Generic selectors
Exact matches only
Search in title
Search in content
Post Type Selectors
Search in posts
Search in pages
Filter by Categories
15th National Conference of the IAOMFP, Chennai, 2006
Abstract
Abstracts from current literature
Acne in India: Guidelines for management - IAA Consensus Document
Addendum
Announcement
Art & Psychiatry
Article
Articles
Association Activities
Association Notes
Award Article
Book Review
Brief Report
Case Analysis
Case Letter
Case Letters
Case Notes
Case Report
Case Reports
Clinical and Laboratory Investigations
Clinical Article
Clinical Studies
Clinical Study
Commentary
Conference Oration
Conference Summary
Continuing Medical Education
Correspondence
Corrigendum
Cosmetic Dermatology
Cosmetology
Current Best Evidence
Current Issue
Current View
Derma Quest
Dermato Surgery
Dermatopathology
Dermatosurgery Specials
Dispensing Pearl
Do you know?
Drug Dialogues
e-IJDVL
Editor Speaks
Editorial
Editorial Remarks
Editorial Report
Editorial Report - 2007
Editorial report for 2004-2005
Errata
Erratum
Focus
Fourth All India Conference Programme
From Our Book Shelf
From the Desk of Chief Editor
General
Get Set for Net
Get set for the net
Guest Article
Guest Editorial
History
How I Manage?
IADVL Announcement
IADVL Announcements
IJDVL Awards
IJDVL AWARDS 2015
IJDVL Awards 2018
IJDVL Awards 2019
IJDVL Awards 2020
IJDVL International Awards 2018
Images in Clinical Practice
Images in Dermatology
In Memorium
Inaugural Address
Index
Knowledge From World Contemporaries
Leprosy Section
Letter in Response to Previous Publication
Letter to Editor
Letter to the Editor
Letter to the Editor - Case Letter
Letter to the Editor - Letter in Response to Published Article
LETTER TO THE EDITOR - LETTERS IN RESPONSE TO PUBLISHED ARTICLES
Letter to the Editor - Observation Letter
Letter to the Editor - Study Letter
Letter to the Editor - Therapy Letter
Letter to the Editor: Articles in Response to Previously Published Articles
Letters in Response to Previous Publication
Letters to the Editor
Letters to the Editor - Letter in Response to Previously Published Articles
Letters to the Editor: Case Letters
Letters to the Editor: Letters in Response to Previously Published Articles
Media and news
Medicolegal Window
Messages
Miscellaneous Letter
Musings
Net Case
Net case report
Net Image
Net Images
Net Letter
Net Quiz
Net Study
New Preparations
News
News & Views
Obituary
Observation Letter
Observation Letters
Oration
Original Article
ORIGINAL CONTRIBUTION
Original Contributions
Pattern of Skin Diseases
Pearls
Pediatric Dermatology
Pediatric Rounds
Perspective
Presedential Address
Presidential Address
Presidents Remarks
Quiz
Recommendations
Regret
Report
Report of chief editor
Report of Hon : Treasurer IADVL
Report of Hon. General Secretary IADVL
Research Methdology
Research Methodology
Resident page
Resident's Page
Resident’s Page
Residents' Corner
Residents' Corner
Residents' Page
Retraction
Review
Review Article
Review Articles
Reviewers 2022
Revision Corner
Self Assessment Programme
SEMINAR
Seminar: Chronic Arsenicosis in India
Seminar: HIV Infection
Short Communication
Short Communications
Short Report
Snippets
Special Article
Specialty Interface
Studies
Study Letter
Study Letters
Supplement-Photoprotection
Supplement-Psoriasis
Symposium - Contact Dermatitis
Symposium - Lasers
Symposium - Pediatric Dermatoses
Symposium - Psoriasis
Symposium - Vesicobullous Disorders
SYMPOSIUM - VITILIGO
Symposium Aesthetic Surgery
Symposium Dermatopathology
Symposium-Hair Disorders
Symposium-Nails Part I
Symposium-Nails-Part II
Systematic Review and Meta-Analysis
Systematic Reviews and Meta-analyses
Systematic Reviews and Meta-analysis
Tables
Technology
Therapeutic Guideline-IADVL
Therapeutic Guidelines
Therapeutic Guidelines - IADVL
Therapeutics
Therapy
Therapy Letter
Therapy Letters
View Point
Viewpoint
What’s new in Dermatology
Generic selectors
Exact matches only
Search in title
Search in content
Post Type Selectors
Search in posts
Search in pages
Filter by Categories
15th National Conference of the IAOMFP, Chennai, 2006
Abstract
Abstracts from current literature
Acne in India: Guidelines for management - IAA Consensus Document
Addendum
Announcement
Art & Psychiatry
Article
Articles
Association Activities
Association Notes
Award Article
Book Review
Brief Report
Case Analysis
Case Letter
Case Letters
Case Notes
Case Report
Case Reports
Clinical and Laboratory Investigations
Clinical Article
Clinical Studies
Clinical Study
Commentary
Conference Oration
Conference Summary
Continuing Medical Education
Correspondence
Corrigendum
Cosmetic Dermatology
Cosmetology
Current Best Evidence
Current Issue
Current View
Derma Quest
Dermato Surgery
Dermatopathology
Dermatosurgery Specials
Dispensing Pearl
Do you know?
Drug Dialogues
e-IJDVL
Editor Speaks
Editorial
Editorial Remarks
Editorial Report
Editorial Report - 2007
Editorial report for 2004-2005
Errata
Erratum
Focus
Fourth All India Conference Programme
From Our Book Shelf
From the Desk of Chief Editor
General
Get Set for Net
Get set for the net
Guest Article
Guest Editorial
History
How I Manage?
IADVL Announcement
IADVL Announcements
IJDVL Awards
IJDVL AWARDS 2015
IJDVL Awards 2018
IJDVL Awards 2019
IJDVL Awards 2020
IJDVL International Awards 2018
Images in Clinical Practice
Images in Dermatology
In Memorium
Inaugural Address
Index
Knowledge From World Contemporaries
Leprosy Section
Letter in Response to Previous Publication
Letter to Editor
Letter to the Editor
Letter to the Editor - Case Letter
Letter to the Editor - Letter in Response to Published Article
LETTER TO THE EDITOR - LETTERS IN RESPONSE TO PUBLISHED ARTICLES
Letter to the Editor - Observation Letter
Letter to the Editor - Study Letter
Letter to the Editor - Therapy Letter
Letter to the Editor: Articles in Response to Previously Published Articles
Letters in Response to Previous Publication
Letters to the Editor
Letters to the Editor - Letter in Response to Previously Published Articles
Letters to the Editor: Case Letters
Letters to the Editor: Letters in Response to Previously Published Articles
Media and news
Medicolegal Window
Messages
Miscellaneous Letter
Musings
Net Case
Net case report
Net Image
Net Images
Net Letter
Net Quiz
Net Study
New Preparations
News
News & Views
Obituary
Observation Letter
Observation Letters
Oration
Original Article
ORIGINAL CONTRIBUTION
Original Contributions
Pattern of Skin Diseases
Pearls
Pediatric Dermatology
Pediatric Rounds
Perspective
Presedential Address
Presidential Address
Presidents Remarks
Quiz
Recommendations
Regret
Report
Report of chief editor
Report of Hon : Treasurer IADVL
Report of Hon. General Secretary IADVL
Research Methdology
Research Methodology
Resident page
Resident's Page
Resident’s Page
Residents' Corner
Residents' Corner
Residents' Page
Retraction
Review
Review Article
Review Articles
Reviewers 2022
Revision Corner
Self Assessment Programme
SEMINAR
Seminar: Chronic Arsenicosis in India
Seminar: HIV Infection
Short Communication
Short Communications
Short Report
Snippets
Special Article
Specialty Interface
Studies
Study Letter
Study Letters
Supplement-Photoprotection
Supplement-Psoriasis
Symposium - Contact Dermatitis
Symposium - Lasers
Symposium - Pediatric Dermatoses
Symposium - Psoriasis
Symposium - Vesicobullous Disorders
SYMPOSIUM - VITILIGO
Symposium Aesthetic Surgery
Symposium Dermatopathology
Symposium-Hair Disorders
Symposium-Nails Part I
Symposium-Nails-Part II
Systematic Review and Meta-Analysis
Systematic Reviews and Meta-analyses
Systematic Reviews and Meta-analysis
Tables
Technology
Therapeutic Guideline-IADVL
Therapeutic Guidelines
Therapeutic Guidelines - IADVL
Therapeutics
Therapy
Therapy Letter
Therapy Letters
View Point
Viewpoint
What’s new in Dermatology
View/Download PDF

Translate this page into:

Observation Letter
87 (
3
); 404-408
doi:
10.25259/IJDVL_197_20

High-risk human papillomavirus in ruxolitinib-associated sebaceous neoplasms

Department of Dermatology American University of Beirut Medical Center, Beirut, Lebanon
Department of Pathology, American University of Beirut Medical Center, Beirut, Lebanon

Corresponding author: Dr. Ibrahim Khalifeh, Department of Pathology, American University of Beirut Medical Center, P.O. Box 11-0236, Riad El Solh 1107 2020, Beirut, Lebanon. ik08@aub.edu.lb

Licence
This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Hamie L, Bardawil T, Khalifeh I. High-risk human papillomavirus in ruxolitinib-associated sebaceous neoplasms. Indian J Dermatol Venereol Leprol 2021;87:404-8.

Sir,

Ruxolitinib is a JAK1/2 inhibitor approved for polycythemia vera and myelofibrosis in adults. Cutaneous malignancies, namely, nonmelanoma skin cancers, such as squamous cell carcinomas, basal cell carcinomas and Merkel cell carcinoma, have been reported with its use.1,2 In fact, the 5-year efficacy data on ruxolitinib has revealed a significantly higher rate of new-onset basal or squamous cell carcinomas compared to patients on other therapies for myelofibrosis such as hydroxyurea. In addition, these tumors tend to display more aggressive biological behavior and metastatic potential.1,3

The clinical efficacy of ruxolitinib is measured through the elimination of neoplastic cells with the JAK2 mutation.2JAK1/2 inhibitors work by inhibiting proinflammatory cytokines, chemokines and adhesion molecules which can lead to the interruption of certain immune/inflammatory cascades. Despite its obvious benefits, ruxolitinib might push patients towards a relatively immune-suppressed state.2 On extensive review of the English literature, we were unable to find cases of ruxolitinib-induced benign sebaceous tumors with a possible relationship to a high-risk human papillomavirus strain.

A 57-year-old male with myelofibrosis, maintained on ruxolitinib over the past year presented to the dermatology clinic at the American University of Beirut Medical Center, complaining of two growing nodules on the scalp. The bigger lesion was of 5-month duration and the smaller one of 2-month duration. The lesions were asymptomatic; hence, no treatment was sought. On the frontal scalp, there were a 3 × 2 cm and a 1 × 1 cm, skin-colored, firm, oval plaques with areas of hyperkeratosis [Figures 1a and 1b]. Our differential diagnoses included squamous cell carcinoma, keratoacanthoma and adnexal tumors.

A skin-colored to yellowish firm nodule with central hyperkeratosis located on the anterior scalp
Figure 1a:
A skin-colored to yellowish firm nodule with central hyperkeratosis located on the anterior scalp
A skin-colored papule with an elevated border and central depression
Figure 1b:
A skin-colored papule with an elevated border and central depression

On microscopy, both lesions were well-circumscribed with different proportions of sebocytes and germ cells. Both lesions had papillomatous epidermal proliferations with koilocytic changes and mounds of parakeratosis admixed with hemorrhage at the top of the papillae, simulating the diagnosis of verruca vulgaris [Figures 2a - 2d]. The lesions were diffusely immunoreactive to the androgen receptor (nuclear) and epithelial membrane antigen (cytoplasmic/membranous) confirming their sebaceous nature [Figures 2e - 2h]. Consequently, the bigger lesion had more than 50% germ cells and the smaller one had predominantly mature sebocytes; hence, the tumors were diagnosed as a sebaceoma and a sebaceous adenoma, respectively. The patient underwent surgical excision of the lesions and therapy with ruxolitinib was continued.

Basaloid germ cells (80%) admixed with mature sebocytes (20%). The top of the lesion shows mounds of parakeratosis and hemorrhage (H and E,×20)
Figure 2a:
Basaloid germ cells (80%) admixed with mature sebocytes (20%). The top of the lesion shows mounds of parakeratosis and hemorrhage (H and E,×20)
Papillary configurations lined by squamous cells with koilocytic changes (star) and hypergranulosis (arrow) with overlying parakeratosis (arrowhead) (H and E,×10)
Figure 2b:
Papillary configurations lined by squamous cells with koilocytic changes (star) and hypergranulosis (arrow) with overlying parakeratosis (arrowhead) (H and E,×10)
A well-circumscribed lesioncomposed of mature sebocytesand a few germ cells.The epidermis shows mounds of parakeratosis (arrowhead), hemorrhage (arrow) and koilocytes (star) (H and E,×20)
Figure 2c:
A well-circumscribed lesioncomposed of mature sebocytesand a few germ cells.The epidermis shows mounds of parakeratosis (arrowhead), hemorrhage (arrow) and koilocytes (star) (H and E,×20)
Koilocytic cells with enlarged pyknotic, wrinkled nuclei with a surrounding halo (H and E,×40)
Figure 2d:
Koilocytic cells with enlarged pyknotic, wrinkled nuclei with a surrounding halo (H and E,×40)
Diffuse nuclear labelling by androgen receptor antibody (×10)
Figure 2e:
Diffuse nuclear labelling by androgen receptor antibody (×10)
Membranous and cytoplasmic staining by epithelial membrane antigen (×20)
Figure 2f:
Membranous and cytoplasmic staining by epithelial membrane antigen (×20)
Diffuse nuclear labelling by androgen receptor antibody (×20)
Figure 2g:
Diffuse nuclear labelling by androgen receptor antibody (×20)
Membranous and cytoplasmic staining by epithelial membrane antigen (×20)
Figure 2h:
Membranous and cytoplasmic staining by epithelial membrane antigen (×20)

Human papillomavirus status was evaluated by a fluorescently labeled polymerase chain reaction followed by a chip for human papillomavirus markers [Figure 3a]. The quantification of the associated human papillomavirus types was done by the euroarray technique using standard protocols as recommended by the manufacturer (Affymetrix, Santa Clara). In the first step, sections of the viral oncogenes E6 and E7 of the human papillomavirus present in the sample were amplified by polymerase chain reaction using a multiplex primer system and at the same time, labelled with a fluorescent dye. In a second step, the products were detected using an oligonucleotide array whereby the specific binding of a fluorescently labelled polymerase chain reaction product to its corresponding oligonucleotide probe was detected using the Euroimmunmicroarray scanner. The analysis was done for the 30 high and low risk human papillomavirus subtypes (EUROArrayHPV detection kit, EUROIMMUN AG, Germany). Human papillomavirus 66 strain was detected in both lesions [Figure 3b].

The EUROArrayhuman papillomavirus is composed of a total of 72 spots placed in a certain arrangement
Figure 3a:
The EUROArrayhuman papillomavirus is composed of a total of 72 spots placed in a certain arrangement
Scanned microarray showing the signal of each probe. Only human papillomavirus 66 displays a positive signal intensity. PC: DNA positive control. CC-I and CC-II: Cross contamination control: Only one of the two probes should show a signal. If both probes show a signal, this indicates cross contamination between neighboring slide fields. OS I and OS II: Orientation spots for the automatic detection of array positions using EURO Array Scan
Figure 3b:
Scanned microarray showing the signal of each probe. Only human papillomavirus 66 displays a positive signal intensity. PC: DNA positive control. CC-I and CC-II: Cross contamination control: Only one of the two probes should show a signal. If both probes show a signal, this indicates cross contamination between neighboring slide fields. OS I and OS II: Orientation spots for the automatic detection of array positions using EURO Array Scan

Human papillomavirus has emerged as a key etiologic driver in a variety of clinical conditions that range from innocuous lesions to cancers.4,5 It can infect both the cutaneous and mucosal surfaces. These viruses can be categorized into high-risk and low-risk human papillomavirus types, based on their association with cancerous and precursor lesions. The high-risk human papillomavirus types are types 16, 18, 31, 33, 34, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 and 70.4,5

In sebaceous neoplasms, mainly in carcinomas, there is a dichotomization of the pathogenesis. There are sebaceous carcinomas which harb or TP53 or RB1 mutations and a group of carcinomas which are driven by human papillomavirus infections.4 Two main viral proteins, E6 and E7, are largely responsible for the tumor carcinogenesis when incorporated into human DNA. These proteins work by inhibiting the two tumor suppressor proteins; TP53 and Rb, respectively.5 This can explain the development of sebaceous carcinomas in cases that are negative for the driving mutations (p53 and Rb) but positive for human papillomavirus infections.4,5

The segregation of sebaceous carcinomas is important since the human papillomavirus-associated tumors that are more likely to occur in younger individuals, are less aggressive and rarely display worrisome histological phenotypes including higher-grade nuclear features, warranting less aggressive postoperative surveillance.4 Furthermore, the identification of a link connecting human papillomavirus infections and the abrogation of TP53/ Rb function can also explain the reported predisposition of immunosuppressed patients to develop ocular adnexal sebaceous carcinomas. These carcinomas are more likely to occur in solid organ-transplant and HIV infected patients.4

The reported incidence of high-risk human papillomavirus in periocular sebaceous carcinoma ranges from 0% to 57%.5 In contrast, human papillomavirus profiling studies in benign sebaceous tumors are lacking. Interestingly, sebaceomas can rarely portray proliferation of infundibular keratinocytes with hypergranulosis mimicking verruca or seborrheic keratosis.6 No human papillomavirus studies have been done on this variant. Moreover, there is a report of a sebaceous gland hyperplasia accompanied with a papilloma positive for the high-risk human papillomavirus-51.7

In conclusion, our report highlights that the usage of immunomodulators such as ruxolitinib continues to expand the clinicopathological spectrum of human papillomavirus-associated neoplasms.8 One limitation is that polymerase chain reaction is a highly sensitive technique of DNA detection; hence, the presence of human papillomavirus DNA does not necessarily correlate with transcriptional activity.5 This requires more specific sequencing techniques such as in situ hybridization.4 Our future perspectives include performing these techniques on larger cohorts of patients with sebaceous neoplasms to fully understand the molecular landscape of such rare tumors. These studies may help clarify the role of human papillomavirus in sebaceous tumor carcinogenesis and possibly identify targeted or immune-based therapies such as human papillomavirus vaccination in the predisposed individuals to further improve patient outcomes.4

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

  1. , , , , , , et al. Aggressive skin cancers occurring in patients treated with the Janus kinase inhibitor ruxolitinib. J Drugs Dermatol. 2017;16:508-11.
    [Google Scholar]
  2. , , , , , , et al. Aggressive Merkel cell carcinoma after Janus kinase inhibitor ruxolitinib for polycythemia vera. In Vivo. 2019;33:1667-9.
    [CrossRef] [PubMed] [Google Scholar]
  3. , , , , , , et al. Eruptive squamous cell carcinomas with keratoacanthoma like features in a patient treated with ruxolitinib. Br J Dermatol. 2015;173:1098-9.
    [CrossRef] [PubMed] [Google Scholar]
  4. , , , , , , et al. Distinct biological types of ocular adnexal sebaceous carcinoma: HPV driven and virus negative tumors arise through nonoverlapping molecular genetic alterations. Clin Cancer Res. 2019;25:1280-90.
    [CrossRef] [PubMed] [Google Scholar]
  5. , , , , , , et al. p16 expression is not a surrogate marker for high risk human papillomavirus infection in periocular sebaceous carcinoma. Am J Ophthalmol. 2016;170:168-75.
    [CrossRef] [PubMed] [Google Scholar]
  6. , , , . Sebaceoma and related neoplasms with sebaceous differentiation: A clinicopathologic study of 30 cases. Am J Dermatopathol. 2002;24:294-304.
    [CrossRef] [PubMed] [Google Scholar]
  7. , , , . Papilloma and sebaceous gland hyperplasia of the lacrimal caruncle: A case report. Int Med Case Rep J. 2018;11:91-5.
    [CrossRef] [PubMed] [Google Scholar]
  8. , , , . The evolving landscape of HPV related neoplasia in the head and neck. Hum Pathol. 2019;94:29-39.
    [CrossRef] [PubMed] [Google Scholar]

Fulltext Views
3,367

PDF downloads
1,137
View/Download PDF
Download Citations
BibTeX
RIS
Show Sections