Digital Pathology Developments: New Opportunities for Accurate Diagnosis of Primary Cicatricial Alopecias?

Digital Pathology Biopsies

Scarring alopecias—also referred to as primary cicatricial alopecias—are a diverse group of rare disorders that cause irreversible patchy hair loss. There are different types of scarring alopecias, making differential diagnosis challenging.1

As the mechanisms underlying irreversible hair loss remain unclear, there is currently no cure for scarring alopecias, the management of which involves the administration of pharmacological agents to prevent further hair loss and scarring.1

Scarring alopecias have a strong histopathological basis, as they are predominantly caused by the inflammatory destruction of hair follicles. Therefore, the use of new digital tools to mitigate the complexity of histopathological interpretation and enhance research in the histopathology of scarring alopecias may help elucidate the complex mechanisms underlying the destruction of hair follicles, which is key to developing effective treatments.2

Histopathology of scarring alopecias: A group of inflammatory diseases

Despite differences in the histological features, clinical manifestations, and underlying mechanisms among different scarring alopecias, there are also shared histological features across the most common types of scarring alopecia.

Scarring alopecias result from the loss of the bulge immune privilege and extensive inflammatory damage to hair follicles and epithelial hair follicle stem cells (eHFSCs); however, the mechanisms triggering this phenomenon remain unclear. The inflammatory infiltrate is typically found around the bulge region and distal follicle.3

Scarring alopecias are characterized by loss of sebaceous glands and extensive destruction and fibrosis of hair follicles, which lead to irreversible patchy hair loss. Loss of visible follicular ostia and sebaceous glands is accompanied by varying degrees of inflammation. As the disease progresses, the lost epithelium of hair follicles is replaced with scar-like fibrous tissue.2

Other common histological features of scarring alopecias include perifollicular inflammation, extensive desquamation of the inner root sheath, asymmetry of the follicular epithelium, and naked hair shafts.

In contrast to primary cicatricial alopecias, secondary cicatricial alopecias are associated with hair follicle destruction due to radiation, thermal burns, or other types of damage to the scalp skin.1

Role of pathology in diagnosis and management of scarring alopecias

Because of the non-specific clinical signs of alopecia, scalp skin biopsy is the first step of diagnosis in patients with suspected scarring alopecia. Typically, skin biopsies are obtained from areas of the scalp with reduced numbers of hairs and with inflamed hair follicles.1

The observation of vertical sections of scalp skin tissue can reveal inflammatory changes at the dermatoepidermal junction. Such inflammatory alterations are not necessarily seen in horizontal sections; hence, vertical sectioning is preferred for diagnosing scarring alopecias when tissue is limited.2

Hematoxylin and eosin (H&E) is typically used to stain scalp skin tissues for diagnosing scarring alopecias based on the replacement of epithelial tissue in hair follicles with fibrotic tissue. Staining of vertical specimens with Verhoeff-Van Gieson or other elastic stains enables the differentiation of normal dermis and scarred tissues, with the latter lacking elastic fibers.4

Furthermore, staining with periodic acid-Schiff allows the detection of apoptotic cells and thickened basement membrane zone, which are characteristic of scarred tissues.2

Limitations of standard histopathology in diagnosis of scarring alopecias

Inappropriate biopsy site selection, inadequate skin sampling, and inappropriate sample processing and sample orientation at the embedding stage exacerbate the complexity of histopathologic interpretation of skin biopsy images and further complicate disease management.5

Based on the predominant inflammatory cell infiltrate observed in scalp skin biopsies, scarring alopecias can be classified as lymphocytic, neutrophilic, and mixed alopecias. However, the histological features of the different types of scarring alopecias often overlap and may change over time as the disease progresses.2

Therefore, differential diagnosis of different types of scarring alopecias based solely on histopathology can be challenging, especially in the late stages of the disease. For example, although frontal fibrosing alopecia (FFA) and lichen planopilaris (LPP) are two clinically distinct types of scarring alopecias, they are histologically identical.2

Emerging roles and applications of digital pathology in scarring alopecias

Digital pathology is a rapidly advancing field that has opened new avenues for the diagnosis and management of various diseases with histopathological basis, including scarring alopecias.

Digital pathology technologies can be used to comprehensively investigate the clinicopathological characteristics of different types of scarring alopecias and optimize the diagnostic yield of scalp skin biopsies. Additionally, digital tools can be used to identify hair follicles and measure hair shaft diameter to automatically determine the vellus-to-terminal ratio used to identify scarring alopecias types and assess response to treatments.2

Digital technologies can reduce inefficiencies and improve pathology workflows and working practices. Whole-slide imaging (WSI) enables side-by-side comparisons of microscopic slides, as well as high-speed and high-resolution digital analysis of slides. The use of virtual clinicopathological meetings and other digital pathology technologies can also improve the communication between the dermatologist and pathologist, overcoming geographical and time barriers.2

Differential diagnosis of different types of scarring alopecias is challenging. Digital tools can help identify key subtype-specific histological features that are difficult to examine by manual observation of tissue slides under a microscope. For instance, macrophage numbers and polarization seem to differ between LPP and FFA, two alopecia subtypes that are difficult to distinguish based on their histological features.2 Artificial intelligence (AI)-assisted digital tools can be used to accurately determine the number and polarization of macrophages in scalp skin tissues and facilitate the differential diagnosis of LPP and FFA.

Because scarring alopecias are rare conditions, and given that not all patients seek treatment for scarring alopecia, awareness of scarring alopecias among dermatologists and pathologists remains low. Digital technologies can enhance remote learning, thereby increasing awareness of different types of scarring alopecia.2

Challenges and future perspectives

Scarring alopecias are rare, and the histological similarities between types of alopecias make their diagnosis challenging. Although standard histopathology procedures can be used to diagnose and manage scarring alopecia early during the disease course, the histological findings of many alopecia subtypes are subtle and rely on correct sampling and processing techniques.2 Digital pathology may help improve early diagnosis and management of scarring alopecias by accelerating pathology workflows and improving diagnostic accuracy.

Nonetheless, average review times can be longer with WSI than with light microscopy, and optimized ways to store and share large WSI files are warranted.6 Additionally, molecular markers of different types of scarring alopecia are currently lacking. Establishing such biomarkers may help maximize the benefits of using digital pathology for scarring alopecias.


References

  1. Filbrandt R, Rufaut N, Jones L, Sinclair R. Primary cicatricial alopecia: diagnosis and treatment. C Can Med Assoc J = J l’Association medicale  Can. 2013;185(18):1579-1585. doi:10.1503/cmaj.111570
  2. Cummins DM, Chaudhry IH, Harries M. Scarring Alopecias: Pathology and an Update on Digital Developments. Biomedicines. 2021;9(12). doi:10.3390/biomedicines9121755
  3. Harries MJ, Paus R. The pathogenesis of primary cicatricial alopecias. Am J Pathol. 2010;177(5):2152-2162. doi:10.2353/ajpath.2010.100454
  4. Elston D, McCollough M, Warschaw K, Bergfeld W. Elastic tissue in scars and alopecia. J Cutan Pathol. 2000;27:147-152. doi:10.1034/j.1600-0560.2000.027003147.x
  5. Ranjan R, Singh L, Arava SK, Singh MK. Margins in skin excision biopsies: principles and guidelines. Indian J Dermatol. 2014;59(6):567-570. doi:10.4103/0019-5154.143514
  6. Shi W, Georgiou P, Akram A, et al. Diagnostic Pitfalls of Digital Microscopy Versus Light Microscopy in Gastrointestinal Pathology: A Systematic Review. Cureus. 2021;13(8):e17116. doi:10.7759/cureus.17116

 

Christos received his Masters in Cancer Biology from Heidelberg University and PhD from the University of Manchester.  After working as a scientist in cancer research for ten years, Christos decided to switch gears and start a career as a medical writer and editor. He is passionate about communicating science and translating complex science into clear messages for the scientific community and the wider public.

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