Uncommon Presentation of Granulomatosis with Polyangiitis Mimicking Metastatic Lung Cancer

Round 1

Reviewer 1 Report

The authors describe a case of GPA where the radiological findings suggested malignancy. The case highlights the role of adequate tissue sampling, and follow-up after treatment is presented. The case is well-described, the images are adequate, and the discussion reasonable. Although uncommon, such cases are of interest for several specialties.

I have just one comment. Line 98-100: Did the EBUS, BAL, or pleural effusion show any inflammation, giant cells, and/or necrosis? Did any show reactive cells, especially with enough atypia that could be mistaken for dysplastic cells?

Some minor remarks:

Line 113, either “…right lung’s…” instead of ”… right lungs…” or remove both words.

Line 118, “…micro-abscesses” instead of “…micro abscesses.”

Line 132, spell out “GPA” here.

Line 259, should it be”…[8-10].” Instead of “…(8-10).”?

Author Response

Reviewer 1

The authors describe a case of GPA where the radiological findings suggested malignancy. The case highlights the role of adequate tissue sampling, and follow-up after treatment is presented. The case is well-described, the images are adequate, and the discussion reasonable. Although uncommon, such cases are of interest for several specialties.

I have just one comment.

Line 98-100: Did the EBUS, BAL, or pleural effusion show any inflammation, giant cells, and/or necrosis? Did any show reactive cells, especially with enough atypia that could be mistaken for dysplastic cells?

Thank you for this relevant question.

EBUS from station 4R, 4L, 11R and 11L showed no granulomas, giant cells, inflammation, or necrosis. There were no dysplastic/reactive cells. Pleural effusion as well as BAL was without significant occurrence of inflammatory cells. No dysplastic/reactive cells.

We have added this point to the manuscript.

Some minor remarks:

Line 113, either “…right lung’s…” instead of ”… right lungs…” or remove both words.

Line 118, “…micro-abscesses” instead of “…micro abscesses.”

Line 132, spell out “GPA” here.

Line 259, should it be”…[8-10].” Instead of “…(8-10).”?

All these remarks have been corrected.

Reviewer 2 Report

The authors presented a case of present a case of granulomatosis with polyangiitis, clinically and radiologically mimicking metastatic lung cancer, with bilateral pulmonary mass, mediastinal and cervical lymph node involvement, and pleural effusion.

1. Introduction is poor. Few more sentence regarding granulomatosis with polyangiitis are required. Also adequate references should be present in introduction.
   
   
2. The authors used several abbreviations without explanation (e. g. FDG-avid…). An explanation of an abbreviation should be mentioned each time an abbreviation is first mentioned in the text.
3. The authors stated that ‘’PET/CT-scan also revealed FDG-avid enlarged lymph nodes on the left side of the neck’’. Why the biopsy was not taken from enlarged lymph nodes on left side of the neck rather than video assistant thoracoscopy (VATS) with biopsy from the pulmonary tumor. VATS is invasive surgical procedure. Usually I never go for VATS if the enlarged lymph nodes are available on the neck, axilla…
   
   
4. The authors did not mention in clinical presentation whether the patient had any kidney-related symptoms and it is unclear why they decided to do renal biopsy. They just stated under the results paragraph that the kidney biopsy was performed.
5.  Follow-up period (3 months) is too short to draw any serious conclusions.
6. The main question is how this single case adds to the scientific literature?! This is a case of complex autoimmune disease of multifactorial etiology affecting respiratory tract, joints and kidney. Initially it was misdiagnosed for lung cancer although the patient had enough positive variables that condition like this should be suspected. There are several similar cases and larger series described in the literature that do not differ significantly from this case. No new conclusions had been drown from this manuscript.

Author Response

Reviewer 2

The authors presented a case of present a case of granulomatosis with polyangiitis, clinically and radiologically mimicking metastatic lung cancer, with bilateral pulmonary mass, mediastinal and cervical lymph node involvement, and pleural effusion.

1. Introduction is poor. Few more sentence regarding granulomatosis with polyangiitis are required. Also adequate references should be present in introduction.
   
   Thank you for your suggestion. The introduction has now been extended.
   
   
2. The authors used several abbreviations without explanation (e. g. FDG-avid…). An explanation of an abbreviation should be mentioned each time an abbreviation is first mentioned in the text.
   
   FDG stands for 18F-Fluorodeoxyglucose and when used in the sentence FDG avid, it means that the nodes or tumors takes up FDG. We have explained the abbreviation FDG in the same sentence as FDG-avid first is mentioned (line 39-40 in the pre-reviewed manuscript).
   Could you please point out which other several abbreviations need explanation? All the co-authors have read the manuscript rigorously and haven’t found any, thank you.
   
   
3. The authors stated that ‘’PET/CT-scan also revealed FDG-avid enlarged lymph nodes on the left side of the neck’’. Why the biopsy was not taken from enlarged lymph nodes on left side of the neck rather than video assistant thoracoscopy (VATS) with biopsy from the pulmonary tumor. VATS is invasive surgical procedure. Usually I never go for VATS if the enlarged lymph nodes are available on the neck, axilla…
   
   Since all the three diagnostic attempts (EBUS, BAL and cytological examination of pleural effusion) failed to make diagnostic conclusion, it was an urgent need to complete the diagnostic process. Therefore, the reason for VATS was to obtain the reliable material from the thorax, where the primary lesions were localized, and establish the indisputable diagnosis on the histological material. A small FDG-avid lymph node on the neck is often a nonspecific finding and, in a case, where we need to exclude lung cancer, we would prefer to biopsy lesions with more clear malignant features to avoid the risk of prolonging the diagnostic process. At the same time FDG-avid lesions were seen in both parotid glands which often and in most cases represents benign Warthin’s tumors. Furthermore, we have not observed or described any suspect lymph nodes in axilla. This is not mentioned in our manuscript. 
   
   
4. The authors did not mention in clinical presentation whether the patient had any kidney-related symptoms and it is unclear why they decided to do renal biopsy. They just stated under the results paragraph that the kidney biopsy was performed.       
   
   The renal manifestations have been added to case presentation as the reason for renal biopsy.
   
   
5.  Follow-up period (3 months) is too short to draw any serious conclusions.
   
   We have now updated the follow-up to present 14 months excellent outcome. So, we think the serious conclusions can be drawn.
   
   
6. The main question is how this single case adds to the scientific literature?! This is a case of complex autoimmune disease of multifactorial etiology affecting respiratory tract, joints and kidney. Initially it was misdiagnosed for lung cancer although the patient had enough positive variables that condition like this should be suspected. There are several similar cases and larger series described in the literature that do not differ significantly from this case. No new conclusions had been drown from this manuscript.
   
   We don’t agree with these remarks. Furthermore, we will be grateful if this reviewer could provide any additional cases or larger series where the AAV case present “malignancy” at admission “confirmed” by PET scan! Others (see ref.29) report -following Med Pub literature search- 6(!) AAV cases with pulmonal malignancies and 1 only case presenting with pulmonary malignancy at first admission. We have several other AAV patients referred after 2-3 months of lung tumor diagnostics at pulmonary units before ANCA screening has been taken and as you probably every delay influences the outcome. The novelty in this case is the positive PET which provoked the tumor biopsy taking as double diagnosis AAV AND malignancy could not be excluded without histological results!          

Reviewer 3 Report

Uncommon presentation of granulomatosis with polyangiitis (GPA) mimicking metastatic lung cancer

The authors presented a case of granulomatosis with polyangiitis, clinically and radiologically mimicking metastatic lung cancer, with bilateral pulmonary mass, mediastinal and cervical lymph node involvement, and pleural effusion.

- It is unusual to present abbreviations in the title.

- Introduction should be more widened, with citations and references

- Upon detecting enlarged lymph nodes on imaging, and after the bronchoscopic diagnostic algorithm why did the Authors decide on VATS if they could extirpate one of the enlarged lymph nodes of the neck. VATS is a bit risky invasive procedure where and when you have less invasive ones.

-  Although the Authors did show their misdiagnosis in a case where there were enough markers of something else besides cancer it is hard to find what is wanted by this case report where we can find a lot of reported cases in the literature. I can see no novelty here, in the paper, written in the current form.

Conclusions drawn by the authors are mostly general and already known and published. Advice: Maybe the Authors should reflect more on that how the modern diagnostic tool (FDG PET/CT) can mislead the physician on proper diagnosis.

- Mostly good and properly written report with good image referrals and sequence.

Author Response

Reviewer 3

The authors presented a case of granulomatosis with polyangiitis, clinically and radiologically mimicking metastatic lung cancer, with bilateral pulmonary mass, mediastinal and cervical lymph node involvement, and pleural effusion.

- It is unusual to present abbreviations in the title.

Thank you for your suggestion. We have removed the abbreviation from the title to the introduction.

- Introduction should be more widened, with citations and references

The introduction has been extended with citations and references.

- Upon detecting enlarged lymph nodes on imaging, and after the bronchoscopic diagnostic algorithm why did the Authors decide on VATS if they could extirpate one of the enlarged lymph nodes of the neck. VATS is a bit risky invasive procedure where and when you have less invasive ones.

The reason for VATS resulted from the urgent need to obtain the reliable material from the thorax where the primary lesions were localized and establish an undisputable diagnosis on the histological material.
A small FDG-avid lymph node on the neck (not enlarged, 11 mm only) is often a nonspecific finding and, in a case, where we need to exclude lung cancer, we would prefer to biopsy lesions with more clear malignant features to avoid the risk of prolonging the diagnostic process. At the same time FDG-avid lesions were seen in both parotid glands which often and in most cases represents benign Warthin’s tumors and we risk at extirpate a Warthin’s tumor instead of. This will again prolong the diagnostic process.

-  Although the Authors did show their misdiagnosis in a case where there were enough markers of something else besides cancer it is hard to find what is wanted by this case report where we can find a lot of reported cases in the literature. I can see no novelty here, in the paper, written in the current form.

We don’t agree with these remarks. Furthermore, we will be grateful if this reviewer could provide any additional cases or larger series where the AAV present “malignancy” at admission “confirmed” by a PET scan! Others report (see ref. 29)- following Med Pub literature search - 6(!) AAV cases only with pulmonal malignancies and 1 only case presenting with pulmonary malignancy at first admission. We will be grateful if the “lot of reported cases” could be specified. 

Conclusions drawn by the authors are mostly general and already known and published.

After more than 25 years of AAV diagnostics and treatment, we unfortunately still experience delay in referral and delayed ANCA profile screening at pulmonary departments. This is the reason why we submit this manuscript to this top prestigious journal. The PET false malignancy positive findings have been commented in the report.    

Advice: Maybe the Authors should reflect more on that how the modern diagnostic tool (FDG PET/CT) can mislead the physician on proper diagnosis.

FDG is a glucose analog and the increased uptake of FDG in many malignant tumors is due to the increased glucose utilization based on increased expression of glucose transporters and increased activity of hexokinase in many cancerous cells. When interpreting PET/CT findings nuclear medicine specialists must accept that FDG is not specific for cancer. A variety of non-malignant inflammatory processes also have increased glucose utilization and therefore demonstrate increased FDG uptake. Nelson et al (see ref.17), retrospectively explored the potential utility of FDG-PET/CT in the management of GPA as in 3/12 GPA patients they found malignant like lesions and concluded that FDG-PET/CT cannot differentiate between malignancy and inflammatory lesions. Our case confirms this conclusion and shows how correct diagnosis can be achieved within few days.   

- Mostly good and properly written report with good image referrals and sequence.

Thank you.

Round 2

Reviewer 1 Report

The authors have responded well and made proper amendments to the manuscript. I have nothing further to add. 

Reviewer 2 Report

The authors have satisfactorily responded to all my questions and made the necessary changes to the manuscript.
The manuscript has been significantly improoved.
I think the manuscript should be considered for publication in present form.

Reviewer 3 Report

The authors have my thanks for editing and adding all of the stated as well as answering all the questions.

In response to this: "We don’t agree with these remarks. Furthermore, we will be grateful if this reviewer could provide any additional cases or larger series where the AAV present “malignancy” at admission “confirmed” by a PET scan! Others report (see ref. 29)- following Med Pub literature search - 6(!) AAV cases only with pulmonal malignancies and 1 only case presenting with pulmonary malignancy at first admission. We will be grateful if the “lot of reported cases” could be specified. "; I can only say that when put like this with the addition of cANCA - AAV presented then fine, but when putting PET scan with Polyangiitis and granulomatosis you can find 36 papers. Furthermore, with widened introduction and remark on the AAV part, this would stand as correct.

Well-written report.