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What are the Characteristics of the Nodules that are Biopsied but Mistakenly Called Benign?

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We know that there is a big difference between a lung (or pulmonary) nodule and having cancer.  Formal screening studies or just random CT scans done for other reasons will often show nodules that are of questionable significance, leading us to recommend either follow-up imaging or an immediate biopsy, depending on the level of suspicion.  Often, the biopsy gives us an explanation for the nodule: perhaps cancer, but otherwise, perhaps just inflammatory or scar tissue, or else infection.  That answer is usually the right answer, but not always.  There is a chance that a result that comes back as “not cancer” is actually a false negative result: this happens there is actually cancer, but the correct answer wasn’t detected.  What are the features that suggest a greater probability that we can’t necessarily be as confident of a biopsy result that comes back as something other than cancer?

We can get some insight about this question from the published experience from the radiology groups at Cornell University and Mt. Sinai Medical Centers in New York City, who just published on their results of the clinical and imaging features of their false negative CT-guided biopsy results over a three-year period from the beginning of 2002 to the end of 2004 (Dr. Yankelevitz, who has great experience as an expert in CT screening and biopsies and who did a terrific webinar for us on detecting and evaluating lung nodules last year, is the senior author of this paper).   To do this, they reviewed the results from 170 patients in that interval who had an initial biopsy that was reported as negative initially who were then either found to:

  • have a lung cancer later diagnosed
  • have a subsequent procedure (such as a surgery) that confirmed a benign cause, or
  • showed resolution of the questionable nodule, or
  • showed stable findings over at least two years of follow-up that would be considered very consistent with a benign nodule

From this group of 170 patients, further follow-up confirmed a benign cause for 152 of the cases (confirming that there are plenty of benign nodules out there, and these were only the ones suspicious enough to merit an initial biopsy), while 18 were later shown to be false negatives and had a cancer confirmed later (some lung, some other cancers).  An independent radiologist who was not involved with any of the initial biopsy attempts reviewed the films from all of these procedures to assess the technical aspects of each case.  What the group found when they compared the two groups was that the people with false nodules were more likely to have the following features (all differences statistically significant):

  • larger nodules (mean size 27 mm vs. 17 mm)
  • fewer imaging adjustments per attempted biopsy (4.5 vs. 6.4)
  • higher proportion with the tip of the needle not documented to be within the target lesion (24% vs. 5%)
  • more likely to experience a collapsed lung (called a pneumothorax) from the biopsy attempt (50% vs. 22%) — note that many of these were small enough to require hospitalization, a chest tube, or significant interventions

Because some of the features of the case are inter-related (harder cases to biopsy tend to require more imaging adjustments and have a greater chance of not having the needle tip confirmed to be in the lesion, for instance), the investigators also did a multivariate analysis where they removed the effects of certain overlapping features.  When that occurred, they showed that the development of a pneumothorax, the presence of a solitary nodule, and the particular radiologist doing the biopsy procedure were significant factors.

Some of these results may make intuitive sense, but others less so.  Certainly, learning that the less experienced radiologist was less accurate isn’t surprising, though this operator-dependency is worth noting as yet another clear example of where experience and specialization matter.  It’s also very obvious that in cases where the needle tip wasn’t demonstrated to get into the target, the reliability of your biopsy is far more questionable.  And it’s easy to imagine that when lung collapse was observed, this led to earlier termination of the biopsy and fewer attempts.  And in the world of lung nodules, seeing a solitary one is generally more suspicious for cancer than seeing several, which is a pattern more suspicious for inflammatory or infectious changes.

You might think that it would be easier to biopsy a larger mass, and while that’s true, it’s easier to miss the cancer if the larger lesion is actually comprised of a combination of cancer and infection or collapsed lung.  Larger lesions can also have areas of necrosis (cell death) within the center of the tumor, because the cancer can outgrow its blood supply, leading to a sampling from within the area of cancer that fails to demonstrate evidence of a viable cancer.   

Similarly, because imaging adjustments tend to be more needed for difficult cases (smaller, inaccessible lesions), it’s counter-intuitive that the ones requiring fewer adjustments were more accurate.  In this case, it may also be related to larger lesions being accessible but perhaps not sampled in the wrong place. 

As CT screening for lung cancer is likely to become more prevalent, we’re likely to be seeing and biopsying a lot more lung nodules.  Overall, it’s important to remember that the results of this work indicated that a biopsy will often yield a clear and collect answer, but not always.  Suspicious findings still merit follow-up to ensure that findings remain stable or resolve with appropriate treatment.  But it’s also a situation in which it’s helpful to have someone with experience doing the procedure to maximize the probability of coming away with the right answer.  


12 Responses to What are the Characteristics of the Nodules that are Biopsied but Mistakenly Called Benign?

  • cards7up says:

    Dr. West, this is in fine needle biopsy, correct? Would these light up on a PET?
    Take care, Judy

  • Dr West says:

    I should have mentioned that these biopsies were done by fine needle aspiration. There wasn’t really discussion of PET findings, but it would be very reasonable to surmise that the ones larger than about 8 mm would have likely lit up on PET, while smaller ones would have been less likely, even if they were actually cancer.

    -Dr. West

  • shasha says:

    I might not be in the right spot to ask this question but I am so scared right now. I went to the ER this weekend because I was sick , I was told I had brochitis then went home and they called back and told me that the radialoist found a noudle on my right lung , I am 35 and a smoker the lady told me it was the size of to m&m’s on top of each other and one beside . I am getting a ct in the morning or should I say to day and I am so scared. I dont no how big is to big and I have alot of questions and everyone just tell me to wait . that is will be ok but it’s not easy and I am really emotional and trying to hide tears from my kids . I just dont know how to handle this

  • certain spring says:

    Shasha, I see that you also asked this question in the forums, and I posted a response there – it’s easier to do a Q&A in that format:
    http://cancergrace.org/lung/topic/question-about-size-of-noudle/

  • Dr West says:

    I left my comments after certain spring‘s comments on the forum thread.

    -Dr. West

  • tonym says:

    I having a difficult time understanding why the presence of collapsed lung is related to a false negative biopsy. In the case of my mother, who I am concerned may have had a false negative biopsy (a follow up PET scan showed a hot spot and the size of the nodule is larger than before), her collapsed lung didn’t occur until after the biopsy was over. In other words, the pneumothorax (to my understanding) did not happen “during” the biopsy…

  • Julie2009 says:

    Hi Dr West: I had 2 biopsies last year that showed Fibrosis, and now they want to do another CT Scan even though the biopsies were negative for cancer. I feel well, but these nodules are driving me crazy. I thought that the biopsies would end the question if it was cancer of not, but the doctor say I need more follow-up … another CT Scan. I feel like this is now a never ending question and I will need follow up the rest of my life.

  • Dr West says:

    Sometimes if we aren’t having luck doing smaller biopsies, we consider having a surgeon do a video-assisted thoracoscopic surgery (VATS) to remove one or more ambiguous lesions via a small incision and laparoscopy-type instruments. It provides more tissue and has a better chance of delivering a definitive diagnosis than a CT-guided biopsy or bronchoscopic biopsy, which very often is enough to say what’s happening, but not always. It’s also more invasive than a CT-guided biopsy, but if your goal is to get a firmer answer NOW, as opposed to continuing to watch and worry, that would be a potential strategy.

    -Dr. West

  • shalla says:

    I hope it’s OK to respond to a discussion that originated so long before now. . . .

    I had VATS 2 1/2 years ago because nodule/nodules (overlying each other on two different lobes) appeared to have grown per CTand PET/CT results were equivocal. Pathology reported scar tissue.

    Now, I have Stage IV NSCC, with the largest tumor (per CT) in same location as those that were removed.

    How might the CA have been missed 2 1/2 years ago?

  • Dr West says:

    I’m terribly sorry. My leading suspicion is that this was actually a multifocal process years ago, with the growth leading to the removal of the equivocal nodules. Perhaps the pathology showed no cancer because of a sampling error, meaning that the nodules were scar tissue, but the biopsy didn’t happen to detect the cancer in the background that was missed. It’s also possible that there was cancer in the nodules that were removed, but the cancer cells were hard to detect and just missed. Finally, there is an entity called “scar carcinoma”, which means that it is presumed that a cancer grew out of an area of scar tissue. To be honest, I am very far from convinced that this is really what happens, since I think it’s very likely, probably more likely, that the cancer was alongside of scar tissue that was just biopsied at some point before the cancer was detected. Since scar tissue and cancer can be indistinguishable on imaging, it’s very easy to imagine that a biopsy was done on scar tissue because it “faked out” the person who did the biopsy.

    I don’t know your situation, but these situations are often ones in which the cancer process, even if technically stage IV, progresses over a very, very long time, as in several years. If the nodules are only a little larger now but are re-biopsied and found to be cancer, that’s stage IV, but it was actually always stage IV and just an extremely slow-growing process that was not appreciated at the time of the original biopsy 2.5 years ago.

    Good luck.

    -Dr. West

  • Julie2009 says:

    Shalla I am so sorry to hear that you had a false negative biopsy 2 1/2 years ago. When and how were you finlly diagnosed? I also had a needle biopsy in two places over 2 years ago and now I am worried that I had a false negative. What type of treatment are the doctors recommending? Best wishes, Julie

  • shalla says:

    Dr. West and Julie, thank you for your responses.

    It is my understanding that the original nodules were believed to be completely excised. Had the preliminary pathology demonstrated malignancy, both involved lobes would have been removed. In December, 2 1/2 years later, there was a 3 cm “nodule” in the area where the first two were excised, and there were lots of smaller nodules scattered all over both lungs, all lobes. In addition, there was increasing pericardial effusion and increasing pleural effusion over a two week period that included a stint in the hospital to treat a pulmonary embolism and superficial thrombi in my ankle. One of the swollen supraclavicular lymph nodes was removed and sent to pathology. That was when they diagnosed NSCC that had metastasized. I was transitioned off of IV heparin to oral Warfarin which turned out to be ineffective to prevent generalized thromboemboli, both superficial and deep vein (Trousseau syndrome).

    The lymph node tissue was tested EGFR positive, so I started on Tarceva at the same time as I was hospitalized again for DVT’s and other other thrombi. This time, I was discharged on Lovenox (low molecular weight heparin) and oxygen, along with the Tarceva.

    Something has been working. I’ve been off the oxygen for 2 weeks and have no more edema or any other symptoms! (Also, no Tarceva rash—not good.) Tomorrow, I’ll have the first imaging since starting Tarceva, so I’ll find out. . . .

    Anyway, the cancer was progressing quickly in December and I’ll find out tomorrow what’s happened over the past month of treatment.

    Julie, did you have the additional CT scan in 2012? I was having a CT every 6 months, per protocol for nodules, until they were excised. If I had had a CT sometime after the VATS surgery and well before I had symptoms, the tumor growth would have been found early, perhaps early enough to remove the lobes then (and result in cure?) I think it’s a great idea to have one more CT, just to check and make sure all is well, even after a negative biopsy. What is your current status?

    Shalla

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