While there is a lot of variability in the clinical behavior of bronchioloalveolar carcinoma (BAC), there are some commonly observed findings that are now leading lung cancer experts to consider it as a distinct clinical entity worthy of special consideration for management. Among the important areas for potentially special clinical management is in surgical management of early stage disease. As noted in the last post, the most well differentiated BAC lesions have a very low likelihood of demonstrating nodal spread and have a remarkably high survival at 5 years, approaching 100%. However, they can be multifocal through the lungs and are sometimes managed by multiple surgical resections over many years. With that potential to have small, slow-growing lesions emerge over many years and even over decades, but with a very finite amount of lung tissue to work with, BAC lesions have been a leading consideration for smaller, sublobar resections as an alternative to a full lobectomy (see summary of options in post here)that has generally been the default cancer surgery for lung cancer.
Several of the leading thoracic surgeons in the world, particularly those with an interest in BAC and smaller surgeries, converged in NYC in November of 2004 as part of the first “consensus conference” on BAC (I participated on a committee that focused on systemic (whole body)therapy for advanced BAC) to discuss the state of the art and most relevant management questions, from which they produced a report (abstract here). Largely from a collection of Japanese retrospective studies of early stage BAC, a clear picture has emerged. First, lesions that appear on CT as hazy ground-glass opacities (GGOs) (descriptions and examples in prior post) appear to represent noninvasive BAC, while the solid component on CT scans is highly likely to represent invasive adenocarcinoma. Second, smaller lesions (2 cm and smaller) that are predominantly GGO on CT, BAC under the microscope have a remarkably good survival and an exceptionally low likelihood of node involvement.
On the basis of this work, a couple of trials are now being conducted to ask whether small lung cancers can be treated as well with sublobar resections as a full lobectomy. One of these is being conducted in Japan, looking specifically at adenocarcinomas less than 2 cm. A US-based trial, CALGB 140503, is now active and randomizing 1300 patients with peripheral lung cancers up to 2.0 cm to receive either a lobectomy or sublobal resection. The CALGB trial is being conducted with the participation of the other cancer cooperative groups throughout the US, meaning that we’ll be asking this question for a few years to come. In the meantime, lobectomy remains the standard approach for resectable lung cancer, but if there are a subset of people who may be the best candidates for smaller surgeries, who may have cancers least likely to need extensive resection and perhaps most likely to benefit from the sparing of lung tissue that would be valuable to continue to have later, especially if additional lesions need surgery in the future, as may well occur with BAC.
I had previously written about a spectrum from pure bronchioloalveolar carcinoma (BAC) to invasive adenocarcinoma in one of my first posts here, but the real credit for this concept goes back to Dr. Masayuki Noguchi from the National Cancer Center Hospital in Tokyo, Japan, who characterized a classification system for peripheral lung adenocarcinomas back in 1995 (abstract here). This paper led to the “Noguchi” system of grading the more typical adenocarcinomas from A to D, with some important implications. While other proposed classification systems have been developed, and none is uniformly accepted and used, the Noguchi classification system comes up more than others in describing the continuum I alluded to previously that progresses from pure BAC to invasive adenocarcinoma.
Obviously, this was a Japanese study, which has important implications, because the Japanese world of lung cancer i(LC) s different from that in the US or Europe. In Europe, LC is still very disproportionately male, related to tobacco, and about 50% squamous cancers, while Japan is the other extreme, with some studies showing a closer balance of women and men, 30-50% of patients as never-smokers, and remarkably few cases of squamous cancer, with LC being comprised of generally adenocarcinoma and its well-differentiated subset. A North American population generally shows results between these two extremes.
The Noguchi study involved a detailed analysis of 236 patients with peripheral adenocarcinoma lung tumors (near the outer edges of the lung), all 2 cm or less in diameter. The specifics of the grading system and the definitions of the classes are complex and worth knowing only if you’re a pathologist carefully reviewing tissue and describing lung tumors. The important the highlights are that groups A to D are far more common than rare adenocarcinoma subtypes known as tubular and papillary adenocarcinoma, and also that there is a gradation from A to D of most differentiated to least differentiated. Men comprise the vast majority of group D, while the sexes are much more evenly split in the groups that are well differentiated and would be considered BAC or a variant. The likelihood of finding nodal involvement was also related to the Noguchi group; no patients in groups A or B had any lymph node spread of their cancer, compared with 28% in group C and 48% in group D. In addition, pleural involvement and vascular invasion were significantly more common in groups C & D than in groups A & B. Growth and cell division were also factors, with the rate of cell division far higher for the less differentiated cancers. The number of mitoses (my-TOW-sees), or cells in the process of dividing on a detailed look at the slide, was more than 5 per “high-powered field” in only 6% of groups A & B, compared with 26% for group C, and 53% for group D. But the most important factor, correlating with the rates of cancer cell division, was survival, which was 100% after 5 years for groups A & B, but lower as you move stepwise from type C to type D:
(Click on image to enlarge)
This type of trend has also been seen outside of just BAC and adenocarcinoma; I’ve written that tumor grade is well correlated with survival (see prior post), and specifically that people with well-differentiated LC do better overall than those people with poorly differentiated tumors.
One other important point is that this study demonstrated that patients with small, peripheral, and very well differentiated lung adenocarcinomas had a survival of 100%, while none demonstrated evidence of nodal spread. This raised the question of whether it’s necessary to do as extensive a surgery in the setting of a well-differentiated lung adenocarcinoma as you would routinely do for other cancers. If the prognosis is outstanding, perhaps we can do smaller surgeries and still achieve such excellent results. I’ll cover the question of optimal surgery for small and well-differentiated lung adenoarcinomas later. This raises the unusual but welcome question in the field of LC, “what is the least we can do to still nearly assure ourselves of excellent results?” Could less be more?
The decision about pursuing post-operative treatment is often difficult and requires carefully weighing the risks of treatment with potentially challenging and even dangerous chemotherapy against the potential to eradicate micrometastases and actually lead some people to be cured who otherwise wouldn’t be. It’s important to remember that some people are already cured, while others won’t be cured even with treatment. We’re pursuing treatment for the 5-15% higher survival rate at 5 years from adding chemo, presumably representing the proportion of people who have micrometastatic cancer cells that are apparently eradicated by getting 3-4 cycles of platinum-based chemotherapy:
(Click image to enlarge)
The general guidelines we use to assess risk for recurrence include stage of the cancer as the primary focus. I also described the relevance of tumor size as an important factor to stratify risk of recurrence in my recent post on that topic. But there are other potentially relevant factors for people who have cancers that are “on the bubble” about whether they have enough risk to justify the side effects and some real risks of post-operative chemotherapy. Continue reading
While lobectomy or pneumonectomy may be the surgical treatment of choice for most NSCLC tumors in younger, fit patients, a limited resection may be an ideal choice in certain settings. In my previous post I discussed the data supporting a limited resection in older patients, who are likely to have competing health risks that may make it less critical to pursue the most aggressive surgical strategy. Another situation in which a sub-lobar resection may be particularly appealing is when the tumor is quite small and/or has characteristics suggestive of an indolent natural history. In such cases, a lobectomy may be more surgery than is required. There are trials now asking the question of whether patients with the most favorable features based on size or histology (microscopic characteristics) may do as well or better with limited resections than the standard lobectomy or pneumonectomy. Continue reading
Bronchioloalveolar carcinoma, or BAC, is a subtype of lung adenocarcinoma that has a tendency to progress more slowly, stage for stage, than other types of lung cancer. There are many patients who experience symptomatic and significant progression over months, and rarely patients have a very aggressive and fulminant form of the disease. However, many patients with BAC experience slow growth that raises the risk of potentially overtreating it, with the possibility of detrimental effects from that.
As someone with a particular interest and expertise in BAC, I see the situation with BAC as being similar to the issues we face with prostate cancer. Once a blood test for detecting prostate cancer emerged (prostatic serum antigen, or PSA), it became possible to identify 200,000 men in the US per year who had prostate cancer. The problem is while a huge proportion of men will develop prostate cancer as they get older, many will have an indolent cancer that will not really threaten their survival, and for which treatment with surgery or radiation can have significant long-term side effects. A low grade prostate cancer is well known for being a cancer men can “die with, but not of”. In other words, men can have a prostate cancer that would never directly threaten them, and they can go on to a ripe old age before succumbing to heart disease or another non-cancerous condition. Continue reading
The clinical syndrome of BAC is characterized by spread primarily through the lungs, a higher proportion of never-smokers or light former smokers, a greater proportion of women, and often progresses more slowly than most other lung cancers. This clinical and radiographic (scans) scenario isn’t necessarily seen only with “pure BAC” under the microscrope from a biopsy, but rather can be a spectrum from pure BAC to part non-invasive BAC pattern and part invasive adenocarcinoma, and on the other end of the continuum is invasive adenocarcinoma, as shown in the illustration of how these appear under a microscope.
|Pure BAC||Adeno w/BAC Features||Invasive Adeno|