Oral hyperpigmentation

HOW TO TAKE THE POST-TEST: This Clinical Advisor CME activity consists of 3 articles. To obtain credit, you must also read Brown macules on a depigmented skin patch and Vesicular eruption in an ICU patient.

CASE #1

Peutz-Jeghers syndrome (PJS) is characterized by mucocutaneous lentigines, hamartomatous polyposis, and an increased risk of visceral malignancy. The first documented record of the condition appeared in 1896, when John McHutchinson described a set of identical twins with oral and labial pigmentation who died from intussusception and breast cancer.

In 1921, Jan Peutz, a Dutch physician, first described the relationship between mucocutaneous lentigines and intestinal polyps in a Dutch family.¹ It wasn’t until 1949 that Harol Jeghers, an American physician, recognized the relationship between the mucocutaneous lentigines and generalized intestinal polyposis.² In 1954, Andre J. Bruwer introduced the eponym Peutz-Jeghers syndrome.³

PJS is an autosomal dominant disorder that is primarily caused by mutations in the STK11 gene (also known as LKB1) on chromosome 19p13.3, which codes for a serine/threonine kinase. The prevalence is thought to be approximately 1 in 100,000 to 200,000 births. The diagnosis requires the presence of histopathologically confirmed hamartomatous polyps and at least two out of three additional criteria, including mucocutaneous pigmentation, a specific type of gastrointestinal (GI) polyp, and a family history of PJS.

Clinically, 95% of patients with PJS present with light brown to black homogenous pigmented macules, 1 mm to 5 mm in size, which usually develop during childhood. The pigmented macules are normally perioral, periorbital, in the anogenital region, and/or on the ventral aspect of the hands and feet. Pigmentation may also occur in the oral cavity, and these lesions primarily affect the vermilion zone, the labial and buccal mucosa, and the tongue. Fading of the lentigines can occur following puberty, but the oral-buccal mucosal pigmentation tends to be permanent.

Patients with PJS are at increased risk of malignancies including GI, pancreatic, breast, uterine, cervical, and testicular malignancies. The lifetime risk of persons with PJS developing any cancer by age 70 years has been estimated to be 85% to 90%.^4,5 A specific type of GI polyp, which may be found throughout the GI tract but is seen most commonly in the small intestine and colon, usually develops in early adolescence among persons with PJS. These polyps may result in abdominal pain, bleeding, obstruction, or intussusception. Persons with PJS as well as any of their relatives who also may be afflicted with the disease should undergo frequent endoscopic surveillance for removal of polyps throughout the GI tract and should be screened for extraintestinal cancers.⁶

Histologically in PJS, the epidermal basal cell layer shows marked hyperpigmentation, representing increased melanin production. At first glance, it may appear as if the number of melanocytes is also increased. However, DOPA-stained sections have shown that there is no increase in the number of melanocytes.

The main diagnosis in the differential is Laugier-Hunziker syndrome. Laugier-Hunziker is a sporadic disorder, with only one familial case described.⁷ Patients most commonly present with pigmentation that arises on the lips and oral mucosa. The anogenital region and hands are less frequently affected. One distinguishing feature is that approximately half of patients have melanonychia striata of their nails. Another distinguishing feature is that patients tend to present at a mean age of 50 years. The familial history, age at presentation, and presence or absence of melanonychia striata is helpful in distinguishing between the two disorders.

Other disorders to be considered in the differential diagnosis include causes of primary adrenocortical insufficiency, such as Addison disease. Patients with Addison disease may develop hyperpigmented macules on the oral mucosa, but the condition is also accompanied by systemic symptoms such as fatigue, weight loss, hypertension, and GI changes. Drug-induced pigmentation, smoker’s melanosis, blue nevus, pigmentation by foreign bodies, melanocytic nevus, oral melanoma, and idiopathic racial or ethnic melanosis should also be considered in the differential diagnosis of oral pigmented lesions. Other disorders associated with multiple lentigines include Bandler syndrome, Cantú, PTEN gene-related disorders, centrofacial lentiginosis, inherited patterned lentiginosis, Cronkhite-Canada syndrome, Carney complex, and LEOPARD syndrome.

No treatment is necessary for the mucocutaneous lesions unless they appear clinically atypical, at which point a biopsy should be considered to rule out malignancy. Fading of the lentigines may occur with time. Cover-up cosmetics may be appropriate if the patient is cosmetically bothered. Another option for treatment includes cryosurgery, or laser therapy with the Nd:YAG or Q-switched alexandrite lasers. Unfortunately, recurrence may occur after treatment. Patients should be encouraged to avoid sun exposure.

Due to the increased risk of visceral malignancy among people with PJS, surveillance should begin in childhood because of a tendency for the polyps to cause abdominal pain, bleeding, obstruction, or intussusception. Regular screening for other visceral malignancies should also be routinely performed. Genetic counseling may also be recommended if the patient is planning on having children and/or has a family history of the disorder.

The patient in this case was not cosmetically bothered by the mucocuatneous lesions. He was seen by gastroenterology and was found to have the classic polyps of PJS but no evidence of malignancy. He continues to undergo regular screening for gastrointestinal and extraintestinal malignancies.

CASE #2

Addison disease

Addison disease, also known as hypoadrenocorticism, was named after its founder, an English physician by the name of Thomas Addison. He first described the disease in a paper he wrote in 1855, On the Constitutional and Local Effects of Disease of the Supra-Renal Capsules.⁸

Addison disease affects 50 out of every 1 million individuals in the United States. It has no racial predilection. However, females are affected more than males, which is thought to be due to the disease’s autoimmune nature. Typical onset ranges from age 30 years to age 50 years.

Addison disease is an insufficiency of the adrenal gland­more specifically, the adrenal cortex. The adrenal glands are located on top of the kidneys and are composed of the medulla (inner portion) and cortex (outer portion). The cortex is itself broken up into three different zones: zona glomerulosa, zona fasciculata, and zona reticularis. In combination, these three zones produce approximately 50 different steroid hormones including cortisol, aldosterone, and testosterone. When the body undergoes stress it has a great need for cortisol, a glucocorticoid produced by zona glomerulosa. Cortisol is considered the stress hormone and raises blood glucose and blood pressure to help the body adapt. However, too much cortisol can also have detrimental effects.

The production and release of cortisol and other hormones produced by the adrenal gland are controlled by an axis composed of the hypothalamus, the pituitary gland, and the adrenal gland (HPA axis). When an individual undergoes physical stress, the hypothalamus releases corticotropin-releasing hormone (CRH). This hormone stimulates the pituitary gland to release adrenocorticotropic hormone (ACTH). ACTH then enters the bloodstream and signals the adrenal gland to produce and release its hormones, including cortisol. Once enough cortisol has been released, a negative feedback inhibition causes the pituitary gland to stop releasing ACTH and then informs the hypothalamus to stop releasing CRH.

As stated earlier, Addison disease is an insufficiency of the adrenal gland, and the causes may be either primary or secondary. Primary Addison disease is the destruction or dysfunction of 90% of the adrenal gland by autoimmune diseases (most common), infections (such as tuberculosis and deep fungal infections), metastatic tumors, sarcoidosis, hemochromatosis, or amyloidosis.⁹ Secondary Addison disease is caused by insufficient ACTH release by the pituitary gland. This may occur due to pituitary gland surgery, injury, or exogenous steroid usage. Plasma ACTH levels are elevated in primary Addison disease and suppressed in secondary Addison disease.

Patients suffering from primary Addison disease will experience a sinister onset of fatigue, sluggishness, irritability, depression, weakness, and hypotension as a result of decreased levels of adrenal hormones. Oral mucosa changes may be the first presenting sign of the disease and manifest as a diffuse or patchy brown macular pigmentation due to excessive melanin production. Hyperpigmentation may occur anywhere, but most commonly occurs on the vermilion border, ventral tongue, and buccal mucosa. The hyperpigmentation occurs because ACTH and melanocyte-stimulating hormone (MSH) share a precursor molecule called proopiomelanocortin (POMC). Thus, high levels of ACTH cause high levels of MSH, which in turn causes melanocytes to overproduce melanin and cause hyperpigmentation. The hyperpigmentation is not just confined to the oral cavity: As time goes on, patients develop a generalized hyperpigmentation of the skin as well, which is classically known as bronzing. Hyperpigmentation is generally more prominent on the sun-exposed skin and at sites of trauma but may also occur on the axillae, perineum, nipples, palms, hair, and nails. Patients also may have such symptoms as GI upset, vomiting, diarrhea, weight loss, and a craving for salt.

Histologically, Addison disease reveals increased amounts of melanin in the basilar and upper-spinous-layer keratinocytes. It is important to note that the number of melanocytes is not increased. Also, histologic findings are not sufficient for diagnosis in patients of color, as the findings simulate normal findings in darker-skinned individuals.

Oral manifestations of Addison disease may mimic those of Peutz-Jeghers disease and Laugier-Hunziker syndrome. Drug-induced pigmentation, smoker’s melanosis, blue nevus, pigmentation by foreign bodies, melanocytic nevus, oral melanoma, and idiopathic racial or ethnic melanosis should also be considered in the differential diagnosis of oral pigmented lesions. Depending on the localization, diffuse hyperpigmentation may mimic acanthosis nigricans or melasma.

The diagnosis of Addison disease is confirmed by an ACTH stimulation test. If cortisol levels are below 20 µg/ml, then the patient has adrenal insufficiency. Plasma ACTH levels will help to differentiate between primary and secondary Addison disease: Plasma ACTH levels above 100 ng/L indicate primary Addison disease. In patients with secondary Addison disease, ACTH levels will be low and hyperpigmentation will not be clinically evident.

Treatment includes replacement of the missing adrenal hormones. Dosages of corticosteroids should be increased if the patient is undergoing a stressful event such as dental extractions, pregnancy, or invasive procedures. After replacing the missing adrenal hormones, ACTH levels should normalize and over time, the bronzed skin may return to its natural color. Prognosis is good with hormone replacement therapy and patient compliance. However, if Addison disease is not recognized promptly, death may occur in a relatively short period of time.

This patient was found to have primary Addison disease due to autoimmune destruction. She was treated with corticosteroid replacement therapy and the skin pigmentation was improving upon follow-up. 

Damjan Jutric is a third-year dental student at The University of Texas School of Dentistry in Houston. Dr. Robbins is an instructor in the Department of Dermatology at Baylor College of Medicine in Houston.