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Progesterone receptor-positive eruptive syringoma associated with diabetes
Progesterone receptor–positive eruptive syringoma associated with diabetes Penelope C. Timpanidis, Sunil R. Lakhani, and Richard W. Groves London, United Kingdom Syringoma is a benign eccrine tumor that generally forms asymptomatic papules on facial skin. Eruptive forms of the tumor are uncommon and of uncertain cause. We report a case in which eruptive syringoma with clear cell morphology was found to express progesterone receptors, suggesting the possibility of hormonal control of the tumor. (J Am Acad Dermatol 2003;48:S103-4.)
S
yringoma is a common benign eccrine gland neoplasm that generally forms small asymptomatic papules on the eyelids, particularly in women, but widespread (eruptive) variants have been described.1 Histologically, syringomas recapitulate the intraepidermal portion of the eccrine duct and are characterized by the presence of ductal elements in the dermis composed of cuboidal cells with a moderate amount of eosinophilic cytoplasm. In a few patients, a distinct cytologic variant
This supplement is made possible through an unrestricted educational grant from Stiefel Laboratories to the American Academy of Dermatology. From the Department of Dermatology, University College London Hospitals Trust. Reprint requests: Richard W. Groves, University College London Center for Dermatology, Seventh Floor, Jules Thorn Bldg, Middlesex Hospital, Mortimer Street, London, W1T 3AA UK. Copyright © 2003 by the American Academy of Dermatology, Inc. 0190-9622/2003/$30.00 ⫹ 0 doi:10.1067/mjd.2003.159
occurs in which there is glycogen deposition within the ductal cells resulting in a pale or clear cytoplasm.2 These clear cell syringomas are clinically indistinguishable from common syringomas but are frequently seen in association with diabetes mellitus.3 The combination of eruptive and clear cell syringoma is uncommon and only 2 such cases have previously been reported. We report a case of eruptive generalized syringoma, with significant clear cell component, in a male patient of Asian descent and demonstrate expression of progesterone receptors (PR) by the tumor, suggesting the possibility of hormonal control of its development.
CASE REPORT A 55-year-old man from Pakistan presented with a longstanding hyperpigmented eruption on his face, arms, and trunk. The eruption had appeared approximately 10 years earlier and had recently become mildly pruritic. A variety of topical medications had been prescribed including antifungals and topical steroids, but these had been of no benefit. He reported a 20-year history of well-controlled mature-onset diabetes mellitus but had
Fig 1. Numerous skin- to tan-colored papules were present on arms, legs, chest, and face. A, General view of forearm. B, Close-up of lesions demonstrates numerous dermal papules.
S103
S104 Timpanidis, Lakhani, and Groves
J AM ACAD DERMATOL MAY 2003
Fig 2. Low-power examination demonstrates strands of epithelial cells and ductular structures in characteristic tadpole configuration of syringoma. Fig 3. High-power examination demonstrates presence of many clear and vacuolated cells in ductular portion of tumor (arrows).
otherwise previously been well. There was a family history of mature-onset diabetes mellitus and hypertension but not of any skin disease. His only medication was gliclazide (10 mg/d). On examination the eruption consisted of numerous skincolored or brownish papules, 1 to 3 mm in dimater, distributed over the face, chest, back, and arms (Fig 1). There were a few lesions on the proximal thighs. In places, the lesions had coalesced to form plaques 0.5 to 1 cm in diameter. General skin examination revealed no other significant skin lesions and systemic examination was unremarkable. Routine blood investigations revealed a fasting blood sugar of 9.3 mmol/L, but full blood cell count and serum biochemistry produced normal findings. Autoimmune screening revealed a weakly positive antinuclear antibody (1:10). PR (2 nmol/L) and testosterone (18.5 nmol/L) levels were within normal limits. A skin biopsy specimen taken from a typical lesion on the forearm demonstrated numerous ductal structures within a distinct stroma in the dermis, many of which had the characteristic tadpole configuration of a syringoma (Fig 2). High-power examination (Fig 3) demonstrated two cell types within the tumor: small cuboidal cells, typical of ductular epithelium with eccentrically placed nuclei, and a distinct second population with clear, vacuolated cytoplasm. Some ducts contained amorphous secretions within the lumen. Many tumor cells had abundant periodic acid–Schiff positive cytoplasm, strongly suggesting accumulation of glycogen. Because of previous data suggesting hormonal control of syringomas,4 immunohistochemical analysis of estrogen (ER) and PR receptor status was carried out. Using ID5 (antihuman ER receptor, Dako Ltd, High Wickham, UK) and NCL-PGR (antihuman PR receptor, Novocastra Laboratories, UK) as primary antibodies in a standard streptavidin-biotin immunostaining reaction, each receptor was visualized in situ. Appropriate positive and negative controls were included in each staining run. These studies demonstrated that tumor cells were negative for ER and strongly positive for PR.
DISCUSSION Syringomas are adenomas of the acrosyringium, the intraepidermal portion of the eccrine sweat duct.5 Their onset is typically around puberty and the lesions are generally limited to facial skin. Occasionally, however, generalized eruptive syringomas develop in a more widespread distribution. This can occur either as an isolated event or in association with other systemic disease, most notably diabetes mellitus6 or Down syndrome.7 Headington et al5 first described the clear cell variant of syrin-
goma in 1972. Clinically, clear cell syringomas are indistinguishable from the common variant. Electron microscopic and histochemical studies have demonstrated that whereas ordinary syringomas have small amounts of intracellular glycogen deposition, clear cell syringomas are filled with glycogen and have numerous multivesicular bodies. Thus, the tumors are periodic acid–Schiff positive, and diastase renders all but periluminal cells colorless.2 The reason for glycogen accumulation is unclear, though a deficiency or decreased activity of phosphorylase has been suggested.1 Many cases have been reported in Japan, where there appears to be a striking association with diabetes mellitus. According to Hitoshi and Ikuo,6 the association with diabetes mellitus is a unique feature of clear cell syringoma. The definition of clear cell syringoma is problematic and is probably quantitative rather than qualitative.2 Although some tumors are composed entirely of clear cells, many have an intermediate morphology. Our case falls into the latter group, but the eruptive nature of the lesions and the association with diabetes mellitus suggests that biologically this case falls together with those previously described as eruptive clear cell syringomas. The frequent onset of syringomas at or around puberty4 together with an increased frequency in women has led to the suggestion that they may be hormonally controlled. Recent work has shown that many syringomas express PR, although they are rarely ER-receptor positive. We believe that the demonstration of PR-positive receptors in our case strengthens the hypothesis that hormonal control may be important in the pathogenesis of eruptive syringoma. REFERENCES 1. Saitoh A, Ohtake A, Fukuda S, Tamaki K. Clear cells of eccrine glands in a patient with clear cell syringoma associated with diabetes mellitus. Am J Dermatopathol 1993;15:166-8. 2. Feibelman CE, Maize J. Clear cell syringoma: a study by conventional and electron microscopy. Am J Dermatopathol 1984;6:139-50. 3. Furue M, Hori Y, Nakabayashi Y. Clear cell syringoma; association with diabetes mellitus. Am J Dermatopathol 1984;6:131-8. 4. Wallace ML, Smoller BR. Progesterone receptor positivity supports hormonal control of syringomas. J Cutan Pathol 1995;22:442-5. 5. Headington JT, Koski J, Murphy PJ. Clear cell glycogenosis in multiple syringomas. Arch Dermatol 1972;106:353. 6. Hitoshi K, Ikuo Y. Generalized eruptive clear-cell syringoma. Arch Dermatol 1989;125:1716-7. 7. Rhodes L, Verbov J. Widespread syringomata in Downs syndrome. Clin Exp Dermatol 1993;18:333-4.
S
yringoma is a common benign eccrine gland neoplasm that generally forms small asymptomatic papules on the eyelids, particularly in women, but widespread (eruptive) variants have been described.1 Histologically, syringomas recapitulate the intraepidermal portion of the eccrine duct and are characterized by the presence of ductal elements in the dermis composed of cuboidal cells with a moderate amount of eosinophilic cytoplasm. In a few patients, a distinct cytologic variant
This supplement is made possible through an unrestricted educational grant from Stiefel Laboratories to the American Academy of Dermatology. From the Department of Dermatology, University College London Hospitals Trust. Reprint requests: Richard W. Groves, University College London Center for Dermatology, Seventh Floor, Jules Thorn Bldg, Middlesex Hospital, Mortimer Street, London, W1T 3AA UK. Copyright © 2003 by the American Academy of Dermatology, Inc. 0190-9622/2003/$30.00 ⫹ 0 doi:10.1067/mjd.2003.159
occurs in which there is glycogen deposition within the ductal cells resulting in a pale or clear cytoplasm.2 These clear cell syringomas are clinically indistinguishable from common syringomas but are frequently seen in association with diabetes mellitus.3 The combination of eruptive and clear cell syringoma is uncommon and only 2 such cases have previously been reported. We report a case of eruptive generalized syringoma, with significant clear cell component, in a male patient of Asian descent and demonstrate expression of progesterone receptors (PR) by the tumor, suggesting the possibility of hormonal control of its development.
CASE REPORT A 55-year-old man from Pakistan presented with a longstanding hyperpigmented eruption on his face, arms, and trunk. The eruption had appeared approximately 10 years earlier and had recently become mildly pruritic. A variety of topical medications had been prescribed including antifungals and topical steroids, but these had been of no benefit. He reported a 20-year history of well-controlled mature-onset diabetes mellitus but had
Fig 1. Numerous skin- to tan-colored papules were present on arms, legs, chest, and face. A, General view of forearm. B, Close-up of lesions demonstrates numerous dermal papules.
S103
S104 Timpanidis, Lakhani, and Groves
J AM ACAD DERMATOL MAY 2003
Fig 2. Low-power examination demonstrates strands of epithelial cells and ductular structures in characteristic tadpole configuration of syringoma. Fig 3. High-power examination demonstrates presence of many clear and vacuolated cells in ductular portion of tumor (arrows).
otherwise previously been well. There was a family history of mature-onset diabetes mellitus and hypertension but not of any skin disease. His only medication was gliclazide (10 mg/d). On examination the eruption consisted of numerous skincolored or brownish papules, 1 to 3 mm in dimater, distributed over the face, chest, back, and arms (Fig 1). There were a few lesions on the proximal thighs. In places, the lesions had coalesced to form plaques 0.5 to 1 cm in diameter. General skin examination revealed no other significant skin lesions and systemic examination was unremarkable. Routine blood investigations revealed a fasting blood sugar of 9.3 mmol/L, but full blood cell count and serum biochemistry produced normal findings. Autoimmune screening revealed a weakly positive antinuclear antibody (1:10). PR (2 nmol/L) and testosterone (18.5 nmol/L) levels were within normal limits. A skin biopsy specimen taken from a typical lesion on the forearm demonstrated numerous ductal structures within a distinct stroma in the dermis, many of which had the characteristic tadpole configuration of a syringoma (Fig 2). High-power examination (Fig 3) demonstrated two cell types within the tumor: small cuboidal cells, typical of ductular epithelium with eccentrically placed nuclei, and a distinct second population with clear, vacuolated cytoplasm. Some ducts contained amorphous secretions within the lumen. Many tumor cells had abundant periodic acid–Schiff positive cytoplasm, strongly suggesting accumulation of glycogen. Because of previous data suggesting hormonal control of syringomas,4 immunohistochemical analysis of estrogen (ER) and PR receptor status was carried out. Using ID5 (antihuman ER receptor, Dako Ltd, High Wickham, UK) and NCL-PGR (antihuman PR receptor, Novocastra Laboratories, UK) as primary antibodies in a standard streptavidin-biotin immunostaining reaction, each receptor was visualized in situ. Appropriate positive and negative controls were included in each staining run. These studies demonstrated that tumor cells were negative for ER and strongly positive for PR.
DISCUSSION Syringomas are adenomas of the acrosyringium, the intraepidermal portion of the eccrine sweat duct.5 Their onset is typically around puberty and the lesions are generally limited to facial skin. Occasionally, however, generalized eruptive syringomas develop in a more widespread distribution. This can occur either as an isolated event or in association with other systemic disease, most notably diabetes mellitus6 or Down syndrome.7 Headington et al5 first described the clear cell variant of syrin-
goma in 1972. Clinically, clear cell syringomas are indistinguishable from the common variant. Electron microscopic and histochemical studies have demonstrated that whereas ordinary syringomas have small amounts of intracellular glycogen deposition, clear cell syringomas are filled with glycogen and have numerous multivesicular bodies. Thus, the tumors are periodic acid–Schiff positive, and diastase renders all but periluminal cells colorless.2 The reason for glycogen accumulation is unclear, though a deficiency or decreased activity of phosphorylase has been suggested.1 Many cases have been reported in Japan, where there appears to be a striking association with diabetes mellitus. According to Hitoshi and Ikuo,6 the association with diabetes mellitus is a unique feature of clear cell syringoma. The definition of clear cell syringoma is problematic and is probably quantitative rather than qualitative.2 Although some tumors are composed entirely of clear cells, many have an intermediate morphology. Our case falls into the latter group, but the eruptive nature of the lesions and the association with diabetes mellitus suggests that biologically this case falls together with those previously described as eruptive clear cell syringomas. The frequent onset of syringomas at or around puberty4 together with an increased frequency in women has led to the suggestion that they may be hormonally controlled. Recent work has shown that many syringomas express PR, although they are rarely ER-receptor positive. We believe that the demonstration of PR-positive receptors in our case strengthens the hypothesis that hormonal control may be important in the pathogenesis of eruptive syringoma. REFERENCES 1. Saitoh A, Ohtake A, Fukuda S, Tamaki K. Clear cells of eccrine glands in a patient with clear cell syringoma associated with diabetes mellitus. Am J Dermatopathol 1993;15:166-8. 2. Feibelman CE, Maize J. Clear cell syringoma: a study by conventional and electron microscopy. Am J Dermatopathol 1984;6:139-50. 3. Furue M, Hori Y, Nakabayashi Y. Clear cell syringoma; association with diabetes mellitus. Am J Dermatopathol 1984;6:131-8. 4. Wallace ML, Smoller BR. Progesterone receptor positivity supports hormonal control of syringomas. J Cutan Pathol 1995;22:442-5. 5. Headington JT, Koski J, Murphy PJ. Clear cell glycogenosis in multiple syringomas. Arch Dermatol 1972;106:353. 6. Hitoshi K, Ikuo Y. Generalized eruptive clear-cell syringoma. Arch Dermatol 1989;125:1716-7. 7. Rhodes L, Verbov J. Widespread syringomata in Downs syndrome. Clin Exp Dermatol 1993;18:333-4.