Hyperpigmented Macules and Patches on the Face: Exogenous Ochronosis or Lichen Planus Pigmentosus?

We present a case of a patient with a 10-year history of blue-black macules and patches on the face and an associated history of skin-lightening cream usage. The skin lightening cream contained hydroquinone, which is often associated with exogenous ochronosis (EO). Interestingly, the biopsy did not show characteristic findings of ochronosis, confusing the final diagnosis, however discontinuing the skin-lightening creams halted the progression of the patient's skin lesions supporting a diagnosis of EO. EO presents as asymptomatic hyperpigmentation after using products containing hydroquinone. This condition is most common in Black populations, likely due to the increased use of skin care products and bleaching cream containing hydroquinone in these populations. Topical hydroquinone is FDA-approved to treat melasma, chloasma, freckles, senile lentigines, and hyperpigmentation and is available by prescription only in the US and Canada. However, with the increased use of skin-lightening creams in certain populations, it is important for dermatologists to accurately recognize the clinical features of exogenous ochronosis to differentiate it from similar dermatoses. An earlier diagnosis can prevent the progression to severe presentations with papules and nodules. We summarize the clinical presentations diagnostic features, and treatment pearls, concluding with a discussion of the differential diagnoses.  J Drugs Dermatol. 2024;23(7):567-568.     doi:10.36849/JDD.8248.

Upregulation of caveolae-associated structural proteins in the hair follicle bulge of lichen planopilaris and frontal fibrosing alopecia.

Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are primary cicatricial alopecia that cause a major impact on quality of life due to irreversible hair loss and symptoms as itching, burning and pain. They are characterized by permanent loss of hair follicle stem cells (HFSCs) by pathomechanisms still poorly understood, resulting in poor efficacy of currently available treatments. Caveolae are flask-shaped lipid rafts invaginated within the plasma membrane of multiple cell types. Although their role in the HF physiology and pathophysiology is relatively unknown, we have previously demonstrated that the primary structural component of caveolae (caveolin-1 or Cav1) is upregulated in FFA. Thus, we propose to investigate the expression and localization of caveolae-associated structural proteins (Cav1, Cav2, and Cavin-1) and HFSCs (identified by K15) in both LPP and FFA. We analyzed 4 patients with LPP biopsied in affected and non-affected (NA) scalp, 4 patients with FFA biopsied in affected scalp and 4 healthy controls. Affected scalp of LPP and FFA demonstrated increased levels of Cav1 and Cavin-1 compared with HC and LPP-NA. Moreover, Cav1, Cav2 and Cavin1 all exhibit high colocalization with K15 and their expression appears to be negatively correlated, supporting the hypothesis that these proteins are important players in LPP/FFA and may serve as therapeutic targets in future treatments.

Gene-Environment Interaction Between CYP1B1 and Oral Contraception on Frontal Fibrosing Alopecia.

Importance: Frontal fibrosing alopecia (FFA) is an increasingly prevalent form of follicular lichen planus, causing irreversible hair loss predominantly in postmenopausal individuals. An earlier genome-wide meta-analysis of female FFA identified risk loci in genes implicated in self-antigen presentation and T-cell homeostasis, including HLA-B*07:02, ST3GAL1, and SEMA4B. However, CYP1B1, which is important for hormone metabolism, was also implicated with the substitution of serine for asparagine at position 453 (c.1358A>G, p.Asn453Ser) exhibiting a protective effect against FFA. Increasing understanding of genetic and environmental variables and their interactions will improve understanding of disease pathogenesis and has the potential to inform risk mitigation strategies. Objective: To investigate whether oral contraceptive pill (OCP) use modulates the protective effect of the common missense variant in CYP1B1 (c.1358A>G, p.Asn453Ser) on FFA risk. Design, Setting, and Participants: This gene-environment interaction study using a case-control design enrolled female patients with FFA from UK-based dermatology clinics. The patients were matched with unrelated age- and ancestry-matched female control individuals derived from UK Biobank in a 1:66 ratio, determined by the first 4 principal components from genome-wide genotypes. Data were collected from July 2015 to September 2017, and analyzed from October 2022 to December 2023. Main Outcome and Measure: The main outcomes were the modulatory effect of OCP use on the contribution of the CYP1B1 missense variant to female FFA risk and a formal gene-environment interaction test evaluated by a logistic regression model with a multiplicative interaction term, under the assumptions of an additive genetic model interaction term, under the assumptions of an additive genetic model. Results: Of the 489 female patients with FFA, the mean (SD) age was 65.8 (9.7) years, and 370 (75.7%) had a history of OCP use. Of the 34 254 age- and ancestry-matched control individuals, the mean (SD) age was 65.0 (8.4) years, and previous OCP use was reported in 31 177 (91.0%). An association between female FFA and the CYP1B1 risk allele was observed in individuals who reported OCP use (odds ratio, 1.90 [95% CI, 1.50-2.40]; P = 8.41 × 10-8) but not in those with no documented exposure to OCPs (odds ratio, 1.16 [95% CI, 0.82-1.64]; P = .39). A full gene-environment interaction model demonstrated a significant additive statistical interaction between c.1358A, p.453Asn, and history of OCP use on FFA risk (OR for interaction, 1.63 [95% CI, 1.07-2.46]; P = .02). Conclusions and Relevance: This gene-environment interaction analysis suggests that the protective effect of the CYP1B1 missense variant on FFA risk might be mediated by exposure to OCPs. The allele that encodes an asparagine at position 453 of CYP1B1 was associated with increased odds of FFA only in participants with OCP history.

Oral and non-oral lichen planus show genetic heterogeneity and differential risk for autoimmune disease and oral cancer.

Lichen planus (LP) is a T-cell-mediated inflammatory disease affecting squamous epithelia in many parts of the body, most often the skin and oral mucosa. Cutaneous LP is usually transient and oral LP (OLP) is most often chronic, so we performed a large-scale genetic and epidemiological study of LP to address whether the oral and non-oral subgroups have shared or distinct underlying pathologies and their overlap with autoimmune disease. Using lifelong records covering diagnoses, procedures, and clinic identity from 473,580 individuals in the FinnGen study, genome-wide association analyses were conducted on carefully constructed subcategories of OLP (n = 3,323) and non-oral LP (n = 4,356) and on the combined group. We identified 15 genome-wide significant associations in FinnGen and an additional 12 when meta-analyzed with UKBB (27 independent associations at 25 distinct genomic locations), most of which are shared between oral and non-oral LP. Many associations coincide with known autoimmune disease loci, consistent with the epidemiologic enrichment of LP with hypothyroidism and other autoimmune diseases. Notably, a third of the FinnGen associations demonstrate significant differences between OLP and non-OLP. We also observed a 13.6-fold risk for tongue cancer and an elevated risk for other oral cancers in OLP, in agreement with earlier reports that connect LP with higher cancer incidence. In addition to a large-scale dissection of LP genetics and comorbidities, our study demonstrates the use of comprehensive, multidimensional health registry data to address outstanding clinical questions and reveal underlying biological mechanisms in common but understudied diseases.

Evaluation of linear dermatoses by reflectance confocal microscopy in children.

Lichen striatus (LS), linear psoriasis (LPs), linear cutaneous lupus erythematosus (LCLE) and linear lichen planus (LLP) often have similar clinical manifestations, which makes clinical diagnosis with the naked eye difficult; therefore, they are easily misdiagnosed. The purpose of this study was to determine whether reflectance confocal microscopy (RCM) is helpful in differentiating between these four linear dermatoses in children. This retrospective study included 14 patients with LS, nine with LPs, eight with LCLE and 12 with LLP. All patients were analysed using RCM, and biopsies were collected from lesions previously imaged by RCM. For LS, the dermal papillary rings were partially absent, but when present, manifested with small, homogeneously round, bright cells and occasionally highly refractive plump cellular structures, aggregated in clusters. LPs exhibited dark cyst-like structures with small, bright, round cells aggregated at the epidermal level; at the dermal-epidermal junction, homogeneously distributed, enlarged, faint dermal papillary rings and numerous enlarged low-refractive canalicular structures were observed in the superficial dermis. LCLE and LLP exhibited similar manifestations, including epidermal disarray, almost total absence of dermal papillary rings, and various sized refractive structures densely distributed in the dermis. The key distinguishing features of LCLE were the different sized structures mainly clustered around hair follicles, while LLP demonstrated dense structures with a scattered distribution. RCM may be used to distinguish between the key features of LS, LPs, LCLE and LLP in children.

Ocular lichen planus as a cause of recurrent restrictive strabismus.

We report the case of an 80-year-old man with restrictive strabismus in lateral gaze following multiple oculoplastic procedures for idiopathic epiphora. Despite excellent initial response to nasal conjunctival recession with lysis of adhesions and a miminal recession of the medial rectus muscle, the patient suffered recurrence of diplopia associated with limitation of abduction due to aggressive, deep, subconjunctival scarring. Given the history of oral lichen planus (LP), the patient was diagnosed with ocular involvement of LP. He underwent a second conjunctival recession, this time accompanied by an intensive LP treatment regimen. Nine months after surgery, he remained diplopia free and orthophoric in primary gaze. Surgeons treating restrictive strabismus in patients with LP should consider implementing systemic and topical immunosuppressive treatment simultaneously with surgical management.

Squamous Cell Carcinoma Arising in Chronic Inflammatory Dermatoses.

Squamous cell carcinoma (SCC) is a known sequela of chronic inflammatory conditions of the skin. Labial discoid lupus erythema-tosus (DLE), oral lichen planus (OLP), and lichen sclerosus have a relatively short lag time from dermatosis onset to manifestation of malignancy; cutaneous DLE, hypertrophic lichen planus, chronic wounds, hidradenitis suppurativa (HS), and necrobiosis lipoidica can be present for decades before an associated malignancy is observed. Vigilant monitoring is essential for orolabial DLE, chronic HS, and chronic wounds because malignancies in these settings are particularly aggressive and often fatal. We summarize what is known about the nature and demographics of SCC arising within chronic inflammatory dermatoses, emphasizing lag time from dermatosis diagnosis to malignancy onset of common inflammatory conditions.

Post-radiation lichen planus: a case report and review of the literature.

BACKGROUND: Lichen planus is a T-cell mediated inflammatory disorder of the skin and mucus membranes and is a rare complication of external beam radiation. CASE PRESENTATION: 64 year old White male who presented to dermatology with a lesion at the lateral aspect of the right thigh. The lesion was first noted 40 years prior and had grown from 1.5 cm to 6.5 cm in the ensuing years. On examination the lesion was raised, hypopigmented, with pearly borders and central ulceration. Wide excision with lymph node dissection demonstrated invasive squamous cell carcinoma, basaloid type, with negative margins. Patient had radiation therapy of the right inguinal nodes. Patient subsequently noted a "blister" on the right upper thigh, which progressed over time to flat, polygonal, intensely pruritic lesions that covered the right lateral thigh from just distal to the hip to the distal third of the femur (Figs. 1, 2). Skin biopsy was positive for lichen planus. He was started on topical triamcinolone with salutary effects on appearance and pruritus. Fig. 1 Lichen planus, right thigh Fig. 2 Closeup, lichen planus, right thigh, demonstrating polygonal papules CONCLUSION: Once more biopsy-proven cases of post-radiation lichen planus are reported, hopefully the exact mechanism can be elucidated. This may identify risk factors and aid in treatment, with the goal of limiting radiation toxicity and palliation of symptoms that may affect the quality of daily life.

Vulvar Lichenoid Dermatoses With Emphasis on the Distinction Between Lichen Sclerosus and Lichen Planus: A 10-Year Study.

OBJECTIVES: Lichen planus (LP) and lichen sclerosus (LS) are the most common vulvar lichenoid dermatoses. The diagnostic challenges are due to site-specific variation in microscopic appearance and small-sized biopsies. Authentication of diagnostic criteria to distinguish LS and LP to uncover any resemblance or divergence in presentation of these conditions is attempted. METHODS: Cases of vulvar LP and LS diagnosed between January 2012 to December 2022 were included. The clinical details included age, presenting symptoms, examination findings, and other organ involvement. Histopathological analysis of epidermal, dermal, and adnexal findings was done. RESULTS: There were 28 cases of vulvar LP and 72 cases of LS, with a median age of 51 and 60 years, respectively. Depigmentation and atrophy were the major clinical features in LS, whereas ulcers/erosions and erythema were more prevalent in LP with a significantly higher incidence of oral involvement. The most diagnostic feature in LS was diffuse dermal sclerosis (76.8%) and interstitial pattern of inflammation (81.4%), whereas the characteristic features in LP cases was a lichenoid pattern of inflammation (85.7%), necrotic keratinocytes, and lymphocytic exocytosis. In 44.4% of LS, unconventional features like compact orthokeratosis, parakeratosis, thickened/wedge-shaped hypergranulosis, and sawtooth rete pegs were noted. Lichen sclerosus with lichenoid inflammation (21.4%) mimicked LP, from which it was distinguished by presence of thickened or diminished granular layer with basal melanin absence (60%) and dermal homogenization (80%). CONCLUSION: Although the classical, well-established variant of LS poses no diagnostic difficulty, the unconventional variant may mimic LP. Identification of the subtle histological clues demonstrated in this study can help to arrive at the correct diagnosis.

Clinical Characterization and Treatment Response of Folliculitis Decalvans Lichen Planopilaris Phenotypic Spectrum: A Unicentre Retrospective Series of 31 Patients.

Folliculitis decalvans and lichen planopilaris phenotypic spectrum has been described as a form of cicatricial alopecia. The aim of this study is to describe the clinical and trichoscopic features and therapeutic management of this condition in a series of patients. A retrospective observational unicentre study was designed including patients with folliculitis decalvans and lichen planopilaris phenotypic spectrum confirmed with biopsy. A total of 31 patients (20 females) were included. The most common presentation was an isolated plaque of alopecia (61.3%) in the vertex. Trichoscopy revealed hair tufting with perifollicular white scaling in all cases. The duration of the condition was the only factor associated with large plaques (grade III) of alopecia (p = 0.026). The mean time to transition from the classic presentation of folliculitis decalvans to folliculitis decalvans and lichen planopilaris phenotypic spectrum was 5.2 years. The most frequently used treatments were topical steroids (80.6%), intralesional steroids (64.5%) and topical antibiotics (32.3%). Nine clinical relapses were detected after a mean time of 18 months (range 12-23 months). Folliculitis decalvans and lichen planopilaris phenotypic spectrum is an infrequent, but probably underdiagnosed, cicatricial alopecia. Treatment with anti-inflammatory drugs used for lichen planopilaris may be an adequate approach.

TAZ acting as a potential pathogenic biomarker to promote the development of lichen planus.

BACKGROUND: Lichen planus is a chronic inflammatory disorder. Transcriptional coactivator with PDZ-binding motif (TAZ/WWTR1) is an important downstream effector of the Hippo pathway which regulates organ size and tissue homeostasis. But little is known about the role of TAZ in lichen planus so far. OBJECTIVE: To explore the expression of TAZ in lichen planus and normal skin, and to discover the relationship between TAZ expression and the clinical characteristics of lichen planus patients. METHODS: The method of immunohistochemistry was performed to quantify the expression of TAZ in 262 patients with lichen planus and 90 control tissues. Western blot and quantitative real-time reverse transcriptase-PCR (qRT-PCR) analysis were performed to examine and compare TAZ expression in 4 cases of fresh lichen planus lesions and normal skin tissues. RESULTS: TAZ was weakly expressed in the basal layers of the epidermis in normal skin tissues with a positive rate of 52.22% (47/90). But in lichen planus, TAZ was strongly expressed in almost the entire epidermis with a positive rate of 81.30% (213/262), and the difference between the two groups was statistically significant (p<0.05). Additionally, TAZ expression was significantly related to the location of the lichen planus, clinical phenotype, smoking, and alcohol preference (p<0.05). Western blot and qRT-PCR showed that the expression of TAZ in protein and mRNA levels in four cases of lichen planus lesions was significantly higher than that in normal skin tissues. CONCLUSION: TAZ may play a regulatory role in the occurrence and development of lichen planus, which might provide a new perspective for studying pathogenesis and theoretical treatment targets.

Photodynamic therapy for refractory erosive oral lichen planus: a case series study.

Oral lichen planus is a chronic inflammatory disease that occurs on the oral mucosa and is an oral potentially malignant disease. Treatment of oral lichen planus aims to promote healing of the erosion, relieve pain, reduce recurrence of the erosion, and prevent canceration. Corticosteroids are the first line of treatment for oral lichen planus. Refractory oral lichen planus is a clinical classification of oral lichen planus that has not responded to corticosteroid treatment for more than 2 months. Topical 5-aminolevulinic acid-mediated photodynamic therapy is an innovative and effective treatment for potentially malignant oral diseases and has been reported as an alternative treatment to conventional therapies for oral lichen planus. On this basis, we report 3 cases of refractory erosive oral lichen planus in which persistent erosive lesions healed after topical application of 5-aminolevulinic acid-mediated photodynamic therapy without any adverse effects or any signs of recurrence. Topical 5-aminolevulinic acid-mediated photodynamic therapy will become an effective clinical treatment for refractory erosive oral lichen planus.

Esophageal Lichen Planus: A Descriptive Multicenter Report.

GOALS: To better understand the characteristics, treatment approaches, and outcomes of patients with esophageal lichen planus (ELP). BACKGROUND: ELP is a rare, often unrecognized and misdiagnosed disorder. Data on this unique patient population are currently limited to small, single-center series. STUDY: A multicenter, retrospective descriptive study was conducted of adults diagnosed with ELP over a 5-year period, between January 1, 2015, and October 10, 2020, from 7 centers across the United States. RESULTS: Seventy-eight patients (average age 65 y, 86% female, 90% Caucasian) were included. Over half had at least 1 extraesophageal manifestation. Esophageal strictures (54%) and abnormal mucosa (50%) were frequent endoscopic findings, with the proximal esophagus the most common site of stricture. Approximately 20% had normal endoscopic findings. Topical steroids (64%) and/or proton pump inhibitors (74%) dominated management; endoscopic response favored steroids (43% vs. 29% respectively). Almost half of the patients required switching treatment modalities during the study period. Adjunctive therapies varied significantly between centers. CONCLUSIONS: Given its at times subtle clinical and endoscopic signs, a high index of suspicion and biopsy will improve ELP diagnosis, especially in those with extraesophageal manifestations. Effective therapies are lacking and vary significantly. Prospective investigations into optimal treatment regimens are necessary.

Painful refractory erosive tongue lichen planus with malignant transformation.

We present a recent case of long standing erosive tongue lichen planus successfully treated by wide excision and reconstruction with a submental artery island flap. Erosive Lichen Planus is a progressive indolent potentially malignant condition that tends to end up with severe somatic or even neuropathic pain and malignant changes towards its final stages as elaborated in the presented commentary.

Chronic diffuse alopecia in women: a retrospective review of histopathologic diagnoses.

INTRODUCTION: The diseases causing chronic diffuse alopecia and having similar clinical findings, namely chronic telogen effluvium, androgenetic alopecia, and the alopecia with overlapping features, should be differentiated. Recently, diffuse variants of lichen planopilaris have been described with histopathologic features of lichen planopilaris but clinically presenting with diffuse hair loss mostly in an androgenetic pattern. OBJECTIVES: To determine the accurate diagnosis underlying chronic diffuse alopecia in women by evaluating histopathologic findings. PATIENTS AND METHODS: The study included 32 patients with diffuse and clinically noncicatricial alopecia for at least 6 months with no identifiable etiologic factor after general medical history, review of organ systems, and appropriate laboratory tests. Two 4 mm punch biopsies, one from vertex and the other from mid-occiput, were obtained and sectioned transversely. RESULTS: The median age was 30.5 years (range: 22-40 years), and the median duration of hair loss was 4 years (range: 1.5-10 years). The histopathologic diagnosis was androgenetic alopecia, chronic telogen effluvium, and overlapping alopecia in 13 (40.6%), three (9.4%), and four (12.5%) patients, respectively. In the remaining 12 (32.5%) patients, a lichenoid inflammatory reaction affecting the infundibulum and isthmus was noted, and the probable diagnosis of diffuse variant of lichen planopilaris was made. LIMITATIONS: The retrospective nature and the small sample size. CONCLUSION: When the clinical diagnosis is not straightforward and no etiologic factor is found, histopathologic examination is mandatory for the accurate diagnosis of the disorder leading to chronic diffuse alopecia in women.

Immune checkpoint inhibitor-induced lichenoid drug eruption-sparing scar burns.

The authors present a striking case of a patient experiencing a lichenoid drug eruption secondary to immunotherapy, curiously sparing scarred skin from past burns. We observed vastly higher amounts of inflammatory lymphoid cells staining for PD-1; 70% in skin with a lichenoid drug reaction and 50% in scarred skin. The lack of a lichenoid reaction at sites of scarred skin may indicate that a basement membrane component may be causative for a lichenoid drug eruption.

Reflectance confocal microscopy as a complementary diagnostic tool for greyish-brown dermatoses in children.

Mastocytosis, lichen planus pigmentosus (LPP), fixed drug eruption (FDE) and café-au-lait macules (CALM) have a similar appearance, often lead to misdiagnosis and missed diagnoses. At the outpatient clinic at Tianjin Children's Hospital in 21 patients with mastocytosis, 18 with LPP, 11 with FDE and 12 with CALM we evaluated the characteristics and distinguishing features of their dermatoses using reflectance confocal microscopy (RCM). In mastocytosis, the dermal papillary rings generally had a significantly increased bright refractive index and the superficial dermis was filled with moderate refractive flocculent material. In LPP, the dermal papillary rings were absent and numerous different-sized cellular structures were densely distributed in the superficial dermis. In FDE, the dermal papillary rings were intact with a significantly increased bright refractive index. In CALM, normal dermal papillary rings were detected with a uniformly slightly increased refractive index and no obvious abnormality in the superficial dermis. RCM allows for real-time visualization of the major key diagnostic and distinguishing features of four greyish-brown dermatoses in children.

A Systematic Review and Bayesian Network Meta-Analysis of Medical Therapies for Lichen Planopilaris.

BACKGROUND: Lichen planopilaris (LPP) is a primary chronic lymphocytic cutaneous disorder that selectively destroys the hair follicles, resulting in scarring alopecia. Unfortunately, current available treatments are not fully effective to stop hair loss, and the level of evidence for medical interventions is weak. OBJECTIVES: The present article aimed to determine the efficacy of the different medical interventions in LPP through a network meta-analysis (NMA). METHODS: A systematic review and meta-analysis were performed including randomized trials that report the outcomes of lichen planopilaris activity index (LPPAI). These articles were pooled and a NMA was conducted. RESULTS: A total of seven studies were identified and included in meta-analysis, comprising 251 LPP patients. The NMA showed the mean difference in LLPAI was significantly superior with the combination of clobetasol plus N-acetylcysteine (mean difference: -2.0, 95% CI = -3.43 to -0.51) and the combination of clobetasol plus pentoxifylline (mean difference: -1.62, 95% CI = -3.0 to -0.25) compared to the treatment of reference (clobetasol). The NMA showed cyclosporine (mean difference: 2.05 95% CI = 0.68-3.49), methotrexate (mean difference: 1.95 95% CI = 1.23-3.17), the combination of methotrexate plus prednisolone (mean difference: 1.56 95% CI = 0.25-2.96) were significantly worse than hydroxychloroquine according to the differences in LLPAI. CONCLUSION: This work is the first NMA in LPP and hence, it can be helpful in serving as an initial step toward better evidence-based decisions in the treatment of this challenging condition. We propose a triple-combined approach consisting of topical clobetasol, hydroxychloroquine, and N-acetylcysteine as resulted in the most effective approach. Considering the poor outcomes observed with pioglitazone, mycophenolate mofetil, and cyclosporine, it is advisable to contemplate the use of these medications in patients who have not responded adequately to more efficacious alternatives.