Dermatopathology

The Diagnosis: Primary Systemic Amyloidosis

Our patient presented with multiple firm waxy nodules on the mucosal surface of the lower lip. Excision biopsy showed thickening of blood vessel walls with abundant amorphous material that was consistent with amyloid. Further staining with Congo red demonstrated brick red amorphous material within the vessel walls on routine light microscopy (Figure 1), and crystal violet stain showed metachromasia (Figure 2). Fine needle aspiration of the abdominal fat-pad showed amyloid. The final diagnosis was primary systemic amyloidosis (PSA).

Figure 1. Congo red staining showed a brick red appearance of amyloid within the vessel walls on routine light microscopy (original magnification ×200).

Figure 2. Crystal violet staining around the blood vessels showed metachromasia (original magnification ×100).

Amyloid is an ubiquitous fibrillar protein arranged in a cross-beta-pleated sheet that is confirmed with x-ray crystallography.^1,2 More than 25 variants of amyloid have been identified.³ Pathologic deposition of amyloid-derived material results in a variable spectrum of clinical findings, collectively known as amyloidosis, with presentations ranging from nonspecific fever or fatigue to frank organ failure, depending on the organ involved. In PSA, immunoglobulin light chains are deposited throughout the body. Associated conditions include malignant or benign monoclonal gammopathy, multiple myeloma, Waldenström macroglobulinemia, malignant lymphoma, heavy chain disease, and chronic lymphocytic leukemia.^2,4 The most commonly involved organ systems are the heart, lungs, liver, and kidneys. When patients present with unexplained heart failure, orthostatic hypotension, hepatomegaly, peripheral neuropathy, carpal tunnel syndrome, or renal insufficiency, amyloidosis should always be considered in the differential diagnosis.³

Cutaneous lesions of PSA tend to be vascular due to amyloid infiltration of blood vessel walls, manifesting as petechiae, purpura, ecchymoses, or nonhealing ulcers. Pinch purpura frequently are seen in the periorbital region after minor trauma and are recognized as a clinical indicator of PSA.^2,4 Xerostomia from amyloid infiltrates in salivary glands is extremely common, and cases of amyloid in the eyes, bones, and thyroid gland have been reported.² Macroglossia is seen in 12% to 40% of cases; coupled with xerostomia, it can lead to oropharyngeal dysphagia.^2,5

Systemic amyloidosis can be further divided into primary (idiopathic or multiple myeloma associated) or secondary to chronic inflammatory conditions or infections; the key difference is the protein from which the abnormal amyloid is derived.^1,4 The presence of cutaneous amyloidosis renders the need to rule out systemic disease because amyloidosis may be a purely localized or systemic process.⁴ Nodular amyloidosis is a localized form of amyloid that also has immunoglobulin light chain deposits and clinically appears exactly the same as PSA; however, the deposits are restricted to the skin.^1,2,4,5

Characteristic biopsy findings in cutaneous amyloidosis include amorphous orange-red amyloid deposits on hematoxylin and eosin–stained sections. The gold standard for amyloid detection is apple green birefringence under polarized light with Congo red stain or electron microscopy.^6,7 Other stains used to identify amyloid include crystal violet, methyl violet, periodic acid–Schiff, Sirius red, pagoda red, Dylon stain, and thioflavine T.^1,2 Confirmation of systemic disease can be accomplished by fine needle aspiration of abdominal fat-pads or rectal mucosal biopsies.^1,3,4 Biopsy of accessory salivary glands also has been reported to be very sensitive and specific.²

Treatment options remain limited; localized cutaneous disease may respond to topical corticosteroids, calcineurin inhibitors, or phototherapy. Primary systemic amyloidosis can be treated with a combination of steroids, melphalan, or colchicine often followed by autologous stem cell transplantation⁸; however, these regimens are not always curative and patients often have a poor prognosis.¹

The Diagnosis: Primary Systemic Amyloidosis

Our patient presented with multiple firm waxy nodules on the mucosal surface of the lower lip. Excision biopsy showed thickening of blood vessel walls with abundant amorphous material that was consistent with amyloid. Further staining with Congo red demonstrated brick red amorphous material within the vessel walls on routine light microscopy (Figure 1), and crystal violet stain showed metachromasia (Figure 2). Fine needle aspiration of the abdominal fat-pad showed amyloid. The final diagnosis was primary systemic amyloidosis (PSA).

Figure 1. Congo red staining showed a brick red appearance of amyloid within the vessel walls on routine light microscopy (original magnification ×200).

Figure 2. Crystal violet staining around the blood vessels showed metachromasia (original magnification ×100).

Amyloid is an ubiquitous fibrillar protein arranged in a cross-beta-pleated sheet that is confirmed with x-ray crystallography.^1,2 More than 25 variants of amyloid have been identified.³ Pathologic deposition of amyloid-derived material results in a variable spectrum of clinical findings, collectively known as amyloidosis, with presentations ranging from nonspecific fever or fatigue to frank organ failure, depending on the organ involved. In PSA, immunoglobulin light chains are deposited throughout the body. Associated conditions include malignant or benign monoclonal gammopathy, multiple myeloma, Waldenström macroglobulinemia, malignant lymphoma, heavy chain disease, and chronic lymphocytic leukemia.^2,4 The most commonly involved organ systems are the heart, lungs, liver, and kidneys. When patients present with unexplained heart failure, orthostatic hypotension, hepatomegaly, peripheral neuropathy, carpal tunnel syndrome, or renal insufficiency, amyloidosis should always be considered in the differential diagnosis.³

Cutaneous lesions of PSA tend to be vascular due to amyloid infiltration of blood vessel walls, manifesting as petechiae, purpura, ecchymoses, or nonhealing ulcers. Pinch purpura frequently are seen in the periorbital region after minor trauma and are recognized as a clinical indicator of PSA.^2,4 Xerostomia from amyloid infiltrates in salivary glands is extremely common, and cases of amyloid in the eyes, bones, and thyroid gland have been reported.² Macroglossia is seen in 12% to 40% of cases; coupled with xerostomia, it can lead to oropharyngeal dysphagia.^2,5

Systemic amyloidosis can be further divided into primary (idiopathic or multiple myeloma associated) or secondary to chronic inflammatory conditions or infections; the key difference is the protein from which the abnormal amyloid is derived.^1,4 The presence of cutaneous amyloidosis renders the need to rule out systemic disease because amyloidosis may be a purely localized or systemic process.⁴ Nodular amyloidosis is a localized form of amyloid that also has immunoglobulin light chain deposits and clinically appears exactly the same as PSA; however, the deposits are restricted to the skin.^1,2,4,5

Characteristic biopsy findings in cutaneous amyloidosis include amorphous orange-red amyloid deposits on hematoxylin and eosin–stained sections. The gold standard for amyloid detection is apple green birefringence under polarized light with Congo red stain or electron microscopy.^6,7 Other stains used to identify amyloid include crystal violet, methyl violet, periodic acid–Schiff, Sirius red, pagoda red, Dylon stain, and thioflavine T.^1,2 Confirmation of systemic disease can be accomplished by fine needle aspiration of abdominal fat-pads or rectal mucosal biopsies.^1,3,4 Biopsy of accessory salivary glands also has been reported to be very sensitive and specific.²

Treatment options remain limited; localized cutaneous disease may respond to topical corticosteroids, calcineurin inhibitors, or phototherapy. Primary systemic amyloidosis can be treated with a combination of steroids, melphalan, or colchicine often followed by autologous stem cell transplantation⁸; however, these regimens are not always curative and patients often have a poor prognosis.¹

The Diagnosis: Primary Systemic Amyloidosis

Our patient presented with multiple firm waxy nodules on the mucosal surface of the lower lip. Excision biopsy showed thickening of blood vessel walls with abundant amorphous material that was consistent with amyloid. Further staining with Congo red demonstrated brick red amorphous material within the vessel walls on routine light microscopy (Figure 1), and crystal violet stain showed metachromasia (Figure 2). Fine needle aspiration of the abdominal fat-pad showed amyloid. The final diagnosis was primary systemic amyloidosis (PSA).

Figure 1. Congo red staining showed a brick red appearance of amyloid within the vessel walls on routine light microscopy (original magnification ×200).

Figure 2. Crystal violet staining around the blood vessels showed metachromasia (original magnification ×100).

Amyloid is an ubiquitous fibrillar protein arranged in a cross-beta-pleated sheet that is confirmed with x-ray crystallography.^1,2 More than 25 variants of amyloid have been identified.³ Pathologic deposition of amyloid-derived material results in a variable spectrum of clinical findings, collectively known as amyloidosis, with presentations ranging from nonspecific fever or fatigue to frank organ failure, depending on the organ involved. In PSA, immunoglobulin light chains are deposited throughout the body. Associated conditions include malignant or benign monoclonal gammopathy, multiple myeloma, Waldenström macroglobulinemia, malignant lymphoma, heavy chain disease, and chronic lymphocytic leukemia.^2,4 The most commonly involved organ systems are the heart, lungs, liver, and kidneys. When patients present with unexplained heart failure, orthostatic hypotension, hepatomegaly, peripheral neuropathy, carpal tunnel syndrome, or renal insufficiency, amyloidosis should always be considered in the differential diagnosis.³

Cutaneous lesions of PSA tend to be vascular due to amyloid infiltration of blood vessel walls, manifesting as petechiae, purpura, ecchymoses, or nonhealing ulcers. Pinch purpura frequently are seen in the periorbital region after minor trauma and are recognized as a clinical indicator of PSA.^2,4 Xerostomia from amyloid infiltrates in salivary glands is extremely common, and cases of amyloid in the eyes, bones, and thyroid gland have been reported.² Macroglossia is seen in 12% to 40% of cases; coupled with xerostomia, it can lead to oropharyngeal dysphagia.^2,5

Systemic amyloidosis can be further divided into primary (idiopathic or multiple myeloma associated) or secondary to chronic inflammatory conditions or infections; the key difference is the protein from which the abnormal amyloid is derived.^1,4 The presence of cutaneous amyloidosis renders the need to rule out systemic disease because amyloidosis may be a purely localized or systemic process.⁴ Nodular amyloidosis is a localized form of amyloid that also has immunoglobulin light chain deposits and clinically appears exactly the same as PSA; however, the deposits are restricted to the skin.^1,2,4,5

Characteristic biopsy findings in cutaneous amyloidosis include amorphous orange-red amyloid deposits on hematoxylin and eosin–stained sections. The gold standard for amyloid detection is apple green birefringence under polarized light with Congo red stain or electron microscopy.^6,7 Other stains used to identify amyloid include crystal violet, methyl violet, periodic acid–Schiff, Sirius red, pagoda red, Dylon stain, and thioflavine T.^1,2 Confirmation of systemic disease can be accomplished by fine needle aspiration of abdominal fat-pads or rectal mucosal biopsies.^1,3,4 Biopsy of accessory salivary glands also has been reported to be very sensitive and specific.²

Treatment options remain limited; localized cutaneous disease may respond to topical corticosteroids, calcineurin inhibitors, or phototherapy. Primary systemic amyloidosis can be treated with a combination of steroids, melphalan, or colchicine often followed by autologous stem cell transplantation⁸; however, these regimens are not always curative and patients often have a poor prognosis.¹

To the Editor:
Acrokeratoelastoidosis (AKE) is a rare disease first described by Costa¹ in 1953. Typically it is only a cosmetic nuisance in the majority of patients and presents as asymptomatic, small, firm, flesh-colored to yellowish, round to polygonal papules with occasional keratosis or umbilication on the radial and ulnar margins of the hands and/or feet.^1-3 In some cases, the lesions occur on the anterior aspects of the wrists, fingers, or lower legs.¹ The lesions are always bilaterally distributed. Acrokeratoelastoidosis is a chronic skin disorder that commonly presents during childhood or adolescence, but presentation in adulthood also has been described.³ Histologically, AKE always shows hyperkeratosis, acanthosis, decrease of elastic tissue, and elastorrhexis of remaining elastic fibers. Plaque-type lesions are rare. We describe a patient who presented with plaques on the radial and ulnar margins of the hands.

A 36-year-old Chinese woman presented with asymptomatic, small, firm papules of 6 months’ duration that initially developed on the hands and gradually increased in number, coalescing into plaques. The feet were spared. She had no medical history of hyperhidrosis, chronic trauma, friction, or excessive sun exposure, and no family history of similar symptoms. No prior therapy had been attempted.

Physical examination showed nonconfluent, firm, flesh-colored to yellowish, translucent, smooth papules with wavy edges that were symmetrically distributed on the radial and ulnar margins of the hands; some papules had coalesced into plaques (Figure 1). A biopsy specimen taken from a plaque on the hypothenar eminence of the right hand revealed focal hyperkeratosis, hypergranulosis, acanthosis, and mild chronic inflammation with hematoxylin and eosin stain (Figure 2A). Aldehyde fuchsin staining showed fragmented and rarefied elastic fibers in the reticular dermis (Figure 2B). The patient was diagnosed with AKE. Oral tretinoin 10 mg twice daily was initiated and resulted in an evident response after 2 weeks of treatment. However, the patient stopped taking the medication because of pruritus and dry skin and the lesions then reappeared.

Figure 1. Nonconfluent, firm, flesh-colored to yellowish, translucent, smooth papules distributed on the radial margin of the hand; some of papules coalesced into plaques.

Figure 2. Histopathology revealed hyperkeratosis, hypergranulosis, acanthosis, and mild chronic inflammation (A) (H&E, original magnification ×250 [inset, original magnification ×400]), as well as fragmented elastic fibers in the reticular dermis (B) (Aldehyde fuchsin, original magnification ×400 [inset, original magnification ×100]).

Acrokeratoelastoidosis is a rare keratotic disorder. It seems to have no racial or ethnic predilection and occurs more frequently in women.^4,5 It also is rare in China, with few cases reported, all women.⁵ The reason for the gender predilection in China remains unknown. The course is chronic, but it may rapidly progress during pregnancy.⁶

The pathogenesis of AKE is still unresolved.^2,3 Although many cases are sporadic,⁵ it appears to be inherited in an autosomal-dominant fashion, most likely related to chromosome 2.⁷ Typically, AKE presents as papules that are discrete and bilaterally distributed in the palmoplantar margins,^2,3 but some of the papules in our patient coalesced into plaques, which is unique. The histologic hallmarks indicated that the lesions were AKE.

The differential diagnosis of AKE includes hereditary papulotranslucent acrokeratoderma, focal acral hyperkeratosis, and keratoelastoidosis marginalis.⁸ Hereditary papulotranslucent acrokeratoderma also is inherited in an autosomal-dominant fashion and shares similar acral, translucent, keratotic papules with AKE, but there is no chronic inflammatory cell infiltrate, degeneration of collagenous fibers, or fragmentation of elastic fibers. The clinical appearance of focal acral hyperkeratosis is similar to AKE, but no changes are revealed in the elastic tissue.⁹ Because AKE, focal acral hyperkeratosis, and hereditary papulotranslucent acrokeratoderma have similar lesions and overlapping histologic changes, they may be considered variants of the same entity.⁴ Keratoelastoidosis marginalis, also called degenerative collagenous plaques of the hand, mainly affects white individuals aged 40 to 60 years with a history of  prolonged sun exposure. Papules often are distributed over the junction of the dorsal and palmar skin and less often on the ulnar sides of the hands.  The clinical lesions are similar to those in our patient, but histopathology of keratoelastoidosis marginalis shows  amorphous, basophilic, elastotic masses and thickened, fragmented, calcified elastic fibers in the upper and mid dermis.

Therapies including liquid nitrogen, topical salicylic acid, methotrexate, dapsone, tar, cryotherapy, systemic prednisone, retinoic acid, clobetasone cream,⁵ and erbium:YAG laser¹⁰ have been applied. Thus far, no optimal treatment has been recommended and no tendency of spontaneous resolution has been previously reported in the literature. Our patient responded to tretinoin, but the lesions recurred after withdrawal of the medication; therefore, tretinoin may not be an optimal treatment option. Because the lesions are limited to the skin and AKE is only considered a cosmetic problem with a good prognosis, we recommend a wait-and-watch approach.

Acknowledgment—We thank Rashmi Sarkar, MD, New Delhi, India, for her assistance.

To the Editor:
Acrokeratoelastoidosis (AKE) is a rare disease first described by Costa¹ in 1953. Typically it is only a cosmetic nuisance in the majority of patients and presents as asymptomatic, small, firm, flesh-colored to yellowish, round to polygonal papules with occasional keratosis or umbilication on the radial and ulnar margins of the hands and/or feet.^1-3 In some cases, the lesions occur on the anterior aspects of the wrists, fingers, or lower legs.¹ The lesions are always bilaterally distributed. Acrokeratoelastoidosis is a chronic skin disorder that commonly presents during childhood or adolescence, but presentation in adulthood also has been described.³ Histologically, AKE always shows hyperkeratosis, acanthosis, decrease of elastic tissue, and elastorrhexis of remaining elastic fibers. Plaque-type lesions are rare. We describe a patient who presented with plaques on the radial and ulnar margins of the hands.

A 36-year-old Chinese woman presented with asymptomatic, small, firm papules of 6 months’ duration that initially developed on the hands and gradually increased in number, coalescing into plaques. The feet were spared. She had no medical history of hyperhidrosis, chronic trauma, friction, or excessive sun exposure, and no family history of similar symptoms. No prior therapy had been attempted.

Physical examination showed nonconfluent, firm, flesh-colored to yellowish, translucent, smooth papules with wavy edges that were symmetrically distributed on the radial and ulnar margins of the hands; some papules had coalesced into plaques (Figure 1). A biopsy specimen taken from a plaque on the hypothenar eminence of the right hand revealed focal hyperkeratosis, hypergranulosis, acanthosis, and mild chronic inflammation with hematoxylin and eosin stain (Figure 2A). Aldehyde fuchsin staining showed fragmented and rarefied elastic fibers in the reticular dermis (Figure 2B). The patient was diagnosed with AKE. Oral tretinoin 10 mg twice daily was initiated and resulted in an evident response after 2 weeks of treatment. However, the patient stopped taking the medication because of pruritus and dry skin and the lesions then reappeared.

Figure 1. Nonconfluent, firm, flesh-colored to yellowish, translucent, smooth papules distributed on the radial margin of the hand; some of papules coalesced into plaques.

Figure 2. Histopathology revealed hyperkeratosis, hypergranulosis, acanthosis, and mild chronic inflammation (A) (H&E, original magnification ×250 [inset, original magnification ×400]), as well as fragmented elastic fibers in the reticular dermis (B) (Aldehyde fuchsin, original magnification ×400 [inset, original magnification ×100]).

Acrokeratoelastoidosis is a rare keratotic disorder. It seems to have no racial or ethnic predilection and occurs more frequently in women.^4,5 It also is rare in China, with few cases reported, all women.⁵ The reason for the gender predilection in China remains unknown. The course is chronic, but it may rapidly progress during pregnancy.⁶

The pathogenesis of AKE is still unresolved.^2,3 Although many cases are sporadic,⁵ it appears to be inherited in an autosomal-dominant fashion, most likely related to chromosome 2.⁷ Typically, AKE presents as papules that are discrete and bilaterally distributed in the palmoplantar margins,^2,3 but some of the papules in our patient coalesced into plaques, which is unique. The histologic hallmarks indicated that the lesions were AKE.

The differential diagnosis of AKE includes hereditary papulotranslucent acrokeratoderma, focal acral hyperkeratosis, and keratoelastoidosis marginalis.⁸ Hereditary papulotranslucent acrokeratoderma also is inherited in an autosomal-dominant fashion and shares similar acral, translucent, keratotic papules with AKE, but there is no chronic inflammatory cell infiltrate, degeneration of collagenous fibers, or fragmentation of elastic fibers. The clinical appearance of focal acral hyperkeratosis is similar to AKE, but no changes are revealed in the elastic tissue.⁹ Because AKE, focal acral hyperkeratosis, and hereditary papulotranslucent acrokeratoderma have similar lesions and overlapping histologic changes, they may be considered variants of the same entity.⁴ Keratoelastoidosis marginalis, also called degenerative collagenous plaques of the hand, mainly affects white individuals aged 40 to 60 years with a history of  prolonged sun exposure. Papules often are distributed over the junction of the dorsal and palmar skin and less often on the ulnar sides of the hands.  The clinical lesions are similar to those in our patient, but histopathology of keratoelastoidosis marginalis shows  amorphous, basophilic, elastotic masses and thickened, fragmented, calcified elastic fibers in the upper and mid dermis.

Therapies including liquid nitrogen, topical salicylic acid, methotrexate, dapsone, tar, cryotherapy, systemic prednisone, retinoic acid, clobetasone cream,⁵ and erbium:YAG laser¹⁰ have been applied. Thus far, no optimal treatment has been recommended and no tendency of spontaneous resolution has been previously reported in the literature. Our patient responded to tretinoin, but the lesions recurred after withdrawal of the medication; therefore, tretinoin may not be an optimal treatment option. Because the lesions are limited to the skin and AKE is only considered a cosmetic problem with a good prognosis, we recommend a wait-and-watch approach.

Acknowledgment—We thank Rashmi Sarkar, MD, New Delhi, India, for her assistance.

To the Editor:
Acrokeratoelastoidosis (AKE) is a rare disease first described by Costa¹ in 1953. Typically it is only a cosmetic nuisance in the majority of patients and presents as asymptomatic, small, firm, flesh-colored to yellowish, round to polygonal papules with occasional keratosis or umbilication on the radial and ulnar margins of the hands and/or feet.^1-3 In some cases, the lesions occur on the anterior aspects of the wrists, fingers, or lower legs.¹ The lesions are always bilaterally distributed. Acrokeratoelastoidosis is a chronic skin disorder that commonly presents during childhood or adolescence, but presentation in adulthood also has been described.³ Histologically, AKE always shows hyperkeratosis, acanthosis, decrease of elastic tissue, and elastorrhexis of remaining elastic fibers. Plaque-type lesions are rare. We describe a patient who presented with plaques on the radial and ulnar margins of the hands.

A 36-year-old Chinese woman presented with asymptomatic, small, firm papules of 6 months’ duration that initially developed on the hands and gradually increased in number, coalescing into plaques. The feet were spared. She had no medical history of hyperhidrosis, chronic trauma, friction, or excessive sun exposure, and no family history of similar symptoms. No prior therapy had been attempted.

Physical examination showed nonconfluent, firm, flesh-colored to yellowish, translucent, smooth papules with wavy edges that were symmetrically distributed on the radial and ulnar margins of the hands; some papules had coalesced into plaques (Figure 1). A biopsy specimen taken from a plaque on the hypothenar eminence of the right hand revealed focal hyperkeratosis, hypergranulosis, acanthosis, and mild chronic inflammation with hematoxylin and eosin stain (Figure 2A). Aldehyde fuchsin staining showed fragmented and rarefied elastic fibers in the reticular dermis (Figure 2B). The patient was diagnosed with AKE. Oral tretinoin 10 mg twice daily was initiated and resulted in an evident response after 2 weeks of treatment. However, the patient stopped taking the medication because of pruritus and dry skin and the lesions then reappeared.

Figure 1. Nonconfluent, firm, flesh-colored to yellowish, translucent, smooth papules distributed on the radial margin of the hand; some of papules coalesced into plaques.

Figure 2. Histopathology revealed hyperkeratosis, hypergranulosis, acanthosis, and mild chronic inflammation (A) (H&E, original magnification ×250 [inset, original magnification ×400]), as well as fragmented elastic fibers in the reticular dermis (B) (Aldehyde fuchsin, original magnification ×400 [inset, original magnification ×100]).

Acrokeratoelastoidosis is a rare keratotic disorder. It seems to have no racial or ethnic predilection and occurs more frequently in women.^4,5 It also is rare in China, with few cases reported, all women.⁵ The reason for the gender predilection in China remains unknown. The course is chronic, but it may rapidly progress during pregnancy.⁶

The pathogenesis of AKE is still unresolved.^2,3 Although many cases are sporadic,⁵ it appears to be inherited in an autosomal-dominant fashion, most likely related to chromosome 2.⁷ Typically, AKE presents as papules that are discrete and bilaterally distributed in the palmoplantar margins,^2,3 but some of the papules in our patient coalesced into plaques, which is unique. The histologic hallmarks indicated that the lesions were AKE.

The differential diagnosis of AKE includes hereditary papulotranslucent acrokeratoderma, focal acral hyperkeratosis, and keratoelastoidosis marginalis.⁸ Hereditary papulotranslucent acrokeratoderma also is inherited in an autosomal-dominant fashion and shares similar acral, translucent, keratotic papules with AKE, but there is no chronic inflammatory cell infiltrate, degeneration of collagenous fibers, or fragmentation of elastic fibers. The clinical appearance of focal acral hyperkeratosis is similar to AKE, but no changes are revealed in the elastic tissue.⁹ Because AKE, focal acral hyperkeratosis, and hereditary papulotranslucent acrokeratoderma have similar lesions and overlapping histologic changes, they may be considered variants of the same entity.⁴ Keratoelastoidosis marginalis, also called degenerative collagenous plaques of the hand, mainly affects white individuals aged 40 to 60 years with a history of  prolonged sun exposure. Papules often are distributed over the junction of the dorsal and palmar skin and less often on the ulnar sides of the hands.  The clinical lesions are similar to those in our patient, but histopathology of keratoelastoidosis marginalis shows  amorphous, basophilic, elastotic masses and thickened, fragmented, calcified elastic fibers in the upper and mid dermis.

Therapies including liquid nitrogen, topical salicylic acid, methotrexate, dapsone, tar, cryotherapy, systemic prednisone, retinoic acid, clobetasone cream,⁵ and erbium:YAG laser¹⁰ have been applied. Thus far, no optimal treatment has been recommended and no tendency of spontaneous resolution has been previously reported in the literature. Our patient responded to tretinoin, but the lesions recurred after withdrawal of the medication; therefore, tretinoin may not be an optimal treatment option. Because the lesions are limited to the skin and AKE is only considered a cosmetic problem with a good prognosis, we recommend a wait-and-watch approach.

Acknowledgment—We thank Rashmi Sarkar, MD, New Delhi, India, for her assistance.

Extramammary Paget disease (EMPD), which was first described by Crocker¹ in a patient with erythematous patches on the penis and scrotum, is morphologically identical to mammary Paget disease (MPD) of the nipple. The principal difference between EMPD and MPD is anatomic location. Extramammary Paget disease predominantly affects apocrine gland–bearing areas including the vulva, scrotum, and perianal areas. Although EMPD is not a common condition, it must be considered in the differential diagnosis for patients with chronic genital or perianal dermatitis. Primary EMPD must be distinguished from secondary epithelial involvement by an underlying invasive carcinoma that originates from sites such as the gastrointestinal or genitourinary systems (secondary EMPD).

Although multicentric primary EMPD is not uncommon among Eastern Asians, as there have been several reports in the literature from Japan,^2-5 multicentric EMPD in white individuals is rare.⁶ We report a case of primary EMPD that was established when no underlying malignancies were detected.

Case Report
A 63-year-old white man presented to the dermatology clinic with a pruritic rash involving the groin of 8 years’ duration. Over-the-counter antifungal agents provided no improvement. Confluent erythematous and macerated plaques on the scrotum, shaft of the penis, bilateral inguinal areas, and perineum were noted on clinical examination (Figure 1). There also were well-demarcated, 4×5-cm, erythematous, velvety plaques on the right axilla and a small erythematous plaque on the left axilla. Systemic workup including colonoscopy, cystoscopy, and magnetic resonance imaging of the abdomen and pelvis were unremarkable. A positron emission tomography–computed tomography scan revealed foci of hypermetabolic activity in the bilateral inguinal nodes that were interpreted as evidence of an inflammatory process.

Figure 1. Confluent erythematous and macerated plaques on the scrotum, shaft of the penis, bilateral inguinal areas, and perineum.

Fourteen biopsies were taken from the clinically involved regions in the genital area to delineate the extent of involvement. They all showed intraepidermal carcinoma characterized by large cells with clear cytoplasm and large hyperchromatic nuclei throughout the epidermis, which were more abundant in the basilar and lower portions of the epidermis (Figure 2). There was no evidence of underlying carcinoma in the dermis.

Figure 2. Histopathologic examination of the genital region showed Paget cells with large round and oval hyperchromatic nuclei and abundant pale cytoplasm (H&E, original magnification ×400).

On immunohistochemical staining, the neoplastic cells were diffusely and strongly positive for cytokeratin 7 (Figure 3) and moderately positive for carcinoembryonic antigen, estrogen and progesterone receptors, and ERBB2 (formerly HER-2/neu). Additional immunostaining for cytokeratin 20 and gross cystic disease fluid protein 15 were negative. High-molecular-weight keratin staining highlighted background epithelium and spared neoplastic cells. Mucicarmine staining highlighted mucin within the cytoplasm of neoplastic cells. Ultrastructural studies showed evidence of apocrine differentiation in the neoplastic cells with deeply indented, bean-shaped nuclei and clear cytoplasm with inconspicuous organelles. Clinically unaffected skin from the periumbilical region also was biopsied. The histology demonstrated Toker cells characterized by clear cytoplasm, small vesicular nuclei, and the absence of hyperchromasia (Figure 4).

Figure 3. Immunohistochemical staining for cytokeratin 7 showed diffusely positive clear cells in the epidermis (H&E, original magnification ×200).

The patient was treated with 6 cycles of 5-aminolevulinic acid 20% photodynamic therapy but showed no improvement. Imiquimod cream 5% resulted in mild clinical improvement in the axillae but caused severe irritation in the groin and was discontinued after 3 months. A radiology consultation obtained 6 years prior to presentation determined that the risk associated with radiation therapy outweighed any possible benefits. Although localized disease persisted, repeated biopsies and positron emission tomography–computed tomography scans did not show any evidence of invasion or metastasis, respectively. Three years after initial presentation, groin lesions progressed to become more erythematous and vegetative. The corresponding histology demonstrated EMPD. An ancillary test (polymerase chain reaction analysis) for low- and high-risk human papillomavirus was negative.

Comment
Primary EMPD has been well documented in the literature to have a favorable prognosis if adequately treated. The few cases reported from Japan on EMPD without underlying adenocarcinoma had good outcomes.^2,3 Further reports of multicentric EMPD involving 2 or 3 sites in the axillae and/or genital region did not reveal any progression to invasive carcinomas after adequate follow-up.^3-9 Indeed, many of these cases, particularly those in the genital region, were aggressively treated with surgery, topical chemotherapy, immunomodulatory agents, and radiation; therefore, their natural course is not known.² A Japanese studyconducted at 75 medical institutions (1987-1991) included 46 EMPD patients with multiple (ie, 2 or 3) sites of involvement.¹⁰ Some of the patients with a combination of genital and axillary lesions were followed without any treatment. None of the EMPD patients with axillary involvement developed invasive carcinoma after 4- to 12-year follow-up.¹⁰

Figure 4. Histopathologic examination of clinically unaffected skin of the periumbilical region revealed Toker cells with round nuclei and pale cytoplasm (arrows) scattered in the lower epidermis (H&E, original magnification ×400).

Toker cells, which were first described in 1970,¹¹ have been recognized as precursors to EMPD.^12-14 Toker cells are intraepithelial cells with clear to pale-staining cytoplasm that are smaller in size than Paget cells but larger than neighboring keratinocytes. They are found in approximately 10% of normal nipples.^11,14 Toker cells show vesicular chromatin, whereas Paget cells are hyperchromatic with prominent nucleoli.¹² Willman et al¹⁵ examined 11 vulvectomies for the presence of Toker cells in association with mammarylike glands of the vulva. They demonstrated the presence of Toker cells in 4 (36%) of the samples.¹⁵ Additionally, Van der Putte et al¹⁶ observed Toker cells in an areolar lesion in a 47-year-old woman with MPD without underlying adenocarcinoma, suggesting that cases of MPD and EMPD confined to epithelial cells may be derived from Toker cells. Toker cells have been associated in the pathogenesis of 2 other benign entities, including clear cell papulosis^17,18 and cutaneous hamartoma with pagetoid cells.¹⁹

Primary EMPD has the potential to develop in several regions of the skin that contain apocrine glands. Our patient presented with persistent genital lesions for many years without any concerns of axillary disease. Interestingly, biopsies from normal-appearing skin in the periumbilical region revealed clear cells (Figure 4). Likewise, Toker cells have been described in biopsies from clinically unaffected skin of the axillae in some cases where EMPD was identified in the genital regions.^3,5 Genital lesions were the main clinical presentation and preceded axillary involvement in most instances.^3,5,9 Therefore, biopsies from uninvolved apocrine sites (ie, axillary and periumbilical skin) should be considered in these patients. Based on our observation, we speculate that multicentric primary EMPD starts with Toker cell hyperplasia with a propensity to evolve into neoplasia in sites with apocrine or mammarylike glands.

Primary and secondary EMPD cannot be distinguished by histopathology and immunohistochemistry has a limited role.^20,21 However, immunostaining with CDX2 (a caudal-type homeobox protein) might be helpful in differentiating primary EMPD from secondary EMPD extending from underlying anorectal adenocarcinomas.²² Primary EMPD has been treated with surgical excision.^2,3,8 Despite the high recurrence rate after surgery, the prognosis for localized primary EMPD disease has been favorable.

Conclusion
Our case suggests that Toker cell hyperplasia is a precursor to primary EMPD. In patients with established EMPD, other apocrine gland–bearing areas should be examined for multicentric disease. Lastly, the clinical course in our patient supports the hypothesis that primary multicentric EMPD has a favorable outcome. The Table lists the characteristics of MPD and EMPD and describes their development with respect to Toker cells. More studies are required to further outline the cytologic characteristics of Toker cells and to distinguish primary EMPD from secondary EMPD.

Extramammary Paget disease (EMPD), which was first described by Crocker¹ in a patient with erythematous patches on the penis and scrotum, is morphologically identical to mammary Paget disease (MPD) of the nipple. The principal difference between EMPD and MPD is anatomic location. Extramammary Paget disease predominantly affects apocrine gland–bearing areas including the vulva, scrotum, and perianal areas. Although EMPD is not a common condition, it must be considered in the differential diagnosis for patients with chronic genital or perianal dermatitis. Primary EMPD must be distinguished from secondary epithelial involvement by an underlying invasive carcinoma that originates from sites such as the gastrointestinal or genitourinary systems (secondary EMPD).

Although multicentric primary EMPD is not uncommon among Eastern Asians, as there have been several reports in the literature from Japan,^2-5 multicentric EMPD in white individuals is rare.⁶ We report a case of primary EMPD that was established when no underlying malignancies were detected.

Case Report
A 63-year-old white man presented to the dermatology clinic with a pruritic rash involving the groin of 8 years’ duration. Over-the-counter antifungal agents provided no improvement. Confluent erythematous and macerated plaques on the scrotum, shaft of the penis, bilateral inguinal areas, and perineum were noted on clinical examination (Figure 1). There also were well-demarcated, 4×5-cm, erythematous, velvety plaques on the right axilla and a small erythematous plaque on the left axilla. Systemic workup including colonoscopy, cystoscopy, and magnetic resonance imaging of the abdomen and pelvis were unremarkable. A positron emission tomography–computed tomography scan revealed foci of hypermetabolic activity in the bilateral inguinal nodes that were interpreted as evidence of an inflammatory process.

Figure 1. Confluent erythematous and macerated plaques on the scrotum, shaft of the penis, bilateral inguinal areas, and perineum.

Fourteen biopsies were taken from the clinically involved regions in the genital area to delineate the extent of involvement. They all showed intraepidermal carcinoma characterized by large cells with clear cytoplasm and large hyperchromatic nuclei throughout the epidermis, which were more abundant in the basilar and lower portions of the epidermis (Figure 2). There was no evidence of underlying carcinoma in the dermis.

Figure 2. Histopathologic examination of the genital region showed Paget cells with large round and oval hyperchromatic nuclei and abundant pale cytoplasm (H&E, original magnification ×400).

On immunohistochemical staining, the neoplastic cells were diffusely and strongly positive for cytokeratin 7 (Figure 3) and moderately positive for carcinoembryonic antigen, estrogen and progesterone receptors, and ERBB2 (formerly HER-2/neu). Additional immunostaining for cytokeratin 20 and gross cystic disease fluid protein 15 were negative. High-molecular-weight keratin staining highlighted background epithelium and spared neoplastic cells. Mucicarmine staining highlighted mucin within the cytoplasm of neoplastic cells. Ultrastructural studies showed evidence of apocrine differentiation in the neoplastic cells with deeply indented, bean-shaped nuclei and clear cytoplasm with inconspicuous organelles. Clinically unaffected skin from the periumbilical region also was biopsied. The histology demonstrated Toker cells characterized by clear cytoplasm, small vesicular nuclei, and the absence of hyperchromasia (Figure 4).

Figure 3. Immunohistochemical staining for cytokeratin 7 showed diffusely positive clear cells in the epidermis (H&E, original magnification ×200).

The patient was treated with 6 cycles of 5-aminolevulinic acid 20% photodynamic therapy but showed no improvement. Imiquimod cream 5% resulted in mild clinical improvement in the axillae but caused severe irritation in the groin and was discontinued after 3 months. A radiology consultation obtained 6 years prior to presentation determined that the risk associated with radiation therapy outweighed any possible benefits. Although localized disease persisted, repeated biopsies and positron emission tomography–computed tomography scans did not show any evidence of invasion or metastasis, respectively. Three years after initial presentation, groin lesions progressed to become more erythematous and vegetative. The corresponding histology demonstrated EMPD. An ancillary test (polymerase chain reaction analysis) for low- and high-risk human papillomavirus was negative.

Comment
Primary EMPD has been well documented in the literature to have a favorable prognosis if adequately treated. The few cases reported from Japan on EMPD without underlying adenocarcinoma had good outcomes.^2,3 Further reports of multicentric EMPD involving 2 or 3 sites in the axillae and/or genital region did not reveal any progression to invasive carcinomas after adequate follow-up.^3-9 Indeed, many of these cases, particularly those in the genital region, were aggressively treated with surgery, topical chemotherapy, immunomodulatory agents, and radiation; therefore, their natural course is not known.² A Japanese studyconducted at 75 medical institutions (1987-1991) included 46 EMPD patients with multiple (ie, 2 or 3) sites of involvement.¹⁰ Some of the patients with a combination of genital and axillary lesions were followed without any treatment. None of the EMPD patients with axillary involvement developed invasive carcinoma after 4- to 12-year follow-up.¹⁰

Figure 4. Histopathologic examination of clinically unaffected skin of the periumbilical region revealed Toker cells with round nuclei and pale cytoplasm (arrows) scattered in the lower epidermis (H&E, original magnification ×400).

Toker cells, which were first described in 1970,¹¹ have been recognized as precursors to EMPD.^12-14 Toker cells are intraepithelial cells with clear to pale-staining cytoplasm that are smaller in size than Paget cells but larger than neighboring keratinocytes. They are found in approximately 10% of normal nipples.^11,14 Toker cells show vesicular chromatin, whereas Paget cells are hyperchromatic with prominent nucleoli.¹² Willman et al¹⁵ examined 11 vulvectomies for the presence of Toker cells in association with mammarylike glands of the vulva. They demonstrated the presence of Toker cells in 4 (36%) of the samples.¹⁵ Additionally, Van der Putte et al¹⁶ observed Toker cells in an areolar lesion in a 47-year-old woman with MPD without underlying adenocarcinoma, suggesting that cases of MPD and EMPD confined to epithelial cells may be derived from Toker cells. Toker cells have been associated in the pathogenesis of 2 other benign entities, including clear cell papulosis^17,18 and cutaneous hamartoma with pagetoid cells.¹⁹

Primary EMPD has the potential to develop in several regions of the skin that contain apocrine glands. Our patient presented with persistent genital lesions for many years without any concerns of axillary disease. Interestingly, biopsies from normal-appearing skin in the periumbilical region revealed clear cells (Figure 4). Likewise, Toker cells have been described in biopsies from clinically unaffected skin of the axillae in some cases where EMPD was identified in the genital regions.^3,5 Genital lesions were the main clinical presentation and preceded axillary involvement in most instances.^3,5,9 Therefore, biopsies from uninvolved apocrine sites (ie, axillary and periumbilical skin) should be considered in these patients. Based on our observation, we speculate that multicentric primary EMPD starts with Toker cell hyperplasia with a propensity to evolve into neoplasia in sites with apocrine or mammarylike glands.

Primary and secondary EMPD cannot be distinguished by histopathology and immunohistochemistry has a limited role.^20,21 However, immunostaining with CDX2 (a caudal-type homeobox protein) might be helpful in differentiating primary EMPD from secondary EMPD extending from underlying anorectal adenocarcinomas.²² Primary EMPD has been treated with surgical excision.^2,3,8 Despite the high recurrence rate after surgery, the prognosis for localized primary EMPD disease has been favorable.

Conclusion
Our case suggests that Toker cell hyperplasia is a precursor to primary EMPD. In patients with established EMPD, other apocrine gland–bearing areas should be examined for multicentric disease. Lastly, the clinical course in our patient supports the hypothesis that primary multicentric EMPD has a favorable outcome. The Table lists the characteristics of MPD and EMPD and describes their development with respect to Toker cells. More studies are required to further outline the cytologic characteristics of Toker cells and to distinguish primary EMPD from secondary EMPD.

Extramammary Paget disease (EMPD), which was first described by Crocker¹ in a patient with erythematous patches on the penis and scrotum, is morphologically identical to mammary Paget disease (MPD) of the nipple. The principal difference between EMPD and MPD is anatomic location. Extramammary Paget disease predominantly affects apocrine gland–bearing areas including the vulva, scrotum, and perianal areas. Although EMPD is not a common condition, it must be considered in the differential diagnosis for patients with chronic genital or perianal dermatitis. Primary EMPD must be distinguished from secondary epithelial involvement by an underlying invasive carcinoma that originates from sites such as the gastrointestinal or genitourinary systems (secondary EMPD).

Although multicentric primary EMPD is not uncommon among Eastern Asians, as there have been several reports in the literature from Japan,^2-5 multicentric EMPD in white individuals is rare.⁶ We report a case of primary EMPD that was established when no underlying malignancies were detected.

Case Report
A 63-year-old white man presented to the dermatology clinic with a pruritic rash involving the groin of 8 years’ duration. Over-the-counter antifungal agents provided no improvement. Confluent erythematous and macerated plaques on the scrotum, shaft of the penis, bilateral inguinal areas, and perineum were noted on clinical examination (Figure 1). There also were well-demarcated, 4×5-cm, erythematous, velvety plaques on the right axilla and a small erythematous plaque on the left axilla. Systemic workup including colonoscopy, cystoscopy, and magnetic resonance imaging of the abdomen and pelvis were unremarkable. A positron emission tomography–computed tomography scan revealed foci of hypermetabolic activity in the bilateral inguinal nodes that were interpreted as evidence of an inflammatory process.

Figure 1. Confluent erythematous and macerated plaques on the scrotum, shaft of the penis, bilateral inguinal areas, and perineum.

Fourteen biopsies were taken from the clinically involved regions in the genital area to delineate the extent of involvement. They all showed intraepidermal carcinoma characterized by large cells with clear cytoplasm and large hyperchromatic nuclei throughout the epidermis, which were more abundant in the basilar and lower portions of the epidermis (Figure 2). There was no evidence of underlying carcinoma in the dermis.

Figure 2. Histopathologic examination of the genital region showed Paget cells with large round and oval hyperchromatic nuclei and abundant pale cytoplasm (H&E, original magnification ×400).

On immunohistochemical staining, the neoplastic cells were diffusely and strongly positive for cytokeratin 7 (Figure 3) and moderately positive for carcinoembryonic antigen, estrogen and progesterone receptors, and ERBB2 (formerly HER-2/neu). Additional immunostaining for cytokeratin 20 and gross cystic disease fluid protein 15 were negative. High-molecular-weight keratin staining highlighted background epithelium and spared neoplastic cells. Mucicarmine staining highlighted mucin within the cytoplasm of neoplastic cells. Ultrastructural studies showed evidence of apocrine differentiation in the neoplastic cells with deeply indented, bean-shaped nuclei and clear cytoplasm with inconspicuous organelles. Clinically unaffected skin from the periumbilical region also was biopsied. The histology demonstrated Toker cells characterized by clear cytoplasm, small vesicular nuclei, and the absence of hyperchromasia (Figure 4).

Figure 3. Immunohistochemical staining for cytokeratin 7 showed diffusely positive clear cells in the epidermis (H&E, original magnification ×200).

The patient was treated with 6 cycles of 5-aminolevulinic acid 20% photodynamic therapy but showed no improvement. Imiquimod cream 5% resulted in mild clinical improvement in the axillae but caused severe irritation in the groin and was discontinued after 3 months. A radiology consultation obtained 6 years prior to presentation determined that the risk associated with radiation therapy outweighed any possible benefits. Although localized disease persisted, repeated biopsies and positron emission tomography–computed tomography scans did not show any evidence of invasion or metastasis, respectively. Three years after initial presentation, groin lesions progressed to become more erythematous and vegetative. The corresponding histology demonstrated EMPD. An ancillary test (polymerase chain reaction analysis) for low- and high-risk human papillomavirus was negative.

Comment
Primary EMPD has been well documented in the literature to have a favorable prognosis if adequately treated. The few cases reported from Japan on EMPD without underlying adenocarcinoma had good outcomes.^2,3 Further reports of multicentric EMPD involving 2 or 3 sites in the axillae and/or genital region did not reveal any progression to invasive carcinomas after adequate follow-up.^3-9 Indeed, many of these cases, particularly those in the genital region, were aggressively treated with surgery, topical chemotherapy, immunomodulatory agents, and radiation; therefore, their natural course is not known.² A Japanese studyconducted at 75 medical institutions (1987-1991) included 46 EMPD patients with multiple (ie, 2 or 3) sites of involvement.¹⁰ Some of the patients with a combination of genital and axillary lesions were followed without any treatment. None of the EMPD patients with axillary involvement developed invasive carcinoma after 4- to 12-year follow-up.¹⁰

Figure 4. Histopathologic examination of clinically unaffected skin of the periumbilical region revealed Toker cells with round nuclei and pale cytoplasm (arrows) scattered in the lower epidermis (H&E, original magnification ×400).

Toker cells, which were first described in 1970,¹¹ have been recognized as precursors to EMPD.^12-14 Toker cells are intraepithelial cells with clear to pale-staining cytoplasm that are smaller in size than Paget cells but larger than neighboring keratinocytes. They are found in approximately 10% of normal nipples.^11,14 Toker cells show vesicular chromatin, whereas Paget cells are hyperchromatic with prominent nucleoli.¹² Willman et al¹⁵ examined 11 vulvectomies for the presence of Toker cells in association with mammarylike glands of the vulva. They demonstrated the presence of Toker cells in 4 (36%) of the samples.¹⁵ Additionally, Van der Putte et al¹⁶ observed Toker cells in an areolar lesion in a 47-year-old woman with MPD without underlying adenocarcinoma, suggesting that cases of MPD and EMPD confined to epithelial cells may be derived from Toker cells. Toker cells have been associated in the pathogenesis of 2 other benign entities, including clear cell papulosis^17,18 and cutaneous hamartoma with pagetoid cells.¹⁹

Primary EMPD has the potential to develop in several regions of the skin that contain apocrine glands. Our patient presented with persistent genital lesions for many years without any concerns of axillary disease. Interestingly, biopsies from normal-appearing skin in the periumbilical region revealed clear cells (Figure 4). Likewise, Toker cells have been described in biopsies from clinically unaffected skin of the axillae in some cases where EMPD was identified in the genital regions.^3,5 Genital lesions were the main clinical presentation and preceded axillary involvement in most instances.^3,5,9 Therefore, biopsies from uninvolved apocrine sites (ie, axillary and periumbilical skin) should be considered in these patients. Based on our observation, we speculate that multicentric primary EMPD starts with Toker cell hyperplasia with a propensity to evolve into neoplasia in sites with apocrine or mammarylike glands.

Primary and secondary EMPD cannot be distinguished by histopathology and immunohistochemistry has a limited role.^20,21 However, immunostaining with CDX2 (a caudal-type homeobox protein) might be helpful in differentiating primary EMPD from secondary EMPD extending from underlying anorectal adenocarcinomas.²² Primary EMPD has been treated with surgical excision.^2,3,8 Despite the high recurrence rate after surgery, the prognosis for localized primary EMPD disease has been favorable.

Conclusion
Our case suggests that Toker cell hyperplasia is a precursor to primary EMPD. In patients with established EMPD, other apocrine gland–bearing areas should be examined for multicentric disease. Lastly, the clinical course in our patient supports the hypothesis that primary multicentric EMPD has a favorable outcome. The Table lists the characteristics of MPD and EMPD and describes their development with respect to Toker cells. More studies are required to further outline the cytologic characteristics of Toker cells and to distinguish primary EMPD from secondary EMPD.

To the Editor:
A 35-year-old man presented with asymptomatic multiple waxy firm papules on the dorsal aspect of the hands (Figure 1). On complete clinical examination, multiple similar lesions were found on the face and the lateral aspect of the neck; slightly pruritic, clustered, erythematous papules were seen in the pubic area. Deep longitudinal furrows on the glabella and swelling of the ears (Figure 2) also were present. Histology revealed a dermal infiltrate of fibroblasts (Figure 3). Abundant mucin deposition between collagen bundles stained positive with Alcian blue, confirming the diagnosis of generalized lichen myxedematosus (GLM). A thorough laboratory evaluation revealed λ light chain gammopathy. Bone marrow examination was normal. Thyroid function tests and radiography did not detect any abnormalities.

Being a musician, the patient traveled frequently and therefore did not present for follow-up. The disease ran its course. Approximately 6 months later he presented with a generalized eruption with weakness and intense bone pain. Progression to multiple myeloma was confirmed by serum protein electrophoresis and plain radiography, which revealed lytic lesions of the skull.

Generalized lichen myxedematosus, or scleromyxedema, is a form of papular mucinosis. It is a cutaneous mucinosis characterized by a generalized papular and sclerodermoid eruption, mucin deposition, increased fibroblast proliferation, fibrosis, and monoclonal gammopathy in the absence of thyroid disease. It is a rare disease that does not have a gender predilection and affects men and women aged 30 to 80 years.^1,2

Clinically, GLM is characterized by a widespread symmetric eruption of small, closely spaced, waxy, firm, dome-shaped or flat-topped papules that measure 2 to 3 mm in diameter. Papules commonly form clusters on the face, neck, distal forearms, and hands. The affected skin may have a shiny sclerodermatous appearance.²

Histologically, there is a pronounced mucin deposition within the upper and mid reticular dermis, along with a proliferation of irregularly arranged fibroblasts and fibrosis.³ Collagen bundles appear pushed together into fascicles by the mucinous deposits.⁴  

Generalized lichen myxedematosus should be distinguished from nephrogenic systemic fibrosis, granuloma annulare, amyloidosis, and Hansen disease. In nearly 83% of cases there is an accompanying paraproteinemia, most commonly an IgG λ light chain elevation.² Monoclonal gammopathy of IgG with λ light chain has been considered as a fibroblast growth factor. Paraprotein levels do not correlate with the extent or progression of the disease.¹ Nonparaprotein factors also can be responsible for excess fibroblast proliferation.² It still is not elucidated as to how the abnormal mucin production results from the proliferation of fibroblasts.

Patients with GLM must be closely followed. The course of the disease is chronic and progressive. Extracutaneous manifestations may involve the gastrointestinal, musculoskeletal, cardiovascular, pulmonary, and central nervous systems, most likely because of mucin deposition in various organs.^1,4 In these cases, the life expectancy is limited. Possibility of progression to multiple myeloma is less than 10%.¹ Waldenström macroglobulinemia, Hodgkin lymphoma, and non-Hodgkin lymphomas all have been associated with GLM.² Although extremely uncommon, spontaneous resolution has been reported after as long as a decade.⁵

Treatment of GLM, including melphalan, plasmapheresis, corticosteroids, cyclophosphamide, methotrexate, thalidomide, electron beam therapy, intravenous immunoglobulin therapy, extracorporeal photochemotherapy, high-dose chemotherapy with autologous stem cell rescue, and melphalan with autologous peripheral blood stem cell transplant are considered to improve the prognosis of this noncurable disease.⁶ As there is still no consensus on the treatment of scleromyxedema, multicenter studies on therapeutic schemes and responses are anticipated.

Generalized lichen myxedematosus is an instructive example of skin lesions being the presenting sign of a systemic disease. Progression to multiple myeloma in our patient made the prognosis less favorable.

To the Editor:
A 35-year-old man presented with asymptomatic multiple waxy firm papules on the dorsal aspect of the hands (Figure 1). On complete clinical examination, multiple similar lesions were found on the face and the lateral aspect of the neck; slightly pruritic, clustered, erythematous papules were seen in the pubic area. Deep longitudinal furrows on the glabella and swelling of the ears (Figure 2) also were present. Histology revealed a dermal infiltrate of fibroblasts (Figure 3). Abundant mucin deposition between collagen bundles stained positive with Alcian blue, confirming the diagnosis of generalized lichen myxedematosus (GLM). A thorough laboratory evaluation revealed λ light chain gammopathy. Bone marrow examination was normal. Thyroid function tests and radiography did not detect any abnormalities.

Being a musician, the patient traveled frequently and therefore did not present for follow-up. The disease ran its course. Approximately 6 months later he presented with a generalized eruption with weakness and intense bone pain. Progression to multiple myeloma was confirmed by serum protein electrophoresis and plain radiography, which revealed lytic lesions of the skull.

Generalized lichen myxedematosus, or scleromyxedema, is a form of papular mucinosis. It is a cutaneous mucinosis characterized by a generalized papular and sclerodermoid eruption, mucin deposition, increased fibroblast proliferation, fibrosis, and monoclonal gammopathy in the absence of thyroid disease. It is a rare disease that does not have a gender predilection and affects men and women aged 30 to 80 years.^1,2

Clinically, GLM is characterized by a widespread symmetric eruption of small, closely spaced, waxy, firm, dome-shaped or flat-topped papules that measure 2 to 3 mm in diameter. Papules commonly form clusters on the face, neck, distal forearms, and hands. The affected skin may have a shiny sclerodermatous appearance.²

Histologically, there is a pronounced mucin deposition within the upper and mid reticular dermis, along with a proliferation of irregularly arranged fibroblasts and fibrosis.³ Collagen bundles appear pushed together into fascicles by the mucinous deposits.⁴  

Generalized lichen myxedematosus should be distinguished from nephrogenic systemic fibrosis, granuloma annulare, amyloidosis, and Hansen disease. In nearly 83% of cases there is an accompanying paraproteinemia, most commonly an IgG λ light chain elevation.² Monoclonal gammopathy of IgG with λ light chain has been considered as a fibroblast growth factor. Paraprotein levels do not correlate with the extent or progression of the disease.¹ Nonparaprotein factors also can be responsible for excess fibroblast proliferation.² It still is not elucidated as to how the abnormal mucin production results from the proliferation of fibroblasts.

Patients with GLM must be closely followed. The course of the disease is chronic and progressive. Extracutaneous manifestations may involve the gastrointestinal, musculoskeletal, cardiovascular, pulmonary, and central nervous systems, most likely because of mucin deposition in various organs.^1,4 In these cases, the life expectancy is limited. Possibility of progression to multiple myeloma is less than 10%.¹ Waldenström macroglobulinemia, Hodgkin lymphoma, and non-Hodgkin lymphomas all have been associated with GLM.² Although extremely uncommon, spontaneous resolution has been reported after as long as a decade.⁵

Treatment of GLM, including melphalan, plasmapheresis, corticosteroids, cyclophosphamide, methotrexate, thalidomide, electron beam therapy, intravenous immunoglobulin therapy, extracorporeal photochemotherapy, high-dose chemotherapy with autologous stem cell rescue, and melphalan with autologous peripheral blood stem cell transplant are considered to improve the prognosis of this noncurable disease.⁶ As there is still no consensus on the treatment of scleromyxedema, multicenter studies on therapeutic schemes and responses are anticipated.

Generalized lichen myxedematosus is an instructive example of skin lesions being the presenting sign of a systemic disease. Progression to multiple myeloma in our patient made the prognosis less favorable.

To the Editor:
A 35-year-old man presented with asymptomatic multiple waxy firm papules on the dorsal aspect of the hands (Figure 1). On complete clinical examination, multiple similar lesions were found on the face and the lateral aspect of the neck; slightly pruritic, clustered, erythematous papules were seen in the pubic area. Deep longitudinal furrows on the glabella and swelling of the ears (Figure 2) also were present. Histology revealed a dermal infiltrate of fibroblasts (Figure 3). Abundant mucin deposition between collagen bundles stained positive with Alcian blue, confirming the diagnosis of generalized lichen myxedematosus (GLM). A thorough laboratory evaluation revealed λ light chain gammopathy. Bone marrow examination was normal. Thyroid function tests and radiography did not detect any abnormalities.

Being a musician, the patient traveled frequently and therefore did not present for follow-up. The disease ran its course. Approximately 6 months later he presented with a generalized eruption with weakness and intense bone pain. Progression to multiple myeloma was confirmed by serum protein electrophoresis and plain radiography, which revealed lytic lesions of the skull.

Generalized lichen myxedematosus, or scleromyxedema, is a form of papular mucinosis. It is a cutaneous mucinosis characterized by a generalized papular and sclerodermoid eruption, mucin deposition, increased fibroblast proliferation, fibrosis, and monoclonal gammopathy in the absence of thyroid disease. It is a rare disease that does not have a gender predilection and affects men and women aged 30 to 80 years.^1,2

Clinically, GLM is characterized by a widespread symmetric eruption of small, closely spaced, waxy, firm, dome-shaped or flat-topped papules that measure 2 to 3 mm in diameter. Papules commonly form clusters on the face, neck, distal forearms, and hands. The affected skin may have a shiny sclerodermatous appearance.²

Histologically, there is a pronounced mucin deposition within the upper and mid reticular dermis, along with a proliferation of irregularly arranged fibroblasts and fibrosis.³ Collagen bundles appear pushed together into fascicles by the mucinous deposits.⁴  

Generalized lichen myxedematosus should be distinguished from nephrogenic systemic fibrosis, granuloma annulare, amyloidosis, and Hansen disease. In nearly 83% of cases there is an accompanying paraproteinemia, most commonly an IgG λ light chain elevation.² Monoclonal gammopathy of IgG with λ light chain has been considered as a fibroblast growth factor. Paraprotein levels do not correlate with the extent or progression of the disease.¹ Nonparaprotein factors also can be responsible for excess fibroblast proliferation.² It still is not elucidated as to how the abnormal mucin production results from the proliferation of fibroblasts.

Patients with GLM must be closely followed. The course of the disease is chronic and progressive. Extracutaneous manifestations may involve the gastrointestinal, musculoskeletal, cardiovascular, pulmonary, and central nervous systems, most likely because of mucin deposition in various organs.^1,4 In these cases, the life expectancy is limited. Possibility of progression to multiple myeloma is less than 10%.¹ Waldenström macroglobulinemia, Hodgkin lymphoma, and non-Hodgkin lymphomas all have been associated with GLM.² Although extremely uncommon, spontaneous resolution has been reported after as long as a decade.⁵

Treatment of GLM, including melphalan, plasmapheresis, corticosteroids, cyclophosphamide, methotrexate, thalidomide, electron beam therapy, intravenous immunoglobulin therapy, extracorporeal photochemotherapy, high-dose chemotherapy with autologous stem cell rescue, and melphalan with autologous peripheral blood stem cell transplant are considered to improve the prognosis of this noncurable disease.⁶ As there is still no consensus on the treatment of scleromyxedema, multicenter studies on therapeutic schemes and responses are anticipated.

Generalized lichen myxedematosus is an instructive example of skin lesions being the presenting sign of a systemic disease. Progression to multiple myeloma in our patient made the prognosis less favorable.