Reviewer ’s report  
 
Title: Benign metastasizing leiomyoma presenting as multiple  cystic pulmonary nodules: A case 
report  
 
Version: 0 Date: 07 De c 2016  
 
Reviewer: Bradley J. Quade  
 
Reviewer's report:  
 
General. This brief manuscript describes a very uncommon and quite enigmatic neoplastic 
process in which a histologically benign smooth muscle tumor exhibits the biological phenotype 
of metastasis in a remarkably cli nically benign fashion. I have termed this phenomena as being 
"quasi -malignant".  
Background. Page 5. Lines 54 - 55. Although myomectomy and hysterectomy often precede 
BML, it is not clear that such a temporal relationship is a prerequisite. Preceding hyst erectomy or 
myomectomy, however, does make arriving at the correct diagnosis much more challenging.  
Discussion. Page 8. Line 115. Another entity important to consider in the differential diagnosis is 
lymphangioleiomyomatosis. Lymphangioleiomyomatosis may be seen as an isolated process in 
women of reproductive age, as well as in men and women with tuberous sclerosis. It is important 
to make this distinction because lymphangioleiomyomatosis, particularly in women, can be 
relentlessly progressive, leading to either lung transplant or death, and it may be amenable to 
therapies targeting the mTOR pathway. Both lymphangioleiomyomatosis and tuberous sclerosis 
are due to an activation of one of the TSC genes, and consequently patients may benefit from 
medical genet ics consultation. Of note given the prominence of the cystification in this case, 
lymphangioleiomyomatosis lesions may be cystic. It would be important to know that these 
related entities had been carefully excluded in this case. One clinically feasible wa y to check this 
possibility would be to stain the pulmonary lesion with the antibody called HMB -45. Another 
less feasible way would be to use a molecular methodology that interrogates the TSC genes. 
Finally, careful history and physical examination may con tribute to excluding this important 
alternative.  
Discussion. The hypothesis that these pulmonary lesions were due to dissemination from the 
uterine leiomyoma could be proven by showing a shared genetic abnormality among all of the 
lesions in both the prim ary and metastatic sites. There are at least three approaches to 
documenting this. The first and most indirect method is to document in activation of the same X 
chromosome, indicating a clonal relationship between all of the lesions. The second method 
migh t be to sequence exons from the gene MED12, which is mutated in up to 70% of uterine 
leiomyoma this, in both the presumptive source and the distant lesions. The same mutation 
should be found in all samples. The third method would be to show that they have the same 
chromosomal rearrangements (e.g., translocation involving the HMGA2 gene on chromosome 
12) by FISH.  
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
No 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
No 
 
Are you able to assess any statistics in the manuscript or would you recommend an  
additional statistical review?  
If an additional statistical review is recommended, please specify w hat aspects require further  
assessment in your comments to the editors.  
 
Not relevant to this manuscript  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration  of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an  
organisation that may in any way gain or lose fi nancially from the publication of this  
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose  
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the  
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds  or has applied for patents relating to the content of the manuscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the above, write 'I declare that I have no competing interests' 
below.  If you r reply is yes to any, please give details below.  
 
None  
 
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