A Case of Adult-Onset Eccrine Angiomatous Hamartoma—The Comparison with Epithelioid Hemangioma

Round 1

Reviewer 1 Report

There are some typos, e.g.: line 30 (erratomatous = angiomatous), line 98 (anti-endomysial antibody / EMA) - note: EMA = epithelial membrane antibody.

Please specify in a short paragraph why these vascular lesions fulfil the requirements of a classic HAMARTOMA (and/or a venular malformation).

Additionally:

Please point out that your cases do not fulfil all the requirements/underpinnings of CLASSIC ECRRINE ANGIOMATOUS HAMARTOMA rather than the criteria of a "forme fruste"-like variant of EAH - and that so far for these lesions no clearly defined histopathological terminology exists.

Author Response

Responses to the comments of Reviewer #1

Comments to the Author:

There are some typos, e.g.: line 30 (erratomatous = angiomatous), line 98 (anti-endomysial antibody / EMA) - note: EMA = epithelial membrane antibody.

Response: We apologized for these errors, we have corrected the words.

Please specify in a short paragraph why these vascular lesions fulfil the requirements of a classic HAMARTOMA (and/or a venular malformation).

Response: The diagnostic criteria for EAH include close association of eccrine structures with capillary hemangioma structures. We have changed the pathology picture in Figure 3b to a more appropriate one. This picture contains increased number of eccrine structures and numerous capillary channels surrounding or intermingled with the eccrine structures. Although the element of hamartoma may be weak, we consider this finding is valuable, because the close association of eccrine glands and capillaries is important for the diagnosis of EAH. We appreciated for your valuable suggestion.

Please point out that your cases do not fulfil all the requirements/underpinnings of CLASSIC ECRRINE ANGIOMATOUS HAMARTOMA rather than the criteria of a "forme fruste"-like variant of EAH - and that so far for these lesions no clearly defined histopathological terminology exists.

Response: Thank you for your great informative suggestion. These comments had been supplemented in the text. Again, thank you for your advice.

Reviewer 2 Report

This is a case report of eccrine angiomatous hamartoma (EAH), which rarely develops in adults. This article is well-written, but it needs major revision in some aspects.

Specific comments:

1. EAH is a rare cutaneous lesion characterized by the proliferation of multiple eccrine structures and vascular elements with a preferred distribution on an extremity at birth, or appearing in early childhood. On the other hand, epithelioid hemangioma (also called ALHE) is often located in the head and neck region, especially around the ears. ALHE is characterized histologically by proliferations of capillary-sized vessels with epithelioid endothelial cells accompanied by eosinophils and lymphocytes. In Case 2, there were neither enlarged endothelial cells protruding into the lumen nor numerous eosinophils in the histopathological pictures, which were not typical to demonstrate ALHE.
2. Except ALHE, the clinical differential diagnoses of EAH include vascular malformations, tufted angioma, smooth muscle hamartoma, glomus tumor, blue rubber bleb nevus, eccrine nevus, and sudoriparous angioma. The authors are suggested to provide a table including the demographics and histopathological features of the differential diagnoses of EAH (as mentioned above) with more relevant discussion to make this article achieve a clinical utility.
3. Eccrine erratomatous hemangioma often presents with hyperhidrosis, pain or hypertrichosis due to hamartomatous components. Please provide relevant information in the case presentation.
4. Please provide relevant IHC information for EAH diagnosis, such as negative D2-40 for visualization of lymphatics, positive S-100 protein for eccrine structures and factor VIII-related antigen for delineation of vascular structures.

Minor comments

1. Please correct the misspelled words and typos:

-- Line 27, Keywords: eccrine “eruptive” hemangioma (EAH)

-- Line 30, Eccrine “erratomatous” hemangioma (EAH) is a relatively rare benign……

2. (Line 72 and 80) enlarged blood vessels in the endothelium……. Are you mean “enlarged endothelial cells lining blood vessels”?

Author Response

Responses to the comments of Reviewer #2

Specific comments:

1. EAH is a rare cutaneous lesion characterized by the proliferation of multiple eccrine structures and vascular elements with a preferred distribution on an extremity at birth, or appearing in early childhood. On the other hand, epithelioid hemangioma (also called ALHE) is often located in the head and neck region, especially around the ears. ALHE is characterized histologically by proliferations of capillary-sized vessels with epithelioid endothelial cells accompanied by eosinophils and lymphocytes. In Case 2, there were neither enlarged endothelial cells protruding into the lumen nor numerous eosinophils in the histopathological pictures, which were not typical to demonstrate ALHE.

Response: Thank you very much for your valuable comments. Although eosinophilic infiltration is not so obvious, endothelial cells enlargement and protruding into the lumen apparent in the HE section. We have supplemented the picture as a figure 5b.

2. Except ALHE, the clinical differential diagnoses of EAH include vascular malformations, tufted angioma, smooth muscle hamartoma, glomus tumor, blue rubber bleb nevus, eccrine nevus, and sudoriparous angioma. The authors are suggested to provide a table including the demographics and histopathological features of the differential diagnoses of EAH (as mentioned above) with more relevant discussion to make this article achieve a clinical utility.

Response: Thank you for your great suggestion. We have added the table at the bottom of the discussion section.

3. Eccrine erratomatous hemangioma often presents with hyperhidrosis, pain or hypertrichosis due to hamartomatous components. Please provide relevant information in the case presentation.

Response: Thank you for your advice. This information has been supplemented in the text.

4. Please provide relevant IHC information for EAH diagnosis, such as negative D2-40 for visualization of lymphatics, positive S-100 protein for eccrine structures and factor VIII-related antigen for delineation of vascular structures.

Response: Thank you very much for your advice. Although we could not perform IHC for these proteins, we have supplemented the information which you pointed out.

Minor comments

1. Please correct the misspelled words and typos:

-- Line 27, Keywords: eccrine “eruptive” hemangioma (EAH)

-- Line 30, Eccrine “erratomatous” hemangioma (EAH) is a relatively rare benign……

Response: We apologized for our mistakes. These words were corrected.

2. (Line 72 and 80) enlarged blood vessels in the endothelium……. Are you mean “enlarged endothelial cells lining blood vessels”?

Response: Thank you for your advice. We have changed the sentence.

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

Table 1: what does the frequency mean? Please specify this.

Author Response

Q; Table 1: what does the frequency mean? Please specify this.

A; As for the meaning of "frequency," it means the number of cases reported in English for EAH, Eccrine nevus, Tufted angioma, and blue rubber bleb nevus syndrome. While as for smooth muscle hamartoma, it means one patient occurs per 2600 births. To avoid confusion, we have changed the number of acquired cases reported in English to be consistent with other diseases. Thank you very much for your suggestion.