Lymphangioleiomyomatosis: No Longer Ultra-rare

Lymphangioleiomyomatosis (LAM) is a female-predominant low-grade neoplasm that causes progressive cystic lung destruction. LAM is caused by mutations in the tuberous sclerosis complex (TSC) genes and can either be seen in association with TSC (TSC-LAM) or occur sporadically in women without TSC (sporadic LAM or S-LAM) (1). Although cysts consistent with LAM have been described in men with TSC (2), S-LAM is almost exclusively restricted to women (1).

LAM is a rare disease. Estimating the prevalence of LAM is important to determine the true disease burden, determine feasibility of future trials, and appropriately plan for healthcare needs. Initial LAM prevalence estimates derived from case series in the United Kingdom, France, and Japan ranged from about 1 to 2 cases per million (3–5). Assuming relatively equal distribution of men and women, this translated to an LAM prevalence of approximately 2–4 cases per million women. The largest study evaluating the prevalence of LAM was conducted by Harknett and colleagues (6). In this analysis, a total of 1,001 cases of LAM were identified across seven countries (United States, United Kingdom, Canada, New Zealand, Germany, Australia, and Switzerland) by using the data obtained from national LAM patient advocacy organizations. This study estimated the prevalence of LAM to be approximately 5 (range, 3.4–7.8) cases per million women (6).

In this issue of the Journal, Lynn and colleagues (pp. 456–458) estimated the prevalence of LAM across four countries in Europe (Denmark, Ireland, the Netherlands, and Norway) by collating the number of cases of LAM in that country’s expert center and dividing it by the female population using national census data (7). The pooled prevalence of LAM in this analysis was 23.5 cases per million adult women and 19 cases per million women, substantially higher than prior estimates. The major strength of this analysis lies in the smart use of national referral centers across countries with relatively smaller populations, thus maximizing the chances of regional patient identification. The relatively similar prevalence across the four countries also increases confidence in these estimates. Although the possibility of these estimates being unique to Northern European countries rather than representative of the worldwide LAM prevalence cannot be excluded, it is worth mentioning that there is no known regional or racial variability in the worldwide prevalence of LAM and that these estimates are also consistent with some of the maximal regional estimates reported in the previous analysis by Harknett and colleagues (6). Interestingly, a trend toward higher prevalence of LAM in countries with smaller populations was also noted in the study by Harknett and colleagues (6). There are 2,353 living U.S.-based patients with LAM registered with The LAM Foundation (E. Williams, oral communication, 7 December 2023), which would equate to an approximate LAM prevalence of about 14 cases per million women and about 18 cases per million adult females in the United States, roughly in keeping with the current report. Consistent with this, although not all UK patients receive their care at the nationally commissioned UK LAM Center, applying this method to their caseload suggests a prevalence of 17 cases per million adult women.

There is a striking variability in the number of TSC-LAM cases across the four countries, with TSC-LAM representing about 10% of the total LAM cases in Ireland and Norway and 35–40% in Denmark and the Netherlands. TSC has an incidence of 1 in 6,000 live births, with an estimated prevalence of 70–120 cases per million and no known sex differences (1, 8). Assuming that one-third of adult women with TSC have LAM (9), the number of women with TSC-LAM in the four countries should range from 325 to 550, higher than the numbers identified in this analysis. This paradox in terms of LAM clinics and natural history cohorts being primarily composed of S-LAM as opposed to TSC-LAM is well documented (10) and likely driven by a combination of differences in prioritization of other TSC-related health issues over LAM, regional differences in LAM screening practices in women with TSC, concentration of these patients in the TSC clinics as opposed to LAM clinics, and possibly differences in disease severity between TSC-LAM and S-LAM. Considering that the cases in this analysis were derived from pulmonary referral centers, the prevalence of S-LAM may be estimated with more confidence than TSC-LAM. The estimated prevalence of women with S-LAM in the current analysis would be 16.62 (range, 13.61–23.38) cases per million adult women (7). This is in contrast to an estimated S-LAM prevalence of approximately 3 (range, 2.5–3.6) per million adult women from prior analyses (11).

There are several reasons for the increase in prevalence estimates in the current study compared with the prior estimates (Figure 1), including, but not limited to, the overall increase in lifespan, increased understanding and awareness of LAM, increased screening for LAM in women with TSC (8, 12), the development of a noninvasive diagnostic biomarker (13), effective treatment that stabilizes disease progression (14), clinical practice guidelines (15–17), an expanding worldwide clinic network, and, arguably most significantly, the more widespread use of computed tomography leading to identification of pulmonary cysts that might otherwise have evaded detection. This concept of increasing prevalence over time in a rare disease spurred by progress in deciphering the molecular pathogenesis, increased awareness and case recognition, and improved means to achieve diagnostic confirmation, is not novel to LAM and has been reported in other rare lung diseases (18). Specifically in the context of LAM, since the publication of the prior LAM prevalence estimates (6), there has been the development of VEGF-D (serum vascular endothelial growth factor-D) as a noninvasive biomarker that can help obviate the need for invasive procedures such as lung biopsy for diagnostic confirmation. This has almost certainly resulted in an increase in the number of cases of LAM to go from suspected/probable LAM to confirmed LAM. The advent of sirolimus as an effective treatment for LAM has resulted in improved survival (19), thus also potentially contributing to the increased prevalence over time. Progress in LAM is happening at an unparalleled pace. With increased awareness of LAM and the expansion of the worldwide LAM clinic network, the prevalence reported by Lynn and colleagues (7) should be treated as a minimum estimate, and it would not be surprising if, a decade from now, the prevalence of LAM is determined to be even higher than the current estimates.

Figure 1.

Bar graph depicting the estimated prevalence of lymphangioleiomyomatosis (LAM) (cases per million women) over the past 25 years.