Clear Cell Papulosis

Background

This rare disease occurs almost exclusively in Asian children and is characterized by flat, hypopigmented papules, usually on the lower trunk.

OUTLINE

Epidemiology

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/Immunohistochemistry/Electron Microscopy

Differential Diagnosis

Commonly Used Terms

EPIDEMIOLOGY CHARACTERIZATION

INCIDENCE Rare

AGE RANGE-MEDIAN Children

GEOGRAPHY Predominately Asian children

Clear cell papulosis (pagetoid papulosis) in a non-Asian patient.

Gianotti R, Cambiaghi S, Locatelli A, Gelmetti C.

Institute of Dermatological Sciences, IRCCS Ospedale Maggiore di Milano, University of Milan, Italy.
Dermatology 2001;203(3):260-1 Abstract quote
Clear cell papulosis is a recently described disorder which is characterized by multiple flat, slightly elevated, hypopigmented papules, distributed mainly on the lower part of the trunk of healthy children.

Histologically, the disease shows 'clear cells' with a pagetoid appearance spread among keratinocytes in basal and suprabasal layers of the epidermis. These cells stain for AE1, CEA and EMA, making a relationship to eccrine or apocrine elements likely. All cases reported until now describe Asian children. The first European child with clear cell papulosis is presented.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

GENERAL

Clear cell papulosis of the skin.

Lee JY, Chao SC.

Department of Dermatology, National Cheng-Kung University Hospital, Tainan, Taiwan.
Br J Dermatol 1998 Apr;138(4):678-83 Abstract quote
Clear cell papulosis is a new entity first described in 1987. To date, six patients have been reported: all were young Taiwanese children. The disease is characterized clinically by multiple small, whitish maculopapules distributed along the milk line and by the presence of large, benign pagetoid cells in the epidermis resembling the clear cell of the nipple. The significance of this entity lies in its potential histogenetic link with Paget's disease of the skin.

We report four new Taiwanese patients, three girls and one boy, aged between 21 months and 4 years. Two were sisters. Small hypopigmented macules first appeared on the pubis. They were eventually distributed bilaterally along the milk line but were most numerous in the public area. The disease may easily be overlooked when the macules are tiny or few in number and thus display no clear milk-line distribution, or when they occur in white-skinned individuals. Histologically, solitary large clear cells with large, round pale nuclei were detected in the basal layer of the hypomelaninized epidermis. The numbers of clear cells varied on haematoxylin and eosin staining and were only small in two patients.

The cytoplasm of the clear cells was decorated by antikeratin AE1 and anticarcinoembryonic antigen antibodies. AE1 was the best marker of the clear cell. Some of the AE1-positive cells were tadpole-like in shape and were situated well above the basal layer. Ultrastructurally, large clumps of disintegrated or vacuolated mucin granules were present in the cytoplasm of the clear cells. The melanocytes appeared normal; the suprabasal keratinocytes were essentially devoid of melanosomes. The pathological findings in the present study support the hypothesis that these clear cells are an aberrant derivative of sweat gland cells in the epidermis and are potentially the precursor cells giving rise to mammary and extramammary Paget's disease.

The differential diagnosis includes chicken pox scars, idiopathic guttate hypomelanosis, hypomelanotic tinea versicolor, anetoderma and early, hypopigmented lesions of Paget's disease.

VARIANTS

HISTOLOGICAL TYPES CHARACTERIZATION

GENERAL

Clear cell papulosis of the skin. A new entity with histogenetic implications for cutaneous Paget's disease.

Kuo TT, Chan HL, Hsueh S.

Department of Pathology, Chang Gung Medical College, Taipei, Taiwan, Republic of China.

Am J Surg Pathol 1987 Nov;11(11):827-34 Abstract quote
A new skin condition characterized by multiple white papular eruptions was observed in two young brothers.

Histologic study revealed many benign pagetoid clear cells in the basal layer of the acanthotic epidermis with decreased pigmentation. These cells contained cytoplasmic mucin and were positive for keratin AE1/AE3, carcinoembryonic antigen, and epithelial membrane antigen. The staining pattern was identical to that of extramammary Paget's disease. The presence of mucin granules and cytoplasmic filaments corresponding to AE1/AE3 were confirmed ultrastructurally. Comparative histochemical and immunohistochemical studies with normal eccrine sweat glands, Toker's nipple clear cells, and Paget cells of mammary and extramammary Paget's disease suggest that these clear cells are an aberrant derivative of sweat-gland epithelial cells in the epidermis. AE1/AE3 is an excellent marker for the "clear cells" of both the condition described and the cells in the nipple.

The term "clear cell papulosis" is proposed for this new entity. The clear cell identified provides evidence for the existence of potential precursor cells in the epidermis for cutaneous Paget's disease.

Clear cell papulosis: report of three cases of a newly recognized disease.

Kuo TT, Huang CL, Chan HL, Yang LJ, Chen MJ.

Department of Pathology, Chang Gung Memorial Hospital, Tao Yuan, Taiwan.
J Am Acad Dermatol 1995 Aug;33(2 Pt 1):230-3 Abstract quote
BACKGROUND: Clear cell papulosis is a newly described disease. Since the first report in 1987, no other cases have been reported.

OBJECTIVE: Our purpose was to describe three more newly identified cases that further characterize this disease.

METHODS: Formalin-fixed and paraffin-embedded biopsy specimens were used for histochemical and immunohistochemical studies.

RESULTS: The three patients included two boys and, for the first time, a girl. All three had multiple white papules on the lower part of the abdomen, with or without scattered lesions along the milk lines bilaterally. The main histopathologic finding was the presence of clear cells scattered mainly among the basal cells of the acanthotic epidermis. The clear cells were variably stained by mucicarmine, colloidal iron, alcian blue (pH 2.5), periodic acid-Schiff, the anticytokeratin antibody AE1, carcinoembryonic antigen, epithelial membrane antigen, and gross cystic disease fluid protein-15.

CONCLUSION: Clear cell papulosis is a unique clinicopathologic entity. The clear cells were confirmed to be sweat gland secretory cells by their positive immunostaining with gross cystic disease fluid protein-15. The latter was also present in eccrine sweat gland coil cells. However, whether the clear cells were eccrine or apocrine secretory cells could not be determined.

VARIANTS

SPECIAL STAINS/IMMUNOPEROXIDASE/
OTHER CHARACTERIZATION

SPECIAL STAINS

IMMUNOPEROXIDASE

Clear cell papulosis: an immunohistochemical study to determine histogenesis

You Chan Kim
David A. Mehregan
and Dongsik Bang

J Cutan Pathol 2002;29:11 Abstract quote

Clear cell papulosis is a rarely described disease characterized by multiple white maculopapules. Histopathologically, diagnostic clear cells are seen mainly among the basal cells of the epidermis. The origin of the clear cells has been thought to be eccrine or apocrine secretory cells in the epidermis because of the positive immunostaining with anticytokeratin antibody AE1, carcinoembryonic antigen (CEA), epithelial membrane antigen, and gross cystic disease fluid protein-15. IKH-4 and CEA have been reported to stain the eccrine secretory cells, but not the apocrine secretory cells. On the contrary, lysozyme has been reported to stain apocrine glands, but not eccrine glands. CAM5.2 has been reported to show a positive reaction to staining in secretory cells of eccrine glands, but only occasional weak staining in the inner surface of eccrine ducts.

In our study, the clear cells in the epidermis stained with IKH-4, CEA and CAM5.2, but not with lysozyme. These results suggest that the clear cells may be eccrine secretory cells.

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

EXTRA-MAMMARY PAGET'S DISEASE

Depigmented genital extramammary Paget's disease: a possible histogenetic link to Toker's clear cells and clear cell papulosis.

Chen YH, Wong TW, Lee JY.

Department of Dermatology, National Cheng-Kung University Hospital, Tainan, Taiwan.
J Cutan Pathol 2001 Feb;28(2):105-8 Abstract quote
BACKGROUND: The histogenesis of extramammary Paget's disease (EMPD) is still controversial. Benign pagetoid cells of the nipple first described by Toker and the similar clear cells found in white maculopapules of clear cell papulosis (CCP) have been proposed to be potential precursor cells giving rise to EMPD and primary intraepidermal Paget's disease in the nipple. The observation of a rare case of depigmented EMPD provided us with a chance to examine further the interesting Toker's clear cell/CCP hypothesis.

METHODS: We performed pathologic studies, including Fontana-Masson stain and immunostaining for AE1/AE3 and S100P, on a new case of depigmented EMPD manifesting a 4 x 3 cm hypopigmented-depigmented patch on the root of the penis.

RESULTS: The lesion showed extensive intraepithelial proliferation of atypical pagetoid cells with markedly reduced epidermal melaninization but nearly normal numbers of melanocytes. The tumor cells were strongly positive for AE1/AE3 by immunostaining. Some tumor cells displayed tadpole-like morphology resembling the pagetoid cells of CCP. Such morphology was not observed in two random examples of non-depigmented genital EMPD.

CONCLUSIONS: The findings of tadpole-shaped pagetoid cells and depigmentation in the present case suggest that depigmented EMPD may be histogenetically related to CCP. Depigmented EMPD should be considered in the differential diagnosis of vitiligo, depigmented mycosis fungoides and lichen sclerosus located along the milk line.

PAGETOID DYSKERATOSIS

Pagetoid dyskeratosis of the prepuce. An incidental histologic finding resembling extramammary Paget's disease.

Val-Bernal JF, Garijo MF.

Department of Anatomical Pathology, Marques de Valdecilla University Hospital, Medical Faculty, University of Cantabria, Santander, Spain.

J Cutan Pathol 2000 Sep;27(8):387-91 Abstract quote
BACKGROUND: Pale cells resembling those of paget's disease have been seen as an incidental finding within the epidermis in a variety of benign papules most commonly located in intertriginous areas. This lesion, called pagetoid dyskeratosis, is considered a reactive process in which a small part of the normal population of keratinocytes is induced to proliferate. Among the inductors friction is suspected. As far as we know, these cells have not been reported in the penis.

METHODS: Here we describe the location of the lesion in the foreskin and the incidence of this lesion in a group of 281 unselected patients surgically treated for phimosis. In selected cases histochemical staining and immunohistochemical studies were performed.

RESULTS: Pagetoid dyskeratosis was found in 105 cases (37.4%) but only in 5 cases (1.8%) the lesion was conspicuous. The cells of pagetoid dyskeratosis show an immunohistochemical profile different from the surrounding keratinocytes characterized by premature keratinization. Pagetoid dyskeratosis cells must be distinguished from the artefactual clear cells of the epidermis, from reactive melanocytes, and from pale-cell acanthosis. In cases in which pagetoid dyskeratosis shows a florid expression there is a hazard of overdiagnosis to the patient. The main differential diagnosis includes extramammary Paget's disease, pagetoid squamous cell carcinoma in situ, epidermotropic metastasis, superficial spreading malignant melanoma, clear cell papulosis, and penile koilocytoses.

CONCLUSIONS: The pathologist should be familiar with the histologic features of pagetoid dyskeratosis in the foreskin in order to avoid misdiagnosis and unnecessary treatment. Routine histologic study is usually sufficient to identify the lesion.

Weedon D. Weedon's Skin Pathology. Churchill Livingstone. 1997.
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.

Commonly Used Terms

Hypopigmented lesions of the skin

Skin Rash

Last Updated 3/13/2002

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Copyright � 2002 The Doctor's Doctor

Epidemiology
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Commonly Used Terms

EPIDEMIOLOGY	CHARACTERIZATION
INCIDENCE	Rare
AGE RANGE-MEDIAN	Children
GEOGRAPHY	Predominately Asian children
Clear cell papulosis (pagetoid papulosis) in a non-Asian patient. Gianotti R, Cambiaghi S, Locatelli A, Gelmetti C. Institute of Dermatological Sciences, IRCCS Ospedale Maggiore di Milano, University of Milan, Italy.	Dermatology 2001;203(3):260-1 Abstract quote Clear cell papulosis is a recently described disorder which is characterized by multiple flat, slightly elevated, hypopigmented papules, distributed mainly on the lower part of the trunk of healthy children. Histologically, the disease shows 'clear cells' with a pagetoid appearance spread among keratinocytes in basal and suprabasal layers of the epidermis. These cells stain for AE1, CEA and EMA, making a relationship to eccrine or apocrine elements likely. All cases reported until now describe Asian children. The first European child with clear cell papulosis is presented.

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
Clear cell papulosis of the skin. Lee JY, Chao SC. Department of Dermatology, National Cheng-Kung University Hospital, Tainan, Taiwan.	Br J Dermatol 1998 Apr;138(4):678-83 Abstract quote Clear cell papulosis is a new entity first described in 1987. To date, six patients have been reported: all were young Taiwanese children. The disease is characterized clinically by multiple small, whitish maculopapules distributed along the milk line and by the presence of large, benign pagetoid cells in the epidermis resembling the clear cell of the nipple. The significance of this entity lies in its potential histogenetic link with Paget's disease of the skin. We report four new Taiwanese patients, three girls and one boy, aged between 21 months and 4 years. Two were sisters. Small hypopigmented macules first appeared on the pubis. They were eventually distributed bilaterally along the milk line but were most numerous in the public area. The disease may easily be overlooked when the macules are tiny or few in number and thus display no clear milk-line distribution, or when they occur in white-skinned individuals. Histologically, solitary large clear cells with large, round pale nuclei were detected in the basal layer of the hypomelaninized epidermis. The numbers of clear cells varied on haematoxylin and eosin staining and were only small in two patients. The cytoplasm of the clear cells was decorated by antikeratin AE1 and anticarcinoembryonic antigen antibodies. AE1 was the best marker of the clear cell. Some of the AE1-positive cells were tadpole-like in shape and were situated well above the basal layer. Ultrastructurally, large clumps of disintegrated or vacuolated mucin granules were present in the cytoplasm of the clear cells. The melanocytes appeared normal; the suprabasal keratinocytes were essentially devoid of melanosomes. The pathological findings in the present study support the hypothesis that these clear cells are an aberrant derivative of sweat gland cells in the epidermis and are potentially the precursor cells giving rise to mammary and extramammary Paget's disease. The differential diagnosis includes chicken pox scars, idiopathic guttate hypomelanosis, hypomelanotic tinea versicolor, anetoderma and early, hypopigmented lesions of Paget's disease.
VARIANTS

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
Clear cell papulosis of the skin. A new entity with histogenetic implications for cutaneous Paget's disease. Kuo TT, Chan HL, Hsueh S. Department of Pathology, Chang Gung Medical College, Taipei, Taiwan, Republic of China.	Am J Surg Pathol 1987 Nov;11(11):827-34 Abstract quote A new skin condition characterized by multiple white papular eruptions was observed in two young brothers. Histologic study revealed many benign pagetoid clear cells in the basal layer of the acanthotic epidermis with decreased pigmentation. These cells contained cytoplasmic mucin and were positive for keratin AE1/AE3, carcinoembryonic antigen, and epithelial membrane antigen. The staining pattern was identical to that of extramammary Paget's disease. The presence of mucin granules and cytoplasmic filaments corresponding to AE1/AE3 were confirmed ultrastructurally. Comparative histochemical and immunohistochemical studies with normal eccrine sweat glands, Toker's nipple clear cells, and Paget cells of mammary and extramammary Paget's disease suggest that these clear cells are an aberrant derivative of sweat-gland epithelial cells in the epidermis. AE1/AE3 is an excellent marker for the "clear cells" of both the condition described and the cells in the nipple. The term "clear cell papulosis" is proposed for this new entity. The clear cell identified provides evidence for the existence of potential precursor cells in the epidermis for cutaneous Paget's disease.
Clear cell papulosis: report of three cases of a newly recognized disease. Kuo TT, Huang CL, Chan HL, Yang LJ, Chen MJ. Department of Pathology, Chang Gung Memorial Hospital, Tao Yuan, Taiwan.	J Am Acad Dermatol 1995 Aug;33(2 Pt 1):230-3 Abstract quote BACKGROUND: Clear cell papulosis is a newly described disease. Since the first report in 1987, no other cases have been reported. OBJECTIVE: Our purpose was to describe three more newly identified cases that further characterize this disease. METHODS: Formalin-fixed and paraffin-embedded biopsy specimens were used for histochemical and immunohistochemical studies. RESULTS: The three patients included two boys and, for the first time, a girl. All three had multiple white papules on the lower part of the abdomen, with or without scattered lesions along the milk lines bilaterally. The main histopathologic finding was the presence of clear cells scattered mainly among the basal cells of the acanthotic epidermis. The clear cells were variably stained by mucicarmine, colloidal iron, alcian blue (pH 2.5), periodic acid-Schiff, the anticytokeratin antibody AE1, carcinoembryonic antigen, epithelial membrane antigen, and gross cystic disease fluid protein-15. CONCLUSION: Clear cell papulosis is a unique clinicopathologic entity. The clear cells were confirmed to be sweat gland secretory cells by their positive immunostaining with gross cystic disease fluid protein-15. The latter was also present in eccrine sweat gland coil cells. However, whether the clear cells were eccrine or apocrine secretory cells could not be determined.
VARIANTS

SPECIAL STAINS/IMMUNOPEROXIDASE/ OTHER	CHARACTERIZATION
SPECIAL STAINS
IMMUNOPEROXIDASE
Clear cell papulosis: an immunohistochemical study to determine histogenesis You Chan Kim David A. Mehregan and Dongsik Bang	J Cutan Pathol 2002;29:11 Abstract quote Clear cell papulosis is a rarely described disease characterized by multiple white maculopapules. Histopathologically, diagnostic clear cells are seen mainly among the basal cells of the epidermis. The origin of the clear cells has been thought to be eccrine or apocrine secretory cells in the epidermis because of the positive immunostaining with anticytokeratin antibody AE1, carcinoembryonic antigen (CEA), epithelial membrane antigen, and gross cystic disease fluid protein-15. IKH-4 and CEA have been reported to stain the eccrine secretory cells, but not the apocrine secretory cells. On the contrary, lysozyme has been reported to stain apocrine glands, but not eccrine glands. CAM5.2 has been reported to show a positive reaction to staining in secretory cells of eccrine glands, but only occasional weak staining in the inner surface of eccrine ducts. In our study, the clear cells in the epidermis stained with IKH-4, CEA and CAM5.2, but not with lysozyme. These results suggest that the clear cells may be eccrine secretory cells.

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
EXTRA-MAMMARY PAGET'S DISEASE
Depigmented genital extramammary Paget's disease: a possible histogenetic link to Toker's clear cells and clear cell papulosis. Chen YH, Wong TW, Lee JY. Department of Dermatology, National Cheng-Kung University Hospital, Tainan, Taiwan.	J Cutan Pathol 2001 Feb;28(2):105-8 Abstract quote BACKGROUND: The histogenesis of extramammary Paget's disease (EMPD) is still controversial. Benign pagetoid cells of the nipple first described by Toker and the similar clear cells found in white maculopapules of clear cell papulosis (CCP) have been proposed to be potential precursor cells giving rise to EMPD and primary intraepidermal Paget's disease in the nipple. The observation of a rare case of depigmented EMPD provided us with a chance to examine further the interesting Toker's clear cell/CCP hypothesis. METHODS: We performed pathologic studies, including Fontana-Masson stain and immunostaining for AE1/AE3 and S100P, on a new case of depigmented EMPD manifesting a 4 x 3 cm hypopigmented-depigmented patch on the root of the penis. RESULTS: The lesion showed extensive intraepithelial proliferation of atypical pagetoid cells with markedly reduced epidermal melaninization but nearly normal numbers of melanocytes. The tumor cells were strongly positive for AE1/AE3 by immunostaining. Some tumor cells displayed tadpole-like morphology resembling the pagetoid cells of CCP. Such morphology was not observed in two random examples of non-depigmented genital EMPD. CONCLUSIONS: The findings of tadpole-shaped pagetoid cells and depigmentation in the present case suggest that depigmented EMPD may be histogenetically related to CCP. Depigmented EMPD should be considered in the differential diagnosis of vitiligo, depigmented mycosis fungoides and lichen sclerosus located along the milk line.
PAGETOID DYSKERATOSIS
Pagetoid dyskeratosis of the prepuce. An incidental histologic finding resembling extramammary Paget's disease. Val-Bernal JF, Garijo MF. Department of Anatomical Pathology, Marques de Valdecilla University Hospital, Medical Faculty, University of Cantabria, Santander, Spain.	J Cutan Pathol 2000 Sep;27(8):387-91 Abstract quote BACKGROUND: Pale cells resembling those of paget's disease have been seen as an incidental finding within the epidermis in a variety of benign papules most commonly located in intertriginous areas. This lesion, called pagetoid dyskeratosis, is considered a reactive process in which a small part of the normal population of keratinocytes is induced to proliferate. Among the inductors friction is suspected. As far as we know, these cells have not been reported in the penis. METHODS: Here we describe the location of the lesion in the foreskin and the incidence of this lesion in a group of 281 unselected patients surgically treated for phimosis. In selected cases histochemical staining and immunohistochemical studies were performed. RESULTS: Pagetoid dyskeratosis was found in 105 cases (37.4%) but only in 5 cases (1.8%) the lesion was conspicuous. The cells of pagetoid dyskeratosis show an immunohistochemical profile different from the surrounding keratinocytes characterized by premature keratinization. Pagetoid dyskeratosis cells must be distinguished from the artefactual clear cells of the epidermis, from reactive melanocytes, and from pale-cell acanthosis. In cases in which pagetoid dyskeratosis shows a florid expression there is a hazard of overdiagnosis to the patient. The main differential diagnosis includes extramammary Paget's disease, pagetoid squamous cell carcinoma in situ, epidermotropic metastasis, superficial spreading malignant melanoma, clear cell papulosis, and penile koilocytoses. CONCLUSIONS: The pathologist should be familiar with the histologic features of pagetoid dyskeratosis in the foreskin in order to avoid misdiagnosis and unnecessary treatment. Routine histologic study is usually sufficient to identify the lesion.