A Rapidly Growing Nodule on the Eyebrow of a Pediatric Patient

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript describes a nice case  of a rare malignant tumor a in pediatric patient. Globally, the manuscript is well written and the case is concisely discussed.

However, there is one issue that the authors should better  discuss and that is the prognosis of this tumour, which it would appear generally poor. To this regard, they  cite some published that reported hat hidradenocarcinoma has a high recurrence and metastasis rate (lines 90-92). However, according with a large series observational study on 289 cases (see Gao et al. Prognostic analysis of hidradenocarcinoma: a SEER-based observational study Ann Med. 2022; 54(1): 454–463), the mean 10-year OS and CSS of patients with hidradenocarcinomas  were 60.2% and 90.5%, respectively,  allowing these authors to state that HC is a malignant tumor  with a relatively good  prognosis. However, only six patients had distant metastases, accounting for 2.4%. These results contrast greatly with the general and authors views.  In this series analysis, at the time of diagnosis, the tumour size of most patients was within 20 mm, suggesting that this may also be one of the reasons for the good prognosis.  Another reason for the discrepancy  could also be a bias in diagnosis as evidenced by Kazakov , as the clear-cut histologic distinction between the atypical hidroadenoma and hidroadenocarcinoma may  be challenging  (see Kazakov DV et al Am J Dermatopathol. 2009;31(3):236–247)

The author should better describe the clinical appearance of hidroadenocarcinoma (size, color, tenderness, etc), especially with regard to the benign counterpart (begin of discussion).  

Finally,  in  two out three of previously described pediatric cases, the site of the tumor was the retroauricolar region and this should be mentioned (end of discussion). 

The quality of the histologic figures should be improved (brightness, contrast)

Comments on the Quality of English Language

Moderate editing of english anguage is required.

Author Response

Replies:

• We specified the relatively good prognosis by including the referenced study, which, being based on almost 300 cases, is certainly very reliable.
• Based on the literature, we added, as you suggested, that it is very difficult to clinically distinguish between hidroadenoma and hidroadenocarcinoma.
• We added that both pediatric cases had retroauricular localization.
• We adjusted the brightness and contrast of the images.
• We edited the english language.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript reports an extraordinary case of a dermal poorly differentiated carcinoma in an 11-year-old girl. After one year of follow-up, the patient is alive and disease-free.

The case is very interesting, but the diagnosis of hidradenocarcinoma, while plausible, has not been clearly demonstrated. Most of the images are taken at a lower magnification, and while the round eosinophilic poorly differentiated cells are visible, it would be beneficial to better illustrate the presence of squamous cells, clear cells, and ductal structures.

The authors' assertion that CK7 and CK8/18 positivity indicates sweat gland differentiation or p63 squamous differentiation is not entirely accurate, as these markers can be positive in a wide range of tumors. Notably, the lesion was positive for GATA3, which is more typical of apocrine tumors.

Additionally, while EMA is considered a reliable marker of sebaceous differentiation, it can also stain some areas of various cutaneous carcinomas. However, it should not be considered typical of ductal differentiation, as the authors suggest. Instead, CEA is usually the preferred antibody for highlighting ducts, but this marker is not mentioned in the manuscript.

Most importantly, metastasis should be the primary differential diagnosis to rule out when dealing with a poorly differentiated dermal carcinoma with aggressive features in a pediatric patient (and also in adults). This point is not sufficiently emphasized in the manuscript and is only briefly mentioned as an "academic" differential diagnosis among other possibilities.

As a minor correction, the letters indicating the images in Figure 2 are incorrectly labeled (e.g., "b" in the lower left does not correspond to EMA). 

Comments on the Quality of English Language

The term "root of the eyebrow" may sound a bit unusual, as the parts of the eyebrow are typically referred to as medial, middle (central), and lateral.

Author Response

Replies:

• We have replaced one of the images (the 2a) with another at a higher magnification, where squamous cells are more clearly visible. The clear cells are appreciable in image 2b.
• We have stated that CK7/CK17 are markers of adnexal differentiation, including various structures such as apocrine glands, not only eccrine ones.
• Metastasis was ruled out for several reasons: a 'top-down' pattern of histological involvement, the presence of well-differentiated areas in a previous biopsy, the patient's prepubertal age (which makes ovarian malignancies unlikely), immunohistochemistry excluding tumors from other sites, and negative staging on imaging. We have added this.
• We have added that GATA3 positivity suggests apocrine differentiation.
• The EMA figure is labeled correctly.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors did not address to the major points of criticism regarding other prognostic results (see Gao et al) and the difficulties in histopathological differential diagnosis between the so-called atypical  hidroadenoma e hidroadenocarcinoma. This could be one of the reason for the purported relatively good prognosis of this malignancy.

I believe that a more critical view of the prognostic discrepancies emerging in the literature should have been made, as suggested.

Comments on the Quality of English Language

Good quality

Author Response

Replies:

• We added more than 70 words to explain the concepts: the difficulty in diagnosing atypical hidradenoma and how this bias may influence the conflicting prognostic data in the literature, which we clarified further.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript presents a remarkable case of a poorly differentiated dermal carcinoma in an 11-year-old girl. After one year of follow-up, the patient remains alive and disease-free.

The case is very interesting, and following the revisions, the diagnosis of hidradenocarcinoma has been adequately justified. Furthermore, many of the issues raised in the previous review have been addressed, and the quality of the images has significantly improved. However, images 3C and 3D, although remain unchanged from the initial version, appear much darker.

Author Response

Replies:

• We have modified, as requested by the reviewers, the brightness and contrast of all the images, including 3C and 3D, where the brightness was too high and the contrast too low.