How Long A Period of Follow-Up is Long Enough to Be Confident a Ground Glass Opacity Won't Grow?

Howard (Jack) West, MD, Founder and President

GGO over timeAn interesting article from Japan was published out in the Journal of Thoracic Oncology that asks how long a duration of follow-up imaging of a ground-glass opacity (GGO) is really needed to be confident it's going to remain stable and not grow.   It's very common to see small lung nodules that are ambiguous in their significance, for which follow-up scans are typically recommended rather than diving into a biopsy, and non-solid, hazy GGOs are another form of lung lesion that might possibly represent a lung cancer but are also the way a little inflammation or small infection would appear.   Even when they turn out to be something technically called cancer based on its appearance under the microscope, it's often a non-invasive adenocarcinoma (sometimes termed bronchioloalveolar carcinoma, or BAC, but shifting in terminology to adenocarcinoma in situ, or AIS) or minimally invasive adenocarcinoma (MIA), in which the invasive component is less than 5 mm in diameter.  Even when they grow, it can be at an extremely slow pace.

The report in question looked retrospectively at what happened to 108 GGOs or partially solid nodules (less than 50% solid, more than half hazy and non-solid-appearing on chest CT) in 61 patients, some of whom had a prior history of a resected lung cancer, and some of whom had multiple foci of lung lesions.  This wasn't a typical population that we'd define as high risk for lung cancer in North America: 2/3 were women, and 2/3 were never-smokers.  Though they included lesions up to 3 cm, nearly 2/3 (64%) were 1 cm or smaller in diameter, and another 31% were 1.1 to 2 cm.  

With a median follow-up of 4.2 years, they found that 39 of the 108 lesions either became larger (29) and/or increased in their solid component (17); the others remained stable (within 1 mm) over time, which in some cases went out a decade or longer.   Because this was a retrospective review, they didn't have a fixed protocol for when or how to do surgery or other interventions, but over the period of follow-up, 21 patients with 26 lesions underwent surgery. The authors report that in most cases, they turned out to be a pre-malignant lesion like atypical adenomatous hyperplasia (AAH) or AIS or perhaps MIA. Though they don't speak to the survival, the implication is that these patients all did very well, though I suspect the patients who didn't undergo surgery also did extremely well.  Notably, 19 of the 21 tumors (90%) tested for an EGFR mutation were positive, further underscoring that this is a very specific population in Japan that can't be readily extrapolated to a global population.

The main point of their report was that all of the lesions that demonstrated any change in size or increased solid component did so within 3 years of the start of follow-up, so that should probably be an appropriate outer limit for regular repeat scans before relaxing some and feeling that it's unlikely the lesion(s) in question will change with longer follow-up.  That's consistent with the general guidelines: though there's some variability among the different professional groups, in most cases, 2-3 years of stability is considered to be sufficient to consider a lesion as benign.

What I think is also critically important is the distinction between an extremely slowly changing nodule, even one that is technically called an indolent cancer, and one that is actually a threat to a person's survival over the next few years, or perhaps EVER.  What this report shows is that any lesion that doesn't change over three years is clinically insignificant.  However, it doesn't say that a lesion that grows by 2 mm over 2.5 years is actually a threat: even if it's called a cancer technically, it might actually only become a problem if it grows over 40 more years.  

We don't know that for sure, and our general mindset in cancer management is to treat everything in this realm aggressively.  The danger, though, is that as we do more and more chest CTs for lung cancer screening or just because someone coughs once in the emergency room, we're going to find a lot of lung lesions that cause a great deal of anxiety, many follow-up scans, and potentially surgeries for a problem that is only a problem based its relationship as a cousin of a truly threatening cancer.  It is important for doctors and patients to recognize the potential for "over-diagnosis" of clinically insignificant things, so that we don't have the treatment be far worse than the underlying disease.  

This isn't to say that lung cancer isn't a terrifying disease that takes a heartbreaking toll, but rather that it's important to recognize the biologic variability in how different things that technically all fall under the broad term of "lung cancer" actually behave.  We don't want to under-treat or over-treat patients.  One important thing about this work is that it highlights that lung nodules can be amazingly stable for years and years, even in some people who have many of them.  We may do more harm by going in with guns blazing to treat them.





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