Speculating on spicules: Our incomplete knowledge of trichodysplasia spinulosa
By Warren R. Heymann, MD, FAAD
December 15, 2021
Vol. 3, No. 49
For inexplicable reasons, there are certain differential diagnoses that I find particularly satisfying, one being disorders responsible for facial follicular spicules: follicular mucinosis (1), pityriasis folliculorum (Demodex folliculorum) (2), follicular hyperkeratotic spicules (myeloma immunoglobulin or cryoglobulin) (3), follicular porokeratosis (4), trichostasis spinulosa (vellus hairs) (5), keratosis pilaris, lichen planopilaris, lichen spinulosus, and trichodysplasia spinulosa (6). Clinical-pathologic correlation will usually allow for a precise diagnosis. This commentary will focus on trichodysplasia spinulosa (TS).
TS is a rare disorder observed in immunocompromised hosts, either in association with solid organ transplantations (mostly renal) or hematologic malignancies; it is caused by the trichodysplasia spinulosa-associated polyomavirus (TSPyV). Clinically, TS is characterized by papules and spicules, most commonly affecting the face with rare involvement of the trunk and extremities. Nonscarring alopecia of eyebrows and eyelashes may be observed. Lesions are usually asymptomatic, although they may be pruritic. Untreated TS may result in facial disfigurement from leonine facies. (6, 7, 8) Histologically TS demonstrates follicular dilatation, absence of a papilla, proliferation of inner root sheath cells with enlarged trichohyalin granules, and infundibular keratin plugs. (9) Although immunoperoxidase studies, electron microscopy, and PCR have confirmed TSPyV in the inner root sheath, these studies are not necessary to render the diagnosis of TS.
According to Sheu et al, “Human polyomaviruses (HPyVs) are small, nonenveloped, double-stranded DNA viruses that express tumour antigen proteins. Fourteen species of polyomaviruses have been discovered in humans, and since the 2008 discovery of the first cutaneous polyomavirus — Merkel cell polyomavirus (MCPyV) — six more species have been detected in the skin: trichodysplasia spinulosa-associated polyomavirus (TSPyV), HPyV6, HPyV7, HPyV9, HPyV10, and HPyV13. Of these cutaneous species, only MCPyV, TSPyV, HPyV6, and HPyV7 have been definitively associated with diseases of the skin, most commonly in immunocompromised individuals. MCPyV is a predominant aetiology in Merkel cell carcinomas. TSPyV is one of the aetiological factors of trichodysplasia spinulosa. HPyV6 and HPyV7 have been recently linked to pruritic skin eruptions.” Sampling suggests that TSPyV is transmitted by respiratory or orofecal transmission, with primary transmission occurring during childhood. (10)
Approximately 10% of healthy children up to 2 years old have the infection; the overall prevalence is 75% in older age groups. (11) Interestingly, it has been demonstrated that anti-TSPyV IgM seroconversion is detected prior to the onset of TS, while IgG seroconversion is detectable only after TS has appeared clinically. This suggests that TS is caused by primary infection, rather than reactivation in immunocompromised patients. (10) The pathogenesis of TS lesions has not been completely elucidated, although TSPyV-PP2A binding may compromise PP2A’s ability to deactivate MAPK cascade proteins, resulting in cellular proliferation characteristic of TS. Additionally, increased retinoblastoma protein phosphorylation, leading to inactivation, may play a critical role in DNA repair and cell-cycle regulation contributing to TS development. (9) (The retinoblastoma protein is a tumor suppressor that is dysfunctional in multiple cancers.)
There are no established guidelines for treating TS. A reasonable first step is to decrease iatrogenic immunosuppression, if possible, as improvement of TS may be dramatic with this maneuver. (6) Oral valganciclovir and topical cidofovir have been considered the most effective therapies. (8) Adding a topical retinoid such as adapalene to the regimen may be beneficial. (12) Other recently reported successful therapies include oral leflunomide (because of its reported anti-DNA-viral activity) (13) and photodynamic therapy. (14)
In conclusion, even though TS is considered rare, the increasing frequency of solid organ transplantations and iatrogenic immunosuppression raises the likelihood of encountering TS in practice. Further research about the role of TSPyV in health and disease should help unravel mysteries of TS, leading to novel therapies that diminish the potential for cosmetic disfigurement. Before too long the pathogenesis of spiculation in TS will no longer be a matter of speculation.
Point to Remember: Even though the differential diagnosis of centrofacial follicular spicules is broad, the diagnosis of trichodysplasia spinulosa should be straightforward, based on the clinical scenario and biopsy confirmation. Ongoing research will further define the interactions of TSPyV and the inner root sheath that may enable the development of novel antiviral therapies.
Our expert’s viewpoint
Mary Gail Mercurio, MD, FAAD
Professor, Department of Dermatology
University of Rochester Medical Center, Rochester, New York
TS is one of a plethora of cutaneous manifestations resulting from iatrogenic immunosuppression. As pointed out by Dr. Heymann, TS is associated with a specific polyomavirus (PV), trichodysplasia spinulosa-associated polyomavirus (TSPyV). Polyomaviruses were previously grouped with papillomaviruses until taxonomists re-classified them into a unique family because of the burgeoning identification of additional species. Merkel cell polyomavirus (MCPyV), discovered by the advent of new sequencing technology termed next generation sequencing, is the most notable in our field because of its association with the aggressive form of skin cancer. Additional dermatologic associations may likely be on the horizon for what now sum up to more than a dozen unique PVs.
TS is an uncommon entity however its recognition is important because of the potential for evolution to infiltrative lesions causing facial disfigurement and nonscarring alopecia. These features can dramatically impact quality of life on the heels of surviving cancer and transplantation. The clinical features can be misleading at a glance and, in our reported case (reference 12), the patient had been diagnosed with perioral dermatitis and treated for that disorder without improvement for months. As the pathology of TS is quite specific, with strikingly large trichohyalin granules occupying the follicular epithelium, the key is to recognize the unique clinical morphology and have the index of suspicion to perform the biopsy. It was one of my astute dermatology residents that immediately appreciated the spiculed lesions amidst the bland papules and hence the need for a confirmatory biopsy given the clinical scenario. The improvement in this case was swift and dramatic with a very grateful patient looking like a different person at her follow-up visit. Awareness of this entity is increasingly relevant as more transplants are performed, and this case highlights the importance of prioritizing lesional morphology to help formulate an inclusive differential diagnosis. The language of dermatology, including comprehension of the all-important primary skin lesion, is an essential foundation taught in dermatology residency that enables translation of clinical observations to decision making that clinches the diagnosis. As I say (maybe too often) you can never look at too many clinical images!
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Rusk AM, Crute MM, Goebel J, Schecter MG, Gupta A, Schwentker AR, Sheth AP, Lucky AW. Pediatric trichodysplasia spinulosa: A report of 2 cases and review of the literature. Pediatr Dermatol. 2020 Nov;37(6):1023-1029.
Shah PR, Esaa FS, Gupta P, Mercurio MG. Trichodysplasia spinulosa successfully treated with adapalene 0.1% gel and oral valganciclovir in a renal transplant recipient. JAAD Case Rep. 2019 Dec 24;6(1):23-25.
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