Simultaneous Central Nervous System and Cutaneous Relapse in Acute Myeloid Leukemia

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript is essentially confirmatory, as the cutaneous and central nervous system localizations of acute myeloid leukemia recurrences as well as their prognostic significance have been repeatedly reported in the literature. However, simultaneous cutis and CNS leukemia recurrence makes the described case of some interest. There are a few revisions/clarifications that are necessary to make this acceptable for publication:
1) was the immunophenotype of leukemic cells performed at diagnosis and at recurrence superimposable? Was CD 56, usually involved in cell adesion mediating extramedullary infiltration, expressed?
2) the authors do not specify whether, at the time of extramedullary recurrence, a bone marrow sample was studied to exclude systemic AML recurrence
3) was FISH analysis performed on the blast cells of the cutaneous recurrence and in the cerebrospinal fluid to identify the presence of trisomy 8 described in leukemic blasts at diagnosis?

 

Author Response

Comments 1: Was the immunophenotype of leukemic cells performed at diagnosis and at recurrence superimposable? Was CD 56, usually involved in cell adesion mediating extramedullary infiltration, expressed?

Response 1: Yes, it was performed both at diagnosis and recurrance. The revised text reflecting this addition can be found in the Case-Report section, page 3, lines 102–106: "a repeat bone marrow biopsy identified 68% myeloid blasts expressing the immunophenotypic markers CD13, CD15, CD33, CD36, CD38, CD45, CD56, CD65S, CD71, CD86, and HLA-DR. Additionally, cytogenetic and molecular analyses revealed trisomy 8 and mutations in NPM1, ASXL1, ETV6, and EZH2" and in the Case-Report section, page 3, lines 134–139 "The isolated blast cell population tested positive for the markers CD15, CD33, CD45, CD56, and CD64, and was negative for CD4, CD11b, CD13, CD14, CD34, CD36, CD86, CD117, and HLA-DR. FISH analysis on cerebrospinal fluid wes not performed. To complete the diagnostic assessment, a re-evaluation of the bone marrow was conducted, confirming the absence of bone marrow involvement by the disease." Thank you for pointing this out. 

 

Comments 2: The authors do not specify whether, at the time of extramedullary recurrence, a bone marrow sample was studied to exclude systemic AML recurrence

Response 2: Yes, it was performed. The revised text reflecting this addition can be found in the Case-Report section, page 3, lines 137–139: "To complete the diagnostic assessment, a re-evaluation of the bone marrow was conducted, confirming the absence of bone marrow involvement by the disease," to the dedicated section. We agree with this comment.

Comments 3: Was FISH analysis performed on the blast cells of the cutaneous recurrence and in the cerebrospinal fluid to identify the presence of trisomy 8 described in leukemic blasts at diagnosis?
Response 3: No, FISH analysis wasn't performed; in fact, we don't routinely do this type of analysis on liquor and skin biopsies at our center. We have highlighted this in the caption of Figure 1, page 4, lines 166–167.

Reviewer 2 Report

Comments and Suggestions for Authors

• While CNS involvement and cutaneous relapse in AML have been individually reported, the simultaneous occurrence presenting initially with cranial nerve multineuritis alongside leukemia cutis is uncommon, making this case moderately novel. 

• It  would be important to emphasize explicitly why simultaneous cranial nerve multineuritis and leukemia cutis is clinically distinct or rare compared to previously reported cases.

• Provide a clearer explanation regarding why nerve biopsy was not pursued. This is a very important method that was omitted.

• The discussion should be improved regarding the MRI findings, addressing diagnostic imaging limitations, "possible thickening without enhancement" are somewhat ambiguous.

• A comparison is needed regarding prognosis and survival outcomes relative to similar published cases.

Author Response

Comments 1: While CNS involvement and cutaneous relapse in AML have been individually reported, the simultaneous occurrence presenting initially with cranial nerve multineuritis alongside leukemia cutis is uncommon, making this case moderately novel. It  would be important to emphasize explicitly why simultaneous cranial nerve multineuritis and leukemia cutis is clinically distinct or rare compared to previously reported cases.

Response 1: We appreciate the reviewer’s insightful remark highlighting the moderate novelty of our case and the importance of contextualizing it within the existing literature. We emphasize that this dual presentation as an initial sign of AML relapse is rarely reported and poses significant diagnostic challenges. To support this point, we also conducted a focused literature search on PubMed, which confirmed the paucity of similar cases. The revised text reflecting this addition can be found in the Case-Report section, page 5, lines 195–201; It is also included in our response to Comment 4:

 

Comments 2: Provide a clearer explanation regarding why nerve biopsy was not pursued. This is a very important method that was omitted.

Response 2: We agree with this comment. We have accordingly added a clarification in the Case-Report sections, page 4, line 140-144 to explain the reasons why nerve biopsy was not performed. “Unfortunately, nerve biopsy—the gold standard for diagnosing leukemic infiltration—was not performed due to the high risk of permanent neurological deficits and technical challenges associated with sampling the affected cranial nerves, resulting in only a presumptive diagnosis of cranial nerve involvement secondary to possible neuroleukemiosis.”

 

Comments 3: The discussion should be improved regarding the MRI findings, addressing diagnostic imaging limitations, "possible thickening without enhancement" are somewhat ambiguous.

Response 3: We agree with this comment. We have revised the manuscript to provide a more detailed interpretation of the MRI findings and to highlight the diagnostic limitations of cranial nerve imaging in this context. The revised text addressing this point is in the Case-Report section, page 3, line 128-131: “Given the evidence of cranial multineuritis, a contrast-enhanced magnetic resonance imaging (MRI) was performed, demonstrating an equivocal thickening of the left oculomotor nerve on drive sequences, without contrast enhancement or T2 hyperintensity. The finding remained uncertain due to the subtle asymmetry compared to the contralateral nerve and the variable visualization of the nerve across imaging planes.”

Comments 4: A comparison is needed regarding prognosis and survival outcomes relative to similar published cases.

Response 4: Thank you for your comment, which is both timely and pertinent. While we acknowledge that comparing our patient's outcome with similar cases documented in the literature could be beneficial, there is a limited number of reports addressing cases of simultaneous cutaneous and central nervous system (CNS) recurrence. We fully agree that outcome comparisons can add clinical value; however, in this case, we found it unfeasible due to the extreme rarity and heterogeneity of published reports. However, we added this sentence in the Discussion section, page 5, lines 195–201: "While central nervous system involvement and cutaneous relapse in AML have been individually reported, the simultaneous occurrence with cranial nerve multineuritis alongside leukemia cutis is uncommon. Literature reports a few cases of acute lymphoblastic leukemia (ALL) or AML presenting with leukemia cutis and facial nerve palsy [Gold et al., 2014; Ergin et al., 2013; Bilawsky et al., 2006; Salutari et al., 1996]. Our case differs from prior reports by documenting multiple cranial nerve involvement concurrent with leukemia cutis during AML relapse, a combination that is both unusual and clinically significant."

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Authors  have addressed previous  comments.  However,   the  discussion needs  some change:

"Timely diagnosis and aggressive multimodal treatment, including intrathecal 227
therapy and stem cell transplantation, are crucial."

 What  would  be the   recommendation   for a  " diagnosis" if a nerve  biopsy   is not  possible like  in this case is ?

 

It is  also recommended  to check for typos in the reviewed  version.

Author Response

Comment: "Timely diagnosis and aggressive multimodal treatment, including intrathecal therapy and stem cell transplantation, are crucial." What would be the recommendation for a " diagnosis" if a nerve biopsy is not possible like in this case is ?"   Response: Thank you for this comment. When nerve biopsy is not feasible, the diagnosis of leukemic cranial neuropathy relies on the integration of clinical, laboratory, and radiological findings. In our case, although MRI was unremarkable and the first lumbar puncture was negative, the subsequent CSF analysis detected leukemic cells, strongly supporting CNS involvement. Furthermore, the histological confirmation of concomitant leukemia cutis provided additional evidence of systemic relapse with extramedullary involvement, indirectly supporting the neurological findings. We had already mentioned this point in the Discussion; however, we have now revised the text to clarify it further, explicitly emphasizing the importance of integrating clinical features, CSF findings, radiological data, and, when available, histological results from other tissues in such complex diagnostic scenarios. We have incorporated these two additions in the Discussion and Conclusions sections, at lines 212-217 and 230-231 on pages 5 and 6, respectively.