated on May 25 to include a more detailed discussion of the prevalence estimates of uterine cancer.

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President Joe Biden’s proposed Advanced Research Projects Agency-Health would be a welcome partner to NCI—particularly in conducting large, collaborative clinical investigations, NCI Director Ned Sharpless said.“I think having ARPA-H as part of the NIH is good for the NCI,” Sharpless said April 11 in his remarks at the annual meeting of the American Association for Cancer Research. “How this would fit with the ongoing efforts in cancer at the NCI is still something to work out.”
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