Dark-Colored Lesions: Brown, Blue, Gray, or Black Disorders
Peter J. Lynch
Hyperpigmentation is commonly present on the skin of the genitalia. It may occur diffusely or as individual pigmented lesions. The basis for this hyperpigmentation includes physiologic (hormonal, racial, etc.) pigmentation, postinflammatory hyperpigmentation (PIH), some infections, and some benign or malignant neoplasms. Most dark colors arise as a result of melanin pigmentation. Melanin pigment is made within cytoplasmic organelles (melanosomes) in melanocytes that lie along the basement membrane of the epithelium. The amount of color in both normal skin and various lesions is determined by several factors: the density of melanocytes, the amount of melanin produced per melanocyte, and the transfer rate of the melanized melanosomes to the 30 or so keratinocytes that surround each melanocyte. The density of melanocytes does not vary appreciably in people of different racial backgrounds, but it does vary by site. Genital tissue, for instance, has about 50% more melanocytes per unit of area than does truncal skin. The development of increased pigmentation is dependent on genetic factors (variability in racial groups) and hormonal factors (especially in women). It is also dependent on acquired factors such as ultraviolet light (UVL), the presence of inflammation (particularly that involving basal layer damage), and some types of infection (notably HPV infection in the genital and perigenital areas). Increased pigmentation also occurs when there is proliferation in the number of normally melanized keratinocytes (epithelial hyperplasia) and/or when there is an increased retention of normally melanized keratinocytes in the stratum corneum. For a few disorders in this chapter, heme pigment rather than melanin explains the presence of the dark color.
Physiological Hyperpigmentation
In physiological hyperpigmentation, deep tan, brown, dark-brown, or even black pigmentation occurs as symmetrical, flat, smooth-surfaced, asymptomatic darkening of the anogenital skin. The most commonly affected sites include the median raphe of the penis and scrotum in male patients and the labia majora and outer edges of the labia minora in female patients (Figs. 9-1 and 9-2).1,2 The perianal skin in both genders usually displays some degree of physiologic hyperpigmentation. Appreciable variation in hue occurs across racial groups and also from person to person even within a given racial group. The degree of pigmentation can be so light as to be hardly noticeable or may be so dark as to be almost black in color.
The diagnosis of physiological hyperpigmentation is made on a clinical basis. Dermoscopy is nonspecific and may take on the characteristics of the condition that produced the hyperpigmentation. The differential diagnosis includes PIH, but this latter color change follows a history of inflammation, may have some residual red or red-brown hues, tends be patchier, and is generally less symmetrically distributed. If biopsy is carried out because of concern by either patient or the clinician, increased melanin will be found in both the melanocytes and keratinocytes, which line the basal layer of the epithelium. Physiological
hyperpigmentation of the genitalia occurs because of the greater density of melanocytes in the genitals compared to surrounding skin. These areas of hyperpigmentation will darken further under the influence of both endogenous and exogenous sex hormones. This darkening is particularly notable during pregnancy. Darkening will also occur due to the presence of increased melanocyte-stimulating hormone in neonates and in patients with disorders such as Addison disease due to the marked disturbance in pituitary-adrenal axis function.
hyperpigmentation of the genitalia occurs because of the greater density of melanocytes in the genitals compared to surrounding skin. These areas of hyperpigmentation will darken further under the influence of both endogenous and exogenous sex hormones. This darkening is particularly notable during pregnancy. Darkening will also occur due to the presence of increased melanocyte-stimulating hormone in neonates and in patients with disorders such as Addison disease due to the marked disturbance in pituitary-adrenal axis function.
 Fig. 9-1. Physiologic hyperpigmentation regularly occurs on the scrotum. |
 Fig. 9-2. Darker-complected women are likely to show hyperpigmentation of the labia minora and posterior fourchette, and perianal skin is often dark in both sexes. |
Treatment of physiological hyperpigmentation is not necessary or even desirable. However, it is worth noting that patient obsession with anogenital hyperpigmentation has led to the provision of bleaching services by both licensed and unlicensed practitioners.
Acanthosis Nigricans
The prevalence of acanthosis nigricans (AN) varies with skin color and race. It is present in about 20%-25% of African American, 20% of Hispanic, and 5% of Caucasian children and adolescents.3 Acanthosis nigricans was an uncommon disorder 50 years ago, but it is found much more often in recent years due to the marked increase of obesity, especially in children. While acanthosis nigricans is most often found in those who are obese, it also occurs with various endocrinopathies, malignancies, the metabolic syndrome, and the use of some medications.
Acanthosis nigricans appears as poorly demarcated light brown to dark brown lesions around the neck, in the axillae, and in the crural folds (Fig. 9-3). Rarely, it develops in other folded areas of the body and on the genitalia. The hyperpigmentation initially is flat but gradually thickening occurs. Characteristically, there are elevated linear ridges running parallel to one another. The surface of the lesions is slightly “bumpy” and often feels either velvety or slightly rough on palpation. Skin tags are frequently present within well-developed lesions (Fig. 9-4). Acanthosis nigricans is asymptomatic or mildly pruritic, but it is troubling to the patient because it suggests the appearance of dirty skin.
Multiple classifications for the various forms of AN have been published, but they have not proven to be of much help clinically, and in any event, there is no agreement on which approach should be used. The same can be said about the many proposals for the determination of severity. The diagnosis is established clinically, but there is a characteristic dermoscopic appearance. There are brown dots in a linear configuration that corresponds to
the parallel ridges of skin.4 If biopsied for confirmation, a characteristic pattern can be found. This includes orthokeratotic hyperkeratosis, papillomatosis, and increased melanin in the epidermis and stratum corneum. Dermal inflammation, melanocytosis and surprisingly, given the name of the disorder, are even acanthosis, usually absent. The major condition to be considered in the list of differential diagnoses is atopic dermatitis/lichen simplex chronicus in which some degree of PIH has occurred.
the parallel ridges of skin.4 If biopsied for confirmation, a characteristic pattern can be found. This includes orthokeratotic hyperkeratosis, papillomatosis, and increased melanin in the epidermis and stratum corneum. Dermal inflammation, melanocytosis and surprisingly, given the name of the disorder, are even acanthosis, usually absent. The major condition to be considered in the list of differential diagnoses is atopic dermatitis/lichen simplex chronicus in which some degree of PIH has occurred.
 Fig. 9-3. The medial thigh is often affected by the linear folds of acanthosis nigricans, and this condition is common in overweight patients. |
 Fig. 9-4. Acanthosis nigricans is manifested by hyperpigmentation in skin folds caused by papillomatous changes in the skin, often associated with skin tags as has occurred on this man’s perineum and medial thigh. |
Treatment of acanthosis nigricans is problematic. Topical retinoids and trichloroacetic acid peels can be tried, but often, the side effects are perceived as worse than the disorder. Oral retinoids and metformin may be helpful. However, the appearance can be improved through weight loss or effective treatment for any associated endocrinopathy or malignancy. Evaluation of patients with acanthosis nigricans is usually desirable because of the frequently associated presence of increased insulin levels, insulin resistance, abnormal glucose levels, hypertension, and elevated lipid levels.3 Rarely in adults, acanthosis nigricans is associated with the development of malignancy, especially that involving the gastrointestinal tract. This association should be considered in those middle aged or older who lack endocrinopathy, are nonobese, have appreciable pruritus, or have a recent history of unintentional weight loss.
Postinflammatory Hyperpigmentation
Inflammation affects melanocytes in two ways. First, severely damaged melanocytes discontinue the production of melanin with resulting hypopigmentation. Second, mildly damaged melanocytes react with increased melanin production and hyperpigmentation. PIH is an example of the second mechanism wherein hyperpigmentation develops at the site of current or previous inflammation. Inflammation may be an inherent component of a skin disease or inflammation may develop at the site of trauma such as might occur following the use of liquid nitrogen, application of trichloroacetic acid, or following laser therapy. Even tanning after mild sunburn can be considered as an example of external PIH and dark color occurring with acne lesions would be an example of internal PIH. PIH is clinically recognized as light to dark brown, nonpalpable macules and patches occurring in fair-skinned individuals, whereas darker colors, sometimes displaying hues of gray, blue, or black, occur in darker-skinned individuals (Fig. 9-5). The distribution and intensity of hyperpigmentation are dependent on the underlying cause of the preceding inflammation.
 Fig. 9-5. This patient with hidradenitis suppurativa shows brown macules of postinflammatory hyperpigmentation from old inflamed cysts and eschars. |
Diseases such as lichen sclerosus and lichen planus, in which inflammation preferentially damages the basal layer of the epithelium, with resultant take-up of melanin by dermal macrophages (melanophages), are more likely to be associated with darker gray or even black pigmentation than occurs with other inflammatory disorders (Figs. 9-6 and 9-7). Not surprisingly, patients with naturally darker skin color more commonly develop PIH, and this observation appears to be independent of ethenicity.5 Similarly, because normal genital color is generally darker than surrounding skin, inflammation in genital tissue is particularly likely to cause PIH. Pruritic skin disorders that lead to scratching and/or rubbing will usually develop more pigmentation than will nonpruritic conditions.
A history of prior trauma or previous inflammation is an important diagnostic clue but sometimes such a history cannot be obtained. This is particularly true in instances such as anogenital lichen planus and lichen sclerosus where extraordinarily long-lasting hyperpigmentation may first be noted a very long time after any clinical evidence of inflammation has resolved. In some
instances in which a history of previous inflammation cannot be obtained, a biopsy will be necessary to confirm a diagnosis of PIH. This is particularly true for pigmented macules or patches where the pigment density is variable or where gray or black hues are present. The histology usually demonstrates increased epidermal melanin, melanophages in the superficial dermis and a few nonspecific inflammatory cells around blood vessels in the papillary dermis.5 Dermoscopy is often nonspecific but may show changes of the original cause of the underlying inflammation.4
instances in which a history of previous inflammation cannot be obtained, a biopsy will be necessary to confirm a diagnosis of PIH. This is particularly true for pigmented macules or patches where the pigment density is variable or where gray or black hues are present. The histology usually demonstrates increased epidermal melanin, melanophages in the superficial dermis and a few nonspecific inflammatory cells around blood vessels in the papillary dermis.5 Dermoscopy is often nonspecific but may show changes of the original cause of the underlying inflammation.4
 Fig. 9-6. Postinflammatory hyperpigmentation is fairly common in the setting of lichen sclerosus, where there is inflammation and disruption of the dermal epidermal junction, also the location of melanocytes. |
Because PIH usually resolves over several to many months, treatment is most often unnecessary. However, the presence of pigmentation sometimes obscures continuing low-grade inflammation. Thus, if the pigmentation persists longer than expected, biopsy can be obtained to determine whether or not subclinical inflammation is present. If such is present, anti-inflammatory treatment, such as with topical steroids, should be administered. Topical fading agents, such as 4% hydroquinone, may improve pigmentation located in the epidermis but are of little or no use for pigment lying deeper in dermal melanophages. Other approaches for the treatment of PIH have been summarized in the 2018 review by Kaufman et al.5
 Fig. 9-7. Lichen planus is another disease that disrupts the dermal epidermal junction and produces marked, fairly long-lasting postinflammatory color change on dry, keratinized skin. |
Seborrheic Keratosis (pl: Seborrheic Keratoses)
Seborrheic keratoses (SK) are extremely common, benign growths. Their prevalence increases with age. Most individuals over the age of 40 years have at least 1 or 2 lesions and often 50-100 may be present. Most are located on the trunk, but occasionally, they are noted on the proximal limbs and hair-bearing skin of the anogenital area. Seborrheic keratoses present as sharply marginated, square shouldered, tan, brown, gray, or black papules 8-15 mm wide and 2-10 mm tall (Figs. 9-8 and 9-9). Rarely, very large seborrheic keratoses (“giant” SKs) are encountered (Fig. 9-10). The sharp margination and square shoulders (clifflike transition to surrounding normal skin) contribute to a characteristic “stuck on” appearance. The surface often contains visible scale and is usually rough on palpation. However, in some instances, the surface has a smooth “waxy” feeling simulating a drop of candle wax on the surface of the skin (Fig. 9-11). However, in these smooth lesions, the presence of scale can be identified if the surface is gently scraped with a blade held perpendicular to the top of the lesion.
The presence of scale is a very helpful point in distinguishing seborrheic keratoses from those of nevi, lentigines, and melanomas. Small, characteristic surface pits
may be found when magnification is used in the examination. Specifically, dermoscopy can be very helpful in recognizing these minute pits.6 Genital seborrheic keratoses may also be quite difficult to differentiate from both pigmented genital warts and HPV-related intraepithelial neoplasia. They may also resemble pigmented basal cell carcinomas. Because differentiation of seborrheic keratosis from these lesions is so important, most genital seborrheic keratoses should be biopsied and all SKs exhibiting inflammation, erosion, ulceration, or bleeding must be biopsied.
may be found when magnification is used in the examination. Specifically, dermoscopy can be very helpful in recognizing these minute pits.6 Genital seborrheic keratoses may also be quite difficult to differentiate from both pigmented genital warts and HPV-related intraepithelial neoplasia. They may also resemble pigmented basal cell carcinomas. Because differentiation of seborrheic keratosis from these lesions is so important, most genital seborrheic keratoses should be biopsied and all SKs exhibiting inflammation, erosion, ulceration, or bleeding must be biopsied.
 Fig. 9-8. A typical seborrheic keratosis is a tan, well-demarcated, flattopped, rough, keratotic, or warty papule that can be mistaken for a wart. |
The cause of seborrheic keratoses is unknown, but frequent familial patterns regarding age at onset and number of lesions suggest that both genetic and aging factors play a role. It is of considerable interest that somatic mutations in fibroblast growth factor receptor 3 (FGFR3) are found in 50%-75% of seborrheic keratoses. Mutations also occur in multiple other genes such as PIK3CA, TERT, and DPH3.7 These same mutations may also be found in other lesions that behave in a malignant fashion, whereas malignancy rarely, if ever, develops in seborrheic keratoses; the reasons explaining this discrepancy are not completely known, but additional discussion of this topic can be found elsewhere.8 Controversy exists as to whether or not human papillomavirus (HPV) infection plays any role in the development of anogenital seborrheic keratosis, and we doubt that it does. Others, however, disagree.9
 Fig. 9-9. Seborrheic keratoses are accompanied by similar seborrheic keratoses on other areas of the body, such as the trunk. |
 Fig. 9-10. An occasional seborrheic keratosis such as this one can be large, and show multiple colors, mimicking melanoma or HPV-associated squamous intraepithelial neoplasia, also called HSIL (high-grade squamous intraepithelial lesion). Although dermoscopy can be useful, a biopsy should be performed for any question. |
Biopsy is desirable in any instance of uncertainty regarding the diagnosis. No therapy is necessary for
clinically typical, or histologically proven, seborrheic keratoses. Lesions that are irritated by clothing and those that are particularly bothersome to the patient may be treated with cryotherapy or with shave excision. The latter is preferred for anogenital SKs as it provides a specimen for histological examination. Recently, the U.S. Food and Drug Administration granted approval for medical therapy with 40% hydrogen peroxide (Eskata). It is moderately effective when used for thin seborrheic keratoses such as those that occur on the face, but it is not recommended for those that occur elsewhere on the body.
clinically typical, or histologically proven, seborrheic keratoses. Lesions that are irritated by clothing and those that are particularly bothersome to the patient may be treated with cryotherapy or with shave excision. The latter is preferred for anogenital SKs as it provides a specimen for histological examination. Recently, the U.S. Food and Drug Administration granted approval for medical therapy with 40% hydrogen peroxide (Eskata). It is moderately effective when used for thin seborrheic keratoses such as those that occur on the face, but it is not recommended for those that occur elsewhere on the body.
 Fig. 9-11. The shine on the surface of this seborrheic keratosis demonstrates the smooth, waxy rather than rough texture of this lesion. |
Genital Varicosities
Varicosities may be small or large. Large dilated vessels are usually blue in color (Fig. 9-12). Such varicose veins occur on the vulva with appreciable frequency. In fact, they develop in about 10% of women who are pregnant, and this incidence increases with parity.10 Fortunately, there is usually regression following parturition, but they are almost certain to recur with subsequent pregnancies. Vulvar varices also frequently can be observed in pregnant or nonpregnant women as part of the pelvic congestion syndrome, which is a pelvic chronic pain syndrome associated with pelvic varicosities.11
Varicosities are less common on the penis and scrotum. Scrotal varicocele is the analog of the female pelvic congestion syndrome. However, the varices that occur with varicocele are contained entirely within the scrotal sac, rather than within the skin of the scrotum, and while they are palpable (so-called bag of worms), their dusky blue color is somewhat muted, if visible at all.12 Very small diameter dilated vessels (“spider veins”) are more likely to be dusky or dark red (Fig. 9-13). Such telangiectasias occur commonly on the scrotum and often tiny angiokeratomas (see Chapter 6) overly these small telangiectatic vessels (Fig. 9-14).
 Fig. 9-12. Large dilated varicosities are most common during pregnancy or can occur in associated with pelvic congestion syndrome. These occur deep below the skin in men in varicoceles. |
 Fig. 9-13. More common in men are more superficial small and medium red vessels on the scrotum. |
 Fig. 9-14. Occasionally, angiokeratomas occur along the course of the superficial vessels. |
Varicosities are identified by their disappearance following compression with a glass slide (diascopy). Treatment for large varicose veins lies outside the scope of this chapter. Therapy for small telangiectatic vessels is not ordinarily necessary, but when bleeding repeatedly follows trauma, they may require electrosurgical destruction.
Genital Melanosis (Lentiginosis)
Genital melanosis and genital lentiginosis have been used interchangeably by clinicians, but, strictly speaking, the latter term is only applicable to those lesions that demonstrate a lentigolike histologic pattern on biopsy. Since this is not present in all cases, we prefer the term genital melanosis.
Clinical Presentation
Pigmented lesions of melanocytic type are common on the genitalia with a prevalence estimated to be about 10%-15% in both men and women.6 In women, about 60%-70% of all vulvar pigmented lesions are due to vulvar melanosis, and this is probably true for men as well.6
Genital melanosis consists of one or more nonpalpable, nonelevated macules and patches of pigmentation (Figs. 9-15, 9-16, 9-17). They develop mostly in midlife at an average age of about 40 years but can occur as early as the late teens or as late as age 80 years. This pigmentation occurs most often on mucous membranes or modified mucous membranes, but it can also arise on keratinizing skin. Specifically, in women, most of these pigmented patches are found on the labia minora, followed by the labia majora, and when multiple lesions are present, they frequently develop on both labia.13 In men, most lesions occur on the glans penis and inner aspects of the prepuce, but penile shaft and urethral meatus involvement is also possible6 (Fig. 9-18). Lesions may be either solitary or multifocal with the latter occurring slightly more frequently. There is a great deal of variation in the size and color of the pigmentation. Lesions are mostly small (5-10 mm), but many are considerably larger with up to 2 cm.6,13,14 Asymmetry in distribution of multifocal lesions is common, and the configuration of individual lesions can be angular. The pigmentation color may be tan, brown, blue, or black, but when multiple lesions are present, the color is fairly consistent among all of the lesions. There is often pigment variegation (“speckling”) within the lesions and occasionally small areas of hypopigmentation are noted. The borders may be either poorly or sharply marginated. For the first few years, there is usually some increase in the diameter of the lesions and/or darkening of the pigmentation, but with the passage of time, stabilization of size and color occurs.
 Fig. 9-15. These macules of genital lentiginosis are irregular in color, size, and shape and are indistinguishable from melanoma in situ. The encroachment of lesions onto dry, keratinized skin is unusual. |
 Fig. 9-16. This patient has only one area of lentiginosis, a patch of irregularly brown color ranging from tan to nearly black in the right vestibule and medial labium majus. |
Diagnosis
The correct diagnosis is often suggested, perhaps aided by dermoscopy, on clinical examination.6,13 However, in the vast majority of instances, biopsy should be undertaken to
rule out both benign conditions (eg, PIH) as well as malignancy (eg, superficial forms of melanoma). It cannot be emphasized enough how much genital melanosis clinically resembles melanoma and how little use simple guides for identifying melanomas (such as the widely publicized ABCDE approach) are in separating melanosis from melanoma. However, it is worth noting that patients with genital melanosis essentially never develop melanoma within their melanosis lesions but nevertheless have a very interesting, complicated, and controversial relationship to melanoma. Specifically, patients with melanosis seem to have greater than chance possibility of a family history of melanoma, a past personal history of melanoma (almost always at a nongenital site) and, on follow up, development of a melanoma (again, at a nongenital site).13,14
rule out both benign conditions (eg, PIH) as well as malignancy (eg, superficial forms of melanoma). It cannot be emphasized enough how much genital melanosis clinically resembles melanoma and how little use simple guides for identifying melanomas (such as the widely publicized ABCDE approach) are in separating melanosis from melanoma. However, it is worth noting that patients with genital melanosis essentially never develop melanoma within their melanosis lesions but nevertheless have a very interesting, complicated, and controversial relationship to melanoma. Specifically, patients with melanosis seem to have greater than chance possibility of a family history of melanoma, a past personal history of melanoma (almost always at a nongenital site) and, on follow up, development of a melanoma (again, at a nongenital site).13,14
 Fig. 9-17. These two nearly black macules of lentiginosis have occurred in a setting of lichen sclerosus. |
 Fig. 9-18. Tan irregular macules of lentiginosis occur in men as well, most often on the glans or ventral prepuce, but also on the shaft. |
 Fig. 9-19. This patient with lichen sclerosus shows discrete macules of variably dark brown color. |
Although it is reflected in only a few published studies, we believe that genital melanosis is particularly likely to arise from within an area of lichen sclerosus13 (Fig. 9-19). But note that when very young patients are diagnosed with genital melanosis, the oral mucous membranes should be inspected for the presence of similar lentiginous pigmentation. When this is found, consideration should be given to the possibility that any one of several rarely encountered conditions such as Peutz-Jeghers syndrome, Laugier-Hunziker syndrome, Bannayan-Riley-Ruvalcaba syndrome, LEOPARD syndrome, and the several syndromes with lentigines and cardiocutaneus myxomas may be present.13
MELANOSIS Diagnosis
Dark (usually black) flat, smooth, 5- to 25-mm patch
Asymmetric or angular configuration
Located primarily on nonkeratinizing (mucosal) tissue
Unchanging appearance (if patient has previously been aware of the lesion)
Incisional biopsy to rule out dysplasia and malignancy
Dermoscopy of lentiginosis requires an experienced dermoscopist, and there is no one pattern.6 The parallel pattern with uniform linear and curved structures was found in 52.5% of lesions, with globular pattern in 32.5% of lesions, and a ringlike pattern in 50% of lesions, more in those with multiple lesions than those with a solitary lesion. A biopsy is imperative. Histologically most, but not all, specimens of genital melanosis demonstrate lentiginous elongation of the rete ridges with slight hyperproliferation of benign-appearing melanocytes within the basal layer. There are usually at least a few scattered pigmented macrophages (“melanophages”) present within the dermis.
Pathophysiology
The cause of genital melanosis is not known and the following is speculation. The uncommon, though greater than chance, presence of a family history of melanoma, the infrequent past personal history of melanoma, and the slight risk for the future development of a melanoma at a nongenital site makes one wonder about a genetic predisposition for the development of this pigmentary disorder. (And, as noted above, genital lentigines may occur in a number of heritable conditions, again suggesting a genetic etiologic component.) Finally, while there is usually no history of an associated dermatological problem in patients with melanosis, the development of melanosis in an area of lichen sclerosus raises the question of an immunological problem playing a role in the etiology of both disorders.
Management
Genital melanosis, once it has stabilized in appearance, is believed to be a benign condition. There appears to be no tendency for the lesion, or lesions, to progress to melanoma in spite of their ominous clinical appearance. Once a diagnosis of genital melanosis is histologically confirmed, further therapy is not required. Essentially, all of the reported patients remained free of melanoma development within their lesions for as long as they were followed. However, because of the small number of reported patients and the relatively short duration of reported follow-up, one should probably conclude that the natural history of these melanosis lesions remains unclear. In any event, close follow-up is indeed strongly encouraged. This is particularly necessary regarding patients whose melanosis arose at the site of genital lichen sclerosus as it is possible that there is a relationship between lichen sclerosus and melanoma just as there is with another malignancy, squamous cell carcinoma. Thus, in a Finnish study, the authors found that women with lichen sclerosus of the vulva were much more likely to develop vulvar melanoma in their lichen sclerosus than were women without evidence of lichen sclerosus.15 On the other hand, it should be acknowledged that there is considerable controversy regarding the differentiation of atypical genital nevi (AGNMT) from that of “true” genital melanomas in these quite young patients.16 At any rate, long-term follow-up of patients with genital melanosis is advisable but periodic re-biopsy is not necessary unless either the patient reports a changed appearance or change is noted by the clinician at the time of examination. Having clinical photographs from the time at first diagnosis can be very helpful in this regard.
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