A Rare Case of Plasmablastic Lymphoma in a Patient with HIV and SARS-CoV-2 Infections

Round 1

Reviewer 1 Report

Overall impression:

An English language edit is needed – suggest checking the literature to ensure the terminology used throughout the article is standard

Terminology in Title: “Non-Hodgkin's large B-cell plasmablastic lymphoma”

• The word order is not standard for describing lymphoma according to the WHO classification and common usage
• Plasmablastic Lymphoma (PBL) is an aggressive B-cell non-Hodgkin lymphoma

Abstract:

Line 13: Poorly written first sentence makes no sense. Does the author mean to say that oral lesions commonly associated with HIV infection are… ?

Line 17:  sentence: Poorly worded, not the standard terminology, saying NHL is the most common lymphoma in HIV infection is not helpful (by far most of lymphoma consists of ‘NHL’, but it is the aggressive B cell subtypes of NHL that are found in the HIV infected). Perhaps the author means that NHL is the most common cancer in People living with HIV (PLWH)? Regarding lymphoma in PLWH, the incidence is increased for aggressive B-cell NHL, as well as Hodgkin lymphoma. CD4 lymphocytes are indeed decreased, but not uniformly ‘small number’, so that is not a helpful summary statement.

Introduction:

The long discussion of various HIV oral lesions is informative, but the wrong way round for a case report of a PBL oral lesion. This is not a review. The flow can be improved and a clearer focus on cancer vs infective lesions, is needed.

Line 71: See above for CD4 count, this is too simplistic to say <100 in HIV NHL

Line 83: “no severe co-morbidities at the time” …. Obviously the diagnosis of advanced HIV infection was missed in October, and the underlying lymphoma was probably already present but unrecognised

Case presentation:

Line 128: Ascertain that all these antibodies are written correctly from a pathological point of view. It seems excessive to devote a whole sentence to the technique of kappa/lambda staining?

Line 155: check the literature for standard way to phrase ‘medullary aspiration’

Line 169:

You say evolution was favourable, but need to mention that PBL cases are reported to relapse within a median of 6 months despite often achieving complete remission during first-line treatment

Discussion:

Line 175: I do not understand this sentence

Line 183: The association between PBL and HIV infection is much stronger than that. The majority of PBL cases would be associated with HIV. Another aspect missing from discussion, is that HIV negative PBL typically responds worse to treatment than PBL in PLWH – this can be due to the HIV viraemia that responds to ARV thereby modulating the pathogenetic stimulus, or it can be the much older age of HIV negative PBL patients, etc.

Conclusion:

Line 209: Is ‘dental expertise’ really the primary expertise needed for the appropriate management of oral manifestations of HIV infection? Would infectious and oncological expertise not be equally important in this case?

Line 213: This is not a worthy conclusive statement to this paper, it is stating the obvious.

Line 215: This final statement focuses solely on vague speculation of SARS-COV-2 itself being responsible for the evolution of this patient’s PBL, and not on the drug cocktails that were given just before diagnosis and their putative influence on evolution, or the fact that the patient may have been unwell due to the PBL that was undiscovered, while symptoms wrongly attributed to SARS-COV-2 infection

Author Response

Title - Rare case of 

Line 13 – HIV (The lesions commonly associated with the HIV infection include oral candidiasis)

Line 17 - cancer in People living with HIV (PLWH), the incidence is increased for aggressive B-cell NHL.

Line 52-58 – deleted Oral  histoplasmosis is a granulomatous fungal infection caused by Histoplasma capsulatum, it occurs as chronic ulcerated areas located on the back of the tongue, palate, and vestibular mucosa, and is usually associated with advanced HIV infection [5]. Oral manifestations of Cryptococcosis are quite unusual, very few cases have been reported in the literature. The lesions consist of nonspecific ulcerations of the oral mucosa, but the def-inite diagnosis of oral cryptococcosis is very difficult, tissue biopsy is required for diagnosis [5].

Line 67-69 – deleted  The lesion may appear as a red-purple spot, ulcer, or nodule or mass. Intraoral KS (Kapo-si's Sarcoma) occurs on the strongly keratinized mucosa, the palate being the site in more than 90% of reported cases

Line 70-72 - Deleted : NHL is the most common lymphoma associated with HIV infection and is usually seen in the late stages with a CD4 lymphocyte count of less than 100 / mm3. It

Line 83 – delete and no significant comorbidities at that time

Line 128: Ascertain that all these antibodies are written correctly from a pathological point of view. It seems excessive to devote a whole sentence to the technique of kappa/lambda staining?

I replace with - The following primary antibodies were used, after antigen retrieval in citrate buffer: AE1/AE3; cluster designation (CD)20; CD3; CD38; CD138/ Syndecan-1; CD56; PAX5; anaplastic lymphoma kinase (ALK1); KI67; anti-Kappa; anti-Lambda.

Line 154 – deleted -  Medullary aspiration puncture  

I replaced with - Bone marrow aspiration

Line 169: Added - evaluation showed a favorable evolution 6 months after diagnosis, but need to mention that PBL cases are reported to relapse within a median of 6 months despite often achiev-ing complete remission during first-line treatment

Line 175: deleted and should be a wake-up call to any patient, both HIV-infected and immunocompetent

Line 183: The prognosis of patients with PbL is generally poor, the average survival rate is 6-9 months [20]. Patients with localized disease have a better prognosis, also, several studies in HIV-infected patients diagnosed with PbL have shown that the favorable outcome is more common in HIV-positive patients, administration of antiretroviral therapy has a par-ticularly important role to play [20].

Line 209: oncological expertise

Line 213: delete -  Early initiation of ARV therapy has a beneficial role in the management of HIV pa-tients, reducing the risk of infections and associated malignancies [22].

Line 215: I changed

Author Response File: Author Response.docx

Reviewer 2 Report

In this manuscript, Campeanu et al. present a case report of a patient diagnosed with a plasmablastic lymphoma, HIV infection, and a recent infection of SARS-COVID-2. This is a well-described and interesting case. I have some minor suggestions:

1. It would be very informative to add immunohistochemistry or in situ hybridization for EVB in the tumor. 

2. Authors can add a timeline showing time points for diagnosing different infections and lymphoma. In addition, they could add other data like treatments, viral loads, etc. This can give the reader a better visualization of the case’s story. 

3. If needed, please be consistent with the lymphoma terminology throughout the manuscript. For example, I saw ‘plasmablastic lymphoma’ and large ‘B-cell plasmablastic lymphoma’. 

4. You can elaborate (in the introduction and/or discussion) more about virus interactions, cooperative or synergistic mechanisms when they co-exist in a host.

5. The authors mention in the discussion: ‘Regarding SARS-COV-2 infection, recent studies suggest that it has a pro-oncogenic effect, either directly through the inflammatory environment…’ To my knowledge, an oncogenic virus acting directly infects the cell that becomes tumoral and participates in the transforming process by either expressing viral oncogenes or altering normal cell physiology that finally ends in cancer. Please clarify this point. 

6. The authors say in the abstract: ‘The lesions commonly associated with the infection include…’ Please specify what infection you are talking about. 

7. Please review grammar and the use of abbreviations throughout the text. 

Author Response

1. It would be very informative to add immunohistochemistry or in situ hybridization for EVB in the tumor. 

I corrected

1. Authors can add a timeline showing time points for diagnosing different infections and lymphoma. In addition, they could add other data like treatments, viral loads, etc. This can give the reader a better visualization of the case’s story.  (see fig 3)

1. For example, I saw ‘plasmablastic lymphoma’ and large ‘B-cell plasmablastic lymphoma’. 

Line 149 - Delete - Non-Hodgkin's large B-cell

1. You can elaborate (in the introduction and/or discussion) more about virus interactions, cooperative or synergistic mechanisms when they co-exist in a host.

In HIV infected patients, EBV infection causes atypical lymphoproliferations, and malignant transformations of lymphoid cells through a combination of mechanisms including use of virus-encoded transforming genes, stimulation of diverse cytokines, and interaction with receptors for the tumor necrosis factor (TNF) family of cytokines. (K L McClain, Epstein-Barr virus and HIV-AIDS-associated diseases, Biomed Pharmacother . 2001 Sep;55(7):348-52), Latent EBV can be reactivated and become a lytic infection. Ting Chen et al in study in a study conducted in 2019, at the beginning of the pandemic, reported the presence of IgM EBV in several patients with COVID 19, . In these patients, more severe forms of the disease were more common, with higher CRP values, corticosteroids were used more frequently.

1. The authors mention in the discussion: ‘Regarding SARS-COV-2 infection, recent studies suggest that it has a pro-oncogenic effect, either directly through the inflammatory environment…’ To my knowledge, an oncogenic virus acting directly infects the cell that becomes tumoral and participates in the transforming process by either expressing viral oncogenes or altering normal cell physiology that finally ends in cancer. Please clarify this point. 

 Line 203,204 - either directly by blocking the autophagic flux, and also leading to immune escape by downregulation of major histocompatibility complex I (MHC-I),

1. The authors say in the abstract: ‘The lesions commonly associated with the infection include…’ Please specify what infection you are talking about. 

 I changed

1. Please review grammar and the use of abbreviations throughout the text. 

I corrected

Author Response File: Author Response.docx