Unravelling the Complexities of Atypical Alopecia: The Significance of Scalp Biopsies in Accurate Diagnosis and Personalized Treatment

Abstract

Androgenetic alopecia is chronic and progressive hair loss, but atypical presentations like diffuse pattern alopecia (DUPA) and retrograde alopecia can pose diagnostic challenges. This review explores the nuances of these conditions, highlighting the potential for overlapping etiologies and the limitations of relying solely on clinical examination. The critical role of scalp biopsies in differentiating between AGA, scarring alopecias, and other dermatological conditions is emphasized. This review aims to empower clinicians to make informed decisions and optimize treatment strategies for patients with complex hair loss patterns by providing a comprehensive understanding of the diagnostic process.

Keywords

Androgenetic alopecia, diffuse unpatterned alopecia (DUPA), retrograde alopecia, scalp biopsy, scarring alopecia.

Introduction

Hair loss is a common concern affecting millions of people worldwide. While androgenetic alopecia (AGA) is the most prevalent form, defined by the progressive miniaturisation of follicles in androgen-dependent regions in androgen-dependent regions1Atypical presentations of alopecia such as diffuse pattern alopecia (DUPA) and its variants  can present diagnostic and therapeutic challenges. These conditions may mimic or coexist with other forms of alopecia, including scarring alopecias like lichen planopilaris (LPP) and its variant can pose diagnostic challenges due to their ability to mimic other hair loss conditions.1,2 This review aims to provide an overview of atypical alopecias, highlighting the importance of scalp biopsies in differentiating between various etiologies and guiding personalized treatment strategies.

2. Androgenetic Alopecia (AGA): The Common Denominator

Androgenetic Alopecia (AGA) is the most common form of hair loss in both men and women characterized by gradual follicular miniaturization due to androgens acting on generally susceptible hair follicles miniaturization due to androgens acting on genetically susceptible hair follicles 3,4.The primary androgen involved is dihydrotestosterone (DHT), converted from testosterone by 5α-reductase in the dermal papilla. AGA has a Polygenic inheritance pattern with major risk loci identified on the X-chromosome and chromosome 20p115. In women, AGA presents as female pattern hair loss, with thinning in the central scalp while preserving the frontal hairline4.While the exact pathogenesis remains unclear the interplay between genetic predisposition and androgens is crucial in AGA development 3,5.

3. Atypical Alopecia Patterns:

3.1 Diffuse Pattern Alopecia (DUPA):

Diffuse Pattern Alopecia (DUPA) encompasses various forms of hair loss, including androgenetic alopecia in both males and females. Female Pattern hair loss (FPHL) is the primary causes of hair loss in adult women, characterized by reduced hair density over the mid-frontal scalp and crown 6. Interestingly, FPHL can also affect a small subset of men, presenting as a distinct clinical variant of androgenetic alopecia 7 the pathogenesis of these conditions involves genetic, hormonal, and environmental factors leading to progressive follicular miniaturization6.Diagnosis can be challenging, as FPHL telogen effluvium and diffuse alopecia areata may have similar clinical manifestations. Careful examination, dermoscopy and sometimes scalp biopsy are necessary for accurate diagnosis8. Treatment options have expanded beyond FDA-approved modalities like topical minoxidil and oral finasteride, with combination therapies showing promise in managing these conditions 9 7

1. 2. Retrograde Alopecia:

Retrograde alopecia refers to hair loss that begins at the nape of the neck and progresses upward, often associated with androgenic alopecia (AGA). Retrograde prevalence increases with AGA severity and can impact hair transplantation eligibility 10. AGA involves multifactorial mechanisms, including microinflammation, which may contribute to treatment resistance. This chronic, low-grade inflammation is characterized by perifollicular infiltrates and fibrosis in the upper follicle region. AGA progression is marked by shortened anagen phase and follicular miniaturization 11. Diagnosis of hair loss disorder requires careful consideration of various factors, including genetic predisposition, endocrine influences and immune processes. Treatment approaches should be tailored to the specific underlying mechanism of each hair loss condition.12

4. The Significance of Scalp Biopsies in Diagnosing Atypical Alopecia

4.1 Distinguishing Between AGA and Atypical Patterns:

Scalp biopsies play a crucial role in differentiating between various types of alopecia, particularly when clinical examination and patient history are inconclusive. Horizontal sections of scalp biopsies allow for quantitative and morphometric analysis of hair follicles, providing valuable insights into distinguishing androgenetic alopecia (AGA) from alopecia areata (AA). Key histological features AA over AGA include lower anagen:non-anagen hair ratio, presence of pigment casts, and peribulbar inflammation 13. While clinical presentation and dermoscopy can help identify diffuse alopecia pattern, scalp biopsies remain essential for definitive diagnosis in challenging cases8.Immunohistochemical analysis can further aid in differentiating AA from AGA, especially in cases with diffuse patterns in androgen-dependent areas 14. The importance of biopsies is underscored by the prevalence of alopecia pattern mimicry, which can complicate clinical diagnosis and management.

4.2 Identifying Scarring Alopecias:

Scarring alopecias, including Lichen planopilaris (LPP), are characterized by irreversible hair follicle destruction leading to permanent hair loss. Early diagnosis and treatment are crucial to halt progression. Scalp biopsies are essential for accurate diagnosis and classification 15. Key histological features of LPP include absence of arrector pili muscles and sebaceous glands, perifollicular lymphocytic infiltrate, and superficial wedge-shaped scarring 16.Frontal fibrosing alopecia (FAA), a variant of LPP may show deeper perifollicular inflammation 17. Primary cicatricial alopecias are classified as lymphocytic, neutrophilic or mixed based on the inflammatory infiltrate 18. Treatment options include immunomodulatory, immunosuppressive or anti-infectious agents, depending on the specific diagnosis. Multiple biopsies may be necessary due to similar clinical presentations among different scarring alopecias 18.

4.3 Ruling Out Other Dermatological Conditions:

Scalp biopsies play a crucial role in diagnosing hair loss and ruling out various dermatological conditions. They are essential for confirming diagnoses, especially in cases of cicatricial alopecia 19. The biopsy process involves careful site selection, optimal technique and proper specimen processing, followed by informed histological interpretation 20. However, biopsies are rarely needed in children for hair loss condition 21. A comprehensive approach to diagnosing hair loss includes a thorough clinical history physical examination, laboratory tests, and the use of dermoscopy or trichoscopy 21 22. This approach helps differentiate between congenital and acquired hair loss, as well as focal versus diffuse and scarring versus nonscarring types 21, Early diagnosis and appropriate treatment are crucial for managing the emotional and social impact of hair loss on patients.22

4.4 Procedure and Interpretation:

A scalp biopsy is a valuable diagnostic tool for hair and scalp disorders, particularly in differentiating between scarring and non-scarring alopecias 23. The procedure typically involves obtaining one or two 4-mm punch biopsies, which are then sectioned horizontally or both horizontally and vertically 24. Horizontal sections are preferred as they allow for follicular counts and ratios, crucial for diagnosing non-scarring alopecia and detecting focal changes in scarring alopecia. This histopathological interpretation requires expertise due to the complexity of follicular structures in different hair cycle stages. Successful evaluation depends on careful biopsy site selection, optimal technique and proper specimen processing 20. Accurate interpretation necessitates both qualitative (morphology, inflammation, fibrosis) and quantitative is essential requiring clinicians to provide relevant patient information and clinical differential diagnosis.25

5. Current Practices and Potential Biases

5.1 Gender Bias in Biopsy Practices:

Androgenetic Alopecia (AGA) is a prevalent form of hair loss affecting both cisgender and transgender individuals. Gender-affirming hormone therapy significantly impacts AGA incidence, with transgender patients receiving masculinizing treatment showing 2.5 times higher rates compared to cisgender women 26.

5.2 Impact of Bias on Diagnosis and Treatment:

Gender Bias can significantly impact the diagnosis and treatment of alopecia in both men and women. Research shows that female patients are more likely to be misdiagnosed as “overanxious” even with positive test results. Potentially leading to delayed or inappropriate treatment 27.

6. Treatment Strategies for Atypical Alopecia

6.1 Addressing Underlying Causes:

Treatment for atypical alopecia should be tailored to the underlying cause.

6.2 Medical Therapies:

Medical therapies commonly used for AGA, such as finasteride and minoxidil, may also be effective for some cases of atypical alopecia. However, their efficacy may vary depending on the specific etiology.28

6.3 Surgical Options:

Hair transplantation may be an option for individuals with stable hair loss due to atypical alopecia. However, careful patient selection is crucial to ensure successful outcomes.29

6.4 Emerging Therapies:

Emerging therapies, such as platelet-rich plasma (PRP) and stem cell-based treatments, hold promise for the treatment of various forms of alopecia. However, further research is needed to determine their efficacy and safety.30

7. CONCLUSION

Atypical alopecia patterns, including DUPA and retrograde alopecia. It can present diagnostic and therapeutic challenges. Scalp biopsies play a crucial role in differentiating between AGA, scarring alopecias, and other dermatological conditions, guiding personalized treatment strategies. Clinicians should be aware of potential biases in biopsy practices and consider scalp biopsies in all patients with unexplained or atypical hair loss. By embracing a comprehensive diagnostic approach, we can improve outcomes for individuals with complex hair loss patterns. Further research is needed to elucidate the underlying mechanisms of atypical alopecias and develop more effective therapies.

REFRENCES

1. Okwundu N, Ekpo F, Ghaferri J, Fivenson D. Atypical Presentation of Lichen Planopilaris: Presentation of Two Cases and Review. J Clin Res Dermatol. 2020 Mar 16;7(1):1–5.
2. Yoo LJH, Meah N, Wall D, McDonald I. Diffuse Lichen Planopilaris Masquerading as Diffuse Alopecia Areata. Case Rep Dermatol. 2024 Mar 25;16(1):83–7.
3. Abdelkader A, Y. Abdallah I, Abdeen A, E. Ibrahim S. ANDROGENETIC ALOPECIA: AN OVERVIEW. Benha J Appl Sci. 2024 Feb 26;9(2):37–50.
4. Price VH. Androgenetic Alopecia in Women. J Investig Dermatol Symp Proc. 2003 Jun;8(1):24–7.
5. Lolli F, Pallotti F, Rossi A, Fortuna MC, Caro G, Lenzi A, et al. Androgenetic alopecia: a review. Endocrine. 2017 Jul;57(1):9–17.
6. Ramos PM, Miot HA. Female Pattern Hair Loss: a clinical and pathophysiological review. An Bras Dermatol. 2015 Aug;90(4):529–43.
7. Kerkemeyer KL, De Carvalho LT, Jerjen R, John J, Sinclair RD, Pinczewski J, et al. Female pattern hair loss in men: A distinct clinical variant of androgenetic alopecia. J Am Acad Dermatol. 2021 Jul;85(1):260–2.
8. Werner B, Mulinari-Brenner F. Clinical and histological challenge in the differential diagnosis of diffuse alopecia: female androgenetic alopecia, telogen effluvium and alopecia areata - part I. An Bras Dermatol. 2012 Oct;87(5):742–7.
9. Sharma A, Shirolikar M, Mhatre M. Managing patterned hair loss – a hair raising task! Cosmoderma. 2021 Oct 9;1:55.
10. Mohamed A, Al Khalawany M, Abdalkarim I. Retrograde Alopecia: Prevalence, Patterns, Dermoscopic Features among Egyptian Men: A Cross Sectional Study. Int J Med Arts. 2023 May 1;5(5):3286–90.
11. Chew EGY, Ho BS ?Y., Ramasamy S, Dawson T, Tennakoon C, Liu X, et al. Comparative transcriptome profiling provides new insights into mechanisms of androgenetic alopecia progression. Br J Dermatol. 2017 Jan;176(1):265–9.
12. Wolff H, Fischer TW, Blume-Peytavi U. The Diagnosis and Treatment of Hair and Scalp Diseases. Dtsch Ärztebl Int [Internet]. 2016 May 27 [cited 2025 Feb 17]; Available from: https://www.aerzteblatt.de/10.3238/arztebl.2016.0377
13. Yadav D, Khandpur S, Ramam M, Singh MK, Sharma VK. Utility of Horizontal Sections of Scalp Biopsies in Differentiating between Androgenetic Alopecia and Alopecia Areata. Dermatology. 2018;234(3–4):137–47.
14. Kamyab K, Rezvani M, Seirafi H, Mortazavi S, Teymourpour A, Abtahi S, et al. Distinguishing immunohistochemical features of alopecia areata from androgenic alopecia. J Cosmet Dermatol. 2019 Feb;18(1):422–6.
15. Tandon YK, Somani N, Cevasco NC, Bergfeld WF. A histologic review of 27 patients with lichen planopilaris. J Am Acad Dermatol. 2008 Jul;59(1):91–8.
16. Tandon YK, Somani N, Cevasco NC, Bergfeld WF. A histologic review of 27 patients with lichen planopilaris. J Am Acad Dermatol. 2008 Jul;59(1):91–8.
17. Wong D, Goldberg LJ. The depth of inflammation in frontal fibrosing alopecia and lichen planopilaris: A potential distinguishing feature. J Am Acad Dermatol. 2017 Jun;76(6):1183–4.
18. Abal-Díaz L, Soria X, Casanova-Seuma JM. Alopecias cicatriciales. Actas Dermo-Sifiliográficas. 2012 Jun;103(5):376–87.
19. Jackson AJ, Price VH. How to Diagnose Hair Loss. Dermatol Clin. 2013 Jan;31(1):21–8.
20. Knopp E. The scalp biopsy for hair loss and its interpretation. Semin Cutan Med Surg. 2015 Jun;34(2):57–66.
21. Castelo-Soccio L. Diagnosis and management of hair loss in children. Curr Opin Pediatr. 2016 Aug;28(4):483–9.
22. Ahanogbe I, Gavino ACP. Evaluation and Management of the Hair Loss Patient in the Primary Care Setting. Prim Care Clin Off Pract. 2015 Dec;42(4):569–89.
23. Miteva M. Scalp Biopsy in Hair Disorders. In: Grimalt R, editor. Techniques in the Evaluation and Management of Hair Diseases [Internet]. 1st ed. CRC Press; 2021 [cited 2025 Feb 19]. p. 62–70. Available from: https://www.taylorfrancis.com/books/9781000348200/chapters/10.1201/9780367855147-7
24. Miteva M. Hair Pathology. In: Alopecia [Internet]. Elsevier; 2019 [cited 2025 Feb 19]. p. 23–41. Available from: https://linkinghub.elsevier.com/retrieve/pii/B9780323548250000028
25. Sperling LC. Scarring alopecia and the dermatopathologist. J Cutan Pathol. 2001 Aug;28(7):333–42.
26. Gao JL, Sanz J, Tan N, King DS, Modest AM, Dommasch ED. Androgenetic alopecia incidence in transgender and gender diverse populations: A retrospective comparative cohort study. J Am Acad Dermatol. 2023 Sep;89(3):504–10.
27. Elderkin-Thompson V, Waitzkin H. Differences in clinical communication by gender. J Gen Intern Med. 1999 Feb;14(2):112–21.
28. Kassira S, Korta DZ, Chapman LW, Dann F. Review of treatment for alopecia totalis and alopecia universalis. Int J Dermatol. 2017 Aug;56(8):801–10.
29. Rousso DE, Kim SW. A Review of Medical and Surgical Treatment Options for Androgenetic Alopecia. JAMA Facial Plast Surg. 2014 Nov;16(6):444–50.
30. Gupta AK, Renaud HJ, Rapaport JA. Platelet-rich Plasma and Cell Therapy. Dermatol Clin. 2021 Jul;39(3):429–45.