Cutis

Median canaliform nail dystrophy is a nail abnormality that typically involves one or both thumbnails. The first case of this disorder was recorded by Heller¹ in 1928. Median canaliform nail dystrophy presents as a central longitudinal groove of the nail plate, extending proximally from the end of the nail.² This condition is usually not inherited. However, it may be acquired following trauma to the nail. We describe a man with familial median canaliform nail dystrophy and discuss the differential diagnosis.

Case Report

A 68-year-old man presented with bilateral dystrophy of his thumbnails. The nail abnormality initially appeared at 34 years of age with no preceding trauma to the digits. His older brother and his mother also had developed the same nail changes as young adults. Neither the patient nor his brother or mother rubbed their proximal thumbnail fold with the tip of their second finger; the absence of this behavioral activity was repeatedly confirmed by both the patient and his wife during several subsequent office visits.

Examination of both thumbnails showed an asymptomatic distal fissure with a fir tree–like pattern (Figure). Proximally, the nail plates showed transverse grooves. In addition, the lunula was red and enlarged.

Please refer to the PDF to view the figure

Comment

Median canaliform nail dystrophy appears as a long longitudinal groove extending from either the proximal nail fold or a more distal portion of the nail plate to the end of the nail. Lateral extensions of this fissure create a conspicuous inverted fir tree–like pattern. In severe cases, the nail can split along the groove.³ Thickening of the proximal nail fold, enlargement of the lunula, and redness of the lunula also may occur.^4-9

The diagnosis of this condition is usually established based on clinical features because pathologic correlation is rarely available. However, specimens for microscopic evaluation have occasionally been provided. Parakeratosis, as well as an accumulation of melanin within and between the nail bed keratinocytes, was demonstrated in the evaluation of an affected nail by Heller¹⁰ in 1927. Subsequently, parakeratosis and intranuclear pigmentation were found within the longitudinal canal of the affected nail plate of a 12-year-old girl with median canaliform nail dystrophy who was described by Robinson and Weidman¹¹ in 1948.

Median canaliform nail dystrophy may present following trauma to the nail plate or nail matrix.^3-7,12-15 In addition, coexisting conditions such as either soft tissue in the nail defect or dental caries have been observed in some patients with median canaliform nail dystrophy. In one case, a 19-year-old woman presented with a flabby filament of fleshy tissue that was observed within the dystrophic nail canal.¹⁴ The tissue was extracted, and the nail abnormality resolved. Subsequently, the nail dystrophy, including the associated tissue, reappeared.¹⁴ Tooth decay associated with median canaliform nail dystrophy was reported in a 23-year-old woman with a deformity that involved many of the nails on both of her hands. Her nail condition spontaneously cleared after 3 carious teeth were extracted.¹⁶

Medication was postulated as the causative factor for the development of median canaliform nail dystrophy in 3 patients who were receiving isotretinoin. The first, reported by Bottomley and Cunliffe¹⁷ in 1992, was a 38-year-old woman who developed median canaliform nail dystrophy 6 weeks after beginning treatment with isotretinoin. Her thumbnail returned to normal 4 weeks after she discontinued the drug.¹⁷ The second patient, described by Griego et al⁴ in 1995, was an 18-year-old man who developed median canaliform nail dystrophy of both thumbnails after starting therapy with isotretinoin for his acne. The nail disfigurement became distinct after 4 months of treatment; his new thumbnail dystrophy resolved 5 months after he discontinued the medication.⁴ A third patient was reported by Dharmagunawardena and Charles-Holmes¹² in 1997. They described a 19-year-old man who developed median canaliform nail dystrophy in both thumbnails within 4 weeks after starting treatment with isotretinoin for his acne. His nails returned to normal 3 months after completing a 5-month course of isotretinoin therapy.¹²

Familial median canaliform nail dystrophy has not been associated with any systemic syndromes. In our patient and his family, the nail dystrophy was not congenital but rather appeared as an acquired abnormality of the nails in adulthood.

The etiology of median canaliform nail dystrophy is unknown.^5,7,13,16-18 It usually is an acquired condition. Nail matrix trauma may precede the onset; however, an associated nail injury has often not occurred.^{3-7,12-16,19-21} This nail dystrophy is not considered to be inherited. The familial occurrence of median canaliform nail dystrophy has rarely been described. Indeed, to the best of our knowledge, in addition to our patient, only 3 families with median canaliform nail dystrophy have been described.^20,22,23 In the first such family, a 16-year-old girl with bilateral median canaliform nail dystrophy of her thumbnails since the age of 13 years had a mother with similar-appearing thumbnails.²⁰ A second such family also included a mother and daughter.²² Long longitudinal grooves were present in the daughter's left thumbnail since the age of 11 years; her mother had a similar dystrophy involving her right thumbnail that began when she was 12 years old. Her mother, currently 34 years old, still has recurrent episodes of spontaneously resolving median canaliform nail dystrophy. The family had no history of other hereditary diseases.²² The third family in which median canaliform nail dystrophy occurred was reported by Bossi²³ in the Italian literature in 1965. Our patient and his brother and mother represent the fourth such family.

The differential diagnosis of median canaliform nail dystrophy includes habit tic deformity (Table). It also includes other causes of longitudinal splits in the nail plate such as direct trauma to the nail unit. In addition, digital mucous cyst (synovial cyst), lichen striatus, nail-patella syndrome, pterygium, Raynaud disease, and trachyonychia are other conditions in which a longitudinal nail defect has been described.^5,7,30,31

Please refer to the PDF to view the table

Habit tic deformity is usually present in one or both thumbnails and results in alteration of the normal nail growth. It is caused by the constant or habitual rubbing of the thumb's proximal nail fold by the tip of the second digit. The subsequent damage to the nail matrix causes clinical changes in the nail plate that appear different than those of median canaliform nail dystrophy. The habit tic deformity produces transverse ridges along the central nail plate depression instead of a longitudinal groove with lateral projections. The depth of the central nail plate canal depends on the intensity of the inflicted trauma by the index finger to the matrix of the thumbnail. In addition, the lunula may appear red and enlarged.^9,29 Also, the proximal nail fold may be swollen.^5,13

Median canaliform nail dystrophy has occasionally been described to periodically disappear; often, the nail defect reappears in these individuals.^{4-7,13,15,17,24} In some patients, the central nail defect is replaced by a longitudinal ridge^5,6; however, in most patients, such as ours, the condition does not resolve spontaneously. Keeping the nail length short and buffing the surface of the nail can prevent the edge of the nail plate from catching on clothing and other objects.⁵ Covering the nail plate with tape or a nail wrap also can aid in ensuring that jagged edges are not present.^4,7 

Conclusion

Familial median canaliform nail dystrophy has rarely been described. Our patient had adult onset of his condition involving both thumbnails with associated red macrolunula. His brother and his mother also experienced the same nail dystrophy. Including our patient and his family, median canaliform nail dystrophy has only been reported in 4 families. The mode of inheritance for median canaliform nail dystrophy in these families remains to be determined. 

Median canaliform nail dystrophy is a nail abnormality that typically involves one or both thumbnails. The first case of this disorder was recorded by Heller¹ in 1928. Median canaliform nail dystrophy presents as a central longitudinal groove of the nail plate, extending proximally from the end of the nail.² This condition is usually not inherited. However, it may be acquired following trauma to the nail. We describe a man with familial median canaliform nail dystrophy and discuss the differential diagnosis.

Case Report

A 68-year-old man presented with bilateral dystrophy of his thumbnails. The nail abnormality initially appeared at 34 years of age with no preceding trauma to the digits. His older brother and his mother also had developed the same nail changes as young adults. Neither the patient nor his brother or mother rubbed their proximal thumbnail fold with the tip of their second finger; the absence of this behavioral activity was repeatedly confirmed by both the patient and his wife during several subsequent office visits.

Examination of both thumbnails showed an asymptomatic distal fissure with a fir tree–like pattern (Figure). Proximally, the nail plates showed transverse grooves. In addition, the lunula was red and enlarged.

Please refer to the PDF to view the figure

Comment

Median canaliform nail dystrophy appears as a long longitudinal groove extending from either the proximal nail fold or a more distal portion of the nail plate to the end of the nail. Lateral extensions of this fissure create a conspicuous inverted fir tree–like pattern. In severe cases, the nail can split along the groove.³ Thickening of the proximal nail fold, enlargement of the lunula, and redness of the lunula also may occur.^4-9

The diagnosis of this condition is usually established based on clinical features because pathologic correlation is rarely available. However, specimens for microscopic evaluation have occasionally been provided. Parakeratosis, as well as an accumulation of melanin within and between the nail bed keratinocytes, was demonstrated in the evaluation of an affected nail by Heller¹⁰ in 1927. Subsequently, parakeratosis and intranuclear pigmentation were found within the longitudinal canal of the affected nail plate of a 12-year-old girl with median canaliform nail dystrophy who was described by Robinson and Weidman¹¹ in 1948.

Median canaliform nail dystrophy may present following trauma to the nail plate or nail matrix.^3-7,12-15 In addition, coexisting conditions such as either soft tissue in the nail defect or dental caries have been observed in some patients with median canaliform nail dystrophy. In one case, a 19-year-old woman presented with a flabby filament of fleshy tissue that was observed within the dystrophic nail canal.¹⁴ The tissue was extracted, and the nail abnormality resolved. Subsequently, the nail dystrophy, including the associated tissue, reappeared.¹⁴ Tooth decay associated with median canaliform nail dystrophy was reported in a 23-year-old woman with a deformity that involved many of the nails on both of her hands. Her nail condition spontaneously cleared after 3 carious teeth were extracted.¹⁶

Medication was postulated as the causative factor for the development of median canaliform nail dystrophy in 3 patients who were receiving isotretinoin. The first, reported by Bottomley and Cunliffe¹⁷ in 1992, was a 38-year-old woman who developed median canaliform nail dystrophy 6 weeks after beginning treatment with isotretinoin. Her thumbnail returned to normal 4 weeks after she discontinued the drug.¹⁷ The second patient, described by Griego et al⁴ in 1995, was an 18-year-old man who developed median canaliform nail dystrophy of both thumbnails after starting therapy with isotretinoin for his acne. The nail disfigurement became distinct after 4 months of treatment; his new thumbnail dystrophy resolved 5 months after he discontinued the medication.⁴ A third patient was reported by Dharmagunawardena and Charles-Holmes¹² in 1997. They described a 19-year-old man who developed median canaliform nail dystrophy in both thumbnails within 4 weeks after starting treatment with isotretinoin for his acne. His nails returned to normal 3 months after completing a 5-month course of isotretinoin therapy.¹²

Familial median canaliform nail dystrophy has not been associated with any systemic syndromes. In our patient and his family, the nail dystrophy was not congenital but rather appeared as an acquired abnormality of the nails in adulthood.

The etiology of median canaliform nail dystrophy is unknown.^5,7,13,16-18 It usually is an acquired condition. Nail matrix trauma may precede the onset; however, an associated nail injury has often not occurred.^{3-7,12-16,19-21} This nail dystrophy is not considered to be inherited. The familial occurrence of median canaliform nail dystrophy has rarely been described. Indeed, to the best of our knowledge, in addition to our patient, only 3 families with median canaliform nail dystrophy have been described.^20,22,23 In the first such family, a 16-year-old girl with bilateral median canaliform nail dystrophy of her thumbnails since the age of 13 years had a mother with similar-appearing thumbnails.²⁰ A second such family also included a mother and daughter.²² Long longitudinal grooves were present in the daughter's left thumbnail since the age of 11 years; her mother had a similar dystrophy involving her right thumbnail that began when she was 12 years old. Her mother, currently 34 years old, still has recurrent episodes of spontaneously resolving median canaliform nail dystrophy. The family had no history of other hereditary diseases.²² The third family in which median canaliform nail dystrophy occurred was reported by Bossi²³ in the Italian literature in 1965. Our patient and his brother and mother represent the fourth such family.

The differential diagnosis of median canaliform nail dystrophy includes habit tic deformity (Table). It also includes other causes of longitudinal splits in the nail plate such as direct trauma to the nail unit. In addition, digital mucous cyst (synovial cyst), lichen striatus, nail-patella syndrome, pterygium, Raynaud disease, and trachyonychia are other conditions in which a longitudinal nail defect has been described.^5,7,30,31

Please refer to the PDF to view the table

Habit tic deformity is usually present in one or both thumbnails and results in alteration of the normal nail growth. It is caused by the constant or habitual rubbing of the thumb's proximal nail fold by the tip of the second digit. The subsequent damage to the nail matrix causes clinical changes in the nail plate that appear different than those of median canaliform nail dystrophy. The habit tic deformity produces transverse ridges along the central nail plate depression instead of a longitudinal groove with lateral projections. The depth of the central nail plate canal depends on the intensity of the inflicted trauma by the index finger to the matrix of the thumbnail. In addition, the lunula may appear red and enlarged.^9,29 Also, the proximal nail fold may be swollen.^5,13

Median canaliform nail dystrophy has occasionally been described to periodically disappear; often, the nail defect reappears in these individuals.^{4-7,13,15,17,24} In some patients, the central nail defect is replaced by a longitudinal ridge^5,6; however, in most patients, such as ours, the condition does not resolve spontaneously. Keeping the nail length short and buffing the surface of the nail can prevent the edge of the nail plate from catching on clothing and other objects.⁵ Covering the nail plate with tape or a nail wrap also can aid in ensuring that jagged edges are not present.^4,7 

Conclusion

Familial median canaliform nail dystrophy has rarely been described. Our patient had adult onset of his condition involving both thumbnails with associated red macrolunula. His brother and his mother also experienced the same nail dystrophy. Including our patient and his family, median canaliform nail dystrophy has only been reported in 4 families. The mode of inheritance for median canaliform nail dystrophy in these families remains to be determined. 

Median canaliform nail dystrophy is a nail abnormality that typically involves one or both thumbnails. The first case of this disorder was recorded by Heller¹ in 1928. Median canaliform nail dystrophy presents as a central longitudinal groove of the nail plate, extending proximally from the end of the nail.² This condition is usually not inherited. However, it may be acquired following trauma to the nail. We describe a man with familial median canaliform nail dystrophy and discuss the differential diagnosis.

Case Report

A 68-year-old man presented with bilateral dystrophy of his thumbnails. The nail abnormality initially appeared at 34 years of age with no preceding trauma to the digits. His older brother and his mother also had developed the same nail changes as young adults. Neither the patient nor his brother or mother rubbed their proximal thumbnail fold with the tip of their second finger; the absence of this behavioral activity was repeatedly confirmed by both the patient and his wife during several subsequent office visits.

Examination of both thumbnails showed an asymptomatic distal fissure with a fir tree–like pattern (Figure). Proximally, the nail plates showed transverse grooves. In addition, the lunula was red and enlarged.

Please refer to the PDF to view the figure

Comment

Median canaliform nail dystrophy appears as a long longitudinal groove extending from either the proximal nail fold or a more distal portion of the nail plate to the end of the nail. Lateral extensions of this fissure create a conspicuous inverted fir tree–like pattern. In severe cases, the nail can split along the groove.³ Thickening of the proximal nail fold, enlargement of the lunula, and redness of the lunula also may occur.^4-9

The diagnosis of this condition is usually established based on clinical features because pathologic correlation is rarely available. However, specimens for microscopic evaluation have occasionally been provided. Parakeratosis, as well as an accumulation of melanin within and between the nail bed keratinocytes, was demonstrated in the evaluation of an affected nail by Heller¹⁰ in 1927. Subsequently, parakeratosis and intranuclear pigmentation were found within the longitudinal canal of the affected nail plate of a 12-year-old girl with median canaliform nail dystrophy who was described by Robinson and Weidman¹¹ in 1948.

Median canaliform nail dystrophy may present following trauma to the nail plate or nail matrix.^3-7,12-15 In addition, coexisting conditions such as either soft tissue in the nail defect or dental caries have been observed in some patients with median canaliform nail dystrophy. In one case, a 19-year-old woman presented with a flabby filament of fleshy tissue that was observed within the dystrophic nail canal.¹⁴ The tissue was extracted, and the nail abnormality resolved. Subsequently, the nail dystrophy, including the associated tissue, reappeared.¹⁴ Tooth decay associated with median canaliform nail dystrophy was reported in a 23-year-old woman with a deformity that involved many of the nails on both of her hands. Her nail condition spontaneously cleared after 3 carious teeth were extracted.¹⁶

Medication was postulated as the causative factor for the development of median canaliform nail dystrophy in 3 patients who were receiving isotretinoin. The first, reported by Bottomley and Cunliffe¹⁷ in 1992, was a 38-year-old woman who developed median canaliform nail dystrophy 6 weeks after beginning treatment with isotretinoin. Her thumbnail returned to normal 4 weeks after she discontinued the drug.¹⁷ The second patient, described by Griego et al⁴ in 1995, was an 18-year-old man who developed median canaliform nail dystrophy of both thumbnails after starting therapy with isotretinoin for his acne. The nail disfigurement became distinct after 4 months of treatment; his new thumbnail dystrophy resolved 5 months after he discontinued the medication.⁴ A third patient was reported by Dharmagunawardena and Charles-Holmes¹² in 1997. They described a 19-year-old man who developed median canaliform nail dystrophy in both thumbnails within 4 weeks after starting treatment with isotretinoin for his acne. His nails returned to normal 3 months after completing a 5-month course of isotretinoin therapy.¹²

Familial median canaliform nail dystrophy has not been associated with any systemic syndromes. In our patient and his family, the nail dystrophy was not congenital but rather appeared as an acquired abnormality of the nails in adulthood.

The etiology of median canaliform nail dystrophy is unknown.^5,7,13,16-18 It usually is an acquired condition. Nail matrix trauma may precede the onset; however, an associated nail injury has often not occurred.^{3-7,12-16,19-21} This nail dystrophy is not considered to be inherited. The familial occurrence of median canaliform nail dystrophy has rarely been described. Indeed, to the best of our knowledge, in addition to our patient, only 3 families with median canaliform nail dystrophy have been described.^20,22,23 In the first such family, a 16-year-old girl with bilateral median canaliform nail dystrophy of her thumbnails since the age of 13 years had a mother with similar-appearing thumbnails.²⁰ A second such family also included a mother and daughter.²² Long longitudinal grooves were present in the daughter's left thumbnail since the age of 11 years; her mother had a similar dystrophy involving her right thumbnail that began when she was 12 years old. Her mother, currently 34 years old, still has recurrent episodes of spontaneously resolving median canaliform nail dystrophy. The family had no history of other hereditary diseases.²² The third family in which median canaliform nail dystrophy occurred was reported by Bossi²³ in the Italian literature in 1965. Our patient and his brother and mother represent the fourth such family.

The differential diagnosis of median canaliform nail dystrophy includes habit tic deformity (Table). It also includes other causes of longitudinal splits in the nail plate such as direct trauma to the nail unit. In addition, digital mucous cyst (synovial cyst), lichen striatus, nail-patella syndrome, pterygium, Raynaud disease, and trachyonychia are other conditions in which a longitudinal nail defect has been described.^5,7,30,31

Please refer to the PDF to view the table

Habit tic deformity is usually present in one or both thumbnails and results in alteration of the normal nail growth. It is caused by the constant or habitual rubbing of the thumb's proximal nail fold by the tip of the second digit. The subsequent damage to the nail matrix causes clinical changes in the nail plate that appear different than those of median canaliform nail dystrophy. The habit tic deformity produces transverse ridges along the central nail plate depression instead of a longitudinal groove with lateral projections. The depth of the central nail plate canal depends on the intensity of the inflicted trauma by the index finger to the matrix of the thumbnail. In addition, the lunula may appear red and enlarged.^9,29 Also, the proximal nail fold may be swollen.^5,13

Median canaliform nail dystrophy has occasionally been described to periodically disappear; often, the nail defect reappears in these individuals.^{4-7,13,15,17,24} In some patients, the central nail defect is replaced by a longitudinal ridge^5,6; however, in most patients, such as ours, the condition does not resolve spontaneously. Keeping the nail length short and buffing the surface of the nail can prevent the edge of the nail plate from catching on clothing and other objects.⁵ Covering the nail plate with tape or a nail wrap also can aid in ensuring that jagged edges are not present.^4,7 

Conclusion

Familial median canaliform nail dystrophy has rarely been described. Our patient had adult onset of his condition involving both thumbnails with associated red macrolunula. His brother and his mother also experienced the same nail dystrophy. Including our patient and his family, median canaliform nail dystrophy has only been reported in 4 families. The mode of inheritance for median canaliform nail dystrophy in these families remains to be determined. 

Muir-Torre syndrome (MTS) is an autosomal-dominant condition characterized by sebaceous skin tumors and visceral neoplasms.1 The first descriptions of this syndrome came independently from Muir et al2 and Torre.3 Advances in genetic research have demonstrated that MTS is a phenotypic subset of hereditary nonpolyposis colorectal cancer and, in most cases, arises from germline mutations in genes encoding for mismatch repair (MMR) proteins. We report a case of MTS and review the relevant literature.

Case Report A 49-year-old white man presented to a dermatologist with the complaint of a cyst on the right side of his neck. The lesion was excised, and the histopathology results revealed a sebaceous epithelioma. One year later, the patient underwent a screening colonoscopy. Two polyps were removed, with the histopathology results demonstrating one juvenile polyp and one tubulovillous adenoma. Follow-up colonoscopy results one year later revealed a sessile lesion in the sigmoid colon for which the results of a biopsy demonstrated adenocarcinoma. Because of this malignancy and the patient's strong family history, a subtotal colectomy was performed. The patient subsequently developed new papules and nodules on his forehead and back (Figures 1 and 2). The histopathology of 3 of these lesions revealed sebaceous epitheliomas (Figure 3). The patient later developed a keratoacanthoma.

Please refer to the PDF to view the figure

The patient's family history is remarkable for colon cancer in his maternal grandmother, mother, father, paternal aunt, paternal uncle, and sister. His mother was diagnosed with colon cancer at 52 years of age. His father was diagnosed at 63 years of age and died at age 67. His sister was diagnosed at 40 years of age and died at age 42. Two brothers are apparently unaffected. The patient has 5 children aged 21 to 32 years, none of whom have been screened for malignancy. Results of immunohistochemical studies performed on the colonic tumor revealed a lack of normal expression of MMR proteins hMSH2 and hMSH6. Similarly, immunohistochemical studies performed on a sebaceous epithelioma demonstrated absent hMSH2 and hMSH6 expression (Figure 4). Molecular analysis was performed on the colonic tumor by protein truncation assay, and results revealed a mutation in the hMSH2 gene. Further testing of the tissue revealed high-grade microsatellite instability.

Please refer to the PDF to view the figure

Based on these clinical, histopathologic, and molecular findings, the patient was diagnosed with MTS. Because both the patient's maternal and paternal families are affected, it is unclear from which parent this patient inherited the disorder. 

Comment

Muir-Torre syndrome is inherited in an autosomal-dominant manner, demonstrating a high degree of penetrance with variable expression.4 Since 1982, more than 200 cases of MTS have been described in the literature. The mean age at diagnosis is 53 years, with the male-to-female ratio being 2:1.5,6 Clinically, the diagnosis usually is made by the presence of at least one sebaceous neoplasm associated with at least one primary visceral malignancy. Multiple keratoacanthomas and a visceral neoplasm occurring in the setting of a positive family history also fulfills diagnostic criteria.7,8 In one review, sebaceous tumors were found to precede the visceral malignancy in 22% of patients, occur concurrently in 6% of patients, and appear after the internal malignancy in 56% of patients.6 The sebaceous tumors required to make a diagnosis of MTS include sebaceous adenomas, sebaceous epitheliomas, and sebaceous carcinomas. Sebaceous adenomas are the most common diagnostic skin lesion in MTS. Sebaceous hyperplasia, though seen in patients with MTS, does not fulfill diagnostic criteria.8 Clinically, most sebaceous tumors have a nonspecific appearance, most often presenting as a pink to yellowish papule or nodule. Some lesions may be umbilicated, resembling molluscum contagiosum. Histopathologically, sebaceous adenomas are characterized by sebaceous lobules with a peripheral germinative layer of small basaloid cells that transition to mature sebaceous cells centrally. In sebaceous epitheliomas, the peripherally located small basaloid cells outnumber the mature sebaceous component. Sebaceous carcinoma demonstrates an architecturally malignant basaloid neoplasm with cytologic atypia, scattered mitoses, and variable sebaceous differentiation.9,10 Pagetoid spread may be seen, particularly in the periocular variant. Immunohistochemically, these tumors demonstrate positive staining for keratin, epithelial membrane antigen, and androgen receptors.11,12 Although sebaceous neoplasms may occur sporadically, cystic sebaceous tumors are specifically reported for MTS.9,13 Keratoacanthomas occurring in the setting of MTS may be of the ordinary type or demonstrate sebaceous differentiation.6 In general, sebaceous gland tumors are rare lesions. An archival review of the histopathologic specimens stored in the dermatology department at the Mayo Clinic over a 60-year period found only 59 patients with one or more of these lesions. Of these 59 patients, 25 (42%) had one or more visceral malignancies.14 Visceral malignancies reported in patients with MTS include gastrointestinal, urogenital, breast, hematologic, head and neck, lung, mesothelioma, pancreas, melanoma, biliary, paraganglioma, and chondrosarcoma. Gastrointestinal malignancies, particularly colonic tumors, are the most common (61%), followed by urogenital cancers (22%). It is not uncommon for patients to have multiple primary visceral neoplasms.6,7 Frequently, the visceral malignancies of MTS patients display a surprisingly indolent course with long survival despite metastatic disease.1,8 Because MTS is now recognized as a phenotypic subset of hereditary nonpolyposis colorectal cancer, it is not surprising that the spectrum of internal malignancies in MTS is almost identical to that of hereditary nonpolyposis colorectal cancer syndrome.15 The management of MTS patients and their families requires a multidisciplinary approach, including the primary care physician, dermatologist, gastroenterologist, surgeon, and oncologist. From the dermatologist's perspective, sebaceous adenomas and sebaceous epitheliomas should be completely excised. Given their aggressive growth pattern and metastatic potential, sebaceous carcinomas should undergo wide excision.8,16 Mohs micrographic surgery has been successfully used to excise eyelid sebaceous carcinomas.17 Chemoprophylaxis with oral isotretinoin alone or in combination with interferon alfa has been shown to suppress the development of sebaceous neoplasms in MTS.18 Over the past decade, advances in genetic research have established MTS as a fuller phenotypic expression of hereditary nonpolyposis colorectal cancer.6,19 MTS and hereditary nonpolyposis colorectal cancer are caused by a germline mutation in one of the DNA MMR genes hMSH2, hMLH1, hPMS2, or hMSH6.15,20 MMR proteins ensure genomic integrity by identifying and excising mismatches of single nucleotide bases, as well as mismatches that result from insertions and deletions that occur during DNA replication.21 A person with an inherited MMR mutation develops a complete MMR defect when the corresponding MMR gene is inactivated by a "second hit."22 This MMR defect results in an accumulation of replication errors resulting in tumorigenesis. Tumors associated with a DNA MMR defect exhibit microsatellite instability, which is characterized by size variations in microsatellite sequences in tumor DNA compared with matching normal DNA.21 Microsatellite instability and germline mutations in MMR genes are frequently detected in families with MTS and hereditary nonpolyposis colorectal cancer. In one study, Kruse et al19 found microsatellite instability in 23 of 24 skin tumors from 16 patients with MTS. Microsatellite instability was found in at least 1 skin tumor from all 16 patients. All 7 visceral tumors from these MTS patients demonstrated microsatellite instability.19 Machin et al23 also found microsatellite instability in all cutaneous and visceral tumors from 6 patients with MTS. Entius et al24 identified microsatellite instability in 9 of 13 tumors of MTS patients and 0 of 8 sporadic sebaceous tumors. The 2 most frequently affected MMR genes in hereditary nonpolyposis colorectal cancer and MTS are hMSH2 and hMLH1. In hereditary nonpolyposis colorectal cancer, hMSH2 accounts for 53% and hMLH1 accounts for 36% of germline mutations. In MTS, 92% of germline mutations occur in hMSH2 and 8% in hMLH1.15 The pathogenicity of hMSH6 mutations is not clear. Mutations in this gene alone have not been linked to high-grade microsatellite instability and are not associated with the hereditary nonpolyposis colorectal cancer and MTS phenotype (Baudhuin LM, Burgart LJ, Leontovich O, et al, unpublished data, 2004).25 As demonstrated in this case, loss of protein expression for hMSH2 and hMSH6 is highly correlated with germline mutations in hMSH2. It has not been clearly elucidated why a lack of hMSH6 expression occurs in association with germline mutations in hMSH2. Because these proteins bind as MMR complexes, it is possible that the loss of one binding partner of a complex affects the proper expression of the other partner (Baudhuin LM, Burgart LJ, Leontovich O, et al, unpublished data, 2004). Sebaceous gland neoplasms are rare tumors; in patients with MTS, these tumors frequently precede or occur concurrently with the visceral malignancy. Recognition of these lesions and differentiating them from sporadic sebaceous gland tumors is therefore critical in patient management. In the previously mentioned archival study at the Mayo Clinic,14 42% of patients with sebaceous tumors had at least one visceral malignancy. Kruse et al26 found microsatellite instability in 15 of 25 randomly selected sebaceous neoplasms. Subsequently, it was found that 9 of those 15 patients with microsatellite instability–positive sebaceous tumors were identified as having MTS.26 Popnikolov et al27 found loss of MMR (either hMSH2 or hMLH1) in 50% of consecutive sebaceous adenomas and 43% of consecutive sebaceous carcinomas. In those patients who were subsequently found to have an associated malignancy, 80% of sebaceous lesions demonstrated a loss of either hMSH2 or hMLH1. In comparison, 23% of sebaceous lesions not associated with a visceral malignancy showed a loss of hMSH2 or hMLH1.27 Because sebaceous tumors precede the visceral malignancy in one fourth of patients, the identification of sebaceous tumors demonstrating microsatellite instability or MMR loss without an associated visceral malignancy may represent the initial expression of MTS, which would indicate an increased risk of visceral malignancy in these patients. Identifying a germline mutation in one of the DNA MMR genes can be helpful in preselecting patients with sebaceous tumors or multiple keratoacanthomas with an increased risk for visceral malignancy. Screening for microsatellite instability or searching for mutations in either hMSH2 or hMLH1, however, can be arduous, expensive, and time consuming.28,29 Instead, immunohistochemical analysis using antibodies against hMSH2 and hMLH1 proteins in MTS–associated skin tumors may be used as an initial screening for MMR defects. Mathiak et al28 reported immunohistochemical investigation of 28 skin tumors from 17 patients using antibodies against hMLH1 and hMSH2 proteins. Twenty of these tumors were from 10 patients with known germline mutations in hMSH2 or hMLH1; 8 tumors were sporadic. Seventeen of 19 (one sample was not immunoreactive and was not included) tumors from patients with known germline mutations showed a loss of either hMSH2 or hMSH1 expression (89% sensitivity). All 8 sporadic tumors showed normal expression of both hMSH2 and hMLH1 (100% specificity). Overall, in 93% (26/28) of skin tumors, the staining pattern matched the molecular results.28 From these results, we can conclude that immunohistochemical analysis of MTS–related skin tumors is an efficient and cost-effective method of screening for MMR defects. It is important to realize that a negative immunohistochemical analysis result does not exclude an MMR defect because certain germline defects may give rise to MMR proteins that are antigenically recognizable but functionally deficient. In these cases, only molecular germline analysis would disclose the MMR gene defect. Presentation of the MTS phenotype or the identification of a solitary sebaceous neoplasm should suggest a potential hereditary MMR mutation. In theory, all patients with a sebaceous neoplasm should be screened for an MMR defect and MTS. However, as previously mentioned, testing for microsatellite instability and performing mutational analysis on all patients would be impractical and cost prohibitive. Immunohistochemical analysis of neoplasms seems to be an extremely useful and practical initial step in screening for hereditary MMR mutations. If immunohistochemical analysis suggests an MMR mutation, molecular genetic analysis could then be performed. This would provide valuable information to the clinician and enable efficient cancer surveillance along with specific genetic testing and counseling for the patient and family members. 

Muir-Torre syndrome (MTS) is an autosomal-dominant condition characterized by sebaceous skin tumors and visceral neoplasms.1 The first descriptions of this syndrome came independently from Muir et al2 and Torre.3 Advances in genetic research have demonstrated that MTS is a phenotypic subset of hereditary nonpolyposis colorectal cancer and, in most cases, arises from germline mutations in genes encoding for mismatch repair (MMR) proteins. We report a case of MTS and review the relevant literature.

Case Report A 49-year-old white man presented to a dermatologist with the complaint of a cyst on the right side of his neck. The lesion was excised, and the histopathology results revealed a sebaceous epithelioma. One year later, the patient underwent a screening colonoscopy. Two polyps were removed, with the histopathology results demonstrating one juvenile polyp and one tubulovillous adenoma. Follow-up colonoscopy results one year later revealed a sessile lesion in the sigmoid colon for which the results of a biopsy demonstrated adenocarcinoma. Because of this malignancy and the patient's strong family history, a subtotal colectomy was performed. The patient subsequently developed new papules and nodules on his forehead and back (Figures 1 and 2). The histopathology of 3 of these lesions revealed sebaceous epitheliomas (Figure 3). The patient later developed a keratoacanthoma.

Please refer to the PDF to view the figure

The patient's family history is remarkable for colon cancer in his maternal grandmother, mother, father, paternal aunt, paternal uncle, and sister. His mother was diagnosed with colon cancer at 52 years of age. His father was diagnosed at 63 years of age and died at age 67. His sister was diagnosed at 40 years of age and died at age 42. Two brothers are apparently unaffected. The patient has 5 children aged 21 to 32 years, none of whom have been screened for malignancy. Results of immunohistochemical studies performed on the colonic tumor revealed a lack of normal expression of MMR proteins hMSH2 and hMSH6. Similarly, immunohistochemical studies performed on a sebaceous epithelioma demonstrated absent hMSH2 and hMSH6 expression (Figure 4). Molecular analysis was performed on the colonic tumor by protein truncation assay, and results revealed a mutation in the hMSH2 gene. Further testing of the tissue revealed high-grade microsatellite instability.

Please refer to the PDF to view the figure

Based on these clinical, histopathologic, and molecular findings, the patient was diagnosed with MTS. Because both the patient's maternal and paternal families are affected, it is unclear from which parent this patient inherited the disorder. 

Comment

Muir-Torre syndrome is inherited in an autosomal-dominant manner, demonstrating a high degree of penetrance with variable expression.4 Since 1982, more than 200 cases of MTS have been described in the literature. The mean age at diagnosis is 53 years, with the male-to-female ratio being 2:1.5,6 Clinically, the diagnosis usually is made by the presence of at least one sebaceous neoplasm associated with at least one primary visceral malignancy. Multiple keratoacanthomas and a visceral neoplasm occurring in the setting of a positive family history also fulfills diagnostic criteria.7,8 In one review, sebaceous tumors were found to precede the visceral malignancy in 22% of patients, occur concurrently in 6% of patients, and appear after the internal malignancy in 56% of patients.6 The sebaceous tumors required to make a diagnosis of MTS include sebaceous adenomas, sebaceous epitheliomas, and sebaceous carcinomas. Sebaceous adenomas are the most common diagnostic skin lesion in MTS. Sebaceous hyperplasia, though seen in patients with MTS, does not fulfill diagnostic criteria.8 Clinically, most sebaceous tumors have a nonspecific appearance, most often presenting as a pink to yellowish papule or nodule. Some lesions may be umbilicated, resembling molluscum contagiosum. Histopathologically, sebaceous adenomas are characterized by sebaceous lobules with a peripheral germinative layer of small basaloid cells that transition to mature sebaceous cells centrally. In sebaceous epitheliomas, the peripherally located small basaloid cells outnumber the mature sebaceous component. Sebaceous carcinoma demonstrates an architecturally malignant basaloid neoplasm with cytologic atypia, scattered mitoses, and variable sebaceous differentiation.9,10 Pagetoid spread may be seen, particularly in the periocular variant. Immunohistochemically, these tumors demonstrate positive staining for keratin, epithelial membrane antigen, and androgen receptors.11,12 Although sebaceous neoplasms may occur sporadically, cystic sebaceous tumors are specifically reported for MTS.9,13 Keratoacanthomas occurring in the setting of MTS may be of the ordinary type or demonstrate sebaceous differentiation.6 In general, sebaceous gland tumors are rare lesions. An archival review of the histopathologic specimens stored in the dermatology department at the Mayo Clinic over a 60-year period found only 59 patients with one or more of these lesions. Of these 59 patients, 25 (42%) had one or more visceral malignancies.14 Visceral malignancies reported in patients with MTS include gastrointestinal, urogenital, breast, hematologic, head and neck, lung, mesothelioma, pancreas, melanoma, biliary, paraganglioma, and chondrosarcoma. Gastrointestinal malignancies, particularly colonic tumors, are the most common (61%), followed by urogenital cancers (22%). It is not uncommon for patients to have multiple primary visceral neoplasms.6,7 Frequently, the visceral malignancies of MTS patients display a surprisingly indolent course with long survival despite metastatic disease.1,8 Because MTS is now recognized as a phenotypic subset of hereditary nonpolyposis colorectal cancer, it is not surprising that the spectrum of internal malignancies in MTS is almost identical to that of hereditary nonpolyposis colorectal cancer syndrome.15 The management of MTS patients and their families requires a multidisciplinary approach, including the primary care physician, dermatologist, gastroenterologist, surgeon, and oncologist. From the dermatologist's perspective, sebaceous adenomas and sebaceous epitheliomas should be completely excised. Given their aggressive growth pattern and metastatic potential, sebaceous carcinomas should undergo wide excision.8,16 Mohs micrographic surgery has been successfully used to excise eyelid sebaceous carcinomas.17 Chemoprophylaxis with oral isotretinoin alone or in combination with interferon alfa has been shown to suppress the development of sebaceous neoplasms in MTS.18 Over the past decade, advances in genetic research have established MTS as a fuller phenotypic expression of hereditary nonpolyposis colorectal cancer.6,19 MTS and hereditary nonpolyposis colorectal cancer are caused by a germline mutation in one of the DNA MMR genes hMSH2, hMLH1, hPMS2, or hMSH6.15,20 MMR proteins ensure genomic integrity by identifying and excising mismatches of single nucleotide bases, as well as mismatches that result from insertions and deletions that occur during DNA replication.21 A person with an inherited MMR mutation develops a complete MMR defect when the corresponding MMR gene is inactivated by a "second hit."22 This MMR defect results in an accumulation of replication errors resulting in tumorigenesis. Tumors associated with a DNA MMR defect exhibit microsatellite instability, which is characterized by size variations in microsatellite sequences in tumor DNA compared with matching normal DNA.21 Microsatellite instability and germline mutations in MMR genes are frequently detected in families with MTS and hereditary nonpolyposis colorectal cancer. In one study, Kruse et al19 found microsatellite instability in 23 of 24 skin tumors from 16 patients with MTS. Microsatellite instability was found in at least 1 skin tumor from all 16 patients. All 7 visceral tumors from these MTS patients demonstrated microsatellite instability.19 Machin et al23 also found microsatellite instability in all cutaneous and visceral tumors from 6 patients with MTS. Entius et al24 identified microsatellite instability in 9 of 13 tumors of MTS patients and 0 of 8 sporadic sebaceous tumors. The 2 most frequently affected MMR genes in hereditary nonpolyposis colorectal cancer and MTS are hMSH2 and hMLH1. In hereditary nonpolyposis colorectal cancer, hMSH2 accounts for 53% and hMLH1 accounts for 36% of germline mutations. In MTS, 92% of germline mutations occur in hMSH2 and 8% in hMLH1.15 The pathogenicity of hMSH6 mutations is not clear. Mutations in this gene alone have not been linked to high-grade microsatellite instability and are not associated with the hereditary nonpolyposis colorectal cancer and MTS phenotype (Baudhuin LM, Burgart LJ, Leontovich O, et al, unpublished data, 2004).25 As demonstrated in this case, loss of protein expression for hMSH2 and hMSH6 is highly correlated with germline mutations in hMSH2. It has not been clearly elucidated why a lack of hMSH6 expression occurs in association with germline mutations in hMSH2. Because these proteins bind as MMR complexes, it is possible that the loss of one binding partner of a complex affects the proper expression of the other partner (Baudhuin LM, Burgart LJ, Leontovich O, et al, unpublished data, 2004). Sebaceous gland neoplasms are rare tumors; in patients with MTS, these tumors frequently precede or occur concurrently with the visceral malignancy. Recognition of these lesions and differentiating them from sporadic sebaceous gland tumors is therefore critical in patient management. In the previously mentioned archival study at the Mayo Clinic,14 42% of patients with sebaceous tumors had at least one visceral malignancy. Kruse et al26 found microsatellite instability in 15 of 25 randomly selected sebaceous neoplasms. Subsequently, it was found that 9 of those 15 patients with microsatellite instability–positive sebaceous tumors were identified as having MTS.26 Popnikolov et al27 found loss of MMR (either hMSH2 or hMLH1) in 50% of consecutive sebaceous adenomas and 43% of consecutive sebaceous carcinomas. In those patients who were subsequently found to have an associated malignancy, 80% of sebaceous lesions demonstrated a loss of either hMSH2 or hMLH1. In comparison, 23% of sebaceous lesions not associated with a visceral malignancy showed a loss of hMSH2 or hMLH1.27 Because sebaceous tumors precede the visceral malignancy in one fourth of patients, the identification of sebaceous tumors demonstrating microsatellite instability or MMR loss without an associated visceral malignancy may represent the initial expression of MTS, which would indicate an increased risk of visceral malignancy in these patients. Identifying a germline mutation in one of the DNA MMR genes can be helpful in preselecting patients with sebaceous tumors or multiple keratoacanthomas with an increased risk for visceral malignancy. Screening for microsatellite instability or searching for mutations in either hMSH2 or hMLH1, however, can be arduous, expensive, and time consuming.28,29 Instead, immunohistochemical analysis using antibodies against hMSH2 and hMLH1 proteins in MTS–associated skin tumors may be used as an initial screening for MMR defects. Mathiak et al28 reported immunohistochemical investigation of 28 skin tumors from 17 patients using antibodies against hMLH1 and hMSH2 proteins. Twenty of these tumors were from 10 patients with known germline mutations in hMSH2 or hMLH1; 8 tumors were sporadic. Seventeen of 19 (one sample was not immunoreactive and was not included) tumors from patients with known germline mutations showed a loss of either hMSH2 or hMSH1 expression (89% sensitivity). All 8 sporadic tumors showed normal expression of both hMSH2 and hMLH1 (100% specificity). Overall, in 93% (26/28) of skin tumors, the staining pattern matched the molecular results.28 From these results, we can conclude that immunohistochemical analysis of MTS–related skin tumors is an efficient and cost-effective method of screening for MMR defects. It is important to realize that a negative immunohistochemical analysis result does not exclude an MMR defect because certain germline defects may give rise to MMR proteins that are antigenically recognizable but functionally deficient. In these cases, only molecular germline analysis would disclose the MMR gene defect. Presentation of the MTS phenotype or the identification of a solitary sebaceous neoplasm should suggest a potential hereditary MMR mutation. In theory, all patients with a sebaceous neoplasm should be screened for an MMR defect and MTS. However, as previously mentioned, testing for microsatellite instability and performing mutational analysis on all patients would be impractical and cost prohibitive. Immunohistochemical analysis of neoplasms seems to be an extremely useful and practical initial step in screening for hereditary MMR mutations. If immunohistochemical analysis suggests an MMR mutation, molecular genetic analysis could then be performed. This would provide valuable information to the clinician and enable efficient cancer surveillance along with specific genetic testing and counseling for the patient and family members. 

Muir-Torre syndrome (MTS) is an autosomal-dominant condition characterized by sebaceous skin tumors and visceral neoplasms.1 The first descriptions of this syndrome came independently from Muir et al2 and Torre.3 Advances in genetic research have demonstrated that MTS is a phenotypic subset of hereditary nonpolyposis colorectal cancer and, in most cases, arises from germline mutations in genes encoding for mismatch repair (MMR) proteins. We report a case of MTS and review the relevant literature.

Case Report A 49-year-old white man presented to a dermatologist with the complaint of a cyst on the right side of his neck. The lesion was excised, and the histopathology results revealed a sebaceous epithelioma. One year later, the patient underwent a screening colonoscopy. Two polyps were removed, with the histopathology results demonstrating one juvenile polyp and one tubulovillous adenoma. Follow-up colonoscopy results one year later revealed a sessile lesion in the sigmoid colon for which the results of a biopsy demonstrated adenocarcinoma. Because of this malignancy and the patient's strong family history, a subtotal colectomy was performed. The patient subsequently developed new papules and nodules on his forehead and back (Figures 1 and 2). The histopathology of 3 of these lesions revealed sebaceous epitheliomas (Figure 3). The patient later developed a keratoacanthoma.

Please refer to the PDF to view the figure

The patient's family history is remarkable for colon cancer in his maternal grandmother, mother, father, paternal aunt, paternal uncle, and sister. His mother was diagnosed with colon cancer at 52 years of age. His father was diagnosed at 63 years of age and died at age 67. His sister was diagnosed at 40 years of age and died at age 42. Two brothers are apparently unaffected. The patient has 5 children aged 21 to 32 years, none of whom have been screened for malignancy. Results of immunohistochemical studies performed on the colonic tumor revealed a lack of normal expression of MMR proteins hMSH2 and hMSH6. Similarly, immunohistochemical studies performed on a sebaceous epithelioma demonstrated absent hMSH2 and hMSH6 expression (Figure 4). Molecular analysis was performed on the colonic tumor by protein truncation assay, and results revealed a mutation in the hMSH2 gene. Further testing of the tissue revealed high-grade microsatellite instability.

Please refer to the PDF to view the figure

Based on these clinical, histopathologic, and molecular findings, the patient was diagnosed with MTS. Because both the patient's maternal and paternal families are affected, it is unclear from which parent this patient inherited the disorder. 

Comment

Muir-Torre syndrome is inherited in an autosomal-dominant manner, demonstrating a high degree of penetrance with variable expression.4 Since 1982, more than 200 cases of MTS have been described in the literature. The mean age at diagnosis is 53 years, with the male-to-female ratio being 2:1.5,6 Clinically, the diagnosis usually is made by the presence of at least one sebaceous neoplasm associated with at least one primary visceral malignancy. Multiple keratoacanthomas and a visceral neoplasm occurring in the setting of a positive family history also fulfills diagnostic criteria.7,8 In one review, sebaceous tumors were found to precede the visceral malignancy in 22% of patients, occur concurrently in 6% of patients, and appear after the internal malignancy in 56% of patients.6 The sebaceous tumors required to make a diagnosis of MTS include sebaceous adenomas, sebaceous epitheliomas, and sebaceous carcinomas. Sebaceous adenomas are the most common diagnostic skin lesion in MTS. Sebaceous hyperplasia, though seen in patients with MTS, does not fulfill diagnostic criteria.8 Clinically, most sebaceous tumors have a nonspecific appearance, most often presenting as a pink to yellowish papule or nodule. Some lesions may be umbilicated, resembling molluscum contagiosum. Histopathologically, sebaceous adenomas are characterized by sebaceous lobules with a peripheral germinative layer of small basaloid cells that transition to mature sebaceous cells centrally. In sebaceous epitheliomas, the peripherally located small basaloid cells outnumber the mature sebaceous component. Sebaceous carcinoma demonstrates an architecturally malignant basaloid neoplasm with cytologic atypia, scattered mitoses, and variable sebaceous differentiation.9,10 Pagetoid spread may be seen, particularly in the periocular variant. Immunohistochemically, these tumors demonstrate positive staining for keratin, epithelial membrane antigen, and androgen receptors.11,12 Although sebaceous neoplasms may occur sporadically, cystic sebaceous tumors are specifically reported for MTS.9,13 Keratoacanthomas occurring in the setting of MTS may be of the ordinary type or demonstrate sebaceous differentiation.6 In general, sebaceous gland tumors are rare lesions. An archival review of the histopathologic specimens stored in the dermatology department at the Mayo Clinic over a 60-year period found only 59 patients with one or more of these lesions. Of these 59 patients, 25 (42%) had one or more visceral malignancies.14 Visceral malignancies reported in patients with MTS include gastrointestinal, urogenital, breast, hematologic, head and neck, lung, mesothelioma, pancreas, melanoma, biliary, paraganglioma, and chondrosarcoma. Gastrointestinal malignancies, particularly colonic tumors, are the most common (61%), followed by urogenital cancers (22%). It is not uncommon for patients to have multiple primary visceral neoplasms.6,7 Frequently, the visceral malignancies of MTS patients display a surprisingly indolent course with long survival despite metastatic disease.1,8 Because MTS is now recognized as a phenotypic subset of hereditary nonpolyposis colorectal cancer, it is not surprising that the spectrum of internal malignancies in MTS is almost identical to that of hereditary nonpolyposis colorectal cancer syndrome.15 The management of MTS patients and their families requires a multidisciplinary approach, including the primary care physician, dermatologist, gastroenterologist, surgeon, and oncologist. From the dermatologist's perspective, sebaceous adenomas and sebaceous epitheliomas should be completely excised. Given their aggressive growth pattern and metastatic potential, sebaceous carcinomas should undergo wide excision.8,16 Mohs micrographic surgery has been successfully used to excise eyelid sebaceous carcinomas.17 Chemoprophylaxis with oral isotretinoin alone or in combination with interferon alfa has been shown to suppress the development of sebaceous neoplasms in MTS.18 Over the past decade, advances in genetic research have established MTS as a fuller phenotypic expression of hereditary nonpolyposis colorectal cancer.6,19 MTS and hereditary nonpolyposis colorectal cancer are caused by a germline mutation in one of the DNA MMR genes hMSH2, hMLH1, hPMS2, or hMSH6.15,20 MMR proteins ensure genomic integrity by identifying and excising mismatches of single nucleotide bases, as well as mismatches that result from insertions and deletions that occur during DNA replication.21 A person with an inherited MMR mutation develops a complete MMR defect when the corresponding MMR gene is inactivated by a "second hit."22 This MMR defect results in an accumulation of replication errors resulting in tumorigenesis. Tumors associated with a DNA MMR defect exhibit microsatellite instability, which is characterized by size variations in microsatellite sequences in tumor DNA compared with matching normal DNA.21 Microsatellite instability and germline mutations in MMR genes are frequently detected in families with MTS and hereditary nonpolyposis colorectal cancer. In one study, Kruse et al19 found microsatellite instability in 23 of 24 skin tumors from 16 patients with MTS. Microsatellite instability was found in at least 1 skin tumor from all 16 patients. All 7 visceral tumors from these MTS patients demonstrated microsatellite instability.19 Machin et al23 also found microsatellite instability in all cutaneous and visceral tumors from 6 patients with MTS. Entius et al24 identified microsatellite instability in 9 of 13 tumors of MTS patients and 0 of 8 sporadic sebaceous tumors. The 2 most frequently affected MMR genes in hereditary nonpolyposis colorectal cancer and MTS are hMSH2 and hMLH1. In hereditary nonpolyposis colorectal cancer, hMSH2 accounts for 53% and hMLH1 accounts for 36% of germline mutations. In MTS, 92% of germline mutations occur in hMSH2 and 8% in hMLH1.15 The pathogenicity of hMSH6 mutations is not clear. Mutations in this gene alone have not been linked to high-grade microsatellite instability and are not associated with the hereditary nonpolyposis colorectal cancer and MTS phenotype (Baudhuin LM, Burgart LJ, Leontovich O, et al, unpublished data, 2004).25 As demonstrated in this case, loss of protein expression for hMSH2 and hMSH6 is highly correlated with germline mutations in hMSH2. It has not been clearly elucidated why a lack of hMSH6 expression occurs in association with germline mutations in hMSH2. Because these proteins bind as MMR complexes, it is possible that the loss of one binding partner of a complex affects the proper expression of the other partner (Baudhuin LM, Burgart LJ, Leontovich O, et al, unpublished data, 2004). Sebaceous gland neoplasms are rare tumors; in patients with MTS, these tumors frequently precede or occur concurrently with the visceral malignancy. Recognition of these lesions and differentiating them from sporadic sebaceous gland tumors is therefore critical in patient management. In the previously mentioned archival study at the Mayo Clinic,14 42% of patients with sebaceous tumors had at least one visceral malignancy. Kruse et al26 found microsatellite instability in 15 of 25 randomly selected sebaceous neoplasms. Subsequently, it was found that 9 of those 15 patients with microsatellite instability–positive sebaceous tumors were identified as having MTS.26 Popnikolov et al27 found loss of MMR (either hMSH2 or hMLH1) in 50% of consecutive sebaceous adenomas and 43% of consecutive sebaceous carcinomas. In those patients who were subsequently found to have an associated malignancy, 80% of sebaceous lesions demonstrated a loss of either hMSH2 or hMLH1. In comparison, 23% of sebaceous lesions not associated with a visceral malignancy showed a loss of hMSH2 or hMLH1.27 Because sebaceous tumors precede the visceral malignancy in one fourth of patients, the identification of sebaceous tumors demonstrating microsatellite instability or MMR loss without an associated visceral malignancy may represent the initial expression of MTS, which would indicate an increased risk of visceral malignancy in these patients. Identifying a germline mutation in one of the DNA MMR genes can be helpful in preselecting patients with sebaceous tumors or multiple keratoacanthomas with an increased risk for visceral malignancy. Screening for microsatellite instability or searching for mutations in either hMSH2 or hMLH1, however, can be arduous, expensive, and time consuming.28,29 Instead, immunohistochemical analysis using antibodies against hMSH2 and hMLH1 proteins in MTS–associated skin tumors may be used as an initial screening for MMR defects. Mathiak et al28 reported immunohistochemical investigation of 28 skin tumors from 17 patients using antibodies against hMLH1 and hMSH2 proteins. Twenty of these tumors were from 10 patients with known germline mutations in hMSH2 or hMLH1; 8 tumors were sporadic. Seventeen of 19 (one sample was not immunoreactive and was not included) tumors from patients with known germline mutations showed a loss of either hMSH2 or hMSH1 expression (89% sensitivity). All 8 sporadic tumors showed normal expression of both hMSH2 and hMLH1 (100% specificity). Overall, in 93% (26/28) of skin tumors, the staining pattern matched the molecular results.28 From these results, we can conclude that immunohistochemical analysis of MTS–related skin tumors is an efficient and cost-effective method of screening for MMR defects. It is important to realize that a negative immunohistochemical analysis result does not exclude an MMR defect because certain germline defects may give rise to MMR proteins that are antigenically recognizable but functionally deficient. In these cases, only molecular germline analysis would disclose the MMR gene defect. Presentation of the MTS phenotype or the identification of a solitary sebaceous neoplasm should suggest a potential hereditary MMR mutation. In theory, all patients with a sebaceous neoplasm should be screened for an MMR defect and MTS. However, as previously mentioned, testing for microsatellite instability and performing mutational analysis on all patients would be impractical and cost prohibitive. Immunohistochemical analysis of neoplasms seems to be an extremely useful and practical initial step in screening for hereditary MMR mutations. If immunohistochemical analysis suggests an MMR mutation, molecular genetic analysis could then be performed. This would provide valuable information to the clinician and enable efficient cancer surveillance along with specific genetic testing and counseling for the patient and family members. 

Lichen myxedematosus (LM), also called papular mucinosis, was first described by Dubreuilh1 in 1906 and later classified by Montgomery and Underwood2 in 1953. LMs are a group of localized or generalized papular eruptions of unknown etiology categorized as cutaneous mucinoses in which dermal mucin deposition is the distinctive histologic feature.3-5 LM has no relation to endocrine gland disorders, particularly thyroid disease.2,3,6 In their landmark paper, Montgomery and Underwood2 classified 4 clinical types of LM: (1) generalized lichenoid papular eruption, which is also called scleromyxedema, (2) discrete papular form, (3) localized to generalized lichenoid plaques, and (4) urticarial plaques and nodular eruptions that usually evolve into the generalized lichenoid form. In 2001, Rongioletti and Rebora6 updated the classification system. The articles by Montgomery and Underwood2 and Rongioletti and Rebora6 both agree with the existence of the discrete papular form, also called discrete papular LM (DPLM). According to Rongioletti and Rebora,6 DPLM has only been reported in the medical literature 8 times,1,2,7-12 This is unlike scleromyxedema, the most common type of LM, which has been documented in more than 110 cases.6 In this case report, we describe an interesting case of DPLM that was localized to the neck of our patient, and we review the English medical literature. 

Case Report

An 80-year-old black woman presented to our clinic with a 2-month history of a pruritic eruption localized to her neck. Multiple topical steroids and antihistamines had been used without any decrease in the eruption or the pruritus. The woman's medical history was significant for gastric cancer status post a partial gastrectomy 7 years prior, pseudotumor cerebri, hypertension, and osteoporosis. She is followed regularly for these conditions, which are stable. Her medications included acetazolamide, atenolol, nifedipine, rabeprazole sodium, fluoxetine, oxybutynin chloride, alendronate sodium, docusate calcium, and a multivitamin. Prior to the onset of this eruption, the patient had a change in the acetazolamide formulation, which was initially thought to be the culprit. Although she returned to the original formulation for longer than a month, she had no resolution of the symptoms. At that time, she sought evaluation in our clinic. On physical examination, multiple 2- to 4-mm discrete, flesh-colored shiny papules without scale were present over the patient's bilateral and posterior neck (Figure 1). Results of 2 punch biopsies showed splaying of the collagen with mucin present diffusely throughout the dermis. No increase in the number of fibroblasts was seen (Figure 2). Results of colloidal iron stain showed positive results in the papillary dermis and showed mucin mildly throughout the deep dermis (Figure 3), supporting the diagnosis of LM. Complete blood count, chemistry panel, liver function, thyrotropin, and serum protein test results were all within reference range. Pimecrolimus cream has been effective in treating our patient's pruritus. We have followed her for 14 months, and the lesions have remained localized to her neck, with continued normal thyrotropin and serum protein values.

Comment

In 2001, Rongioletti and Rebora6 revised the classification system of LM, categorizing it into 3 broad subsets: (1) generalized papular and sclerodermoid, (2) localized LM, and (3) atypical forms. The first subset, generalized papular and sclerodermoid, represents scleromyxedema. Diagnosis requires a generalized papular and sclerodermoid eruption, monoclonal gammopathy (paraproteinemia), no evidence of thyroid dysfunction, and a histologic triad of fibroblast proliferation, fibrosis, and mucin deposition.6 Scleromyxedema is associated with many systemic disorders that may include numerous organ systems.6,13 Although spontaneous resolution has been reported,14 scleromyxedema typically is a long-term and disfiguring disease6,13 associated with variable morbidity and mortality.15,16 The criteria for diagnosing the subset of localized LM requires a papular eruption, deposits of mucin with variable fibroblast growth, absence of paraproteinemia, and absence of thyroid dysfunction.6 There are 5 subtypes6: DPLM,2,7-9,17-21 acral persistent papular mucinosis (APPM),22-27 cutaneous mucinosis of infancy,28-31 self-healing papular mucinosis (SHPM),32-36 and nodular LM.37,38 All subtypes show small, firm, waxy papules limited to a few areas of the skin, which may coalesce and form nodules or plaques. DPLM can involve any site on the body. APPM exclusively involves both extensor surfaces of the distal upper extremities. Cutaneous mucinosis of infancy is a pediatric variant of DPLM or APPM. SHPM has spontaneous resolution. Nodular LM is characterized by a predominance of nodules.6 All subtypes except for SHPM typically persist long-term. Systemic symptoms were only reported in SHPM.32,33 In general, localized LM is self-limited and associated with a good prognosis.6 The histologic features of LM are summarized in Table 1.5 The pathology lies within the dermis for all types of this disease, and the epidermis is essentially normal.5 The types of LM can be distinguished from one another by 3 histologic clues: (1) mucin distribution pattern, (2) dermal level of mucin deposits, and (3) some extra findings.5 Differentiation can be additionally aided by observing the number of fibroblasts. Common mucin stains include colloidal iron, mucicarmine, and alcian blue at pH 2.5 (but not pH 0.5); common metachromatic mucin stains include toluidine blue, thionine, and methylene blue.3

DPLM is a subtype of localized LM.2,6 Although the lesions can involve any site, DPLM is typically distributed symmetrically to the trunk and limbs. The skin lesions have been described as a variable number of firm, smooth, waxy, or flesh-colored papules 2 to 5 mm in size. Normal serum protein and thyroid function test results verify the diagnosis of DPLM.6 Because Montgomery and Underwood2 originally defined LM as having no relation to any endocrine gland disturbance, we recommend additional random chemistry panel or fasting blood glucose laboratory tests if there is any question that a patient may have diabetes mellitus. Histologically, DPLM may have a diffuse or local pattern of mucin distribution involving the upper and mid reticular dermis. The involved dermis typically shows edema. The amount of fibroblast proliferation is variable. When compared with scleromyxedema, DPLM has no collagen deposition or sclerosis and a lesser amount of fibroblast proliferation.5-7 Some argue that DPLM and APPM are closely related variants.25,27 However, we believe that DPLM and APPM are distinct subtypes of localized LM. DPLM typically affects men (Table 2) and its lesions may be erythematous, larger, and include areas other than the distal upper extremities.4,23,24 In comparison, APPM has an overwhelming female-to-male ratio of 4.7:1.6 APPM also exclusively involves the back of the hands, extensor surface of the wrists, and sometimes the distal forearms.4,6,23 Histologically, APPM typically has more focal mucin deposits, which spare a subepidermal grenz zone, and a normal number of fibroblasts; DPLM has mucin deposits that are more diffuse (compared with APPM), have a variable number of increased fibroblasts, and have an irregular arrangement of collagen bundles.4-6,23

Table 2 summarizes the main features of the 10 DPLM cases reported in the English medical literature.2,7-9,17-21 Our criteria required there be no evidence of paraproteinemia, no history or laboratory evidence of any endocrine disease, no history of human immunodeficiency virus infection, histologic proof of dermal mucin deposits, and specific gross descriptions consistent with DPLM. It should be noted that only 4 of the 8 DPLM cases originally cited by Rongioletti and Rebora⁶ were included in Table 2. Four cases were excluded because 2 reports were written in French,1,12 1 report included a patient with diabetes mellitus,10 and another did not perform a necessary laboratory test to rule out thyroid disease.11 Other cases were excluded because they did not fulfill our criteria.39,40 Among the 10 DPLM patients summarized, 7 were men. The mean age of the group was 51.3 years. Only 3 of the 10 cases reported information on the patient's ethnicity: one was Caucasian,7 one was Asian,8 and our patient was African American. Nine of the 10 cases reported no evidence of paraproteinemia. The single case2 that did not report this finding was published before an association between LM and paraproteinemia was known in the 1960s.41 All 10 cases reported thyroid function test results within reference range. Only 3 of the 10 patients had symptomatic skin lesions, which were mainly pruritus. No systemic symptoms were noted. Three of the 10 patients had solitary skin lesions on areas other than the typical trunk and limbs. One patient had skin lesions only on his lumbar region, another had facial lesions, and our patient had lesions on her neck. Seven of the 10 patients had comorbid medical disorders, including hypertension, migraines, psoriatic erythroderma, psoriasis, seizures, gastric cancer in remission, pseudotumor cerebri, osteoporosis, and hepatitis C. Only hepatitis C was comorbid with more than one DPLM patient.17,20 This may be a coincidence because one patient developed DPLM after contracting hepatitis C,20, while the other patient developed it before contracting hepatitis C.17 Psychiatric illness was limited to depression and was found in 2 cases.20,21 No DPLM cases progressed to scleromyxedema, and none have been reported in the literature.5,6 DPLM rarely resolves on its own. Spontaneous resolution did not occur in any of the 10 reported DPLM cases, and only 2 patients were treated successfully. In Reynolds et al,18 the patient responded to therapy with intralesional corticosteroid injections and flurandrenolide-impregnated tape. In Kaymen et al,19 a patient was treated with a CO2 laser and postoperative intralesional corticosteroid injections. There was no growth after one year. All the other DPLM cases did not have effective therapy, lacked specific details of improvement, or did not report this information.2,7-9,17,20,21 Only Tay and Khoo,8 Enerback and Mobacken,9 and Kaymen et al19 commented on which therapies failed (oral thyroxine, topical corticosteroids, and shave excision, respectively). Our patient complained of persistent itching that did not respond to initial treatment with topical steroids and antihistamine medications. She later received pruritic relief with pimecrolimus cream therapy. However, the skin lesions remained. To our knowledge, this is the first report of pimecrolimus therapy in the treatment of pruritis secondary to DPLM. It is difficult to treat a rare disease such as DPLM when the pathogenesis is unknown, and many treatments have failed. Fortunately, DPLM and the other localized forms of LM are usually self-limited to the skin and have very little or no morbidity, leading some experts to believe that the disorder is unnecessary to treat.6 We believe that treatment is sometimes helpful. In our patient, the DPLM lesions were pruritic and located at a cosmetic area of the neck. The patient and dermatology staff decided to pursue a treatment plan. Therefore, even though localized LM lesions are typically benign, sometimes it is beneficial to treat them, especially if they cause irritating symptoms or cosmetic issues. 

Conclusion

DPLM is a rare variant of localized LM. DPLM can be diagnosed by a thorough history and physical examination; histologic proof of dermal mucin deposits; and ruling out other diseases with laboratory tests for serum protein, thyroid function, and, if the patient is at risk of diabetes mellitus, blood glucose levels. DPLM is a self-limited skin disease, and prognosis is generally good, but it typically persists long-term and may slowly progress. Treatment is usually unnecessary, but it may be recommended if the lesions are symptomatic or cause cosmetic issues. Unfortunately, few treatment plans have been shown to successfully treat DPLM. 

Lichen myxedematosus (LM), also called papular mucinosis, was first described by Dubreuilh1 in 1906 and later classified by Montgomery and Underwood2 in 1953. LMs are a group of localized or generalized papular eruptions of unknown etiology categorized as cutaneous mucinoses in which dermal mucin deposition is the distinctive histologic feature.3-5 LM has no relation to endocrine gland disorders, particularly thyroid disease.2,3,6 In their landmark paper, Montgomery and Underwood2 classified 4 clinical types of LM: (1) generalized lichenoid papular eruption, which is also called scleromyxedema, (2) discrete papular form, (3) localized to generalized lichenoid plaques, and (4) urticarial plaques and nodular eruptions that usually evolve into the generalized lichenoid form. In 2001, Rongioletti and Rebora6 updated the classification system. The articles by Montgomery and Underwood2 and Rongioletti and Rebora6 both agree with the existence of the discrete papular form, also called discrete papular LM (DPLM). According to Rongioletti and Rebora,6 DPLM has only been reported in the medical literature 8 times,1,2,7-12 This is unlike scleromyxedema, the most common type of LM, which has been documented in more than 110 cases.6 In this case report, we describe an interesting case of DPLM that was localized to the neck of our patient, and we review the English medical literature. 

Case Report

An 80-year-old black woman presented to our clinic with a 2-month history of a pruritic eruption localized to her neck. Multiple topical steroids and antihistamines had been used without any decrease in the eruption or the pruritus. The woman's medical history was significant for gastric cancer status post a partial gastrectomy 7 years prior, pseudotumor cerebri, hypertension, and osteoporosis. She is followed regularly for these conditions, which are stable. Her medications included acetazolamide, atenolol, nifedipine, rabeprazole sodium, fluoxetine, oxybutynin chloride, alendronate sodium, docusate calcium, and a multivitamin. Prior to the onset of this eruption, the patient had a change in the acetazolamide formulation, which was initially thought to be the culprit. Although she returned to the original formulation for longer than a month, she had no resolution of the symptoms. At that time, she sought evaluation in our clinic. On physical examination, multiple 2- to 4-mm discrete, flesh-colored shiny papules without scale were present over the patient's bilateral and posterior neck (Figure 1). Results of 2 punch biopsies showed splaying of the collagen with mucin present diffusely throughout the dermis. No increase in the number of fibroblasts was seen (Figure 2). Results of colloidal iron stain showed positive results in the papillary dermis and showed mucin mildly throughout the deep dermis (Figure 3), supporting the diagnosis of LM. Complete blood count, chemistry panel, liver function, thyrotropin, and serum protein test results were all within reference range. Pimecrolimus cream has been effective in treating our patient's pruritus. We have followed her for 14 months, and the lesions have remained localized to her neck, with continued normal thyrotropin and serum protein values.

Comment

In 2001, Rongioletti and Rebora6 revised the classification system of LM, categorizing it into 3 broad subsets: (1) generalized papular and sclerodermoid, (2) localized LM, and (3) atypical forms. The first subset, generalized papular and sclerodermoid, represents scleromyxedema. Diagnosis requires a generalized papular and sclerodermoid eruption, monoclonal gammopathy (paraproteinemia), no evidence of thyroid dysfunction, and a histologic triad of fibroblast proliferation, fibrosis, and mucin deposition.6 Scleromyxedema is associated with many systemic disorders that may include numerous organ systems.6,13 Although spontaneous resolution has been reported,14 scleromyxedema typically is a long-term and disfiguring disease6,13 associated with variable morbidity and mortality.15,16 The criteria for diagnosing the subset of localized LM requires a papular eruption, deposits of mucin with variable fibroblast growth, absence of paraproteinemia, and absence of thyroid dysfunction.6 There are 5 subtypes6: DPLM,2,7-9,17-21 acral persistent papular mucinosis (APPM),22-27 cutaneous mucinosis of infancy,28-31 self-healing papular mucinosis (SHPM),32-36 and nodular LM.37,38 All subtypes show small, firm, waxy papules limited to a few areas of the skin, which may coalesce and form nodules or plaques. DPLM can involve any site on the body. APPM exclusively involves both extensor surfaces of the distal upper extremities. Cutaneous mucinosis of infancy is a pediatric variant of DPLM or APPM. SHPM has spontaneous resolution. Nodular LM is characterized by a predominance of nodules.6 All subtypes except for SHPM typically persist long-term. Systemic symptoms were only reported in SHPM.32,33 In general, localized LM is self-limited and associated with a good prognosis.6 The histologic features of LM are summarized in Table 1.5 The pathology lies within the dermis for all types of this disease, and the epidermis is essentially normal.5 The types of LM can be distinguished from one another by 3 histologic clues: (1) mucin distribution pattern, (2) dermal level of mucin deposits, and (3) some extra findings.5 Differentiation can be additionally aided by observing the number of fibroblasts. Common mucin stains include colloidal iron, mucicarmine, and alcian blue at pH 2.5 (but not pH 0.5); common metachromatic mucin stains include toluidine blue, thionine, and methylene blue.3

DPLM is a subtype of localized LM.2,6 Although the lesions can involve any site, DPLM is typically distributed symmetrically to the trunk and limbs. The skin lesions have been described as a variable number of firm, smooth, waxy, or flesh-colored papules 2 to 5 mm in size. Normal serum protein and thyroid function test results verify the diagnosis of DPLM.6 Because Montgomery and Underwood2 originally defined LM as having no relation to any endocrine gland disturbance, we recommend additional random chemistry panel or fasting blood glucose laboratory tests if there is any question that a patient may have diabetes mellitus. Histologically, DPLM may have a diffuse or local pattern of mucin distribution involving the upper and mid reticular dermis. The involved dermis typically shows edema. The amount of fibroblast proliferation is variable. When compared with scleromyxedema, DPLM has no collagen deposition or sclerosis and a lesser amount of fibroblast proliferation.5-7 Some argue that DPLM and APPM are closely related variants.25,27 However, we believe that DPLM and APPM are distinct subtypes of localized LM. DPLM typically affects men (Table 2) and its lesions may be erythematous, larger, and include areas other than the distal upper extremities.4,23,24 In comparison, APPM has an overwhelming female-to-male ratio of 4.7:1.6 APPM also exclusively involves the back of the hands, extensor surface of the wrists, and sometimes the distal forearms.4,6,23 Histologically, APPM typically has more focal mucin deposits, which spare a subepidermal grenz zone, and a normal number of fibroblasts; DPLM has mucin deposits that are more diffuse (compared with APPM), have a variable number of increased fibroblasts, and have an irregular arrangement of collagen bundles.4-6,23

Table 2 summarizes the main features of the 10 DPLM cases reported in the English medical literature.2,7-9,17-21 Our criteria required there be no evidence of paraproteinemia, no history or laboratory evidence of any endocrine disease, no history of human immunodeficiency virus infection, histologic proof of dermal mucin deposits, and specific gross descriptions consistent with DPLM. It should be noted that only 4 of the 8 DPLM cases originally cited by Rongioletti and Rebora⁶ were included in Table 2. Four cases were excluded because 2 reports were written in French,1,12 1 report included a patient with diabetes mellitus,10 and another did not perform a necessary laboratory test to rule out thyroid disease.11 Other cases were excluded because they did not fulfill our criteria.39,40 Among the 10 DPLM patients summarized, 7 were men. The mean age of the group was 51.3 years. Only 3 of the 10 cases reported information on the patient's ethnicity: one was Caucasian,7 one was Asian,8 and our patient was African American. Nine of the 10 cases reported no evidence of paraproteinemia. The single case2 that did not report this finding was published before an association between LM and paraproteinemia was known in the 1960s.41 All 10 cases reported thyroid function test results within reference range. Only 3 of the 10 patients had symptomatic skin lesions, which were mainly pruritus. No systemic symptoms were noted. Three of the 10 patients had solitary skin lesions on areas other than the typical trunk and limbs. One patient had skin lesions only on his lumbar region, another had facial lesions, and our patient had lesions on her neck. Seven of the 10 patients had comorbid medical disorders, including hypertension, migraines, psoriatic erythroderma, psoriasis, seizures, gastric cancer in remission, pseudotumor cerebri, osteoporosis, and hepatitis C. Only hepatitis C was comorbid with more than one DPLM patient.17,20 This may be a coincidence because one patient developed DPLM after contracting hepatitis C,20, while the other patient developed it before contracting hepatitis C.17 Psychiatric illness was limited to depression and was found in 2 cases.20,21 No DPLM cases progressed to scleromyxedema, and none have been reported in the literature.5,6 DPLM rarely resolves on its own. Spontaneous resolution did not occur in any of the 10 reported DPLM cases, and only 2 patients were treated successfully. In Reynolds et al,18 the patient responded to therapy with intralesional corticosteroid injections and flurandrenolide-impregnated tape. In Kaymen et al,19 a patient was treated with a CO2 laser and postoperative intralesional corticosteroid injections. There was no growth after one year. All the other DPLM cases did not have effective therapy, lacked specific details of improvement, or did not report this information.2,7-9,17,20,21 Only Tay and Khoo,8 Enerback and Mobacken,9 and Kaymen et al19 commented on which therapies failed (oral thyroxine, topical corticosteroids, and shave excision, respectively). Our patient complained of persistent itching that did not respond to initial treatment with topical steroids and antihistamine medications. She later received pruritic relief with pimecrolimus cream therapy. However, the skin lesions remained. To our knowledge, this is the first report of pimecrolimus therapy in the treatment of pruritis secondary to DPLM. It is difficult to treat a rare disease such as DPLM when the pathogenesis is unknown, and many treatments have failed. Fortunately, DPLM and the other localized forms of LM are usually self-limited to the skin and have very little or no morbidity, leading some experts to believe that the disorder is unnecessary to treat.6 We believe that treatment is sometimes helpful. In our patient, the DPLM lesions were pruritic and located at a cosmetic area of the neck. The patient and dermatology staff decided to pursue a treatment plan. Therefore, even though localized LM lesions are typically benign, sometimes it is beneficial to treat them, especially if they cause irritating symptoms or cosmetic issues. 

Conclusion

DPLM is a rare variant of localized LM. DPLM can be diagnosed by a thorough history and physical examination; histologic proof of dermal mucin deposits; and ruling out other diseases with laboratory tests for serum protein, thyroid function, and, if the patient is at risk of diabetes mellitus, blood glucose levels. DPLM is a self-limited skin disease, and prognosis is generally good, but it typically persists long-term and may slowly progress. Treatment is usually unnecessary, but it may be recommended if the lesions are symptomatic or cause cosmetic issues. Unfortunately, few treatment plans have been shown to successfully treat DPLM. 

Lichen myxedematosus (LM), also called papular mucinosis, was first described by Dubreuilh1 in 1906 and later classified by Montgomery and Underwood2 in 1953. LMs are a group of localized or generalized papular eruptions of unknown etiology categorized as cutaneous mucinoses in which dermal mucin deposition is the distinctive histologic feature.3-5 LM has no relation to endocrine gland disorders, particularly thyroid disease.2,3,6 In their landmark paper, Montgomery and Underwood2 classified 4 clinical types of LM: (1) generalized lichenoid papular eruption, which is also called scleromyxedema, (2) discrete papular form, (3) localized to generalized lichenoid plaques, and (4) urticarial plaques and nodular eruptions that usually evolve into the generalized lichenoid form. In 2001, Rongioletti and Rebora6 updated the classification system. The articles by Montgomery and Underwood2 and Rongioletti and Rebora6 both agree with the existence of the discrete papular form, also called discrete papular LM (DPLM). According to Rongioletti and Rebora,6 DPLM has only been reported in the medical literature 8 times,1,2,7-12 This is unlike scleromyxedema, the most common type of LM, which has been documented in more than 110 cases.6 In this case report, we describe an interesting case of DPLM that was localized to the neck of our patient, and we review the English medical literature. 

Case Report

An 80-year-old black woman presented to our clinic with a 2-month history of a pruritic eruption localized to her neck. Multiple topical steroids and antihistamines had been used without any decrease in the eruption or the pruritus. The woman's medical history was significant for gastric cancer status post a partial gastrectomy 7 years prior, pseudotumor cerebri, hypertension, and osteoporosis. She is followed regularly for these conditions, which are stable. Her medications included acetazolamide, atenolol, nifedipine, rabeprazole sodium, fluoxetine, oxybutynin chloride, alendronate sodium, docusate calcium, and a multivitamin. Prior to the onset of this eruption, the patient had a change in the acetazolamide formulation, which was initially thought to be the culprit. Although she returned to the original formulation for longer than a month, she had no resolution of the symptoms. At that time, she sought evaluation in our clinic. On physical examination, multiple 2- to 4-mm discrete, flesh-colored shiny papules without scale were present over the patient's bilateral and posterior neck (Figure 1). Results of 2 punch biopsies showed splaying of the collagen with mucin present diffusely throughout the dermis. No increase in the number of fibroblasts was seen (Figure 2). Results of colloidal iron stain showed positive results in the papillary dermis and showed mucin mildly throughout the deep dermis (Figure 3), supporting the diagnosis of LM. Complete blood count, chemistry panel, liver function, thyrotropin, and serum protein test results were all within reference range. Pimecrolimus cream has been effective in treating our patient's pruritus. We have followed her for 14 months, and the lesions have remained localized to her neck, with continued normal thyrotropin and serum protein values.

Comment

In 2001, Rongioletti and Rebora6 revised the classification system of LM, categorizing it into 3 broad subsets: (1) generalized papular and sclerodermoid, (2) localized LM, and (3) atypical forms. The first subset, generalized papular and sclerodermoid, represents scleromyxedema. Diagnosis requires a generalized papular and sclerodermoid eruption, monoclonal gammopathy (paraproteinemia), no evidence of thyroid dysfunction, and a histologic triad of fibroblast proliferation, fibrosis, and mucin deposition.6 Scleromyxedema is associated with many systemic disorders that may include numerous organ systems.6,13 Although spontaneous resolution has been reported,14 scleromyxedema typically is a long-term and disfiguring disease6,13 associated with variable morbidity and mortality.15,16 The criteria for diagnosing the subset of localized LM requires a papular eruption, deposits of mucin with variable fibroblast growth, absence of paraproteinemia, and absence of thyroid dysfunction.6 There are 5 subtypes6: DPLM,2,7-9,17-21 acral persistent papular mucinosis (APPM),22-27 cutaneous mucinosis of infancy,28-31 self-healing papular mucinosis (SHPM),32-36 and nodular LM.37,38 All subtypes show small, firm, waxy papules limited to a few areas of the skin, which may coalesce and form nodules or plaques. DPLM can involve any site on the body. APPM exclusively involves both extensor surfaces of the distal upper extremities. Cutaneous mucinosis of infancy is a pediatric variant of DPLM or APPM. SHPM has spontaneous resolution. Nodular LM is characterized by a predominance of nodules.6 All subtypes except for SHPM typically persist long-term. Systemic symptoms were only reported in SHPM.32,33 In general, localized LM is self-limited and associated with a good prognosis.6 The histologic features of LM are summarized in Table 1.5 The pathology lies within the dermis for all types of this disease, and the epidermis is essentially normal.5 The types of LM can be distinguished from one another by 3 histologic clues: (1) mucin distribution pattern, (2) dermal level of mucin deposits, and (3) some extra findings.5 Differentiation can be additionally aided by observing the number of fibroblasts. Common mucin stains include colloidal iron, mucicarmine, and alcian blue at pH 2.5 (but not pH 0.5); common metachromatic mucin stains include toluidine blue, thionine, and methylene blue.3

DPLM is a subtype of localized LM.2,6 Although the lesions can involve any site, DPLM is typically distributed symmetrically to the trunk and limbs. The skin lesions have been described as a variable number of firm, smooth, waxy, or flesh-colored papules 2 to 5 mm in size. Normal serum protein and thyroid function test results verify the diagnosis of DPLM.6 Because Montgomery and Underwood2 originally defined LM as having no relation to any endocrine gland disturbance, we recommend additional random chemistry panel or fasting blood glucose laboratory tests if there is any question that a patient may have diabetes mellitus. Histologically, DPLM may have a diffuse or local pattern of mucin distribution involving the upper and mid reticular dermis. The involved dermis typically shows edema. The amount of fibroblast proliferation is variable. When compared with scleromyxedema, DPLM has no collagen deposition or sclerosis and a lesser amount of fibroblast proliferation.5-7 Some argue that DPLM and APPM are closely related variants.25,27 However, we believe that DPLM and APPM are distinct subtypes of localized LM. DPLM typically affects men (Table 2) and its lesions may be erythematous, larger, and include areas other than the distal upper extremities.4,23,24 In comparison, APPM has an overwhelming female-to-male ratio of 4.7:1.6 APPM also exclusively involves the back of the hands, extensor surface of the wrists, and sometimes the distal forearms.4,6,23 Histologically, APPM typically has more focal mucin deposits, which spare a subepidermal grenz zone, and a normal number of fibroblasts; DPLM has mucin deposits that are more diffuse (compared with APPM), have a variable number of increased fibroblasts, and have an irregular arrangement of collagen bundles.4-6,23

Table 2 summarizes the main features of the 10 DPLM cases reported in the English medical literature.2,7-9,17-21 Our criteria required there be no evidence of paraproteinemia, no history or laboratory evidence of any endocrine disease, no history of human immunodeficiency virus infection, histologic proof of dermal mucin deposits, and specific gross descriptions consistent with DPLM. It should be noted that only 4 of the 8 DPLM cases originally cited by Rongioletti and Rebora⁶ were included in Table 2. Four cases were excluded because 2 reports were written in French,1,12 1 report included a patient with diabetes mellitus,10 and another did not perform a necessary laboratory test to rule out thyroid disease.11 Other cases were excluded because they did not fulfill our criteria.39,40 Among the 10 DPLM patients summarized, 7 were men. The mean age of the group was 51.3 years. Only 3 of the 10 cases reported information on the patient's ethnicity: one was Caucasian,7 one was Asian,8 and our patient was African American. Nine of the 10 cases reported no evidence of paraproteinemia. The single case2 that did not report this finding was published before an association between LM and paraproteinemia was known in the 1960s.41 All 10 cases reported thyroid function test results within reference range. Only 3 of the 10 patients had symptomatic skin lesions, which were mainly pruritus. No systemic symptoms were noted. Three of the 10 patients had solitary skin lesions on areas other than the typical trunk and limbs. One patient had skin lesions only on his lumbar region, another had facial lesions, and our patient had lesions on her neck. Seven of the 10 patients had comorbid medical disorders, including hypertension, migraines, psoriatic erythroderma, psoriasis, seizures, gastric cancer in remission, pseudotumor cerebri, osteoporosis, and hepatitis C. Only hepatitis C was comorbid with more than one DPLM patient.17,20 This may be a coincidence because one patient developed DPLM after contracting hepatitis C,20, while the other patient developed it before contracting hepatitis C.17 Psychiatric illness was limited to depression and was found in 2 cases.20,21 No DPLM cases progressed to scleromyxedema, and none have been reported in the literature.5,6 DPLM rarely resolves on its own. Spontaneous resolution did not occur in any of the 10 reported DPLM cases, and only 2 patients were treated successfully. In Reynolds et al,18 the patient responded to therapy with intralesional corticosteroid injections and flurandrenolide-impregnated tape. In Kaymen et al,19 a patient was treated with a CO2 laser and postoperative intralesional corticosteroid injections. There was no growth after one year. All the other DPLM cases did not have effective therapy, lacked specific details of improvement, or did not report this information.2,7-9,17,20,21 Only Tay and Khoo,8 Enerback and Mobacken,9 and Kaymen et al19 commented on which therapies failed (oral thyroxine, topical corticosteroids, and shave excision, respectively). Our patient complained of persistent itching that did not respond to initial treatment with topical steroids and antihistamine medications. She later received pruritic relief with pimecrolimus cream therapy. However, the skin lesions remained. To our knowledge, this is the first report of pimecrolimus therapy in the treatment of pruritis secondary to DPLM. It is difficult to treat a rare disease such as DPLM when the pathogenesis is unknown, and many treatments have failed. Fortunately, DPLM and the other localized forms of LM are usually self-limited to the skin and have very little or no morbidity, leading some experts to believe that the disorder is unnecessary to treat.6 We believe that treatment is sometimes helpful. In our patient, the DPLM lesions were pruritic and located at a cosmetic area of the neck. The patient and dermatology staff decided to pursue a treatment plan. Therefore, even though localized LM lesions are typically benign, sometimes it is beneficial to treat them, especially if they cause irritating symptoms or cosmetic issues. 

Conclusion

DPLM is a rare variant of localized LM. DPLM can be diagnosed by a thorough history and physical examination; histologic proof of dermal mucin deposits; and ruling out other diseases with laboratory tests for serum protein, thyroid function, and, if the patient is at risk of diabetes mellitus, blood glucose levels. DPLM is a self-limited skin disease, and prognosis is generally good, but it typically persists long-term and may slowly progress. Treatment is usually unnecessary, but it may be recommended if the lesions are symptomatic or cause cosmetic issues. Unfortunately, few treatment plans have been shown to successfully treat DPLM.