Hypopigmented Macules

Etiology

Hypopigmented conditions are mostly acquired, rarely congenital.

Congenital conditions include;

• Albinism- Autosomal recessive inheritance
• Piebaldism- Autosomal dominant inheritance[2]
• Hypomelanosis ito (chromosomal defects)

A few of the etiologies associated with acquired hypopigmented conditions are discussed below; 

• Normal aging- Idiopathic guttate melanosis (IGH)
• Environmental factors (cumulative sun exposure and microtrauma)- IGH
• Nutritional deficiencies- Kwashiorkor (a severe protein malnutrition condition), vitamin B12 deficiency, copper and iron deficiency 
• Inflammatory causes- Pityriasis alba (association with atopic dermatitis)
• Vascular causes (venous congestion)- Bier's spots
• Autoimmune causes- Vitiligo, hypopigmented sarcoidosis
• Infectious causes-  1. fungal by Malassezia species- Pityriasis versicolor, 2. bacterial infection by Propionibacterium acne- Progressive macular hypomelanosis (PMH), Mycobacterium leprae - Leprosy, and Treponema pallidum - Leukoderma syphiliticum, 3. protozoal by post-kala-azar dermal leishmaniasis, 4. postviral exanthem- Eruptive hypomelanosis
• Chemical inflammation- Lead-based cosmetics, skin bleaching agents like hydroquinone, etc 
• Post-inflammatory changes- Secondary to any cutaneous inflammatory conditions (eg., lichen striatus, atopic dermatitis), infections (eg., Tinea versicolor, Herpes Zoster, Syphilis), procedures (eg., cryotherapy, dermabrasion) and miscellaneous causes (eg., burns) [3]
• Malignancy- Hypopigmented mycosis fungoides, the tumor of follicular infundibulum
• Inherited conditions- Ash leaf spots in tuberous sclerosis

Epidemiology

Hypopigmentation macules are very common (in both children and adults), seen in at least 1 out of 20 people.[4][5] The prevalence of various hypomelanotic conditions depends on patient demographics (age, sex, race), geography, family history, and exposure to environmental factors. For example, P. alba is more prevalent (90%) in the pediatric age group(<16 years), P.versicolor more prevalent in adolescents and young adults, IGH is more prevalent (80% to 87%) in the adult age group (> 40 years), and vitiligo can affect anyone from a toddler to elderly people. P.alba shows slight male predominance, whereas P.versicolor affects both sexes equally. 

Hansen's disease is more prevalent in developing countries; more than 75% of leprosy cases in the United States are contributed by immigrants. P.alba is often seen in patients with a family history of atopic dermatitis.

Pathophysiology

The pathogenic mechanism is different in various conditions associated with hypomelanosis. Pathophysiology for a few are discussed below:

1. Pityriasis alba - There is no proven cause identified. Most studies suggest that UV light exposure has a causal relationship. UV radiation affects the function of active melanocytes, thereby altering the synthesis of melanin.

2. Pityriasis/Tinea versicolor - Malassezia is a common commensal of healthy skin transforms into a pathogenic (filamentous) form. Factors that contribute to pathogenic conversion are genetic predisposition, environment conditions (heat, humidity), oily skin, and application of oily creams or lotions.[6] The pathogenic form metabolizes fatty acids on the skin, release azelaic acid and other metabolites. Azelaic acid inhibits the dopa-tyrosinase enzyme, which is the rate-limiting enzyme for melanin synthesis, thereby causing hypopigmentation skin lesions.

3. Idiopathic guttate hypomelanosis [IGH] - The predominant involvement of sun-exposed areas in IGH raises suspicion of UV light as a primary factor affecting melanin synthesis. Few studies also suggest that IGH has a positive association with HLA DQ3, repeated microtrauma, and autoimmunity.[7] Histopathologic correlation like structural abnormalities of melanocytes, defective keratinocyte uptake, and decrease melanosomes help to understand the pathogenic mechanisms involved in developing hypopigmented macules in IGH.[8]

4. Vitiligo - Multiple pathogenic mechanisms were proposed. T cell-induced melanocyte apoptosis, autoantibodies to components of melanocytes leads to decreased melanin production and thereby causing hypopigmentation. 

5. Albinism - This is an autosomal recessive disease, associated with a deficiency of tyrosinase enzyme (the rate-limiting enzyme in melanin synthesis). The severity of clinical features depend on the mutation involved.[9]

6. Halo nevus - Based on histopathological findings, the abundance of Langerhans cells in the area of the lesion is responsible for hypopigmentation. This condition is benign. Some also argue that the halo nevus condition has an association with vitiligo.[9]

8. Post-inflammatory hypopigmentation - This condition is associated with trauma or exposure to chemicals (cleaning agents, chemicals used to remove tattoos, or for cosmetic purposes). The pathogenesis in this condition is related to melanocyte injury resulting in decreased melanin, which in turn causes hypopigmented or depigmented patches. Post-inflammatory conditions can also be associated with hyperpigmentation.

9. Ash leaf spots - These are the cutaneous findings associated with the neurocutaneous disorder. The presence of three or more ash leaf spots should raise suspicion of tuberous sclerosis.

Histopathology

Histopathological findings are occasionally required for diagnosis. They are useful in evaluating the underlying pathophysiology to determine the right diagnosis. It gives an overview of the presence of melanin, melanocytes, changes in epidermal cells like acanthosis, hyperkeratosis, parakeratosis, epidermotropism, spongiosis, perivascular lymphocytic infiltrate, etc. A few of the classic histopathologic features of hypomelanotic conditions are spaghetti meatball appearance in

Tinea versicolor, pautrier microabscesses in HMF, absence of melanocytes in vitiligo., decrease in DOPA positive melanocytes (active melanocytes) in IGH, dilated follicular infundibula connected to each and to the overlying epidermis in the tumor of the follicular infundibulum (infundibulomatosis), and many more. Histopathological findings are also useful to determine the status of the disease, e.g., active or inactive stage of vitiligo.[10][11] Immunohistochemical staining can be used to evaluate the peculiar characteristics of cells (like CD4 and CD8 infiltration) in the epidermis.

History and Physical

The differentiation of various hypopigmented conditions is not always possible solely based on the clinical findings of the lesion. A detailed history of the patient, including personal, occupational, and family history, gives a clue about the etiology and severity (inherited/ acquired, benign/malignant) of the condition. The patients, at times, may have extracutaneous signs and symptoms, and a complete physical examination from head to toe is vital to make the right diagnosis. The following questionnaire and examination findings may be useful to evaluate the patients with hypopigmentation macules.  

1. Is the skin lesion present since birth or acquired?

2. If acquired, is it sudden or gradual in onset?

3. Any history of prior inflammation, or exposure to chemical substances?

4. Is the hypopigmentation localized or diffuse?

5. Location of the lesions - which areas are predominantly affected? (sun-exposed areas, or body-folds like axilla, or under the breast)

6. Characters of lesion - this includes:

• Size of the lesions
• Margins-well circumscribed or ill-defined
• Appearance- scaly/non-scaly
• Pattern of distribution
• Unilateral or bilateral
• Stable or progressive 
• Any coalesce of lesions
• Any changes in color
• Any history of pruritus or signs of excoriation
• Any history of prior inflammation, or exposure to chemical substances?
• Any change in the characteristics of lesions due to weather conditions?
• Surrounding skin characteristics

Evaluation

A systematic approach should be followed to reach the right diagnosis.

• Wood's lamp examination - This is used for better visualization of skin lesions to differentiate pigment abnormalities (especially hypopigmented lesions from depigmented lesions). This is done in a darkened room using a Wood's lamp that emits long-wave UVA (Ultraviolet light A) with a wavelength of approximately 365 nm.[12] The light source should be held at 4 to 5 inches away from the skin surface. Normal skin does not fluoresce. Depigmented lesions (eg., vitiligo) and hypopigmented lesions with decreased melanin production are markedly enhanced, appear bright white whereas, hypopigmented lesions with normal melanin (IGH, PMH) are not accentuated. A few of the characteristic features of Wood's lamp examination are orange fluorescence in P. versicolor, red fluorescence localized to follicles in PMH, bright blue-white fluorescence in Vitiligo, etc.[13] Wood's lamp is also used to perform a meticulous search for the presence of more hypopigmented lesions when a patient presents with a single lesion.[14]
• Dermatoscopy - This refers to the skin examination using a skin surface microscope, especially used to evaluate pigment abnormalities of the skin. Dermoscopic findings give details about- nature of pigmentation, edges of the lesion (well-defined/ ill-defined), the appearance of lesions (scaly/ non-scaly), perifollicular hyperpigmentation (seen in Vitiligo), presence of telangiectasia, and characteristics of the surrounding skin.[15]
• KOH mount of skin scrapings - This test is useful to quickly identify fungal infections like Tinea versicolor (Spaghetti and meatball appearance of hyphae) in outpatient settings. The specimen is prepared by adding one drop of 10% KOH to skin scrapings and examining it under the microscope.[16]
• Skin Biopsy - Although skin biopsy gives accurate diagnosis in most conditions, this is not routinely performed; it is used only when the diagnosis is unclear or suspecting infectious causes like leprosy, sarcoidosis, or underlying malignancy. Tissue biopsy is processed and studied under a microscope using various stains like hematoxyline and eosin, Fontana Masson, or Melanin-A stains. Immunofluorescence studies on the specimen could be performed for the presence of antibodies, and infiltration of lymphocytes into the epidermis, etc.[17]
• Electron Microscopy - This is not commonly available in clinical settings, and physicians should rely on other clinical findings. Electron microscopic study of skin lesion gives an insight into ultrastructural details of the lesion and helps differentiate the causes for hypomelanosis. For example, clinical differentiation of ash leaf spots (ALS), a common presentation in the pediatric age group from nevus depigmentosus (ND), is challenging even based on histopathologic findings. The findings under electron microscopy show a decrease in melanosome transfer to keratinocytes in ND, and reduced size and melanization of melanosomes result in the formation of aggregates in keratinocytes in ALS.[5]

Treatment / Management

The management of hypopigmented macules depends on the underlying pathophysiology. Successful repigmentation is often possible with timely diagnosis, removal of offending agents (chemicals, infectious agents), avoiding exposure to sunlight, using sunscreen, and appropriate therapeutic treatment. Repigmentation might not be possible in the congenital/ inherited conditions (associated with chromosomal defects). Therapeutic treatment helps to fasten the process of repigmentation. Repigmentation is achieved by medications, phototherapy, and surgical procedures.

Medications - There are topical and systemic medications. 

• Topical corticosteroids - Low dose corticosteroids are used as first-line drugs in many hypopigmented conditions. They are known to accelerate the repigmentation process. Their use, along with phototherapy, also has great outcomes. Systemic corticosteroids are rarely used to treat hyperpigmentation, for e.g., in vitiligo, to halt the rapid progression of skin lesions.
• Topical calcineurin inhibitors - These are topical immunomodulatory agents (tacrolimus, pimecrolimus), also used as first-line medication. Tacrolimus inhibits the synthesis and release of proinflammatory cytokines, thereby protecting melanocytes from the effects of T-cell and mast-cells. In contrast to topical steroids, tacrolimus does not cause skin atrophy and striae, preferred for treating facial hypomelanosis conditions.
• Vitamin D - The current literature reviews that vitamin D has an association with skin pigmentation. Vitamin D increases melanogenesis by increasing the tyrosinase content in melanocytes by the anti-apoptotic effect.[18]
• Antifungals - These are used in treating Tinea versicolor infection, available in both topical and systemic forms. Topical agents are often used for weeks to months; include selenium sulfide shampoo, 1% or 2% ketoconazole ointment, zinc pyrithione. Oral medications like fluconazole, itraconazole are used for a short duration of therapy.
• Oral isotretinoin- This is used to treat conditions like PMH in which propionibacterium acne is the underlying cause.[13]  
• Emollients - Used to provide a soothing effect in pruritic and scaly skin lesions.
(B3)

Phototherapy - This includes narrow-band ultraviolet B (NBUVB) and psoralen ultraviolet A (PUVA). NBUVB is superior and preferred over PUVA in treating vitiligo. PUVA has comparatively more adverse effects because of the systemic use of psoralen. PUVA is contraindicated in children and pregnant women.[19](A1)

Surgical Procedures - skin grafting, split skin grafting are practiced in treating some localized depigmented and inherited hypopigmented conditions.

Differential Diagnosis

• Some of the common differential diagnoses for hypopigmented macules include P.  alba, P. versicolor, IGH, vitiligo, PMH, post-inflammatory inflammation, and halo nevus.
• P. alba usually is seen in the pediatric age group, patients often have a history of atopic dermatitis, whereas P. versicolor is more prevalent in the adolescent age group, warm and humid conditions, and lesions are predominantly distributed in seborrheic areas (trunk, neck, and arms).[6]
• IGH is more prevalent in the elderly and is hinted by a history of chronic exposure to sunlight and repetitive microtrauma. Lesions usually do not coalesce.
• It is important to differentiate these conditions because the management and prognosis vary. Complete history (family history and any history of autoimmune diseases), physical examination, and areas of distribution of hypopigmented patches help in determining the right diagnosis. Dermoscopy can aid in differentiating vitiligo from other vitiligo-like conditions. Vitiligo patches usually show residual perifollicular pigmentation, which is absent in other conditions. Vitiligo, at times, could be confused with chemical leukoderma and vitiligo-like depigmentation in oncology patients treated with immunotherapy for non-melanoma metastatic cancers.[20]
• Diagnosing hypopigmented mycosis fungoides (HMF) is usually delayed in children (although it is rare), as it is often mistaken with other hypomelanosis conditions like Pityriasis, eczema, vitiligo, PMH, etc. A high rate of suspicion and skin biopsy is required for accurate diagnosis of HMF, and tumor of follicular infundibulum.[21]

Prognosis

Most of the conditions associated with hypopigmentation are benign in nature and have an excellent prognosis. Often, repigmentation can be achieved with prompt diagnosis and treatment. However, the prognosis is not great in inherited conditions. Prognosis in hypomelanosis associated with underlying malignancy differs with the time of diagnosis, as most of them are mistaken for benign conditions like P.alba, IGH resulting in delayed treatment.

Complications

1. Malignancy - Most of the hypopigmented macules lack melanin in the affected area, thereby more prone to the harmful effects of UV radiation on keratinocytes and melanocytes. This renders them more susceptible to skin cancers than the general population. Patients are advised to minimize sun exposure and use sunscreen.

2. Systemic Disorder - Diagnosing the underlying root cause is important to treat the disease condition promptly and to improve the overall health rather than just treating hypomelanosis. For example, the presence of ash leaf spots indicates the possibility of neurocutaneous disorder (tuberous sclerosis).

3. Psychological Impact - This includes anxiety, stress, or depression that could affect an individual with hypopigmented skin lesions.