Dirk M. Elston, MD

The Diagnosis: Collision Tumor

Excisional biopsy and histopathological examination demonstrated a collision tumor composed of a benign intradermal melanocytic nevus, tumor of follicular infundibulum, and an underlying sclerosing epithelial neoplasm, with a differential diagnosis of desmoplastic trichoepithelioma, morpheaform basal cell carcinoma, and microcystic adnexal carcinoma (Figure).

Common acquired melanocytic nevus presents clinically as a macule, papule, or nodule with smooth regular borders. The pigmented variant displays an evenly distributed pigment on the lesion. Intradermal melanocytic nevus often presents as a flesh-colored nodule, as in our case. Histopathologically, benign intradermal nevus typically is composed of a proliferation of melanocytes that exhibit dispersion as they go deeper in the dermis and maturation that manifests as melanocytes becoming smaller and more spindled in the deeper portions of the lesion.¹ These 2 characteristics plus the bland cytology seen in the present case confirm the benign characteristic of this lesion (Figure, B).

In addition to the benign intradermal melanocytic nevus, an adjacent tumor of follicular infundibulum was noted. Tumor of follicular infundibulum is a rare adnexal tumor. It occurs frequently on the head and neck and shows some female predominance.^2,3 Multiple lesions and eruptive lesions are rare forms that also have been reported.⁴ Histopathologically, the tumor demonstrates an epithelial plate that is present in the papillary dermis and is connected to the epidermis at multiple points with attachment to the follicular outer root sheath. Peripheral palisading is characteristically present above an eosinophilic basement membrane (Figure, A). Rare reports have documented sebaceous and eccrine differentiation.^5,6

Tumor of follicular infundibulum has been reported to be associated with other tumors. Organoid nevus (nevus sebaceous), trichilemmal tumor, and fibroma have been reported to occur as a collision tumor with tumor of follicular infundibulum. An association with Cowden disease also has been described.⁷ Biopsies that represent partial samples should be interpreted cautiously, as step sections can reveal basal cell carcinoma.

The term sclerosing epithelial neoplasm describes tumors that share a paisley tielike epithelial pattern and sclerotic stroma. Small specimens often require clinicopathologic correlation (Figure, C). The differential diagnosis includes morpheaform basal cell carcinoma, desmoplastic trichoepithelioma, and microcystic adnexal carcinoma. A panel of stains using Ber-EP4, PHLDA1, cytokeratin 15, and cytokeratin 19 has been proposed to help differentiate these entities.⁸ CD34 and cytokeratin 20 also have been used with varying success in small specimens.^9,10

The Diagnosis: Collision Tumor

Excisional biopsy and histopathological examination demonstrated a collision tumor composed of a benign intradermal melanocytic nevus, tumor of follicular infundibulum, and an underlying sclerosing epithelial neoplasm, with a differential diagnosis of desmoplastic trichoepithelioma, morpheaform basal cell carcinoma, and microcystic adnexal carcinoma (Figure).

Common acquired melanocytic nevus presents clinically as a macule, papule, or nodule with smooth regular borders. The pigmented variant displays an evenly distributed pigment on the lesion. Intradermal melanocytic nevus often presents as a flesh-colored nodule, as in our case. Histopathologically, benign intradermal nevus typically is composed of a proliferation of melanocytes that exhibit dispersion as they go deeper in the dermis and maturation that manifests as melanocytes becoming smaller and more spindled in the deeper portions of the lesion.¹ These 2 characteristics plus the bland cytology seen in the present case confirm the benign characteristic of this lesion (Figure, B).

In addition to the benign intradermal melanocytic nevus, an adjacent tumor of follicular infundibulum was noted. Tumor of follicular infundibulum is a rare adnexal tumor. It occurs frequently on the head and neck and shows some female predominance.^2,3 Multiple lesions and eruptive lesions are rare forms that also have been reported.⁴ Histopathologically, the tumor demonstrates an epithelial plate that is present in the papillary dermis and is connected to the epidermis at multiple points with attachment to the follicular outer root sheath. Peripheral palisading is characteristically present above an eosinophilic basement membrane (Figure, A). Rare reports have documented sebaceous and eccrine differentiation.^5,6

Tumor of follicular infundibulum has been reported to be associated with other tumors. Organoid nevus (nevus sebaceous), trichilemmal tumor, and fibroma have been reported to occur as a collision tumor with tumor of follicular infundibulum. An association with Cowden disease also has been described.⁷ Biopsies that represent partial samples should be interpreted cautiously, as step sections can reveal basal cell carcinoma.

The term sclerosing epithelial neoplasm describes tumors that share a paisley tielike epithelial pattern and sclerotic stroma. Small specimens often require clinicopathologic correlation (Figure, C). The differential diagnosis includes morpheaform basal cell carcinoma, desmoplastic trichoepithelioma, and microcystic adnexal carcinoma. A panel of stains using Ber-EP4, PHLDA1, cytokeratin 15, and cytokeratin 19 has been proposed to help differentiate these entities.⁸ CD34 and cytokeratin 20 also have been used with varying success in small specimens.^9,10

The Diagnosis: Collision Tumor

Excisional biopsy and histopathological examination demonstrated a collision tumor composed of a benign intradermal melanocytic nevus, tumor of follicular infundibulum, and an underlying sclerosing epithelial neoplasm, with a differential diagnosis of desmoplastic trichoepithelioma, morpheaform basal cell carcinoma, and microcystic adnexal carcinoma (Figure).

Common acquired melanocytic nevus presents clinically as a macule, papule, or nodule with smooth regular borders. The pigmented variant displays an evenly distributed pigment on the lesion. Intradermal melanocytic nevus often presents as a flesh-colored nodule, as in our case. Histopathologically, benign intradermal nevus typically is composed of a proliferation of melanocytes that exhibit dispersion as they go deeper in the dermis and maturation that manifests as melanocytes becoming smaller and more spindled in the deeper portions of the lesion.¹ These 2 characteristics plus the bland cytology seen in the present case confirm the benign characteristic of this lesion (Figure, B).

In addition to the benign intradermal melanocytic nevus, an adjacent tumor of follicular infundibulum was noted. Tumor of follicular infundibulum is a rare adnexal tumor. It occurs frequently on the head and neck and shows some female predominance.^2,3 Multiple lesions and eruptive lesions are rare forms that also have been reported.⁴ Histopathologically, the tumor demonstrates an epithelial plate that is present in the papillary dermis and is connected to the epidermis at multiple points with attachment to the follicular outer root sheath. Peripheral palisading is characteristically present above an eosinophilic basement membrane (Figure, A). Rare reports have documented sebaceous and eccrine differentiation.^5,6

Tumor of follicular infundibulum has been reported to be associated with other tumors. Organoid nevus (nevus sebaceous), trichilemmal tumor, and fibroma have been reported to occur as a collision tumor with tumor of follicular infundibulum. An association with Cowden disease also has been described.⁷ Biopsies that represent partial samples should be interpreted cautiously, as step sections can reveal basal cell carcinoma.

The term sclerosing epithelial neoplasm describes tumors that share a paisley tielike epithelial pattern and sclerotic stroma. Small specimens often require clinicopathologic correlation (Figure, C). The differential diagnosis includes morpheaform basal cell carcinoma, desmoplastic trichoepithelioma, and microcystic adnexal carcinoma. A panel of stains using Ber-EP4, PHLDA1, cytokeratin 15, and cytokeratin 19 has been proposed to help differentiate these entities.⁸ CD34 and cytokeratin 20 also have been used with varying success in small specimens.^9,10

The Diagnosis: Erythema Dyschromicum Perstans

Erythema dyschromicum perstans (EDP), also referred to as ashy dermatosis, was first described by Ramirez¹ in 1957 who labeled the patients los cenicientos (the ashen ones). It preferentially affects women in the second decade of life; however, patients of all ages can be affected, with reported cases occurring in children as young as 2 years of age.² Most patients have Fitzpatrick skin type IV, mainly Amerindian, Hispanic South Asian, and Southwest Asian; however, there are cases reported worldwide.³ A genetic predisposition is proposed, as major histocompatibility complex genes associated with HLA-DR4⁎0407 are frequent in Mexican patients with ashy dermatosis and in the Amerindian population.⁴

The etiology of EDP is unknown. Various contributing factors have been reported including alimentary, occupational, and climatic factors,^5,6 yet none have been conclusively demonstrated. High expression of CD36 (thrombospondin receptor not found in normal skin) in spinous and granular layers, CD94 (cytotoxic cell marker) in the basal cell layer and in the inflammatory dermal infiltrate,⁷ and focal keratinocytic expression of intercellular adhesion molecule I (CD54) in the active lesions of EDP, as well as the absence of these findings in normal skin, suggests an immunologic role in the development of the disease.⁸

Erythema dyschromicum perstans presents clinically with blue-gray hyperpigmented macules varying in size and shape and developing symmetrically in both sun-exposed and sun-protected areas of the face, neck, trunk, arms, and sometimes the dorsal hands (Figures 1 and 2). Notable sparing of the palms, soles, scalp, and mucous membranes occurs.

Occasionally, in the early active stage of the disease, elevated erythematous borders are noted surrounding the hyperpigmented macules. Eventually a hypopigmented halo develops after a prolonged duration of disease.⁹ The eruption typically is chronic and asymptomatic, though some cases may be pruritic.¹⁰

Histopathologically, the early lesions of EDP with an erythematous active border reveal lichenoid dermatitis with basal vacuolar change and occasional Civatte bodies. A mild to moderate perivascular lymphohistiocytic infiltrate admixed with melanophages can be seen in the papillary dermis (Figure 3). In older lesions, the inflammatory infiltrate is sparse, and pigment incontinence consistent with postinflammatory pigmentation is prominent, though melanophages extending deep into the reticular dermis may aid in distinguishing EDP from other causes of postinflammatory pigment alteration.^7,11

Erythema dyschromicum perstans and lichen planus pigmentosus (LPP) may be indistinguishable histopathologically and may both be variants of lichen planus actinicus. Lichen planus pigmentosus often differs from EDP in that it presents with brown-black macules and patches often on the face and flexural areas. A subset of cases of LPP also may have mucous membrane involvement. The erythematous border that characterizes the active lesion of EDP is characteristically absent in LPP. In addition, pruritus often is reported with LPP. Direct immunofluorescence is not a beneficial tool in distinguishing the entities.¹²

Other differential diagnoses of predominantly facial hyperpigmentation include a lichenoid drug eruption; drug-induced hyperpigmentation (deposition disorder); postinflammatory hyperpigmentation following atopic dermatitis; contact dermatitis or photosensitivity reaction; early pinta; and cutaneous findings of systemic diseases manifesting with diffuse hyperpigmentation such as lupus erythematosus, dermatomyositis, hemochromatosis, and Addison disease. A detailed history including medication use, thorough clinical examination, and careful histopathologic evaluation will help distinguish these conditions.

Chrysiasis is a rare bluish to slate gray discoloration of the skin that predominantly occurs in sun-exposed areas. It is caused by chronic use of gold salts, which have been used to treat rheumatoid arthritis. UV light may contribute to induce the uptake of gold and subsequently stimulate tyrosinase activity.¹³ Histologic features of chrysiasis include dermal and perivascular gold deposition within the macrophages and endothelial cells as well as extracellular granules. It demonstrates an orange-red birefringence on fluorescent microscopy.^14,15

Minocycline-induced hyperpigmentation is a well-recognized side effect of this drug. It is dose dependent and appears as a blue-black pigmentation that most frequently affects the shins, ankles, and arms.¹⁶ Three distinct types were documented: abnormal discoloration of the skin that has been linked to deposition of pigmented metabolites of minocycline producing blue-black pigmentation at the site of scarring or prior inflammation (type 1); blue-gray pigmentation affecting normal skin, mainly the legs (type 2); and elevated levels of melanin on the sun-exposed areas producing dirty skin syndrome (type 3).^17,18

Topical and systemic corticosteroids, UV light therapy, oral dapsone, griseofulvin, retinoids, and clofazimine are reported as treatment options for ashy dermatosis, though results typically are disappointing.⁷

The Diagnosis: Erythema Dyschromicum Perstans

Erythema dyschromicum perstans (EDP), also referred to as ashy dermatosis, was first described by Ramirez¹ in 1957 who labeled the patients los cenicientos (the ashen ones). It preferentially affects women in the second decade of life; however, patients of all ages can be affected, with reported cases occurring in children as young as 2 years of age.² Most patients have Fitzpatrick skin type IV, mainly Amerindian, Hispanic South Asian, and Southwest Asian; however, there are cases reported worldwide.³ A genetic predisposition is proposed, as major histocompatibility complex genes associated with HLA-DR4⁎0407 are frequent in Mexican patients with ashy dermatosis and in the Amerindian population.⁴

The etiology of EDP is unknown. Various contributing factors have been reported including alimentary, occupational, and climatic factors,^5,6 yet none have been conclusively demonstrated. High expression of CD36 (thrombospondin receptor not found in normal skin) in spinous and granular layers, CD94 (cytotoxic cell marker) in the basal cell layer and in the inflammatory dermal infiltrate,⁷ and focal keratinocytic expression of intercellular adhesion molecule I (CD54) in the active lesions of EDP, as well as the absence of these findings in normal skin, suggests an immunologic role in the development of the disease.⁸

Erythema dyschromicum perstans presents clinically with blue-gray hyperpigmented macules varying in size and shape and developing symmetrically in both sun-exposed and sun-protected areas of the face, neck, trunk, arms, and sometimes the dorsal hands (Figures 1 and 2). Notable sparing of the palms, soles, scalp, and mucous membranes occurs.

Occasionally, in the early active stage of the disease, elevated erythematous borders are noted surrounding the hyperpigmented macules. Eventually a hypopigmented halo develops after a prolonged duration of disease.⁹ The eruption typically is chronic and asymptomatic, though some cases may be pruritic.¹⁰

Histopathologically, the early lesions of EDP with an erythematous active border reveal lichenoid dermatitis with basal vacuolar change and occasional Civatte bodies. A mild to moderate perivascular lymphohistiocytic infiltrate admixed with melanophages can be seen in the papillary dermis (Figure 3). In older lesions, the inflammatory infiltrate is sparse, and pigment incontinence consistent with postinflammatory pigmentation is prominent, though melanophages extending deep into the reticular dermis may aid in distinguishing EDP from other causes of postinflammatory pigment alteration.^7,11

Erythema dyschromicum perstans and lichen planus pigmentosus (LPP) may be indistinguishable histopathologically and may both be variants of lichen planus actinicus. Lichen planus pigmentosus often differs from EDP in that it presents with brown-black macules and patches often on the face and flexural areas. A subset of cases of LPP also may have mucous membrane involvement. The erythematous border that characterizes the active lesion of EDP is characteristically absent in LPP. In addition, pruritus often is reported with LPP. Direct immunofluorescence is not a beneficial tool in distinguishing the entities.¹²

Other differential diagnoses of predominantly facial hyperpigmentation include a lichenoid drug eruption; drug-induced hyperpigmentation (deposition disorder); postinflammatory hyperpigmentation following atopic dermatitis; contact dermatitis or photosensitivity reaction; early pinta; and cutaneous findings of systemic diseases manifesting with diffuse hyperpigmentation such as lupus erythematosus, dermatomyositis, hemochromatosis, and Addison disease. A detailed history including medication use, thorough clinical examination, and careful histopathologic evaluation will help distinguish these conditions.

Chrysiasis is a rare bluish to slate gray discoloration of the skin that predominantly occurs in sun-exposed areas. It is caused by chronic use of gold salts, which have been used to treat rheumatoid arthritis. UV light may contribute to induce the uptake of gold and subsequently stimulate tyrosinase activity.¹³ Histologic features of chrysiasis include dermal and perivascular gold deposition within the macrophages and endothelial cells as well as extracellular granules. It demonstrates an orange-red birefringence on fluorescent microscopy.^14,15

Minocycline-induced hyperpigmentation is a well-recognized side effect of this drug. It is dose dependent and appears as a blue-black pigmentation that most frequently affects the shins, ankles, and arms.¹⁶ Three distinct types were documented: abnormal discoloration of the skin that has been linked to deposition of pigmented metabolites of minocycline producing blue-black pigmentation at the site of scarring or prior inflammation (type 1); blue-gray pigmentation affecting normal skin, mainly the legs (type 2); and elevated levels of melanin on the sun-exposed areas producing dirty skin syndrome (type 3).^17,18

Topical and systemic corticosteroids, UV light therapy, oral dapsone, griseofulvin, retinoids, and clofazimine are reported as treatment options for ashy dermatosis, though results typically are disappointing.⁷

The Diagnosis: Erythema Dyschromicum Perstans

Erythema dyschromicum perstans (EDP), also referred to as ashy dermatosis, was first described by Ramirez¹ in 1957 who labeled the patients los cenicientos (the ashen ones). It preferentially affects women in the second decade of life; however, patients of all ages can be affected, with reported cases occurring in children as young as 2 years of age.² Most patients have Fitzpatrick skin type IV, mainly Amerindian, Hispanic South Asian, and Southwest Asian; however, there are cases reported worldwide.³ A genetic predisposition is proposed, as major histocompatibility complex genes associated with HLA-DR4⁎0407 are frequent in Mexican patients with ashy dermatosis and in the Amerindian population.⁴

The etiology of EDP is unknown. Various contributing factors have been reported including alimentary, occupational, and climatic factors,^5,6 yet none have been conclusively demonstrated. High expression of CD36 (thrombospondin receptor not found in normal skin) in spinous and granular layers, CD94 (cytotoxic cell marker) in the basal cell layer and in the inflammatory dermal infiltrate,⁷ and focal keratinocytic expression of intercellular adhesion molecule I (CD54) in the active lesions of EDP, as well as the absence of these findings in normal skin, suggests an immunologic role in the development of the disease.⁸

Erythema dyschromicum perstans presents clinically with blue-gray hyperpigmented macules varying in size and shape and developing symmetrically in both sun-exposed and sun-protected areas of the face, neck, trunk, arms, and sometimes the dorsal hands (Figures 1 and 2). Notable sparing of the palms, soles, scalp, and mucous membranes occurs.

Occasionally, in the early active stage of the disease, elevated erythematous borders are noted surrounding the hyperpigmented macules. Eventually a hypopigmented halo develops after a prolonged duration of disease.⁹ The eruption typically is chronic and asymptomatic, though some cases may be pruritic.¹⁰

Histopathologically, the early lesions of EDP with an erythematous active border reveal lichenoid dermatitis with basal vacuolar change and occasional Civatte bodies. A mild to moderate perivascular lymphohistiocytic infiltrate admixed with melanophages can be seen in the papillary dermis (Figure 3). In older lesions, the inflammatory infiltrate is sparse, and pigment incontinence consistent with postinflammatory pigmentation is prominent, though melanophages extending deep into the reticular dermis may aid in distinguishing EDP from other causes of postinflammatory pigment alteration.^7,11

Erythema dyschromicum perstans and lichen planus pigmentosus (LPP) may be indistinguishable histopathologically and may both be variants of lichen planus actinicus. Lichen planus pigmentosus often differs from EDP in that it presents with brown-black macules and patches often on the face and flexural areas. A subset of cases of LPP also may have mucous membrane involvement. The erythematous border that characterizes the active lesion of EDP is characteristically absent in LPP. In addition, pruritus often is reported with LPP. Direct immunofluorescence is not a beneficial tool in distinguishing the entities.¹²

Other differential diagnoses of predominantly facial hyperpigmentation include a lichenoid drug eruption; drug-induced hyperpigmentation (deposition disorder); postinflammatory hyperpigmentation following atopic dermatitis; contact dermatitis or photosensitivity reaction; early pinta; and cutaneous findings of systemic diseases manifesting with diffuse hyperpigmentation such as lupus erythematosus, dermatomyositis, hemochromatosis, and Addison disease. A detailed history including medication use, thorough clinical examination, and careful histopathologic evaluation will help distinguish these conditions.

Chrysiasis is a rare bluish to slate gray discoloration of the skin that predominantly occurs in sun-exposed areas. It is caused by chronic use of gold salts, which have been used to treat rheumatoid arthritis. UV light may contribute to induce the uptake of gold and subsequently stimulate tyrosinase activity.¹³ Histologic features of chrysiasis include dermal and perivascular gold deposition within the macrophages and endothelial cells as well as extracellular granules. It demonstrates an orange-red birefringence on fluorescent microscopy.^14,15

Minocycline-induced hyperpigmentation is a well-recognized side effect of this drug. It is dose dependent and appears as a blue-black pigmentation that most frequently affects the shins, ankles, and arms.¹⁶ Three distinct types were documented: abnormal discoloration of the skin that has been linked to deposition of pigmented metabolites of minocycline producing blue-black pigmentation at the site of scarring or prior inflammation (type 1); blue-gray pigmentation affecting normal skin, mainly the legs (type 2); and elevated levels of melanin on the sun-exposed areas producing dirty skin syndrome (type 3).^17,18

Topical and systemic corticosteroids, UV light therapy, oral dapsone, griseofulvin, retinoids, and clofazimine are reported as treatment options for ashy dermatosis, though results typically are disappointing.⁷

The lone star tick (Amblyomma americanum) is distributed throughout much of the eastern United States. It serves as a vector for species of Rickettsia, Ehrlichia, and Borrelia that are an important cause of tick-borne illness (Table). In addition, the bite of the lone star tick can cause impressive local and systemic reactions. Delayed anaphylaxis to ingestion of red meat has been attributed to the bite of A americanum.¹ Herein, we discuss human disease associated with the lone star tick as well as potential tick-control measures.

Tick Characteristics

Lone star ticks are characterized by long anterior mouthparts and an ornate scutum (hard dorsal plate). Widely spaced eyes and posterior festoons also are present. In contrast to some other ticks, adanal plates are absent on the ventral surface in male lone star ticks. Amblyomma americanum demonstrates a single white spot on the female’s scutum (Figure 1). The male has inverted horseshoe markings on the posterior scutum. The female’s scutum often covers only a portion of the body to allow room for engorgement.

Patients usually become aware of tick bites while the tick is still attached to the skin, which provides the physician with an opportunity to identify the tick and discuss tick-control measures as well as symptoms of tick-borne disease. Once the tick has been removed, delayed-type hypersensitivity to the tick antigens continues at the attachment site. Erythema and pruritus can be dramatic. Nodules with a pseudolymphomatous histology can occur. Milder reactions respond to application of topical corticosteroids. More intense reactions may require intralesional corticosteroid injection or even surgical excision.

Most hard ticks have a 3-host life cycle, meaning they attach for one long blood meal during each phase of the life cycle. Because they search for a new host for each blood meal, they are efficient disease vectors. The larval ticks, so-called seed ticks, have 6 legs and feed on small animals. Nymphs and adults feed on larger animals. Nymphs resemble small adult ticks with 8 legs but are sexually immature.

Distribution

Amblyomma americanum has a wide distribution in the United States from Texas to Iowa and as far north as Maine (Figure 2).² Tick attachments often are seen in individuals who work outdoors, especially in areas where new commercial or residential development disrupts the environment and the tick’s usual hosts move out of the area. Hungry ticks are left behind in search of a host.

Disease Transmission

Lone star ticks have been implicated as vectors of Ehrlichia chaffeensis, the agent of human monocytic ehrlichiosis (HME),³ which has been documented from the mid-Atlantic to south-central United States. It may present as a somewhat milder Rocky Mountain spotted fever–like illness with fever and headache or as a life-threatening systemic illness with organ failure. Prompt diagnosis and treatment with a tetracycline has been correlated with a better prognosis.⁴ Immunofluorescent antibody testing and polymerase chain reaction can be used to establish the diagnosis.⁵ Two tick species—A americanum and Dermacentor variabilis—have been implicated as vectors, but A americanum appears to be the major vector.^6,7

The lone star tick also is a vector for Erlichia ewingii, the cause of human ehrlichiosis ewingii. Human ehrlichiosis ewingii is a rare disease that presents similar to HME, with most reported cases occurring in immunocompromised hosts.⁸

A novel member of the Phlebovirus genus, the Heartland virus, was first described in 2 Missouri farmers who presented with symptoms similar to HME but did not respond to doxycycline treatment.⁹ The virus has since been isolated from A americanum adult ticks, implicating them as the major vectors of the disease.¹⁰

Rickettsia parkeri, a cause of spotted fever rickettsiosis, is responsible for an eschar-associated illness in affected individuals.¹¹ The organism has been detected in A americanum ticks collected from the wild. Experiments show the tick is capable of transmitting R parkeri to animals in the laboratory. It is unclear, however, what role A americanum plays in the natural transmission of the disease.¹²

In Missouri, strains of Borrelia have been isolated from A americanum ticks that feed on cottontail rabbits, but it seems unlikely that the tick plays any role in transmission of true Lyme disease^13,14; Borrelia has been shown to have poor survival in the saliva of A americanum beyond 24 hours.¹⁵ Southern tick–associated rash illness is a Lyme disease–like illness with several reported cases due to A americanum.¹⁶ Patients generally present with an erythema migrans–like rash and may have headache, fever, arthralgia, or myalgia.¹⁶ The causative organism remains unclear, though Borrelia lonestari has been implicated.¹⁷ Lone star ticks also transmit tularemia and may transmit Rocky Mountain spotted fever and Q fever.¹³

Bullis fever (first reported at Camp Bullis near San Antonio, Texas) affected huge numbers of military personnel from 1942 to 1943.¹⁸ The causative organism appears to be rickettsial. During one outbreak of Bullis fever, it was noted that A americanum was so numerous that more than 4000 adult ticks were collected under a single juniper tree and more than 1000 ticks were removed from a single soldier who sat in a thicket for 2 hours.¹² No cases of Bullis fever have been reported in recent years,¹² which probably relates to the introduction of fire ants.

Disease Hosts

At Little Rock Air Force Base in Arkansas, A americanum has been a source of Ehrlichia infection. During one outbreak, deer in the area were found to have as many as 2550 ticks per ear,¹⁹ which demonstrates the magnitude of tick infestation in some areas of the United States. Tick infestation is not merely of concern to the US military. Ticks are ubiquitous and can be found on neatly trimmed suburban lawns as well as in rough thickets.

More recently, bites from A americanum have been found to induce allergies to red meat in some patients.¹ IgE antibodies directed against galactose-alpha-1,3-galactose (alpha gal) have been implicated as the cause of this reaction. These antibodies cause delayed-onset anaphylaxis occurring 3 to 6 hours after ingestion of red meat. Tick bites appear to be the most important and perhaps the only cause of IgE antibodies to alpha gal in the United States.¹

Wild white-tailed deer serve as reservoir hosts for several diseases transmitted by A americanum, including HME, human ehrlichiosis ewingii, and Southern tick–associated rash illness.^12,20 Communities located close to wildlife reserves may have higher rates of infection.²¹ Application of acaricides to corn contained in deer feeders has been shown to be an effective method of decreasing local tick populations, which is a potential method for disease control in at-risk areas, though it is costly and time consuming.²²

Tick-Control Measures

Hard ticks produce little urine. Instead, excess water is eliminated via salivation back into the host. Loss of water also occurs through spiracles. Absorption of water from the atmosphere is important for the tick to maintain hydration. The tick produces intensely hygroscopic saliva that absorbs water from surrounding moist air. The humidified saliva is then reingested by the tick. In hot climates, ticks are prone to dehydration unless they can find a source of moist air, usually within a layer of leaf debris.²³ When the leaf debris is stirred by a human walking through the area, the tick can make contact with the human. Therefore, removal of leaf debris is a critical part of tick-control efforts, as it reduces tick numbers by means of dehydration. Tick eggs also require sufficient humidity to hatch. Leaf removal increases the effectiveness of insecticide applications, which would otherwise do little harm to the ticks below if sprayed on top of leaf debris.

Some lone star ticks attach to birds and disseminate widely. Attachments to animal hosts with long-range migration patterns complicate tick-control efforts.²⁴ Animal migration may contribute to the spread of disease from one geographic region to another.

Imported fire ants are voracious eaters that gather and consume ticks eggs. Fire ants provide an excellent natural means of tick control. Tick numbers in places such as Camp Bullis have declined dramatically since the introduction of imported fire ants.²⁵

The lone star tick (Amblyomma americanum) is distributed throughout much of the eastern United States. It serves as a vector for species of Rickettsia, Ehrlichia, and Borrelia that are an important cause of tick-borne illness (Table). In addition, the bite of the lone star tick can cause impressive local and systemic reactions. Delayed anaphylaxis to ingestion of red meat has been attributed to the bite of A americanum.¹ Herein, we discuss human disease associated with the lone star tick as well as potential tick-control measures.

Tick Characteristics

Lone star ticks are characterized by long anterior mouthparts and an ornate scutum (hard dorsal plate). Widely spaced eyes and posterior festoons also are present. In contrast to some other ticks, adanal plates are absent on the ventral surface in male lone star ticks. Amblyomma americanum demonstrates a single white spot on the female’s scutum (Figure 1). The male has inverted horseshoe markings on the posterior scutum. The female’s scutum often covers only a portion of the body to allow room for engorgement.

Patients usually become aware of tick bites while the tick is still attached to the skin, which provides the physician with an opportunity to identify the tick and discuss tick-control measures as well as symptoms of tick-borne disease. Once the tick has been removed, delayed-type hypersensitivity to the tick antigens continues at the attachment site. Erythema and pruritus can be dramatic. Nodules with a pseudolymphomatous histology can occur. Milder reactions respond to application of topical corticosteroids. More intense reactions may require intralesional corticosteroid injection or even surgical excision.

Most hard ticks have a 3-host life cycle, meaning they attach for one long blood meal during each phase of the life cycle. Because they search for a new host for each blood meal, they are efficient disease vectors. The larval ticks, so-called seed ticks, have 6 legs and feed on small animals. Nymphs and adults feed on larger animals. Nymphs resemble small adult ticks with 8 legs but are sexually immature.

Distribution

Amblyomma americanum has a wide distribution in the United States from Texas to Iowa and as far north as Maine (Figure 2).² Tick attachments often are seen in individuals who work outdoors, especially in areas where new commercial or residential development disrupts the environment and the tick’s usual hosts move out of the area. Hungry ticks are left behind in search of a host.

Disease Transmission

Lone star ticks have been implicated as vectors of Ehrlichia chaffeensis, the agent of human monocytic ehrlichiosis (HME),³ which has been documented from the mid-Atlantic to south-central United States. It may present as a somewhat milder Rocky Mountain spotted fever–like illness with fever and headache or as a life-threatening systemic illness with organ failure. Prompt diagnosis and treatment with a tetracycline has been correlated with a better prognosis.⁴ Immunofluorescent antibody testing and polymerase chain reaction can be used to establish the diagnosis.⁵ Two tick species—A americanum and Dermacentor variabilis—have been implicated as vectors, but A americanum appears to be the major vector.^6,7

The lone star tick also is a vector for Erlichia ewingii, the cause of human ehrlichiosis ewingii. Human ehrlichiosis ewingii is a rare disease that presents similar to HME, with most reported cases occurring in immunocompromised hosts.⁸

A novel member of the Phlebovirus genus, the Heartland virus, was first described in 2 Missouri farmers who presented with symptoms similar to HME but did not respond to doxycycline treatment.⁹ The virus has since been isolated from A americanum adult ticks, implicating them as the major vectors of the disease.¹⁰

Rickettsia parkeri, a cause of spotted fever rickettsiosis, is responsible for an eschar-associated illness in affected individuals.¹¹ The organism has been detected in A americanum ticks collected from the wild. Experiments show the tick is capable of transmitting R parkeri to animals in the laboratory. It is unclear, however, what role A americanum plays in the natural transmission of the disease.¹²

In Missouri, strains of Borrelia have been isolated from A americanum ticks that feed on cottontail rabbits, but it seems unlikely that the tick plays any role in transmission of true Lyme disease^13,14; Borrelia has been shown to have poor survival in the saliva of A americanum beyond 24 hours.¹⁵ Southern tick–associated rash illness is a Lyme disease–like illness with several reported cases due to A americanum.¹⁶ Patients generally present with an erythema migrans–like rash and may have headache, fever, arthralgia, or myalgia.¹⁶ The causative organism remains unclear, though Borrelia lonestari has been implicated.¹⁷ Lone star ticks also transmit tularemia and may transmit Rocky Mountain spotted fever and Q fever.¹³

Bullis fever (first reported at Camp Bullis near San Antonio, Texas) affected huge numbers of military personnel from 1942 to 1943.¹⁸ The causative organism appears to be rickettsial. During one outbreak of Bullis fever, it was noted that A americanum was so numerous that more than 4000 adult ticks were collected under a single juniper tree and more than 1000 ticks were removed from a single soldier who sat in a thicket for 2 hours.¹² No cases of Bullis fever have been reported in recent years,¹² which probably relates to the introduction of fire ants.

Disease Hosts

At Little Rock Air Force Base in Arkansas, A americanum has been a source of Ehrlichia infection. During one outbreak, deer in the area were found to have as many as 2550 ticks per ear,¹⁹ which demonstrates the magnitude of tick infestation in some areas of the United States. Tick infestation is not merely of concern to the US military. Ticks are ubiquitous and can be found on neatly trimmed suburban lawns as well as in rough thickets.

More recently, bites from A americanum have been found to induce allergies to red meat in some patients.¹ IgE antibodies directed against galactose-alpha-1,3-galactose (alpha gal) have been implicated as the cause of this reaction. These antibodies cause delayed-onset anaphylaxis occurring 3 to 6 hours after ingestion of red meat. Tick bites appear to be the most important and perhaps the only cause of IgE antibodies to alpha gal in the United States.¹

Wild white-tailed deer serve as reservoir hosts for several diseases transmitted by A americanum, including HME, human ehrlichiosis ewingii, and Southern tick–associated rash illness.^12,20 Communities located close to wildlife reserves may have higher rates of infection.²¹ Application of acaricides to corn contained in deer feeders has been shown to be an effective method of decreasing local tick populations, which is a potential method for disease control in at-risk areas, though it is costly and time consuming.²²

Tick-Control Measures

Hard ticks produce little urine. Instead, excess water is eliminated via salivation back into the host. Loss of water also occurs through spiracles. Absorption of water from the atmosphere is important for the tick to maintain hydration. The tick produces intensely hygroscopic saliva that absorbs water from surrounding moist air. The humidified saliva is then reingested by the tick. In hot climates, ticks are prone to dehydration unless they can find a source of moist air, usually within a layer of leaf debris.²³ When the leaf debris is stirred by a human walking through the area, the tick can make contact with the human. Therefore, removal of leaf debris is a critical part of tick-control efforts, as it reduces tick numbers by means of dehydration. Tick eggs also require sufficient humidity to hatch. Leaf removal increases the effectiveness of insecticide applications, which would otherwise do little harm to the ticks below if sprayed on top of leaf debris.

Some lone star ticks attach to birds and disseminate widely. Attachments to animal hosts with long-range migration patterns complicate tick-control efforts.²⁴ Animal migration may contribute to the spread of disease from one geographic region to another.

Imported fire ants are voracious eaters that gather and consume ticks eggs. Fire ants provide an excellent natural means of tick control. Tick numbers in places such as Camp Bullis have declined dramatically since the introduction of imported fire ants.²⁵

The lone star tick (Amblyomma americanum) is distributed throughout much of the eastern United States. It serves as a vector for species of Rickettsia, Ehrlichia, and Borrelia that are an important cause of tick-borne illness (Table). In addition, the bite of the lone star tick can cause impressive local and systemic reactions. Delayed anaphylaxis to ingestion of red meat has been attributed to the bite of A americanum.¹ Herein, we discuss human disease associated with the lone star tick as well as potential tick-control measures.

Tick Characteristics

Lone star ticks are characterized by long anterior mouthparts and an ornate scutum (hard dorsal plate). Widely spaced eyes and posterior festoons also are present. In contrast to some other ticks, adanal plates are absent on the ventral surface in male lone star ticks. Amblyomma americanum demonstrates a single white spot on the female’s scutum (Figure 1). The male has inverted horseshoe markings on the posterior scutum. The female’s scutum often covers only a portion of the body to allow room for engorgement.

Patients usually become aware of tick bites while the tick is still attached to the skin, which provides the physician with an opportunity to identify the tick and discuss tick-control measures as well as symptoms of tick-borne disease. Once the tick has been removed, delayed-type hypersensitivity to the tick antigens continues at the attachment site. Erythema and pruritus can be dramatic. Nodules with a pseudolymphomatous histology can occur. Milder reactions respond to application of topical corticosteroids. More intense reactions may require intralesional corticosteroid injection or even surgical excision.

Most hard ticks have a 3-host life cycle, meaning they attach for one long blood meal during each phase of the life cycle. Because they search for a new host for each blood meal, they are efficient disease vectors. The larval ticks, so-called seed ticks, have 6 legs and feed on small animals. Nymphs and adults feed on larger animals. Nymphs resemble small adult ticks with 8 legs but are sexually immature.

Distribution

Amblyomma americanum has a wide distribution in the United States from Texas to Iowa and as far north as Maine (Figure 2).² Tick attachments often are seen in individuals who work outdoors, especially in areas where new commercial or residential development disrupts the environment and the tick’s usual hosts move out of the area. Hungry ticks are left behind in search of a host.

Disease Transmission

Lone star ticks have been implicated as vectors of Ehrlichia chaffeensis, the agent of human monocytic ehrlichiosis (HME),³ which has been documented from the mid-Atlantic to south-central United States. It may present as a somewhat milder Rocky Mountain spotted fever–like illness with fever and headache or as a life-threatening systemic illness with organ failure. Prompt diagnosis and treatment with a tetracycline has been correlated with a better prognosis.⁴ Immunofluorescent antibody testing and polymerase chain reaction can be used to establish the diagnosis.⁵ Two tick species—A americanum and Dermacentor variabilis—have been implicated as vectors, but A americanum appears to be the major vector.^6,7

The lone star tick also is a vector for Erlichia ewingii, the cause of human ehrlichiosis ewingii. Human ehrlichiosis ewingii is a rare disease that presents similar to HME, with most reported cases occurring in immunocompromised hosts.⁸

A novel member of the Phlebovirus genus, the Heartland virus, was first described in 2 Missouri farmers who presented with symptoms similar to HME but did not respond to doxycycline treatment.⁹ The virus has since been isolated from A americanum adult ticks, implicating them as the major vectors of the disease.¹⁰

Rickettsia parkeri, a cause of spotted fever rickettsiosis, is responsible for an eschar-associated illness in affected individuals.¹¹ The organism has been detected in A americanum ticks collected from the wild. Experiments show the tick is capable of transmitting R parkeri to animals in the laboratory. It is unclear, however, what role A americanum plays in the natural transmission of the disease.¹²

In Missouri, strains of Borrelia have been isolated from A americanum ticks that feed on cottontail rabbits, but it seems unlikely that the tick plays any role in transmission of true Lyme disease^13,14; Borrelia has been shown to have poor survival in the saliva of A americanum beyond 24 hours.¹⁵ Southern tick–associated rash illness is a Lyme disease–like illness with several reported cases due to A americanum.¹⁶ Patients generally present with an erythema migrans–like rash and may have headache, fever, arthralgia, or myalgia.¹⁶ The causative organism remains unclear, though Borrelia lonestari has been implicated.¹⁷ Lone star ticks also transmit tularemia and may transmit Rocky Mountain spotted fever and Q fever.¹³

Bullis fever (first reported at Camp Bullis near San Antonio, Texas) affected huge numbers of military personnel from 1942 to 1943.¹⁸ The causative organism appears to be rickettsial. During one outbreak of Bullis fever, it was noted that A americanum was so numerous that more than 4000 adult ticks were collected under a single juniper tree and more than 1000 ticks were removed from a single soldier who sat in a thicket for 2 hours.¹² No cases of Bullis fever have been reported in recent years,¹² which probably relates to the introduction of fire ants.

Disease Hosts

At Little Rock Air Force Base in Arkansas, A americanum has been a source of Ehrlichia infection. During one outbreak, deer in the area were found to have as many as 2550 ticks per ear,¹⁹ which demonstrates the magnitude of tick infestation in some areas of the United States. Tick infestation is not merely of concern to the US military. Ticks are ubiquitous and can be found on neatly trimmed suburban lawns as well as in rough thickets.

More recently, bites from A americanum have been found to induce allergies to red meat in some patients.¹ IgE antibodies directed against galactose-alpha-1,3-galactose (alpha gal) have been implicated as the cause of this reaction. These antibodies cause delayed-onset anaphylaxis occurring 3 to 6 hours after ingestion of red meat. Tick bites appear to be the most important and perhaps the only cause of IgE antibodies to alpha gal in the United States.¹

Wild white-tailed deer serve as reservoir hosts for several diseases transmitted by A americanum, including HME, human ehrlichiosis ewingii, and Southern tick–associated rash illness.^12,20 Communities located close to wildlife reserves may have higher rates of infection.²¹ Application of acaricides to corn contained in deer feeders has been shown to be an effective method of decreasing local tick populations, which is a potential method for disease control in at-risk areas, though it is costly and time consuming.²²

Tick-Control Measures

Hard ticks produce little urine. Instead, excess water is eliminated via salivation back into the host. Loss of water also occurs through spiracles. Absorption of water from the atmosphere is important for the tick to maintain hydration. The tick produces intensely hygroscopic saliva that absorbs water from surrounding moist air. The humidified saliva is then reingested by the tick. In hot climates, ticks are prone to dehydration unless they can find a source of moist air, usually within a layer of leaf debris.²³ When the leaf debris is stirred by a human walking through the area, the tick can make contact with the human. Therefore, removal of leaf debris is a critical part of tick-control efforts, as it reduces tick numbers by means of dehydration. Tick eggs also require sufficient humidity to hatch. Leaf removal increases the effectiveness of insecticide applications, which would otherwise do little harm to the ticks below if sprayed on top of leaf debris.

Some lone star ticks attach to birds and disseminate widely. Attachments to animal hosts with long-range migration patterns complicate tick-control efforts.²⁴ Animal migration may contribute to the spread of disease from one geographic region to another.

Imported fire ants are voracious eaters that gather and consume ticks eggs. Fire ants provide an excellent natural means of tick control. Tick numbers in places such as Camp Bullis have declined dramatically since the introduction of imported fire ants.²⁵

As employers search for ways to reduce the cost of providing health care to their employees, there is a growing trend toward narrowed provider networks and exclusive laboratory contracts. In the case of clinical pathology, some of these choices make sense from the employer’s perspective. A complete blood cell count or comprehensive metabolic panel is done on a machine and the result is much the same regardless of the laboratory. So why not have all laboratory tests performed by the lowest bidder?

Laboratories vary in quality and anatomic pathology services are different from blood tests. Each slide must be interpreted by a physician and skill in the interpretation of skin specimens varies widely. Dermatopathology was one of the first subspecialties to be recognized within pathology, as it requires a high level of expertise. Clinicopathological correlation often is key to the accurate interpretation of a specimen. The stakes are high, and a delay in diagnosis of melanoma remains one of the most serious errors in medicine and one of the most common causes for litigation in dermatology.

The accurate interpretation of skin biopsy specimens becomes especially difficult when inadequate or misleading clinical information accompanies the specimen. A study of 589 biopsies submitted by primary care physicians and reported by general pathologists demonstrated a 6.5% error rate. False-negative errors were the most common, but false-positives also were observed.¹ A study of pigmented lesions referred to the University of California, San Francisco, demonstrated a discordance rate of 14.3%.² The degree of discordance would be expected to vary based on the range of diagnoses included in each study.

Board-certified dermatopathologists have varying areas of expertise and there is notable subjectivity in the interpretation of biopsy specimens. In the case of problematic pigmented lesions such as atypical Spitz nevi, there can be low interobserver agreement even among the experts in categorizing lesions as malignant versus nonmalignant (κ=0.30).³ The low concordance among expert dermatopathologists demonstrates that light microscopic features alone often are inadequate for diagnosis. Advanced studies, including immunohistochemical stains, can help to clarify the diagnosis. In the case of atypical Spitz tumors, the contribution of special stains to the final diagnosis is statistically similar to that of hematoxylin and eosin sections and age, suggesting that nothing alone is sufficiently reliable to establish a definitive diagnosis in every case.⁴ Although helpful, these studies are costly, and savings obtained by sending cases to the lowest bidder can evaporate quickly. Costs are higher when factoring in molecular studies, which can run upwards of $3000 per slide; the cost of litigation related to incorrect diagnoses; or the human costs of an incorrect diagnosis.

As a group, dermatopathologists are highly skilled in the interpretation of skin specimens, but challenging lesions are common in the routine practice of dermatopathology. A study of 1249 pigmented melanocytic lesions demonstrated substantial agreement among expert dermatopathologists for less problematic lesions, though agreement was greater for patients 40 years and older (κ=0.67) than for younger patients (κ=0.49). Agreement was lower for patients with atypical mole syndrome (κ=0.31).⁵ These discrepancies occur despite the fact that there is good interobserver reproducibility for grading of individual histological features such as asymmetry, circumscription, irregular confluent nests, single melanocytes predominating, absence of maturation, suprabasal melanocytes, symmetrical melanin, deep melanin, cytological atypia, mitoses, dermal lymphocytic infiltrate, and necrosis.⁶ These results indicate that accurate diagnoses cannot be reliably established simply by grading a list of histological features. Accurate diagnosis requires complex pattern recognition and integration of findings. Conflicting criteria often are present and an accurate interpretation requires considerable judgment as to which features are significant and which are not.

Separation of sebaceous adenoma, sebaceoma, and well-differentiated sebaceous carcinoma is another challenging area, and interobserver consensus can be as low as 11%,⁷ which suggests notable subjectivity in the criteria for diagnosis of nonmelanocytic tumors and emphasizes the importance of communication between the dermatopathologist and clinician when determining how to manage an ambiguous lesion. The interpretation of inflammatory skin diseases, alopecia, and lymphoid proliferations also can be problematic, and expert consultation often is required.

All dermatologists receive substantial training in dermatopathology, which puts them in an excellent position to interpret ambiguous findings in the context of the clinical presentation. Sometimes the dermatologist who has seen the clinical presentation can be in the best position to make the diagnosis. All clinicians must be wary of bias and an objective set of eyes often can be helpful. Communication is crucial to ensure appropriate care for each patient, and policies that restrict the choice of pathologist can be damaging.

As employers search for ways to reduce the cost of providing health care to their employees, there is a growing trend toward narrowed provider networks and exclusive laboratory contracts. In the case of clinical pathology, some of these choices make sense from the employer’s perspective. A complete blood cell count or comprehensive metabolic panel is done on a machine and the result is much the same regardless of the laboratory. So why not have all laboratory tests performed by the lowest bidder?

Laboratories vary in quality and anatomic pathology services are different from blood tests. Each slide must be interpreted by a physician and skill in the interpretation of skin specimens varies widely. Dermatopathology was one of the first subspecialties to be recognized within pathology, as it requires a high level of expertise. Clinicopathological correlation often is key to the accurate interpretation of a specimen. The stakes are high, and a delay in diagnosis of melanoma remains one of the most serious errors in medicine and one of the most common causes for litigation in dermatology.

The accurate interpretation of skin biopsy specimens becomes especially difficult when inadequate or misleading clinical information accompanies the specimen. A study of 589 biopsies submitted by primary care physicians and reported by general pathologists demonstrated a 6.5% error rate. False-negative errors were the most common, but false-positives also were observed.¹ A study of pigmented lesions referred to the University of California, San Francisco, demonstrated a discordance rate of 14.3%.² The degree of discordance would be expected to vary based on the range of diagnoses included in each study.

Board-certified dermatopathologists have varying areas of expertise and there is notable subjectivity in the interpretation of biopsy specimens. In the case of problematic pigmented lesions such as atypical Spitz nevi, there can be low interobserver agreement even among the experts in categorizing lesions as malignant versus nonmalignant (κ=0.30).³ The low concordance among expert dermatopathologists demonstrates that light microscopic features alone often are inadequate for diagnosis. Advanced studies, including immunohistochemical stains, can help to clarify the diagnosis. In the case of atypical Spitz tumors, the contribution of special stains to the final diagnosis is statistically similar to that of hematoxylin and eosin sections and age, suggesting that nothing alone is sufficiently reliable to establish a definitive diagnosis in every case.⁴ Although helpful, these studies are costly, and savings obtained by sending cases to the lowest bidder can evaporate quickly. Costs are higher when factoring in molecular studies, which can run upwards of $3000 per slide; the cost of litigation related to incorrect diagnoses; or the human costs of an incorrect diagnosis.

As a group, dermatopathologists are highly skilled in the interpretation of skin specimens, but challenging lesions are common in the routine practice of dermatopathology. A study of 1249 pigmented melanocytic lesions demonstrated substantial agreement among expert dermatopathologists for less problematic lesions, though agreement was greater for patients 40 years and older (κ=0.67) than for younger patients (κ=0.49). Agreement was lower for patients with atypical mole syndrome (κ=0.31).⁵ These discrepancies occur despite the fact that there is good interobserver reproducibility for grading of individual histological features such as asymmetry, circumscription, irregular confluent nests, single melanocytes predominating, absence of maturation, suprabasal melanocytes, symmetrical melanin, deep melanin, cytological atypia, mitoses, dermal lymphocytic infiltrate, and necrosis.⁶ These results indicate that accurate diagnoses cannot be reliably established simply by grading a list of histological features. Accurate diagnosis requires complex pattern recognition and integration of findings. Conflicting criteria often are present and an accurate interpretation requires considerable judgment as to which features are significant and which are not.

Separation of sebaceous adenoma, sebaceoma, and well-differentiated sebaceous carcinoma is another challenging area, and interobserver consensus can be as low as 11%,⁷ which suggests notable subjectivity in the criteria for diagnosis of nonmelanocytic tumors and emphasizes the importance of communication between the dermatopathologist and clinician when determining how to manage an ambiguous lesion. The interpretation of inflammatory skin diseases, alopecia, and lymphoid proliferations also can be problematic, and expert consultation often is required.

All dermatologists receive substantial training in dermatopathology, which puts them in an excellent position to interpret ambiguous findings in the context of the clinical presentation. Sometimes the dermatologist who has seen the clinical presentation can be in the best position to make the diagnosis. All clinicians must be wary of bias and an objective set of eyes often can be helpful. Communication is crucial to ensure appropriate care for each patient, and policies that restrict the choice of pathologist can be damaging.

As employers search for ways to reduce the cost of providing health care to their employees, there is a growing trend toward narrowed provider networks and exclusive laboratory contracts. In the case of clinical pathology, some of these choices make sense from the employer’s perspective. A complete blood cell count or comprehensive metabolic panel is done on a machine and the result is much the same regardless of the laboratory. So why not have all laboratory tests performed by the lowest bidder?

Laboratories vary in quality and anatomic pathology services are different from blood tests. Each slide must be interpreted by a physician and skill in the interpretation of skin specimens varies widely. Dermatopathology was one of the first subspecialties to be recognized within pathology, as it requires a high level of expertise. Clinicopathological correlation often is key to the accurate interpretation of a specimen. The stakes are high, and a delay in diagnosis of melanoma remains one of the most serious errors in medicine and one of the most common causes for litigation in dermatology.

The accurate interpretation of skin biopsy specimens becomes especially difficult when inadequate or misleading clinical information accompanies the specimen. A study of 589 biopsies submitted by primary care physicians and reported by general pathologists demonstrated a 6.5% error rate. False-negative errors were the most common, but false-positives also were observed.¹ A study of pigmented lesions referred to the University of California, San Francisco, demonstrated a discordance rate of 14.3%.² The degree of discordance would be expected to vary based on the range of diagnoses included in each study.

Board-certified dermatopathologists have varying areas of expertise and there is notable subjectivity in the interpretation of biopsy specimens. In the case of problematic pigmented lesions such as atypical Spitz nevi, there can be low interobserver agreement even among the experts in categorizing lesions as malignant versus nonmalignant (κ=0.30).³ The low concordance among expert dermatopathologists demonstrates that light microscopic features alone often are inadequate for diagnosis. Advanced studies, including immunohistochemical stains, can help to clarify the diagnosis. In the case of atypical Spitz tumors, the contribution of special stains to the final diagnosis is statistically similar to that of hematoxylin and eosin sections and age, suggesting that nothing alone is sufficiently reliable to establish a definitive diagnosis in every case.⁴ Although helpful, these studies are costly, and savings obtained by sending cases to the lowest bidder can evaporate quickly. Costs are higher when factoring in molecular studies, which can run upwards of $3000 per slide; the cost of litigation related to incorrect diagnoses; or the human costs of an incorrect diagnosis.

As a group, dermatopathologists are highly skilled in the interpretation of skin specimens, but challenging lesions are common in the routine practice of dermatopathology. A study of 1249 pigmented melanocytic lesions demonstrated substantial agreement among expert dermatopathologists for less problematic lesions, though agreement was greater for patients 40 years and older (κ=0.67) than for younger patients (κ=0.49). Agreement was lower for patients with atypical mole syndrome (κ=0.31).⁵ These discrepancies occur despite the fact that there is good interobserver reproducibility for grading of individual histological features such as asymmetry, circumscription, irregular confluent nests, single melanocytes predominating, absence of maturation, suprabasal melanocytes, symmetrical melanin, deep melanin, cytological atypia, mitoses, dermal lymphocytic infiltrate, and necrosis.⁶ These results indicate that accurate diagnoses cannot be reliably established simply by grading a list of histological features. Accurate diagnosis requires complex pattern recognition and integration of findings. Conflicting criteria often are present and an accurate interpretation requires considerable judgment as to which features are significant and which are not.

Separation of sebaceous adenoma, sebaceoma, and well-differentiated sebaceous carcinoma is another challenging area, and interobserver consensus can be as low as 11%,⁷ which suggests notable subjectivity in the criteria for diagnosis of nonmelanocytic tumors and emphasizes the importance of communication between the dermatopathologist and clinician when determining how to manage an ambiguous lesion. The interpretation of inflammatory skin diseases, alopecia, and lymphoid proliferations also can be problematic, and expert consultation often is required.

All dermatologists receive substantial training in dermatopathology, which puts them in an excellent position to interpret ambiguous findings in the context of the clinical presentation. Sometimes the dermatologist who has seen the clinical presentation can be in the best position to make the diagnosis. All clinicians must be wary of bias and an objective set of eyes often can be helpful. Communication is crucial to ensure appropriate care for each patient, and policies that restrict the choice of pathologist can be damaging.

To the Editor:

Epidermodysplasia verruciformis (EV) is a rare autosomal-recessive genodermatosis characterized by widespread infection with specific strains of human papillomavirus (HPV). Patients with EV have a unique susceptibility to acquire HPV due to defects in cellular immunity to the presenting antigens.¹ These defects may be related to mutations of the EVER genes or due to acquisition of an immunosuppressive condition.^2,3 Infections with HPV-3 and HPV-10 do not lead to the development of malignancies. However, infection with HPV-5, HPV-8, and HPV-14 can lead to the development of nonmelanoma skin cancers, usually squamous cell carcinomas (SCCs), in approximately 60% of patients.^3,4 This viral condition lasts throughout the patient’s lifetime and presents as tinea versicolor–like macules and patches. These lesions may be confused with seborrheic keratosis or verruca plana.⁵ Lesions typically are hypopigmented but occasionally may be hyperpigmented or erythematous. They often are found on the trunk, but lesions on the face, arms, palms, legs, and soles have been reported.⁵ Mucous membranes are always spared. Epidermodysplasia verruciformis often presents in childhood, except in cases related to acquired immunosuppression. The condition has no sex or racial predilection and no geographical preference.⁵

A 7-year-old boy (Fitzpatrick skin type V) presented with an asymptomatic rash on the trunk (Figure 1), dorsal aspect of the hands, and forehead. The lesions first appeared 5 years prior on the upper back and upper chest and had recently spread to the forehead and frontal aspect of the scalp. The patient had a history of myelomeningocele, which was corrected at birth with surgical placement of a ventriculoperitoneal shunt. The patient was otherwise healthy and met all appropriate developmental milestones for his age group. Family history revealed consanguinity of the patient’s paternal grandparents who were first cousins. The patient’s mother denied any other family member having similar rashes or lesions.

The patient had been treated for pityriasis versicolor on and off for 2 years by another dermatologist. His mother reported faithfully applying ketoconazole cream twice daily for several months with no improvement. She also reported using topical steroids, which did not provide any benefit. The patient and mother denied any associated pruritus, bleeding, burning, or physical discomfort.

Skin examination revealed diffuse, flat, polymorphous, hypopigmented and salmon-colored hyperkeratotic macules and patches with mild scaling on the upper region of the anterior aspect of the chest and upper back (Figure 2A). Additionally, the patient had an extensive number of lesions on the forehead and frontal aspect of the scalp (Figure 2B).

A shave biopsy demonstrated a thick basket weave stratum corneum, koilocytes, and large pale keratinocytes with characteristic blue cytoplasm. These findings were characteristic for EV.

At the patient’s 3-month follow-up visit, he again denied any symptoms associated with the lesions and reported that the appearance was diminishing in severity. On examination there was no evidence of SCC. The mother was advised to discontinue all topical treatments for the patient and return to the office every 3 to 6 months for regular skin surveillance. The mother was further advised to protect the patient from UV radiation with sunscreen and sun-protective clothing.

Epidermodysplasia verruciformis was first reported by Lewandowsky and Lutz⁶ in 1922. This rare condition often presents in childhood and is characterized by a persistent HPV infection and an autosomal-recessive inheritance pattern. Reports in the literature frequently involve kindreds. Often, patients with EV have a family history of first-degree or second-degree consanguinity.⁷

The clinical presentation of EV often resembles a pityriasis versicolor–like eruption. However, pityriasis versicolor is less commonly seen in childhood and is more prevalent in patients aged 21 to 30 years, likely due to increased sebum production and changing hormone levels. Furthermore, it is unusual to see pityriasis versicolor affect the face and scalp.⁸ Lesions of EV vary from hypopigmented and pinkish red macules to confluent patches and hyperkeratotic verrucalike lesions.³ Clinical characteristics also may include dyschromic patches; lesions that resemble flat warts on the trunk, face, and distal arms; and/or lesions that appear similar to seborrheic keratoses on the dorsal aspect of the hands.^9,10

Mutations of the EVER gene downregulate a cell’s ability to adequately attack the HPV antigens.¹¹ Although some patients with EV are found to have mutations of the EVER1 and EVER2 genes, a notable portion of patients with EV lack these mutations. Three other causes of EV include acquisition of immunosuppressive conditions including lymphoma, solid organ transplant, and human immunodeficiency virus. If one suspects autosomal-recessive inheritance of EV, genetic testing such as polymerase chain reaction DNA fragment analysis can be performed to determine if there are mutations on the EVER1 or EVER2 genes.¹²

The inability of patients with EV to mount an immune response to multiple types of HPV increases the risk for developing cutaneous malignancies.⁷ Additionally, it is known that UV radiation diminishes skin cell immunity, and the combination of EV and UV radiation further increases the risk for developing SCCs.¹¹ The development of nonmelanoma skin cancers usually occurs on sun-exposed skin 20 to 30 years after the onset of lesions, with the highest occurrence of SCCs presenting in the fourth decade of life.¹

Protection from UV light exposure is critical to reduce the risk for malignancy. Treatment options for EV lesions have included topical imiquimod 5%, 5-fluorouracil, oral isotretinoin, and intralesional interferon alfa, but patients are often refractory to these interventions. Curettage, surgical excision, electrosurgery, and laser ablation can be effective for individual lesions but carry a greater risk for scarring.¹ Photodynamic therapy with aminolevulinic acid and blue light represents a promising option that deserves further study.

Epidermodysplasia verruciformis should be considered as a differential diagnosis in all patients presenting with disseminated lesions resembling pityriasis versicolor that are unresponsive to treatment. A biopsy will help to establish the diagnosis. Patients should minimize sun exposure and report any skin lesions that are changing in appearance.

To the Editor:

Epidermodysplasia verruciformis (EV) is a rare autosomal-recessive genodermatosis characterized by widespread infection with specific strains of human papillomavirus (HPV). Patients with EV have a unique susceptibility to acquire HPV due to defects in cellular immunity to the presenting antigens.¹ These defects may be related to mutations of the EVER genes or due to acquisition of an immunosuppressive condition.^2,3 Infections with HPV-3 and HPV-10 do not lead to the development of malignancies. However, infection with HPV-5, HPV-8, and HPV-14 can lead to the development of nonmelanoma skin cancers, usually squamous cell carcinomas (SCCs), in approximately 60% of patients.^3,4 This viral condition lasts throughout the patient’s lifetime and presents as tinea versicolor–like macules and patches. These lesions may be confused with seborrheic keratosis or verruca plana.⁵ Lesions typically are hypopigmented but occasionally may be hyperpigmented or erythematous. They often are found on the trunk, but lesions on the face, arms, palms, legs, and soles have been reported.⁵ Mucous membranes are always spared. Epidermodysplasia verruciformis often presents in childhood, except in cases related to acquired immunosuppression. The condition has no sex or racial predilection and no geographical preference.⁵

A 7-year-old boy (Fitzpatrick skin type V) presented with an asymptomatic rash on the trunk (Figure 1), dorsal aspect of the hands, and forehead. The lesions first appeared 5 years prior on the upper back and upper chest and had recently spread to the forehead and frontal aspect of the scalp. The patient had a history of myelomeningocele, which was corrected at birth with surgical placement of a ventriculoperitoneal shunt. The patient was otherwise healthy and met all appropriate developmental milestones for his age group. Family history revealed consanguinity of the patient’s paternal grandparents who were first cousins. The patient’s mother denied any other family member having similar rashes or lesions.

The patient had been treated for pityriasis versicolor on and off for 2 years by another dermatologist. His mother reported faithfully applying ketoconazole cream twice daily for several months with no improvement. She also reported using topical steroids, which did not provide any benefit. The patient and mother denied any associated pruritus, bleeding, burning, or physical discomfort.

Skin examination revealed diffuse, flat, polymorphous, hypopigmented and salmon-colored hyperkeratotic macules and patches with mild scaling on the upper region of the anterior aspect of the chest and upper back (Figure 2A). Additionally, the patient had an extensive number of lesions on the forehead and frontal aspect of the scalp (Figure 2B).

A shave biopsy demonstrated a thick basket weave stratum corneum, koilocytes, and large pale keratinocytes with characteristic blue cytoplasm. These findings were characteristic for EV.

At the patient’s 3-month follow-up visit, he again denied any symptoms associated with the lesions and reported that the appearance was diminishing in severity. On examination there was no evidence of SCC. The mother was advised to discontinue all topical treatments for the patient and return to the office every 3 to 6 months for regular skin surveillance. The mother was further advised to protect the patient from UV radiation with sunscreen and sun-protective clothing.

Epidermodysplasia verruciformis was first reported by Lewandowsky and Lutz⁶ in 1922. This rare condition often presents in childhood and is characterized by a persistent HPV infection and an autosomal-recessive inheritance pattern. Reports in the literature frequently involve kindreds. Often, patients with EV have a family history of first-degree or second-degree consanguinity.⁷

The clinical presentation of EV often resembles a pityriasis versicolor–like eruption. However, pityriasis versicolor is less commonly seen in childhood and is more prevalent in patients aged 21 to 30 years, likely due to increased sebum production and changing hormone levels. Furthermore, it is unusual to see pityriasis versicolor affect the face and scalp.⁸ Lesions of EV vary from hypopigmented and pinkish red macules to confluent patches and hyperkeratotic verrucalike lesions.³ Clinical characteristics also may include dyschromic patches; lesions that resemble flat warts on the trunk, face, and distal arms; and/or lesions that appear similar to seborrheic keratoses on the dorsal aspect of the hands.^9,10

Mutations of the EVER gene downregulate a cell’s ability to adequately attack the HPV antigens.¹¹ Although some patients with EV are found to have mutations of the EVER1 and EVER2 genes, a notable portion of patients with EV lack these mutations. Three other causes of EV include acquisition of immunosuppressive conditions including lymphoma, solid organ transplant, and human immunodeficiency virus. If one suspects autosomal-recessive inheritance of EV, genetic testing such as polymerase chain reaction DNA fragment analysis can be performed to determine if there are mutations on the EVER1 or EVER2 genes.¹²

The inability of patients with EV to mount an immune response to multiple types of HPV increases the risk for developing cutaneous malignancies.⁷ Additionally, it is known that UV radiation diminishes skin cell immunity, and the combination of EV and UV radiation further increases the risk for developing SCCs.¹¹ The development of nonmelanoma skin cancers usually occurs on sun-exposed skin 20 to 30 years after the onset of lesions, with the highest occurrence of SCCs presenting in the fourth decade of life.¹

Protection from UV light exposure is critical to reduce the risk for malignancy. Treatment options for EV lesions have included topical imiquimod 5%, 5-fluorouracil, oral isotretinoin, and intralesional interferon alfa, but patients are often refractory to these interventions. Curettage, surgical excision, electrosurgery, and laser ablation can be effective for individual lesions but carry a greater risk for scarring.¹ Photodynamic therapy with aminolevulinic acid and blue light represents a promising option that deserves further study.

Epidermodysplasia verruciformis should be considered as a differential diagnosis in all patients presenting with disseminated lesions resembling pityriasis versicolor that are unresponsive to treatment. A biopsy will help to establish the diagnosis. Patients should minimize sun exposure and report any skin lesions that are changing in appearance.

To the Editor:

Epidermodysplasia verruciformis (EV) is a rare autosomal-recessive genodermatosis characterized by widespread infection with specific strains of human papillomavirus (HPV). Patients with EV have a unique susceptibility to acquire HPV due to defects in cellular immunity to the presenting antigens.¹ These defects may be related to mutations of the EVER genes or due to acquisition of an immunosuppressive condition.^2,3 Infections with HPV-3 and HPV-10 do not lead to the development of malignancies. However, infection with HPV-5, HPV-8, and HPV-14 can lead to the development of nonmelanoma skin cancers, usually squamous cell carcinomas (SCCs), in approximately 60% of patients.^3,4 This viral condition lasts throughout the patient’s lifetime and presents as tinea versicolor–like macules and patches. These lesions may be confused with seborrheic keratosis or verruca plana.⁵ Lesions typically are hypopigmented but occasionally may be hyperpigmented or erythematous. They often are found on the trunk, but lesions on the face, arms, palms, legs, and soles have been reported.⁵ Mucous membranes are always spared. Epidermodysplasia verruciformis often presents in childhood, except in cases related to acquired immunosuppression. The condition has no sex or racial predilection and no geographical preference.⁵

A 7-year-old boy (Fitzpatrick skin type V) presented with an asymptomatic rash on the trunk (Figure 1), dorsal aspect of the hands, and forehead. The lesions first appeared 5 years prior on the upper back and upper chest and had recently spread to the forehead and frontal aspect of the scalp. The patient had a history of myelomeningocele, which was corrected at birth with surgical placement of a ventriculoperitoneal shunt. The patient was otherwise healthy and met all appropriate developmental milestones for his age group. Family history revealed consanguinity of the patient’s paternal grandparents who were first cousins. The patient’s mother denied any other family member having similar rashes or lesions.

The patient had been treated for pityriasis versicolor on and off for 2 years by another dermatologist. His mother reported faithfully applying ketoconazole cream twice daily for several months with no improvement. She also reported using topical steroids, which did not provide any benefit. The patient and mother denied any associated pruritus, bleeding, burning, or physical discomfort.

Skin examination revealed diffuse, flat, polymorphous, hypopigmented and salmon-colored hyperkeratotic macules and patches with mild scaling on the upper region of the anterior aspect of the chest and upper back (Figure 2A). Additionally, the patient had an extensive number of lesions on the forehead and frontal aspect of the scalp (Figure 2B).

A shave biopsy demonstrated a thick basket weave stratum corneum, koilocytes, and large pale keratinocytes with characteristic blue cytoplasm. These findings were characteristic for EV.

At the patient’s 3-month follow-up visit, he again denied any symptoms associated with the lesions and reported that the appearance was diminishing in severity. On examination there was no evidence of SCC. The mother was advised to discontinue all topical treatments for the patient and return to the office every 3 to 6 months for regular skin surveillance. The mother was further advised to protect the patient from UV radiation with sunscreen and sun-protective clothing.

Epidermodysplasia verruciformis was first reported by Lewandowsky and Lutz⁶ in 1922. This rare condition often presents in childhood and is characterized by a persistent HPV infection and an autosomal-recessive inheritance pattern. Reports in the literature frequently involve kindreds. Often, patients with EV have a family history of first-degree or second-degree consanguinity.⁷

The clinical presentation of EV often resembles a pityriasis versicolor–like eruption. However, pityriasis versicolor is less commonly seen in childhood and is more prevalent in patients aged 21 to 30 years, likely due to increased sebum production and changing hormone levels. Furthermore, it is unusual to see pityriasis versicolor affect the face and scalp.⁸ Lesions of EV vary from hypopigmented and pinkish red macules to confluent patches and hyperkeratotic verrucalike lesions.³ Clinical characteristics also may include dyschromic patches; lesions that resemble flat warts on the trunk, face, and distal arms; and/or lesions that appear similar to seborrheic keratoses on the dorsal aspect of the hands.^9,10

Mutations of the EVER gene downregulate a cell’s ability to adequately attack the HPV antigens.¹¹ Although some patients with EV are found to have mutations of the EVER1 and EVER2 genes, a notable portion of patients with EV lack these mutations. Three other causes of EV include acquisition of immunosuppressive conditions including lymphoma, solid organ transplant, and human immunodeficiency virus. If one suspects autosomal-recessive inheritance of EV, genetic testing such as polymerase chain reaction DNA fragment analysis can be performed to determine if there are mutations on the EVER1 or EVER2 genes.¹²

The inability of patients with EV to mount an immune response to multiple types of HPV increases the risk for developing cutaneous malignancies.⁷ Additionally, it is known that UV radiation diminishes skin cell immunity, and the combination of EV and UV radiation further increases the risk for developing SCCs.¹¹ The development of nonmelanoma skin cancers usually occurs on sun-exposed skin 20 to 30 years after the onset of lesions, with the highest occurrence of SCCs presenting in the fourth decade of life.¹

Protection from UV light exposure is critical to reduce the risk for malignancy. Treatment options for EV lesions have included topical imiquimod 5%, 5-fluorouracil, oral isotretinoin, and intralesional interferon alfa, but patients are often refractory to these interventions. Curettage, surgical excision, electrosurgery, and laser ablation can be effective for individual lesions but carry a greater risk for scarring.¹ Photodynamic therapy with aminolevulinic acid and blue light represents a promising option that deserves further study.

Epidermodysplasia verruciformis should be considered as a differential diagnosis in all patients presenting with disseminated lesions resembling pityriasis versicolor that are unresponsive to treatment. A biopsy will help to establish the diagnosis. Patients should minimize sun exposure and report any skin lesions that are changing in appearance.

Cutaneous Metastasis of Pulmonary Adenocarcinoma

Cutaneous metastasis of pulmonary adenocarcinoma (CMPA) is a rare phenomenon with an overall survival rate of less than 5 months.1,2 Often, CMPA can be the heralding feature of an aggressive systemic malignancy in 2.8% to 22% of reported cases.^2-4 Clinically, CMPAs often present as fixed, violaceous, ulcerated nodules on the chest wall, scalp, or site of a prior procedure.^3,5,6 Other clinical presentations have been described including zosteriform and inflammatory carcinomalike CMPA and CMPA on the tip of the nose.⁷ Histologically, CMPA presents as a subdermal collection of atypical glands arranged as clustered aggregates of infiltrative glands penetrating the dermal stroma (quiz image). The atypical glands have large oval nuclei with high nuclear to cytoplasm ratios with scant pale cytoplasm.

Cutaneous metastasis of pulmonary adenocarcinoma is difficult to distinguish from other metastatic or primary glandular malignancies based on histology alone. Immunohistochemical analysis can aid in the diagnosis of the primary tumor. Pulmonary adenocarcinomas are positive for cytokeratin (CK) 7 and thyroid transcription factor 1 (TTF-1), and they are negative for CK5/6 and CK20.⁷ The differential diagnosis for CMPA includes other internal malignancies such as invasive ductal adenocarcinoma of the breast and gastrointestinal adenocarcinomas (eg, gastric or colorectal carcinoma [CRC]). Additionally, endometriosis and primary sebaceous carcinomas can mimic cutaneous metastatic adenocarcinomas.

Endometriosis can mimic adenocarcinoma, especially when presenting as a subdermal nodule. However, the scattered dermal glands are cytologically banal and are surrounded by uterine-type stroma and extravasated hemorrhage, a classic presentation of endometriosis (Figure 1).

Primary sebaceous carcinoma also can mimic metastatic adenocarcinoma within the skin and is histologically similar to metastatic adenocarcinomas. The most distinguishing feature is sebaceous differentiation characterized by sebocytes, which have a vacuolated cytoplasm giving the nucleus a scalloped appearance, frequently with adjacent ductlike structures (Figure 5). Epidermotropism sometimes is present in sebaceous carcinomas but cannot be relied on as a distinguishing feature. Immunohistochemical analysis also is a helpful tool; these tumors typically are positive for p63 and podoplanin, distinguishing them from negative-staining metastatic adenocarcinomas.^10,11 

Cutaneous Metastasis of Pulmonary Adenocarcinoma

Cutaneous metastasis of pulmonary adenocarcinoma (CMPA) is a rare phenomenon with an overall survival rate of less than 5 months.1,2 Often, CMPA can be the heralding feature of an aggressive systemic malignancy in 2.8% to 22% of reported cases.^2-4 Clinically, CMPAs often present as fixed, violaceous, ulcerated nodules on the chest wall, scalp, or site of a prior procedure.^3,5,6 Other clinical presentations have been described including zosteriform and inflammatory carcinomalike CMPA and CMPA on the tip of the nose.⁷ Histologically, CMPA presents as a subdermal collection of atypical glands arranged as clustered aggregates of infiltrative glands penetrating the dermal stroma (quiz image). The atypical glands have large oval nuclei with high nuclear to cytoplasm ratios with scant pale cytoplasm.

Cutaneous metastasis of pulmonary adenocarcinoma is difficult to distinguish from other metastatic or primary glandular malignancies based on histology alone. Immunohistochemical analysis can aid in the diagnosis of the primary tumor. Pulmonary adenocarcinomas are positive for cytokeratin (CK) 7 and thyroid transcription factor 1 (TTF-1), and they are negative for CK5/6 and CK20.⁷ The differential diagnosis for CMPA includes other internal malignancies such as invasive ductal adenocarcinoma of the breast and gastrointestinal adenocarcinomas (eg, gastric or colorectal carcinoma [CRC]). Additionally, endometriosis and primary sebaceous carcinomas can mimic cutaneous metastatic adenocarcinomas.

Endometriosis can mimic adenocarcinoma, especially when presenting as a subdermal nodule. However, the scattered dermal glands are cytologically banal and are surrounded by uterine-type stroma and extravasated hemorrhage, a classic presentation of endometriosis (Figure 1).

Primary sebaceous carcinoma also can mimic metastatic adenocarcinoma within the skin and is histologically similar to metastatic adenocarcinomas. The most distinguishing feature is sebaceous differentiation characterized by sebocytes, which have a vacuolated cytoplasm giving the nucleus a scalloped appearance, frequently with adjacent ductlike structures (Figure 5). Epidermotropism sometimes is present in sebaceous carcinomas but cannot be relied on as a distinguishing feature. Immunohistochemical analysis also is a helpful tool; these tumors typically are positive for p63 and podoplanin, distinguishing them from negative-staining metastatic adenocarcinomas.^10,11 

Cutaneous Metastasis of Pulmonary Adenocarcinoma

Cutaneous metastasis of pulmonary adenocarcinoma (CMPA) is a rare phenomenon with an overall survival rate of less than 5 months.1,2 Often, CMPA can be the heralding feature of an aggressive systemic malignancy in 2.8% to 22% of reported cases.^2-4 Clinically, CMPAs often present as fixed, violaceous, ulcerated nodules on the chest wall, scalp, or site of a prior procedure.^3,5,6 Other clinical presentations have been described including zosteriform and inflammatory carcinomalike CMPA and CMPA on the tip of the nose.⁷ Histologically, CMPA presents as a subdermal collection of atypical glands arranged as clustered aggregates of infiltrative glands penetrating the dermal stroma (quiz image). The atypical glands have large oval nuclei with high nuclear to cytoplasm ratios with scant pale cytoplasm.

Cutaneous metastasis of pulmonary adenocarcinoma is difficult to distinguish from other metastatic or primary glandular malignancies based on histology alone. Immunohistochemical analysis can aid in the diagnosis of the primary tumor. Pulmonary adenocarcinomas are positive for cytokeratin (CK) 7 and thyroid transcription factor 1 (TTF-1), and they are negative for CK5/6 and CK20.⁷ The differential diagnosis for CMPA includes other internal malignancies such as invasive ductal adenocarcinoma of the breast and gastrointestinal adenocarcinomas (eg, gastric or colorectal carcinoma [CRC]). Additionally, endometriosis and primary sebaceous carcinomas can mimic cutaneous metastatic adenocarcinomas.

Endometriosis can mimic adenocarcinoma, especially when presenting as a subdermal nodule. However, the scattered dermal glands are cytologically banal and are surrounded by uterine-type stroma and extravasated hemorrhage, a classic presentation of endometriosis (Figure 1).

Primary sebaceous carcinoma also can mimic metastatic adenocarcinoma within the skin and is histologically similar to metastatic adenocarcinomas. The most distinguishing feature is sebaceous differentiation characterized by sebocytes, which have a vacuolated cytoplasm giving the nucleus a scalloped appearance, frequently with adjacent ductlike structures (Figure 5). Epidermotropism sometimes is present in sebaceous carcinomas but cannot be relied on as a distinguishing feature. Immunohistochemical analysis also is a helpful tool; these tumors typically are positive for p63 and podoplanin, distinguishing them from negative-staining metastatic adenocarcinomas.^10,11 

What does the patient need to know at the first visit?

When I communicate with alopecia patients at the first visit, I make sure they know that I’m there to help them—that I won’t minimize their concerns and that I understand how important their condition is to them. Alopecia can be frustrating for both the patient and the physician, and there often is a confounding background of psychosocial stress and/or a history of physicians who have dismissed the patient’s concerns about his or her hair loss as trivial. Establishing an effective doctor-patient relationship is key in treating alopecia. Physicians sometimes may be left feeling like the patient wants to keep them in the room until his or her hair regrows, but in reality you simply need to reassure the patient that you are comfortable with the evaluation and treatment of alopecia and that several steps will be required but you will get started today.

How do you use punch biopsies to determine the best treatment options?

My most important tips regarding alopecia diagnosis relate to scalp biopsies, which usually are required in distinguishing chronic cutaneous lupus erythematosus from other scarring alopecias. First, an absorbable gelatin compressed sponge is your best friend. A small strip inserted into the punch biopsy wound results in prompt hemostasis without the need for sutures, and the resulting scar often looks as good or better than that produced by suturing. Next, don’t biopsy the active advancing borders of an alopecia patch, as the findings usually are nonspecific. Instead, biopsy a well-established portion that has been present for at least 4 to 6 months but is still active. In inconclusive cases, a biopsy of a scarred area stained with Verhoeff elastic stain can demonstrate characteristic patterns of elastic tissue loss and often establish a diagnosis. It is important to distinguish chronic cutaneous lupus erythematosus from other forms of scarring alopecia, as it is more likely to respond to antimalarials.

What are your go-to treatments? Are your recommendations anecdotal or evidence based?

There isn’t an extensive arsenal of evidence-based therapy for refractory scarring alopecia, but that doesn’t mean we don’t have effective therapies; it simply means that our treatments are based on experience without accompanying randomized controlled trials. We need to produce more evidence, but patients with severe disease still need to be treated in the meantime. It’s important to remember that therapeutic complacency can result in permanent irreversible scarring. The presence of easily extractable anagen hairs is a sign of active disease. This simple test is helpful to monitor therapeutic progress.

Topical and intralesional corticosteroids can be extremely useful and often are underused. In general, the risk of scarring and atrophy from untreated disease is much greater than that from the corticosteroid. On the scalp, atrophy often presents as erythema, which should not be confused with erythema related to active disease. Dermoscopy is useful to demonstrate that the redness represents dermal atrophy with prominence of the subpapillary plexus of vessels.

When systemic therapy is required, antimalarials, retinoids, dapsone, thalidomide, sulfasalazine, mycophenolate mofetil, and methotrexate have all been used successfully in the setting of cutaneous lupus erythematosus, while topical tazarotene and topical calcineurin inhibitors are generally disappointing.

For the treatment of lichen planopilaris, intralesional corticosteroids, oral retinoids, and excimer laser can be effective. In contrast, antimalarials usually are not effective in preventing disease progression. The peroxisome proliferator-activated receptor-γ agonist pioglitazone can be effective, but reported results vary widely. In my experience, mycophenolate mofetil is generally reliable in patients with refractory disease. Dutasteride can be effective as a first-line therapy in the setting of frontal fibrosing alopecia, although some of the noted improvement may relate to the nonscarring portion of the disease in patients with a background of pattern alopecia.

How do you keep patients compliant with treatment?  

Again, the key to treatment compliance is to establish an effective doctor-patient relationship. Whenever possible, begin with adequately potent therapy to give patients an early response. Don’t hesitate to use prednisone initially for inflammatory scarring alopecia. Patients need to see signs of progress in order to stay compliant with treatment, and long trials of ineffective therapies destroy trust. Adequate doses of intralesional or oral corticosteroids often are appropriate to ensure an early response with subsequent transition to steroid-sparing agents.

What do you do if they refuse treatment? 

Try to find out why—often it’s simply fear of side effects. Patient education is key, and it can help tremendously to share with them the number of patients you have treated safely with the medication in question and assure them that you know how to monitor for the important side effects.

What resources do you recommend to patients for more information? 

It is helpful to keep a handy list of patient advocacy Web sites. Well-established support groups such as the National Alopecia Areata Foundation (https://www.naaf.org) and the Cicatricial Alopecia Research Foundation (http://www.carfintl.org) provide excellent information for patients and help to support research to improve outcomes for these difficult disorders.

What does the patient need to know at the first visit?

When I communicate with alopecia patients at the first visit, I make sure they know that I’m there to help them—that I won’t minimize their concerns and that I understand how important their condition is to them. Alopecia can be frustrating for both the patient and the physician, and there often is a confounding background of psychosocial stress and/or a history of physicians who have dismissed the patient’s concerns about his or her hair loss as trivial. Establishing an effective doctor-patient relationship is key in treating alopecia. Physicians sometimes may be left feeling like the patient wants to keep them in the room until his or her hair regrows, but in reality you simply need to reassure the patient that you are comfortable with the evaluation and treatment of alopecia and that several steps will be required but you will get started today.

How do you use punch biopsies to determine the best treatment options?

My most important tips regarding alopecia diagnosis relate to scalp biopsies, which usually are required in distinguishing chronic cutaneous lupus erythematosus from other scarring alopecias. First, an absorbable gelatin compressed sponge is your best friend. A small strip inserted into the punch biopsy wound results in prompt hemostasis without the need for sutures, and the resulting scar often looks as good or better than that produced by suturing. Next, don’t biopsy the active advancing borders of an alopecia patch, as the findings usually are nonspecific. Instead, biopsy a well-established portion that has been present for at least 4 to 6 months but is still active. In inconclusive cases, a biopsy of a scarred area stained with Verhoeff elastic stain can demonstrate characteristic patterns of elastic tissue loss and often establish a diagnosis. It is important to distinguish chronic cutaneous lupus erythematosus from other forms of scarring alopecia, as it is more likely to respond to antimalarials.

What are your go-to treatments? Are your recommendations anecdotal or evidence based?

There isn’t an extensive arsenal of evidence-based therapy for refractory scarring alopecia, but that doesn’t mean we don’t have effective therapies; it simply means that our treatments are based on experience without accompanying randomized controlled trials. We need to produce more evidence, but patients with severe disease still need to be treated in the meantime. It’s important to remember that therapeutic complacency can result in permanent irreversible scarring. The presence of easily extractable anagen hairs is a sign of active disease. This simple test is helpful to monitor therapeutic progress.

Topical and intralesional corticosteroids can be extremely useful and often are underused. In general, the risk of scarring and atrophy from untreated disease is much greater than that from the corticosteroid. On the scalp, atrophy often presents as erythema, which should not be confused with erythema related to active disease. Dermoscopy is useful to demonstrate that the redness represents dermal atrophy with prominence of the subpapillary plexus of vessels.

When systemic therapy is required, antimalarials, retinoids, dapsone, thalidomide, sulfasalazine, mycophenolate mofetil, and methotrexate have all been used successfully in the setting of cutaneous lupus erythematosus, while topical tazarotene and topical calcineurin inhibitors are generally disappointing.

For the treatment of lichen planopilaris, intralesional corticosteroids, oral retinoids, and excimer laser can be effective. In contrast, antimalarials usually are not effective in preventing disease progression. The peroxisome proliferator-activated receptor-γ agonist pioglitazone can be effective, but reported results vary widely. In my experience, mycophenolate mofetil is generally reliable in patients with refractory disease. Dutasteride can be effective as a first-line therapy in the setting of frontal fibrosing alopecia, although some of the noted improvement may relate to the nonscarring portion of the disease in patients with a background of pattern alopecia.

How do you keep patients compliant with treatment?  

Again, the key to treatment compliance is to establish an effective doctor-patient relationship. Whenever possible, begin with adequately potent therapy to give patients an early response. Don’t hesitate to use prednisone initially for inflammatory scarring alopecia. Patients need to see signs of progress in order to stay compliant with treatment, and long trials of ineffective therapies destroy trust. Adequate doses of intralesional or oral corticosteroids often are appropriate to ensure an early response with subsequent transition to steroid-sparing agents.

What do you do if they refuse treatment? 

Try to find out why—often it’s simply fear of side effects. Patient education is key, and it can help tremendously to share with them the number of patients you have treated safely with the medication in question and assure them that you know how to monitor for the important side effects.

What resources do you recommend to patients for more information? 

It is helpful to keep a handy list of patient advocacy Web sites. Well-established support groups such as the National Alopecia Areata Foundation (https://www.naaf.org) and the Cicatricial Alopecia Research Foundation (http://www.carfintl.org) provide excellent information for patients and help to support research to improve outcomes for these difficult disorders.

What does the patient need to know at the first visit?

When I communicate with alopecia patients at the first visit, I make sure they know that I’m there to help them—that I won’t minimize their concerns and that I understand how important their condition is to them. Alopecia can be frustrating for both the patient and the physician, and there often is a confounding background of psychosocial stress and/or a history of physicians who have dismissed the patient’s concerns about his or her hair loss as trivial. Establishing an effective doctor-patient relationship is key in treating alopecia. Physicians sometimes may be left feeling like the patient wants to keep them in the room until his or her hair regrows, but in reality you simply need to reassure the patient that you are comfortable with the evaluation and treatment of alopecia and that several steps will be required but you will get started today.

How do you use punch biopsies to determine the best treatment options?

My most important tips regarding alopecia diagnosis relate to scalp biopsies, which usually are required in distinguishing chronic cutaneous lupus erythematosus from other scarring alopecias. First, an absorbable gelatin compressed sponge is your best friend. A small strip inserted into the punch biopsy wound results in prompt hemostasis without the need for sutures, and the resulting scar often looks as good or better than that produced by suturing. Next, don’t biopsy the active advancing borders of an alopecia patch, as the findings usually are nonspecific. Instead, biopsy a well-established portion that has been present for at least 4 to 6 months but is still active. In inconclusive cases, a biopsy of a scarred area stained with Verhoeff elastic stain can demonstrate characteristic patterns of elastic tissue loss and often establish a diagnosis. It is important to distinguish chronic cutaneous lupus erythematosus from other forms of scarring alopecia, as it is more likely to respond to antimalarials.

What are your go-to treatments? Are your recommendations anecdotal or evidence based?

There isn’t an extensive arsenal of evidence-based therapy for refractory scarring alopecia, but that doesn’t mean we don’t have effective therapies; it simply means that our treatments are based on experience without accompanying randomized controlled trials. We need to produce more evidence, but patients with severe disease still need to be treated in the meantime. It’s important to remember that therapeutic complacency can result in permanent irreversible scarring. The presence of easily extractable anagen hairs is a sign of active disease. This simple test is helpful to monitor therapeutic progress.

Topical and intralesional corticosteroids can be extremely useful and often are underused. In general, the risk of scarring and atrophy from untreated disease is much greater than that from the corticosteroid. On the scalp, atrophy often presents as erythema, which should not be confused with erythema related to active disease. Dermoscopy is useful to demonstrate that the redness represents dermal atrophy with prominence of the subpapillary plexus of vessels.

When systemic therapy is required, antimalarials, retinoids, dapsone, thalidomide, sulfasalazine, mycophenolate mofetil, and methotrexate have all been used successfully in the setting of cutaneous lupus erythematosus, while topical tazarotene and topical calcineurin inhibitors are generally disappointing.

For the treatment of lichen planopilaris, intralesional corticosteroids, oral retinoids, and excimer laser can be effective. In contrast, antimalarials usually are not effective in preventing disease progression. The peroxisome proliferator-activated receptor-γ agonist pioglitazone can be effective, but reported results vary widely. In my experience, mycophenolate mofetil is generally reliable in patients with refractory disease. Dutasteride can be effective as a first-line therapy in the setting of frontal fibrosing alopecia, although some of the noted improvement may relate to the nonscarring portion of the disease in patients with a background of pattern alopecia.

How do you keep patients compliant with treatment?  

Again, the key to treatment compliance is to establish an effective doctor-patient relationship. Whenever possible, begin with adequately potent therapy to give patients an early response. Don’t hesitate to use prednisone initially for inflammatory scarring alopecia. Patients need to see signs of progress in order to stay compliant with treatment, and long trials of ineffective therapies destroy trust. Adequate doses of intralesional or oral corticosteroids often are appropriate to ensure an early response with subsequent transition to steroid-sparing agents.

What do you do if they refuse treatment? 

Try to find out why—often it’s simply fear of side effects. Patient education is key, and it can help tremendously to share with them the number of patients you have treated safely with the medication in question and assure them that you know how to monitor for the important side effects.

What resources do you recommend to patients for more information? 

It is helpful to keep a handy list of patient advocacy Web sites. Well-established support groups such as the National Alopecia Areata Foundation (https://www.naaf.org) and the Cicatricial Alopecia Research Foundation (http://www.carfintl.org) provide excellent information for patients and help to support research to improve outcomes for these difficult disorders.

Case Report

An 18-year-old Iranian man presented to the dermatology clinic with hair loss of 1 night’s duration. He denied pruritus, pain, discharge, or flaking. The patient had no notable personal, family, or surgical history and was not currently taking any medications. He denied recent travel. The patient reported that he found hair on his pillow upon waking up in the morning prior to coming to the clinic. On physical examination, 2 ants 
(Figure 1) were found on the scalp and alopecia with a vertical linear distribution was noted (Figure 2). Hairs of various lengths were found on the scalp within the distribution of the alopecia. No excoriations, crusting, seborrhea, or other areas of hair loss were detected. Wood lamp examination was negative. Based on these findings, which were concordant with similar findings from prior reports,^1-4 a diagnosis of ant-induced alopecia was made. Hair regrowth was noted within 1 week with full appearance of normal-length hair within 2.5 weeks.

Comment

Ant-induced alopecia is a form of localized hair loss caused by the Pheidole genus, the second largest genus of ants in the world.⁵ These ants can be found worldwide, but most cases of ant-induced alopecia have been from Iran, with at least 1 reported case from Turkey.^1-4,6 An early case series of ant-induced alopecia was reported in 1999,⁶ but the causative species was not described at that time.

The majority of reported cases of ant-induced alopecia are attributed to the barber ant (Pheidole pallidula). This type of alopecia is caused by worker ants within the species hierarchy.^1,4,6 The P pallidula worker ants are dimorphic and are classified as major and minor workers.⁷ Major workers have body lengths ranging up to 6 mm, whereas minor workers have body lengths ranging up to 4 mm. Major workers have larger heads and mandibles than minor workers and also have up to 2 pairs of denticles on the cranium.⁵ The minor workers are foragers and mainly collect food, whereas the major workers defend the nest and store food.⁸ These ants have widespread habitats with the ability to live in indoor and outdoor environments.

The presentation of hair loss caused by these ants is acute. Hair loss usually is confined to one specific area. Some patients may report pruritus or may present with erythematous lesions from ant stings or manual scratching.⁵ None of these signs or symptoms were seen in our patient. Some investigators have suggested that the barber ant is attracted to the hair of individuals with seborrheic dermatitis,¹ but our patient had no medical history of seborrheic dermatitis. Most likely, ants are attracted to excess sebum on the scalp in select individuals in their search for food and cause localized hair destruction.

Localized hair loss, as depicted in our case, should warrant a thorough evaluation for alopecia areata, trichotillomania, and tinea capitis.⁹ Alopecia areata should be considered in individuals with multiple focal patches of hair loss that have a positive hair pull test from peripheral sites of active lesions. Tinea capitis usually has localized sites of hair loss with underlying scaling, crusting, pruritus, erythema, and discharge from lesions, with positive potassium hydroxide preparations or fungal cultures. Trichotillomania typically presents with a spared peripheral fringe of hair. Remaining hairs may be thick and hyperpigmented as a response to repeated pulling, and biopsy often demonstrates fracture or degeneration of the hair shaft. A psychiatric evaluation may be warranted in cases of trichotillomania. Other cases of arthropod-induced hair loss include tick bite alopecia^10,11 and hair loss induced by numerous honeybee stings,¹² and these diagnoses should be suspected in patients with a history of ants on their pillow or in those from endemic areas.

No specific treatment is indicated in cases of 
ant-induced alopecia because hair usually regrows to its normal length without intervention.

Case Report

An 18-year-old Iranian man presented to the dermatology clinic with hair loss of 1 night’s duration. He denied pruritus, pain, discharge, or flaking. The patient had no notable personal, family, or surgical history and was not currently taking any medications. He denied recent travel. The patient reported that he found hair on his pillow upon waking up in the morning prior to coming to the clinic. On physical examination, 2 ants 
(Figure 1) were found on the scalp and alopecia with a vertical linear distribution was noted (Figure 2). Hairs of various lengths were found on the scalp within the distribution of the alopecia. No excoriations, crusting, seborrhea, or other areas of hair loss were detected. Wood lamp examination was negative. Based on these findings, which were concordant with similar findings from prior reports,^1-4 a diagnosis of ant-induced alopecia was made. Hair regrowth was noted within 1 week with full appearance of normal-length hair within 2.5 weeks.

Comment

Ant-induced alopecia is a form of localized hair loss caused by the Pheidole genus, the second largest genus of ants in the world.⁵ These ants can be found worldwide, but most cases of ant-induced alopecia have been from Iran, with at least 1 reported case from Turkey.^1-4,6 An early case series of ant-induced alopecia was reported in 1999,⁶ but the causative species was not described at that time.

The majority of reported cases of ant-induced alopecia are attributed to the barber ant (Pheidole pallidula). This type of alopecia is caused by worker ants within the species hierarchy.^1,4,6 The P pallidula worker ants are dimorphic and are classified as major and minor workers.⁷ Major workers have body lengths ranging up to 6 mm, whereas minor workers have body lengths ranging up to 4 mm. Major workers have larger heads and mandibles than minor workers and also have up to 2 pairs of denticles on the cranium.⁵ The minor workers are foragers and mainly collect food, whereas the major workers defend the nest and store food.⁸ These ants have widespread habitats with the ability to live in indoor and outdoor environments.

The presentation of hair loss caused by these ants is acute. Hair loss usually is confined to one specific area. Some patients may report pruritus or may present with erythematous lesions from ant stings or manual scratching.⁵ None of these signs or symptoms were seen in our patient. Some investigators have suggested that the barber ant is attracted to the hair of individuals with seborrheic dermatitis,¹ but our patient had no medical history of seborrheic dermatitis. Most likely, ants are attracted to excess sebum on the scalp in select individuals in their search for food and cause localized hair destruction.

Localized hair loss, as depicted in our case, should warrant a thorough evaluation for alopecia areata, trichotillomania, and tinea capitis.⁹ Alopecia areata should be considered in individuals with multiple focal patches of hair loss that have a positive hair pull test from peripheral sites of active lesions. Tinea capitis usually has localized sites of hair loss with underlying scaling, crusting, pruritus, erythema, and discharge from lesions, with positive potassium hydroxide preparations or fungal cultures. Trichotillomania typically presents with a spared peripheral fringe of hair. Remaining hairs may be thick and hyperpigmented as a response to repeated pulling, and biopsy often demonstrates fracture or degeneration of the hair shaft. A psychiatric evaluation may be warranted in cases of trichotillomania. Other cases of arthropod-induced hair loss include tick bite alopecia^10,11 and hair loss induced by numerous honeybee stings,¹² and these diagnoses should be suspected in patients with a history of ants on their pillow or in those from endemic areas.

No specific treatment is indicated in cases of 
ant-induced alopecia because hair usually regrows to its normal length without intervention.

Case Report

An 18-year-old Iranian man presented to the dermatology clinic with hair loss of 1 night’s duration. He denied pruritus, pain, discharge, or flaking. The patient had no notable personal, family, or surgical history and was not currently taking any medications. He denied recent travel. The patient reported that he found hair on his pillow upon waking up in the morning prior to coming to the clinic. On physical examination, 2 ants 
(Figure 1) were found on the scalp and alopecia with a vertical linear distribution was noted (Figure 2). Hairs of various lengths were found on the scalp within the distribution of the alopecia. No excoriations, crusting, seborrhea, or other areas of hair loss were detected. Wood lamp examination was negative. Based on these findings, which were concordant with similar findings from prior reports,^1-4 a diagnosis of ant-induced alopecia was made. Hair regrowth was noted within 1 week with full appearance of normal-length hair within 2.5 weeks.

Comment

Ant-induced alopecia is a form of localized hair loss caused by the Pheidole genus, the second largest genus of ants in the world.⁵ These ants can be found worldwide, but most cases of ant-induced alopecia have been from Iran, with at least 1 reported case from Turkey.^1-4,6 An early case series of ant-induced alopecia was reported in 1999,⁶ but the causative species was not described at that time.

The majority of reported cases of ant-induced alopecia are attributed to the barber ant (Pheidole pallidula). This type of alopecia is caused by worker ants within the species hierarchy.^1,4,6 The P pallidula worker ants are dimorphic and are classified as major and minor workers.⁷ Major workers have body lengths ranging up to 6 mm, whereas minor workers have body lengths ranging up to 4 mm. Major workers have larger heads and mandibles than minor workers and also have up to 2 pairs of denticles on the cranium.⁵ The minor workers are foragers and mainly collect food, whereas the major workers defend the nest and store food.⁸ These ants have widespread habitats with the ability to live in indoor and outdoor environments.

The presentation of hair loss caused by these ants is acute. Hair loss usually is confined to one specific area. Some patients may report pruritus or may present with erythematous lesions from ant stings or manual scratching.⁵ None of these signs or symptoms were seen in our patient. Some investigators have suggested that the barber ant is attracted to the hair of individuals with seborrheic dermatitis,¹ but our patient had no medical history of seborrheic dermatitis. Most likely, ants are attracted to excess sebum on the scalp in select individuals in their search for food and cause localized hair destruction.

Localized hair loss, as depicted in our case, should warrant a thorough evaluation for alopecia areata, trichotillomania, and tinea capitis.⁹ Alopecia areata should be considered in individuals with multiple focal patches of hair loss that have a positive hair pull test from peripheral sites of active lesions. Tinea capitis usually has localized sites of hair loss with underlying scaling, crusting, pruritus, erythema, and discharge from lesions, with positive potassium hydroxide preparations or fungal cultures. Trichotillomania typically presents with a spared peripheral fringe of hair. Remaining hairs may be thick and hyperpigmented as a response to repeated pulling, and biopsy often demonstrates fracture or degeneration of the hair shaft. A psychiatric evaluation may be warranted in cases of trichotillomania. Other cases of arthropod-induced hair loss include tick bite alopecia^10,11 and hair loss induced by numerous honeybee stings,¹² and these diagnoses should be suspected in patients with a history of ants on their pillow or in those from endemic areas.

No specific treatment is indicated in cases of 
ant-induced alopecia because hair usually regrows to its normal length without intervention.

The Diagnosis: Idiopathic Guttate Hypomelanosis

A biopsy of the largest lesion from the left leg 
superior to the lateral malleolus was performed. 
 Histopathologic examination revealed solar elastosis, diminished number of focal melanocytes and pigment within keratinocytes compared to uninvolved skin, and presence of hyperkeratosis with flattening of rete ridges. The clinical presentation along with histopathologic analysis confirmed a diagnosis of idiopathic guttate hypomelanosis (IGH). The lesions were treated with short-exposure cryotherapy, which resulted in partial repigmentation after several treatments.

Idiopathic guttate hypomelanosis is a common but underreported condition in elderly patients that usually presents with small, discrete, asymptomatic, hypopigmented macules. The frequency of IGH increases with age.¹ Frequency of the condition is much lower in patients aged 21 to 30 years and does not exceed 7%. Lesions of IGH have a predilection for sun-exposed areas such as the arms and legs but rarely can be seen on the face and trunk. Facial lesions of IGH are more frequently reported in women.¹ The size of lesions can be up to 1.5 cm in diameter. The condition generally is self-limited, but some patients may express aesthetic concerns. Rare cases of IGH in children have been associated with prolonged sun exposure.²

The etiology of IGH is unknown but an association with sun exposure has been noted. Patients with IGH frequently show other signs of photoaging, such as numerous seborrheic keratoses, solar lentigines, xeroses, freckles, and actinic keratoses.¹ Short-term exposure to UVB radiation and psoralen plus UVA therapy has been shown to cause IGH in patients with chronic diseases such as mycosis fungoides.^3-5 One small study that examined renal transplant recipients determined an association between HLA-DQ3 antigens and IGH, whereas HLA-DR8 antigens were not identified in any patients with IGH, indicating it may have some advantage in preventing the development of IGH.⁶ Shin et al¹ reported that IGH was prevalent among patients who regularly traumatized their skin by scrubbing.

Clinically, IGH should be differentiated from other conditions characterized by hypopigmentation, such as pityriasis alba, pityriasis versicolor, postinflammatory hypopigmentation, progressive macular hypomelanosis, and vitiligo. Aside from clinical examination, histopathologic studies are helpful in making a definitive diagnosis. The differential diagnosis of IGH is presented in the Table.

Histopathology of IGH lesions usually reveals slight atrophy of the epidermis with flattening of rete ridges and concomitant hyperkeratosis. A thickened stratum granulosum also has been noted in lesions of IGH.² The diminished number of melanocytes and melanin pigment granules along with hyperkeratosis both appear to contribute to the hypopigmentation noted in IGH.⁷ Ultrastructural studies of lesions of IGH can confirm melanocytic degeneration and a decreased number of melanosomes in melanocytes and keratinocytes.^2,8

There is no uniformly effective treatment of IGH. Topical application of tacrolimus and tretinoin have shown efficacy in repigmenting IGH lesions.^8,9 Short-exposure cryotherapy with a duration of 3 to 
5 seconds, localized chemical peels, and/or local dermabrasion can be helpful.^10-12 CO₂ lasers also have demonstrated promising results.¹³

The Diagnosis: Idiopathic Guttate Hypomelanosis

A biopsy of the largest lesion from the left leg 
superior to the lateral malleolus was performed. 
 Histopathologic examination revealed solar elastosis, diminished number of focal melanocytes and pigment within keratinocytes compared to uninvolved skin, and presence of hyperkeratosis with flattening of rete ridges. The clinical presentation along with histopathologic analysis confirmed a diagnosis of idiopathic guttate hypomelanosis (IGH). The lesions were treated with short-exposure cryotherapy, which resulted in partial repigmentation after several treatments.

Idiopathic guttate hypomelanosis is a common but underreported condition in elderly patients that usually presents with small, discrete, asymptomatic, hypopigmented macules. The frequency of IGH increases with age.¹ Frequency of the condition is much lower in patients aged 21 to 30 years and does not exceed 7%. Lesions of IGH have a predilection for sun-exposed areas such as the arms and legs but rarely can be seen on the face and trunk. Facial lesions of IGH are more frequently reported in women.¹ The size of lesions can be up to 1.5 cm in diameter. The condition generally is self-limited, but some patients may express aesthetic concerns. Rare cases of IGH in children have been associated with prolonged sun exposure.²

The etiology of IGH is unknown but an association with sun exposure has been noted. Patients with IGH frequently show other signs of photoaging, such as numerous seborrheic keratoses, solar lentigines, xeroses, freckles, and actinic keratoses.¹ Short-term exposure to UVB radiation and psoralen plus UVA therapy has been shown to cause IGH in patients with chronic diseases such as mycosis fungoides.^3-5 One small study that examined renal transplant recipients determined an association between HLA-DQ3 antigens and IGH, whereas HLA-DR8 antigens were not identified in any patients with IGH, indicating it may have some advantage in preventing the development of IGH.⁶ Shin et al¹ reported that IGH was prevalent among patients who regularly traumatized their skin by scrubbing.

Clinically, IGH should be differentiated from other conditions characterized by hypopigmentation, such as pityriasis alba, pityriasis versicolor, postinflammatory hypopigmentation, progressive macular hypomelanosis, and vitiligo. Aside from clinical examination, histopathologic studies are helpful in making a definitive diagnosis. The differential diagnosis of IGH is presented in the Table.

Histopathology of IGH lesions usually reveals slight atrophy of the epidermis with flattening of rete ridges and concomitant hyperkeratosis. A thickened stratum granulosum also has been noted in lesions of IGH.² The diminished number of melanocytes and melanin pigment granules along with hyperkeratosis both appear to contribute to the hypopigmentation noted in IGH.⁷ Ultrastructural studies of lesions of IGH can confirm melanocytic degeneration and a decreased number of melanosomes in melanocytes and keratinocytes.^2,8

There is no uniformly effective treatment of IGH. Topical application of tacrolimus and tretinoin have shown efficacy in repigmenting IGH lesions.^8,9 Short-exposure cryotherapy with a duration of 3 to 
5 seconds, localized chemical peels, and/or local dermabrasion can be helpful.^10-12 CO₂ lasers also have demonstrated promising results.¹³

The Diagnosis: Idiopathic Guttate Hypomelanosis

A biopsy of the largest lesion from the left leg 
superior to the lateral malleolus was performed. 
 Histopathologic examination revealed solar elastosis, diminished number of focal melanocytes and pigment within keratinocytes compared to uninvolved skin, and presence of hyperkeratosis with flattening of rete ridges. The clinical presentation along with histopathologic analysis confirmed a diagnosis of idiopathic guttate hypomelanosis (IGH). The lesions were treated with short-exposure cryotherapy, which resulted in partial repigmentation after several treatments.

Idiopathic guttate hypomelanosis is a common but underreported condition in elderly patients that usually presents with small, discrete, asymptomatic, hypopigmented macules. The frequency of IGH increases with age.¹ Frequency of the condition is much lower in patients aged 21 to 30 years and does not exceed 7%. Lesions of IGH have a predilection for sun-exposed areas such as the arms and legs but rarely can be seen on the face and trunk. Facial lesions of IGH are more frequently reported in women.¹ The size of lesions can be up to 1.5 cm in diameter. The condition generally is self-limited, but some patients may express aesthetic concerns. Rare cases of IGH in children have been associated with prolonged sun exposure.²

The etiology of IGH is unknown but an association with sun exposure has been noted. Patients with IGH frequently show other signs of photoaging, such as numerous seborrheic keratoses, solar lentigines, xeroses, freckles, and actinic keratoses.¹ Short-term exposure to UVB radiation and psoralen plus UVA therapy has been shown to cause IGH in patients with chronic diseases such as mycosis fungoides.^3-5 One small study that examined renal transplant recipients determined an association between HLA-DQ3 antigens and IGH, whereas HLA-DR8 antigens were not identified in any patients with IGH, indicating it may have some advantage in preventing the development of IGH.⁶ Shin et al¹ reported that IGH was prevalent among patients who regularly traumatized their skin by scrubbing.

Clinically, IGH should be differentiated from other conditions characterized by hypopigmentation, such as pityriasis alba, pityriasis versicolor, postinflammatory hypopigmentation, progressive macular hypomelanosis, and vitiligo. Aside from clinical examination, histopathologic studies are helpful in making a definitive diagnosis. The differential diagnosis of IGH is presented in the Table.

Histopathology of IGH lesions usually reveals slight atrophy of the epidermis with flattening of rete ridges and concomitant hyperkeratosis. A thickened stratum granulosum also has been noted in lesions of IGH.² The diminished number of melanocytes and melanin pigment granules along with hyperkeratosis both appear to contribute to the hypopigmentation noted in IGH.⁷ Ultrastructural studies of lesions of IGH can confirm melanocytic degeneration and a decreased number of melanosomes in melanocytes and keratinocytes.^2,8

There is no uniformly effective treatment of IGH. Topical application of tacrolimus and tretinoin have shown efficacy in repigmenting IGH lesions.^8,9 Short-exposure cryotherapy with a duration of 3 to 
5 seconds, localized chemical peels, and/or local dermabrasion can be helpful.^10-12 CO₂ lasers also have demonstrated promising results.¹³

The coexistence of more than one cutaneous adnexal neoplasm in a single biopsy specimen is unusual and is most frequently recognized in the context of a nevus sebaceous or Brooke-Spiegler syndrome, an autosomal-dominant inherited disease characterized by cutaneous adnexal neoplasms, most commonly cylindromas and trichoepitheliomas.^1-3 Brooke-Spiegler syndrome is caused by germline mutations in the cylindromatosis gene, CYLD, located on band 16q12; it functions as a tumor suppressor gene and has regulatory roles in development, immunity, and inflammation.¹ Weyers et al³ first recognized the tendency for adnexal collision tumors to present in patients with Brooke-Spiegler syndrome; they reported a patient with Brooke-Spiegler syndrome with spiradenomas found in the immediate vicinity of trichoepitheliomas and in continuity with hair follicles.

Spiradenomas are composed of large, sharply demarcated, rounded nodules of basaloid cells with little cytoplasm (Figure 1).⁴ The basaloid nodules may demonstrate a trabecular architecture, and on close inspection 2 cell types—paler cells with more cytoplasm and darker cells with less cytoplasm—are distinguishable (Figure 2A). Lymphocytes often are scattered within the tumor nodules and/or stroma. In Brooke-Spiegler syndrome, collision tumors containing a spiradenomatous component in collision with trichoepithelioma are not uncommon.¹ Spiradenomas in Brooke-Spiegler syndrome have been reported to contain sebaceous differentiation or foci with an adenoid cystic carcinoma (ACC)–like pattern and are known to occur as hybrid lesions of spiradenoma and cylindroma or trichoepithelioma (as in this case).

Figure 1. Two distinct neoplasms are apparent, side by side, with an intervening hair follicle. The spirade-noma (right) is a large, sharply demarcated, rounded nodule of basaloid cells containing little cytoplasm. The trichoepithelioma (left) is composed of lobules of basaloid cells with a cribriform architecture, surrounded by a fibroblast-rich stroma. Mucin is apparent within the cystic spaces (H&E, original magnification ×2).

In this case, 2 distinct neoplasms (spiradenoma and trichoepithelioma) are apparent, side by side, with an intervening hair follicle (Figure 1). Trichoepitheliomas, also known as cribriform trichoblastomas,⁵ are characterized by lobules of basaloid cells resembling basal cell carcinoma surrounded by a fibroblast-rich stroma. They often contain fingerlike projections and adopt a cribriform morphology within the tumor lobules (Figure 2B).⁴ Numerous horn cysts may be present, but their absence does not preclude the diagnosis. Mucin may be present within the cribriform tumor islands (Figure 2B) but not in the stroma. Characteristically, trichoepitheliomas are distinctly negative for CK7 (Figure 3), and unlike spiradenomas, they lack a myoepithelial component.⁶ This staining pattern in combination with the tumor’s proximity to an adjacent hair follicle makes a diagnosis of trichoepithelioma and spiradenoma collision tumor most likely and supports a clinical suspicion for Brooke-Spiegler syndrome.

Figure 2. Spiradenomas may demonstrate a trabecular architecture, and on close inspection 2 cell types—paler cells with more cytoplasm and darker cells with less cytoplasm—are distinguishable. Lymphocytes are scattered within the tumor nodules and/or stroma (A)(H&E, original magnification ×100).The individual lobules within a trichoepithelioma can adopt a cribriform morphology, and mucin may be present within the cystic spaces (B)(H&E, original magnification ×90).

Although spiradenomas sometimes contain cystic cavities (microcystic change), they typically are filled with finely granular eosinophilic material, not mucin, that is diastase resistant and periodic acid–Schiff positive (Figure 4).⁷ Spiradenomas classically stain positive with CK7 (Figure 3), epithelial membrane antigen, and carcinoembryonic antigen, and have a substantial myoepithelial component, as evidenced by the myoepithelial component staining with p63, S-100, and smooth muscle actin (SMA).^7-9 The distinct lack of staining with CK7 and SMA in the tumor on the left in Figure 3 confirms that these tumors are of different lineage, rather than representing cystic change within a spiradenoma.

Figure 3. Positive staining with CK7 can be noted in the spiradenoma (right) and negative staining is noted in the trichoepithelioma (left)(original magnification ×3).

Figure 4. Cystic cavities within a spiradenoma are filled with finely granular eosinophilic material, not mucin, that is diastase resistant and periodic acid–Schiff positive (H&E, original magnification ×30).

Adenoid cystic carcinoma is a rare neoplasm that may occur in a primary cutaneous form, as a direct extension from an underlying salivary gland neoplasm, or rarely as a focal pattern within spiradenomas occurring both sporadically or in the context of Brooke-Spiegler syndrome.^2,7 The tumor is composed of variably sized cribriform islands of basaloid to pink cells concentrically arranged around glandlike spaces filled with mucin (Figure 5A). In contrast to trichoepithelioma, ACC occurs in the mid to deep dermis, often extending into subcutaneous fat with an infiltrative border, and is not often found in close proximity to hair follicles.⁷ Characteristically, hyaline basement membrane–like material that is periodic acid–Schiff positive is found between the tumor cells and also surrounding the individual lobules. Immunohistochemically, ACC has a myoepithelial component that stains positive with SMA, S-100, and p63; additionally, the tumor cells express low- and high-molecular-weight keratin and demonstrate variable epithelial membrane antigen positivity.¹⁰ In the current case, the superficial location, close association with a hair follicle, and lack of staining with both CK7 (Figure 3) and SMA (not shown) make ACC arising within a spiradenoma a less likely diagnosis.

Cylindromas are composed of basaloid islands interconnected in a jigsaw puzzle configuration (Figure 5B).⁴ Similar to spiradenomas, they also are composed of 2 cell populations. Characteristically, the tumor islands are outlined by a hyalinized eosinophilic basement membrane. Hyalinized droplets of basement membrane zone material also may be noted in the islands. Unlike spiradenomas, they lack both intratumoral lymphocytes and a trabecular growth pattern. Although spiradenocylindromas (cylindroma and spiradenoma collision tumors) are perhaps the most common collision tumor associated with Brooke-Spiegler syndrome, there is no evidence suggesting the presence of a cylindroma in the current case.

Figure 5. Adenoid cystic carcinoma is composed of variably sized cribriform islands of basaloid to pink cells concentrically arranged around glandlike spaces filled with mucin (A)(H&E, original magnification ×20). Cylindromas are composed of basaloid islands interconnected in a jigsaw puzzle configuration. Characteristically, the tumor islands are outlined by a hyalinized eosinophilic basement membrane (B) (H&E, original magnification ×100).

Primary cutaneous mucinous carcinoma is a rare neoplasm with a predilection for the eyelids; lesions occurring outside of this facial distribution, particularly of the breast, warrant a workup for metastatic disease.⁷ It typically occurs in the deeper dermis with involvement of the subcutaneous fat and is characterized by delicate fibrous septa enveloping large lakes of mucin, which contain islands of tumor cells (Figure 6). It has not been reported in association with spiradenomas. In addition, the tumor cells typically are CK7 positive.

Figure 6. Mucinous carcinoma is characterized by delicate fibrous septa enclosing large lakes of mucin containing islands of tumor cells (H&E, original magnification ×20).

The coexistence of more than one cutaneous adnexal neoplasm in a single biopsy specimen is unusual and is most frequently recognized in the context of a nevus sebaceous or Brooke-Spiegler syndrome, an autosomal-dominant inherited disease characterized by cutaneous adnexal neoplasms, most commonly cylindromas and trichoepitheliomas.^1-3 Brooke-Spiegler syndrome is caused by germline mutations in the cylindromatosis gene, CYLD, located on band 16q12; it functions as a tumor suppressor gene and has regulatory roles in development, immunity, and inflammation.¹ Weyers et al³ first recognized the tendency for adnexal collision tumors to present in patients with Brooke-Spiegler syndrome; they reported a patient with Brooke-Spiegler syndrome with spiradenomas found in the immediate vicinity of trichoepitheliomas and in continuity with hair follicles.

Spiradenomas are composed of large, sharply demarcated, rounded nodules of basaloid cells with little cytoplasm (Figure 1).⁴ The basaloid nodules may demonstrate a trabecular architecture, and on close inspection 2 cell types—paler cells with more cytoplasm and darker cells with less cytoplasm—are distinguishable (Figure 2A). Lymphocytes often are scattered within the tumor nodules and/or stroma. In Brooke-Spiegler syndrome, collision tumors containing a spiradenomatous component in collision with trichoepithelioma are not uncommon.¹ Spiradenomas in Brooke-Spiegler syndrome have been reported to contain sebaceous differentiation or foci with an adenoid cystic carcinoma (ACC)–like pattern and are known to occur as hybrid lesions of spiradenoma and cylindroma or trichoepithelioma (as in this case).

Figure 1. Two distinct neoplasms are apparent, side by side, with an intervening hair follicle. The spirade-noma (right) is a large, sharply demarcated, rounded nodule of basaloid cells containing little cytoplasm. The trichoepithelioma (left) is composed of lobules of basaloid cells with a cribriform architecture, surrounded by a fibroblast-rich stroma. Mucin is apparent within the cystic spaces (H&E, original magnification ×2).

In this case, 2 distinct neoplasms (spiradenoma and trichoepithelioma) are apparent, side by side, with an intervening hair follicle (Figure 1). Trichoepitheliomas, also known as cribriform trichoblastomas,⁵ are characterized by lobules of basaloid cells resembling basal cell carcinoma surrounded by a fibroblast-rich stroma. They often contain fingerlike projections and adopt a cribriform morphology within the tumor lobules (Figure 2B).⁴ Numerous horn cysts may be present, but their absence does not preclude the diagnosis. Mucin may be present within the cribriform tumor islands (Figure 2B) but not in the stroma. Characteristically, trichoepitheliomas are distinctly negative for CK7 (Figure 3), and unlike spiradenomas, they lack a myoepithelial component.⁶ This staining pattern in combination with the tumor’s proximity to an adjacent hair follicle makes a diagnosis of trichoepithelioma and spiradenoma collision tumor most likely and supports a clinical suspicion for Brooke-Spiegler syndrome.

Figure 2. Spiradenomas may demonstrate a trabecular architecture, and on close inspection 2 cell types—paler cells with more cytoplasm and darker cells with less cytoplasm—are distinguishable. Lymphocytes are scattered within the tumor nodules and/or stroma (A)(H&E, original magnification ×100).The individual lobules within a trichoepithelioma can adopt a cribriform morphology, and mucin may be present within the cystic spaces (B)(H&E, original magnification ×90).

Although spiradenomas sometimes contain cystic cavities (microcystic change), they typically are filled with finely granular eosinophilic material, not mucin, that is diastase resistant and periodic acid–Schiff positive (Figure 4).⁷ Spiradenomas classically stain positive with CK7 (Figure 3), epithelial membrane antigen, and carcinoembryonic antigen, and have a substantial myoepithelial component, as evidenced by the myoepithelial component staining with p63, S-100, and smooth muscle actin (SMA).^7-9 The distinct lack of staining with CK7 and SMA in the tumor on the left in Figure 3 confirms that these tumors are of different lineage, rather than representing cystic change within a spiradenoma.

Figure 3. Positive staining with CK7 can be noted in the spiradenoma (right) and negative staining is noted in the trichoepithelioma (left)(original magnification ×3).

Figure 4. Cystic cavities within a spiradenoma are filled with finely granular eosinophilic material, not mucin, that is diastase resistant and periodic acid–Schiff positive (H&E, original magnification ×30).

Adenoid cystic carcinoma is a rare neoplasm that may occur in a primary cutaneous form, as a direct extension from an underlying salivary gland neoplasm, or rarely as a focal pattern within spiradenomas occurring both sporadically or in the context of Brooke-Spiegler syndrome.^2,7 The tumor is composed of variably sized cribriform islands of basaloid to pink cells concentrically arranged around glandlike spaces filled with mucin (Figure 5A). In contrast to trichoepithelioma, ACC occurs in the mid to deep dermis, often extending into subcutaneous fat with an infiltrative border, and is not often found in close proximity to hair follicles.⁷ Characteristically, hyaline basement membrane–like material that is periodic acid–Schiff positive is found between the tumor cells and also surrounding the individual lobules. Immunohistochemically, ACC has a myoepithelial component that stains positive with SMA, S-100, and p63; additionally, the tumor cells express low- and high-molecular-weight keratin and demonstrate variable epithelial membrane antigen positivity.¹⁰ In the current case, the superficial location, close association with a hair follicle, and lack of staining with both CK7 (Figure 3) and SMA (not shown) make ACC arising within a spiradenoma a less likely diagnosis.

Cylindromas are composed of basaloid islands interconnected in a jigsaw puzzle configuration (Figure 5B).⁴ Similar to spiradenomas, they also are composed of 2 cell populations. Characteristically, the tumor islands are outlined by a hyalinized eosinophilic basement membrane. Hyalinized droplets of basement membrane zone material also may be noted in the islands. Unlike spiradenomas, they lack both intratumoral lymphocytes and a trabecular growth pattern. Although spiradenocylindromas (cylindroma and spiradenoma collision tumors) are perhaps the most common collision tumor associated with Brooke-Spiegler syndrome, there is no evidence suggesting the presence of a cylindroma in the current case.

Figure 5. Adenoid cystic carcinoma is composed of variably sized cribriform islands of basaloid to pink cells concentrically arranged around glandlike spaces filled with mucin (A)(H&E, original magnification ×20). Cylindromas are composed of basaloid islands interconnected in a jigsaw puzzle configuration. Characteristically, the tumor islands are outlined by a hyalinized eosinophilic basement membrane (B) (H&E, original magnification ×100).

Primary cutaneous mucinous carcinoma is a rare neoplasm with a predilection for the eyelids; lesions occurring outside of this facial distribution, particularly of the breast, warrant a workup for metastatic disease.⁷ It typically occurs in the deeper dermis with involvement of the subcutaneous fat and is characterized by delicate fibrous septa enveloping large lakes of mucin, which contain islands of tumor cells (Figure 6). It has not been reported in association with spiradenomas. In addition, the tumor cells typically are CK7 positive.

Figure 6. Mucinous carcinoma is characterized by delicate fibrous septa enclosing large lakes of mucin containing islands of tumor cells (H&E, original magnification ×20).

The coexistence of more than one cutaneous adnexal neoplasm in a single biopsy specimen is unusual and is most frequently recognized in the context of a nevus sebaceous or Brooke-Spiegler syndrome, an autosomal-dominant inherited disease characterized by cutaneous adnexal neoplasms, most commonly cylindromas and trichoepitheliomas.^1-3 Brooke-Spiegler syndrome is caused by germline mutations in the cylindromatosis gene, CYLD, located on band 16q12; it functions as a tumor suppressor gene and has regulatory roles in development, immunity, and inflammation.¹ Weyers et al³ first recognized the tendency for adnexal collision tumors to present in patients with Brooke-Spiegler syndrome; they reported a patient with Brooke-Spiegler syndrome with spiradenomas found in the immediate vicinity of trichoepitheliomas and in continuity with hair follicles.

Spiradenomas are composed of large, sharply demarcated, rounded nodules of basaloid cells with little cytoplasm (Figure 1).⁴ The basaloid nodules may demonstrate a trabecular architecture, and on close inspection 2 cell types—paler cells with more cytoplasm and darker cells with less cytoplasm—are distinguishable (Figure 2A). Lymphocytes often are scattered within the tumor nodules and/or stroma. In Brooke-Spiegler syndrome, collision tumors containing a spiradenomatous component in collision with trichoepithelioma are not uncommon.¹ Spiradenomas in Brooke-Spiegler syndrome have been reported to contain sebaceous differentiation or foci with an adenoid cystic carcinoma (ACC)–like pattern and are known to occur as hybrid lesions of spiradenoma and cylindroma or trichoepithelioma (as in this case).

Figure 1. Two distinct neoplasms are apparent, side by side, with an intervening hair follicle. The spirade-noma (right) is a large, sharply demarcated, rounded nodule of basaloid cells containing little cytoplasm. The trichoepithelioma (left) is composed of lobules of basaloid cells with a cribriform architecture, surrounded by a fibroblast-rich stroma. Mucin is apparent within the cystic spaces (H&E, original magnification ×2).

In this case, 2 distinct neoplasms (spiradenoma and trichoepithelioma) are apparent, side by side, with an intervening hair follicle (Figure 1). Trichoepitheliomas, also known as cribriform trichoblastomas,⁵ are characterized by lobules of basaloid cells resembling basal cell carcinoma surrounded by a fibroblast-rich stroma. They often contain fingerlike projections and adopt a cribriform morphology within the tumor lobules (Figure 2B).⁴ Numerous horn cysts may be present, but their absence does not preclude the diagnosis. Mucin may be present within the cribriform tumor islands (Figure 2B) but not in the stroma. Characteristically, trichoepitheliomas are distinctly negative for CK7 (Figure 3), and unlike spiradenomas, they lack a myoepithelial component.⁶ This staining pattern in combination with the tumor’s proximity to an adjacent hair follicle makes a diagnosis of trichoepithelioma and spiradenoma collision tumor most likely and supports a clinical suspicion for Brooke-Spiegler syndrome.

Figure 2. Spiradenomas may demonstrate a trabecular architecture, and on close inspection 2 cell types—paler cells with more cytoplasm and darker cells with less cytoplasm—are distinguishable. Lymphocytes are scattered within the tumor nodules and/or stroma (A)(H&E, original magnification ×100).The individual lobules within a trichoepithelioma can adopt a cribriform morphology, and mucin may be present within the cystic spaces (B)(H&E, original magnification ×90).

Although spiradenomas sometimes contain cystic cavities (microcystic change), they typically are filled with finely granular eosinophilic material, not mucin, that is diastase resistant and periodic acid–Schiff positive (Figure 4).⁷ Spiradenomas classically stain positive with CK7 (Figure 3), epithelial membrane antigen, and carcinoembryonic antigen, and have a substantial myoepithelial component, as evidenced by the myoepithelial component staining with p63, S-100, and smooth muscle actin (SMA).^7-9 The distinct lack of staining with CK7 and SMA in the tumor on the left in Figure 3 confirms that these tumors are of different lineage, rather than representing cystic change within a spiradenoma.

Figure 3. Positive staining with CK7 can be noted in the spiradenoma (right) and negative staining is noted in the trichoepithelioma (left)(original magnification ×3).

Figure 4. Cystic cavities within a spiradenoma are filled with finely granular eosinophilic material, not mucin, that is diastase resistant and periodic acid–Schiff positive (H&E, original magnification ×30).

Adenoid cystic carcinoma is a rare neoplasm that may occur in a primary cutaneous form, as a direct extension from an underlying salivary gland neoplasm, or rarely as a focal pattern within spiradenomas occurring both sporadically or in the context of Brooke-Spiegler syndrome.^2,7 The tumor is composed of variably sized cribriform islands of basaloid to pink cells concentrically arranged around glandlike spaces filled with mucin (Figure 5A). In contrast to trichoepithelioma, ACC occurs in the mid to deep dermis, often extending into subcutaneous fat with an infiltrative border, and is not often found in close proximity to hair follicles.⁷ Characteristically, hyaline basement membrane–like material that is periodic acid–Schiff positive is found between the tumor cells and also surrounding the individual lobules. Immunohistochemically, ACC has a myoepithelial component that stains positive with SMA, S-100, and p63; additionally, the tumor cells express low- and high-molecular-weight keratin and demonstrate variable epithelial membrane antigen positivity.¹⁰ In the current case, the superficial location, close association with a hair follicle, and lack of staining with both CK7 (Figure 3) and SMA (not shown) make ACC arising within a spiradenoma a less likely diagnosis.

Cylindromas are composed of basaloid islands interconnected in a jigsaw puzzle configuration (Figure 5B).⁴ Similar to spiradenomas, they also are composed of 2 cell populations. Characteristically, the tumor islands are outlined by a hyalinized eosinophilic basement membrane. Hyalinized droplets of basement membrane zone material also may be noted in the islands. Unlike spiradenomas, they lack both intratumoral lymphocytes and a trabecular growth pattern. Although spiradenocylindromas (cylindroma and spiradenoma collision tumors) are perhaps the most common collision tumor associated with Brooke-Spiegler syndrome, there is no evidence suggesting the presence of a cylindroma in the current case.

Figure 5. Adenoid cystic carcinoma is composed of variably sized cribriform islands of basaloid to pink cells concentrically arranged around glandlike spaces filled with mucin (A)(H&E, original magnification ×20). Cylindromas are composed of basaloid islands interconnected in a jigsaw puzzle configuration. Characteristically, the tumor islands are outlined by a hyalinized eosinophilic basement membrane (B) (H&E, original magnification ×100).

Primary cutaneous mucinous carcinoma is a rare neoplasm with a predilection for the eyelids; lesions occurring outside of this facial distribution, particularly of the breast, warrant a workup for metastatic disease.⁷ It typically occurs in the deeper dermis with involvement of the subcutaneous fat and is characterized by delicate fibrous septa enveloping large lakes of mucin, which contain islands of tumor cells (Figure 6). It has not been reported in association with spiradenomas. In addition, the tumor cells typically are CK7 positive.

Figure 6. Mucinous carcinoma is characterized by delicate fibrous septa enclosing large lakes of mucin containing islands of tumor cells (H&E, original magnification ×20).