Are You Confident of the Diagnosis?
What you should be alert for in the history
Patients will describe a gradual eruption of papules or nodules on sun-exposed skin. Although usually asymptomatic, the lesions may be mildly pruritic and distressful to the patient. It is also important to ask about excess and unprotected sun exposure, petroleum exposure, hydroquinone use, and family history.
Characteristic findings on physical examination
Colloid milium is limited to the skin and tends to be distributed on sun-exposed, actinically damaged areas, particularly the cheeks, periorbital region, nose, ears, neck, dorsal hands, and forearms. Three cases of a unilateral distribution and a case of oral colloid milium have been reported as well.
Adult type: Examination will show crops of 1- to 5-mm yellow-brown or skin-colored, dome-shaped, waxy, semi-translucent, and firm papules that resemble vesicles and express mucoid or gelatinous material with pressure or puncture. The papules may easily bleed with slight trauma and form a cobblestone appearance when they coalesce (Figure 1).
Nodular type: This type is similar to the adult type, but will present as a single nodule or as multiple 5- to-10 mm nodules or plaques that may be “lumpy” and telangiectatic.
Juvenile type: It is clinically indistinguishable from the adult type, but can also occur on normal skin.
Pigmented type: The color of the papules ranges from patchy gray to black. It can be associated with exogenous ochronosis.
Expected results of diagnostic studies
The diagnosis is made after examining a skin biopsy under light microscopy. Because this form of microscopy cannot distinguish colloid from amyloid, certain differentiating stains can be used. If the diagnosis is still inconclusive, electron microscopy may be helpful.
Histologic examination will show fissured homogenous glassy eosinophilic colloid masses deposited in the dermis, with occasional capillary dilation and sparing of the hair follicle and sebaceous gland. There is no inflammation, but a few lymphocytes and mast cells may be present. Colloid milium is positive for periodic acid-Schiff stain and can show green birefringence with Congo Red stain. It is generally negative for methyl (crystal) violet, cytokeratin, and immunoglobulin light chain stains.
Adult type: Islands of colloid material will be in the papillary dermis with extension into the mid dermis. Fracturing clefts split these deposits into smaller islands and have intervening stellate and spindle-shaped fibroblasts. A narrow grenz zone, which spares the subepidermal layer of the papillary dermis from colloid deposition, also exists. Solar elastosis is often present immediately adjacent to colloid deposits.
Nodular type: Deposits are similar to the adult type, but exist in most of the dermis. The epidermis may be atrophic and basal keratinocytes may appear hyalinized due to degeneration.
Pigmented type: Deposits are similar to that of the adult type, but appear light golden, as is characteristic of ochronosis.
Juvenile type: Fissuring colloid masses are seen close to the basal layer of the epidermis and may transition into the dermis. The substance seems to originate from degenerating epidermal keratinocytes and contains damaged organelles and desmosomes. Initially, the deposits have degenerating and clumping tonofilaments that later transform into whorls and wavy bundles. Basement membrane damage is sometimes present. Unlike the other types, there is no grenz zone or solar elastosis, and it is typically negative for Congo Red and positive for antikeratin antibody.
Under the electron microscope, colloid material appears as short, wavy, and branching electron-dense filaments that are 1.5 to 2 nm in diameter, and may show transitional stages between actinic elastoid and colloid.
The differential diagnosis may include systemic amyloidosis, primary cutaneous amyloidosis, basal cell carcinoma, epidermal inclusion cyst, erythropoietic protoporphyria, lipoid proteinosis, molluscum contagiosum, sarcoidosis, sebaceous hyperplasia, steatocystoma multiplex, syringoma, trichoepithelioma, papular mucinosis, and tuberous sclerosus. A careful history and interpretation of the skin biopsy can distinguish colloid milium from all these conditions.
Amyloidosis is the most difficult to rule out clinically and histopathologically. The deposits in colloid milium tend to be larger and have coexisting solar elastosis and epidermal atrophy, whereas amyloidosis is associated with hyperplasia. Immunohistochemically, both colloid and amyloid are periodic acid-Schiff positive and colloid, like amyloid, can show green birefringence with Congo Red. Usually, only amyloid is positive for methyl (crystal) violet, cytokeratin, and immunoglobulin light chain stains.
Under the electron microscope, colloid material appears as short, wavy, and branching electron-dense filaments that are 1.5 to 2 nm in diameter, and may show transitional stages between actinic elastoid and colloid. In contrast, amyloid material appears as straight filaments that are 6 to 10 nm in diameter.
Who is at Risk for Developing this Disease?
Colloid milium is a rare condition of unknown incidence and prevalence. About 100 cases have been reported, with the consensus being that many more exist. Colloid milium can be classified into four types: adult, nodular (or paracolloid), pigmented, and juvenile. The adult form is the most common and is usually seen in middle-aged fair-skinned males. Risk factors include unprotected light exposure (particularly ultraviolet [UV] A), fair complexion, outdoor occupations, and exposure to petroleum derivatives, such as phenols.
Risk factors for the nodular type are less established, but may include sun exposure. The pigmented form seems to occur with chronic use of hydroquinone cream combined with excess sun exposure. The juvenile form develops before puberty and the risk depends on family history.
What is the Cause of the Disease?
Possible risk factors have been identified, but the origin and mechanism of pathogenesis remain unclear. For the adult and nodular forms, unprotected and prolonged UV exposure is likely responsible for the skin degeneration. The development of the adult type on the dorsal hands of 28 oil refinery workers in the tropics and a mechanic, who were all exposed to lubricating oils and sun, suggests an interaction between light and petroleum products.
The pigmented form is associated with chronic use of hydroquinone bleaching cream and sun exposure, probably because phenols present in the cream increase sensitivity to UV damage. Patients with juvenile colloid milium likely have an inherited susceptibility to UV light that can be transmitted autosomal recessively.
The most established theory argues that the colloid deposits are secondary to elastic fiber degeneration. Immunohistochemical evidence includes the presence of microfibrillar proteins like serum amyloid P, sulfur-containing amino acids, and various microfibril-specific sugar residues. The absence of hydroxyproline and hydroxylysine rules out a collagen source.
UV light may either directly damage the elastin or indirectly affect its synthesis by damaging fibroblasts. Additionally, UV exposure may activate elastinolytic enzymes, such as elastase and protease. The juvenile type may be secondary to UV-induced keratinocyte damage.
Systemic Implications and Complications
Colloid milium is limited to the skin. No complications or fatalities have been reported.
No satisfactory therapies are currently available. Treatment options are summarized in the Table 1.
|Medical Treatment||Surgical Procedures||Physical Modalities|
|Topical exfoliating agents||No benefit||Fractional laser resurfacing|
|Systemic ascorbic acid||Erbium: YAG ablative laser resurfacing|
There is no evidence that sun avoidance or sunscreen is therapeutic, but they are thought to be preventive.
Optimal Therapeutic Approach for this Disease
The most novel and promising treatment modality is fractional laser resurfacing, which may be given over five sessions that are spaced by 2 to 4 weeks. The laser creates columns of microthermal zones that extend down to the reticular dermis. Because the emitted energy is absorbed mostly by water, the stratum corneum is not thermally damaged. This treatment requires only topical anesthesia, bland emollients, and sun protection postoperatively, and a healing period of 2 days. Additionally, there have been no reported side effects, such as infection, scarring, or pigmentary changes.
Though ablative resurfacing with the Er:YAG laser also provides excellent results, it requires deep intravenous sedation, extensive postoperative care, and 2 weeks for recovery. Dermabrasion is effective, but appears to have only a moderate success rate. Cryotherapy and chemical peels have not been very useful, likely because of their inability to penetrate the deep papillary dermis. Exfoliating agents and systemic ascorbic acid have also been tried, but their efficacy is inconclusive. Not enough data is available to calculate response rates of these treatment modalities.
The patient should be informed that very few new papules develop after 3 years, but colloid milium does not naturally resolve. Protection from the sun and petroleum derivatives is advised, but whether these precautions are actually preventive is still unclear. No follow-up is needed and it is not yet determined if maintenance therapy is required once successfully treated. If a patient has the juvenile type, genetic counseling is recommended.
What is the Evidence?
Desai, AM, Pielop, JA, Smith-Zagone, MJ, Hsu, S. “Colloid milium: A histopathologic mimicker of nodular amyloidosis”. Arch Dermatol. vol. 142. 2006. pp. 784-5. (A case vignette that describes how colloid milium can be misdiagnosed as nodular amyloidosis.)
Gönül, M, Cakmak, SK, AKiliç, Gül, U, Heper, AO. “Pigmented coalescing papules on the dorsa of the hands: pigmented colloid milium associated with exogenous ochronosis”. J Dermatol. vol. 33. 2006. pp. 287-90. (A case report of a patient with pigmented colloid milium associated with exogenous ochronosis.)
Handfield-Jones, SE, Atherton, DJ, Black, MM, Hashimoto, K, McKee, PH. “Juvenile colloid milium: clinical, histological and ultrastructural features”. J Cutan Pathol. vol. 9. 1991. pp. 434-8. (A case report that discusses the unique features of juvenile colloid milium.)
Hashimoto, K, Black, M. “Colloid milium: a final degeneration product of actinic elastoid”. J Cutan Pathol. vol. 12. 1985. pp. 147-56. (One of the early papers that argued colloid deposits are secondary to degenerated elastic fibers.)
Innocenzi, D, Barduagni, F, Cerio, R, Wolter, M. “UV-induced colloid milium”. Clin Exp Dermatol. vol. 18. 1993. pp. 347-50. (A case report of a woman who developed adult colloid milium after 7 years of UVA exposure for aesthetic reasons.)
Lewis, AT, Le, EH, Quan, LT, Krishnan, B, Schulmeier, J, Hsu, S. “Unilateral colloid milium of the arm”. J Am Acad Dermatol. vol. 46. 2002. pp. S5-7. (One of three reported cases of unilateral colloid milium.)
Ojha, J, Bhattacharyya, I, Islam, NM, Wong, F, Cohen, DM. “Colloid milium of the oral cavity: a rare presentation”. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. vol. 105. 2008. pp. 34-8. (The only reported case of colloid milium on the oral mucosa.)
Patterson, JW, Wilkin, JK, Schatzki, PF. “Nodular colloid degeneration: distinctive histochemical and ultrastructural features”. Cutis. vol. 36. 1985. pp. 355-8. (A case report that describes nodular colloid milium.)
Pourrabbani, S, Marra, DE, Iwasaki, J, Fincher, EF, Ronald, LM. “Colloid milium: a review and update”. J Drugs Dermatol. vol. 6. 2007. pp. 293-6. (A review that discusses the presentation, diagnosis, and current treatment options for colloid milium.)
Touart, DM, Sau, P. “Cutaneous deposition diseases: Part I”. J Am Acad Dermatol. vol. 39. 1998. pp. 149-71. (A review that outlines various cutaneous deposition diseases including colloid milium.)
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