Hypopigmented macules are one of the most common skin lesions encountered in clinical practice. The word hypopigmentation indicates decreased pigmentation, which means significantly reduced melanin compared to the normal skin. This should not be confused with the word depigmentation, which is an indicator of the complete absence of melanin due to the significant loss of melanocytes. Clinically, it is challenging to differentiate hypopigmented disorders from depigmented disorders.
It is important to understand the difference between these conditions since the treatment and prognosis often differ. Hypomelanosis is often benign, may be associated with the function of internal viscera, and rarely associated with malignancy. One of the frequent reasons to seek treatment is the cosmetic appearance, which can cause stress and social stigma (especially in dark-skinned people) in the patients. Repigmentation can be achieved in some cases by the right diagnosis and prompt treatment. A detailed history, clinical signs along with wood's lamp examination, and dermoscopy help in making the right diagnosis. Apart from these, a skin biopsy histopathological findings provide additional information to understand the underlying pathogenesis. This article briefly reviews the common disease conditions associated with hypopigmented macular lesions (size less than 0.5 cm) and patches (more than 0.5cm). A brief idea of the anatomy of the skin and the mechanism of skin pigmentation is important to understand the pathogenesis and histologic findings of hypopigmentation disorders.
Anatomy of the Skin- Skin is the largest organ in the body and is made up of three layers- epidermis, dermis, and hypodermis. The epidermis is again divided into five layers. They are Stratum basal (the deepest layer of the epidermis), S.spinosum, S.granulosum, S.lucidum, and S.corneum (most superficial layer of the epidermis; normally, cells in this layer do not contain any nuclei). Stratum lucidum is present only in the areas of thick skin (eg., palms of hand).
Mechanism of skin pigmentation- It is mainly regulated by keratinocytes and melanocytes present in the basal layer of the epidermis. Melanocytes are embryologically derived from neural crest cells, and their migration to skin and hair is regulated by various transcription factors and signaling pathways. Melanocytes produce a brown pigment - melanin, which protects the skin from potentially harmful UV radiation present in sunlight. Exposure to UV light could potentially cause defects in the DNA of keratinocytes. This leads to overexpression of the P53 gene resulting in increased transcription of the POMC gene (proopiomelanocortin), thereby increasing the synthesis of POMC protein. The POMC protein is cleaved into ACTH and alpha MSH. Alpha MSH binds to the G-protein receptor (MC1R) on melanocyte, activates adenyl cyclase, and mitogen-activated protein (MAP). In turn, this results in the production of eumelanin, tyrosinase, and tyrosinase-related protein. The tyrosinase enzyme converts tyrosine into DOPA and melanin.
Tyrosinase is the rate-limiting enzyme for melanogenesis. Melanin is then packed in melanosomes (lysosome-like organelles) and is transferred to keratinocytes through protease-activated receptors. As the skin ages, the keratinocytes move from the basal to superficial layer along with these ingested melanosomes, which give the brownish tint to the skin. There are two kinds of melanin- pheomelanin and eumelanin. Pheomelanin is predominant in fair-skinned people and eumelanin in dark-skinned people. Eumelanin protects the skin against UV radiation better than pheomelanin.
Hypopigmented conditions are mostly acquired, rarely congenital.
Congenital conditions include;
A few of the etiologies associated with acquired hypopigmented conditions are discussed below;
Hypopigmentation macules are very common (in both children and adults), seen in at least 1 out of 20 people. 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.
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. 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. 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.
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.
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.
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.
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. Immunohistochemical staining can be used to evaluate the peculiar characteristics of cells (like CD4 and CD8 infiltration) in the epidermis.
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:
A systematic approach should be followed to reach the right diagnosis.
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.
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.
Surgical Procedures - skin grafting, split skin grafting are practiced in treating some localized depigmented and inherited hypopigmented conditions.
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.
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.
The patient should be advised to consult a dermatologist if repigmentation is not achieved with effective treatment, or any suspicion arises of neurocutaneous disorder (tuberous sclerosis), HMF, the tumor of follicular infundibulum, or in any doubtful diagnosis. Interprofessional team consultation yields a better prognosis in patients affected by hypomelanosis in conjunction with systemic conditions.
Definitions of Macroscopic Terms
Definitions of Microscopic Terms
Hypopigmented macules are the most common presentation of skin lesions. Often, the skin lesions are benign, and successful repigmentation can be achieved with prompt treatment. The lesions, in some cases, affect patients’ psychological and social well being. Therefore, it is important to continue medical education about hypopigmented skin lesions among healthcare professionals to improve the quality of care for their patients. Things to note-
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