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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Case report
  5. Pathogenesis and aetiology
  6. Clinical presentation and variants
  7. Histopathological and immunohistochemical characteristics
  8. Differential diagnosis
  9. Treatment
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

Clear cell acanthoma (CCA), is an asymptomatic benign lesion of unknown origin and aetiology, which typically presents as a red to brown, dome-shaped papule on the leg. We discuss the case of a patient with an irregular plaque of hypopigmented papules whose diagnosis of CCA was only made by biopsy, and review the characteristic presentation, uncommon variants, locations and associated conditions of this lesion. The diagnosis is based on histopathology and/or immunohistochemistry, but the variable clinical presentation may make diagnosis difficult. The differential diagnosis includes skin tumours and inflammatory and pigmentary dermatoses. The lesions do not regress spontaneously, and excisional removal is the preferred treatment.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Case report
  5. Pathogenesis and aetiology
  6. Clinical presentation and variants
  7. Histopathological and immunohistochemical characteristics
  8. Differential diagnosis
  9. Treatment
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

Clear cell acanthoma (CCA) is a benign epidermal lesion of epidermal keratinocytes, first described by Degos et al.1 and is also known as ‘Degos acanthoma’ or as ‘pale acanthoma’, which describes the characteristic histopathological hallmark.

The typical CCA is a red to brown, dome-shaped, solitary papule or nodule, ranging in size from 3 to 20 mm (Fig. 1). It grows slowly, commonly over a period of 2–10 years, and is often covered by a thin collarette of scale. Most lesions are asymptomatic. Fine and Chernosky described CCA as a ‘clinical hybrid’ with a ‘stuck-on’ appearance. The surface is either crusted or moist, and often contains vascular puncta, which bleed on minor trauma.2 The lesions usually present on the legs in middle-aged to elderly adults, and there is no gender predilection.2–5

image

Figure 1.  Clear cell acanthoma on the leg of an adult male. Used with permission from http://www.visualdx.com© Logicsal Images, Inc.

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Case report

  1. Top of page
  2. Summary
  3. Introduction
  4. Case report
  5. Pathogenesis and aetiology
  6. Clinical presentation and variants
  7. Histopathological and immunohistochemical characteristics
  8. Differential diagnosis
  9. Treatment
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

A 4-year-old African-American boy presented with asymptomatic hypopigmented papules on his left flank, which had been present for some years, but not from birth. During this time, the papules had not changed in size, shape or colour, and had never bled. There was no family history of pigmented skin changes or malignant melanoma.

On physical examination, a number of hypopigmented papules were seen, which coalesced to form a horizontal, linear plaque, 47 × 7 mm in size. Mild blanching was noted on compression. There was no vesiculation, scaling or crusting (Fig. 2). The differential diagnosis included epidermal naevus, lichen striatus, lymphangioma circumscriptum, connective tissue naevus, and other appendegeal tumours.

image

Figure 2.  Our patient a 4 year black male with linear collection of persistent hypopigmented papules on the flank.

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On histological examination of a skin biopsy taken from a lesion, epidermal acanthosis was seen, with proliferation of clear cells containing intracytoplasmic glycogen (Fig. 3). Periodic-acid–Schiff (PAS) staining was positive, and the lesion was also positive for glycogen and diastase. Tests for human papillomavirus and gross cystic disease fluid protein 15 gave negative results.

image

Figure 3.  H & E shows epidermal acanthosis with proliferation of clear cells with introcytoplasmic glycogen. PAS was positive.

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Pathogenesis and aetiology

  1. Top of page
  2. Summary
  3. Introduction
  4. Case report
  5. Pathogenesis and aetiology
  6. Clinical presentation and variants
  7. Histopathological and immunohistochemical characteristics
  8. Differential diagnosis
  9. Treatment
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

The exact pathogenesis of CCA is not understood. It was originally thought to be a benign epidermal tumour, but a more recent hypothesis, suggests that CCA is a reactive inflammatory dermatosis.6 However, it remains unclear whether CCA is a benign tumour or an inflammatory disease.7,8

The concept that CCA could be a benign tumour has been a subject of debate, because of the unclear origins of the tumour. Proposed sites of origin include the epidermis,3,9,10 hair follicles,11 and the acrosyringium/sweat gland.12–14

Ohmishi et al. proposed that CCA is a localized form of inflammatory dermatosis because it has the immunohistochemical characteristics of cytokeratin expression. These same cytokeratin findings are seen in psoriasis, lichen planus and discoid lupus erythematosus.15 Zedek et al.16 confirmed that the immunohistochemistry staining of CCA is similar to the chronic inflammation pattern seen in psoriasis. The occurrence of CCA on top of pre-existing active plaque type psoriasis has been reported, and also supports this hypothesis.17

Other reported associated conditions include varicose veins,18,19 stasis dermatitis,16 seborrhoeic keratosis (SK),20 bacterial dermatitis,16 viral infection,21 ichthyosis,22,23 xerosis,18 atopic dermatitis (AD)6 and insect-bite reactions.16

Further evidence that CCA might be an inflammatory dermatosis includes it clinical presentation,6,24 histopathology of the inflammatory process,16,21,25 and immunohistochemical,17 and dermatoscopical26,27 findings. However, there is a report of CCA as an incidental finding in the wider context of other epidermal histological reaction patterns, such as junctional melanocytic naevus and malignant melanoma.28

Clinical presentation and variants

  1. Top of page
  2. Summary
  3. Introduction
  4. Case report
  5. Pathogenesis and aetiology
  6. Clinical presentation and variants
  7. Histopathological and immunohistochemical characteristics
  8. Differential diagnosis
  9. Treatment
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

The clinical presentations of CCA vary. The differential diagnosis depends on the clinical type of CCA seen in a given patient.5 CCA can be categorized depending on the number of lesions (solitary to multiple). There are many variants of CCA including giant, polypoid/pedunculated, pigmented, eruptive, atypical and cystic patterns (Table 1).

Table 1. Clear cell acanthoma presentations and variants.
Clear cell acanthoma
PresentationsSolitary
Multiple
VariantsGiant
Polypoid/Pedunculated
Pigmented
Eruptive
Atypical
Cystic

Giant clear cell acanthoma

The diameter of CCA is generally reported as 3–20 mm in size but the giant type measures > 40 mm. There are only five reports of giant CCA in the English literature,7,21,29–31 which have been reported on the foot,29 buttock7,30 and perineum,21 and varied in size from 40 to 60 mm. Murphy et al.7 reported one case of giant CCA in a psoriasis plaque on the buttock. The location on top of a psoriatic plaque is unusual. Kim et al.21 reported one case of recurrent giant CCA along a primary excision site.

Polypoid clear cell acanthoma

Polypoid or pedunculated CCA was first reported in 1990 by Petzelbauer et al,32 and currently, there only nine cases have been reported in the English literature.6,9,32–37 The lesions have varied in size from 4 to 30 mm, and have been reported on the thigh,33 popliteal fossa9,32 and lower leg,34 with more unusual locations being the scalp,35 neck,36 nipple6 and scrotum.37

Park et al.6 reported a solitary polypoid nodule CCA on the nipple, and proposed that CCA should be included in the clinical differential diagnosis of polypoid lesions of the nipple. These authors also reviewed the five reported cases of CCA occurring on the nipple in Korean patients. Polypoid nipple lesions have not been reported in white populations. The incidence of nipple eczema in is higher in Korean patients with AD (6.2%) aged > 12 years, compared with those in western countries, which supports the theory that inflammatory dermatosis can cause CCA.6

Yang et al.36 reported a CCA with unusual conditions and location, on top of a pre-existing melanocytic naevus on the neck.

Pigmented clear cell acanthoma

In 1990, Fanti et al. reported the presence of melanocytes within the CCA, confirmed by silver stain in 11 cases. This phenomenon was named as ‘melanoacanthoma’,38 or ‘clear cell melanoacanthoma’ by Pierard.39 The term ‘pigmented CCA’ was proposed by Langer et al.40; they reported an increased number of melanocytes and higher levels of melanin under light microscopy, in contrast to the decrease or lack of melanin pigment found in typical CCA lesions.

Dendritic melanocytes containing large amounts of melanin in lesional keratinocytes have been identified by Masson–Fontana silver and S-100 protein stains.40 This variant is typically presented with brown-pigmented papules which should be considered in the differential diagnosis of other pigmentary lesions and skin tumours.

Eruptive clear cell acanthoma

Eruptive CCA or ‘eruptive hamartomatous CCA’ is a term that has been used in cases where there are multiple CCAs (usually > 20–30 lesions).10,41 To date, > 25 cases have been reported.42,43 The typical presentation is that of multiple lesions, from 1 to 10 mm in diameter, which slowly increase in number over a year.41 The legs are a common location for this variant,10,41,42,44 as well as for typical CCA.5 Eruptive CCA has also been reported on the arms and trunk.10,42

Atypical clear cell acanthoma

Although CCA has been considered to have a benign course, there are two reports indicating a malignant potential.45,46 Grunwald et al.45 reported two cases of ‘atypical CCA’ in 1991 with marked cellular atypia and mitotic figures, and Parsons et al.46 reported a case of squamous cell carcinoma in situ arising within a CCA lesion. In the original article by Degos et al., they speculated that the malignant potential might be due to degenerative proliferative changes.3

Cystic clear cell acanthoma

There is only one report of this variant in the English literature. Hamaguchi et al.47 reported a case of cystic CCA in the suprapubic area of a middle-aged man. On histopathological examination, the lesion was diagnosed as a typical CCA with cystic hair shafts, which was surrounded by a condensed connective-tissue sheath.47

There are a few reports of CCA pre-existing in unusual conditions, e.g. in epidermal naevus,8,48 psoriatic plaque,7,17 melanocytic naevus,36 split-thickness skin graft,49 nipple eczema,6,24,34 urachal duct remnant,50 and healing wounds.51 The precise aetiology of these conditions is still unknown. The presumptive hypothesis of CCA in a split-thickness skin graft is local epidermal injury that results in a defect of metabolic enzymes and/or interferes with glycogen degradation.49 Hsu et al.50 proposed a possible cause for a CCA in an urachal duct remnant, stating that it may arise from a process of inflammation and mild saprophytic infection during the sloughing of the umbilical cord.

Dermatofibromas should be included in the differential diagnosis of CCA. This benign fibrohistiocytic tumour is much more common than CCA, and typically presents as solitary, firm, skin-coloured to pigmented, dome-shaped papules, usually found on the legs. The main clinical feature that differentiates dermatofibromas from other growths is the ‘dimple sign’, which is the apparent downward contracture of skin that occurs when the sides of the lesion are pinched gently. There are many different dermatoscopic patterns of dermatofibromas. Zaballos et al.52 studied 412 dermatofibroma from 292 patients, and found 19 different dermatoscopic patterns. The commonest pattern was a central white patch and a delicate peripheral pigmentary network.52

The histopathological features definitely differentiate between these conditions. Dermatofibroma reveals a nodular dermal proliferation of spindle-shaped fibroblasts, myofibroblasts and/or histiocytes in the reticular dermis. Hyperplasia and hyperpigmentation of the overlying epidermis extend to the subcutaneous tissue in a radial pattern.

The common locations of CCA include the leg, thigh, back, abdomen and chest.5 Uncommon locations include the nipple,6,24 vermilion mucosa of lower lips,53 hallux/toe,54 palm,49 genitalia,21 scrotum,37 suprapubic,47 umbilicus50 and scalp.35

Histopathological and immunohistochemical characteristics

  1. Top of page
  2. Summary
  3. Introduction
  4. Case report
  5. Pathogenesis and aetiology
  6. Clinical presentation and variants
  7. Histopathological and immunohistochemical characteristics
  8. Differential diagnosis
  9. Treatment
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

The histopathological findings are key to the diagnosis of CCA.54,55 The lesion has a well-demarcated psoriasiform acanthosis with pale keratinocytes (clear cells), rich in intracellular glycogen, which stain positively with PAS and can be removed by digestion with diastase. Neutrophilic exocytosis, parakeratotic microabscesses, and dilated blood vessels in the upper dermis may be present.

On histochemical examination, the phosphorylase enzyme that is necessary for degradation of glycogen is found to be absent in the keratinocytes within the CCA lesion.49 Electron microscopy studies reveal glycogen granules in the CCA.19 Dermatoscopy and videodermatoscopy may also be helpful for the diagnosis of CCA.41 The characteristic findings are prominently dilated pinpoint capillary loops (‘bunch of grapes’ appearance),4,26,27 and reticular or linear dermatoscopy patterns have also been reported.27,56

Differential diagnosis

  1. Top of page
  2. Summary
  3. Introduction
  4. Case report
  5. Pathogenesis and aetiology
  6. Clinical presentation and variants
  7. Histopathological and immunohistochemical characteristics
  8. Differential diagnosis
  9. Treatment
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

The clinical differential diagnosis of CCA depends on the clinical presentations and includes AK, actinic keratosis, viral or flat wart, pyogenic granuloma, dermatofibroma, basal cell or squamous cell carcinoma, eccrine poroma, clear cell hidradenoma, and metastatic cancer.33,57

The histopathological differential diagnosis includes clear cell hidradenoma or syringoma, hidroacathoma simplex, large cell acanthoma, and eccrine carcinoma.54

Treatment

  1. Top of page
  2. Summary
  3. Introduction
  4. Case report
  5. Pathogenesis and aetiology
  6. Clinical presentation and variants
  7. Histopathological and immunohistochemical characteristics
  8. Differential diagnosis
  9. Treatment
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

The natural course of CCA is to persist. Garcia-Gavin et al. reported one case where a few of the eruptive CCA spontaneously regressed over a year.41

Treatment options depend on size, location, number of lesions, and the surgical experience of the medical provider. The preferred treatment is lesion removal. Surgical treatments consist of excision, Mohs micrographic surgery, curettage, electrofulguration, cryotherapy and carbon dioxide laser. The last two may be suitable in cases of large, multiple lesions, especially on bony prominences, for which excision is difficult.43,58–60 The number of treatments also varies with the lesion size and number and with the technique used. There are only a few reported cases of recurrence after excision.21,61

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Case report
  5. Pathogenesis and aetiology
  6. Clinical presentation and variants
  7. Histopathological and immunohistochemical characteristics
  8. Differential diagnosis
  9. Treatment
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

We have reviewed the multiple presentations of CCA. The aetiology of CCA, remains unclear and various clinical presentations should be included in the clinical differential diagnosis including other inflammatory and pigmentary lesions and skin tumours. Histopathology and immunohistochemistry are key to diagnosis. Treatment options depend on presentation and patient preference. Clinical monitoring after treatment is prudent, because recurrence and malignant potential have been rarely reported.

Learning points

  1. Top of page
  2. Summary
  3. Introduction
  4. Case report
  5. Pathogenesis and aetiology
  6. Clinical presentation and variants
  7. Histopathological and immunohistochemical characteristics
  8. Differential diagnosis
  9. Treatment
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions
  • CCA is an asymptomatic benign epidermal lesion of unknown origin and aetiology.
  • Typical presentation is a red to brown dome-shaped papules/nodules which varies in number, size, colour, location and associated conditions.
  • The clinical presentation of CCA varies with type and associated conditions.
  • The differential diagnosis includes multiple inflammatory and pigmentary dermatoses and skin tumours.
  • Diagnosis is based on the characteristic histopathological features, including psoriasiform acanthosis, and presence of clear cells that contain intracytoplasmic glycogen.
  • PAS stain is positive, and lesions are glycogen- and diastase-sensitive.
  • The preferred treatment is Excision.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Case report
  5. Pathogenesis and aetiology
  6. Clinical presentation and variants
  7. Histopathological and immunohistochemical characteristics
  8. Differential diagnosis
  9. Treatment
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

CPD questions

  1. Top of page
  2. Summary
  3. Introduction
  4. Case report
  5. Pathogenesis and aetiology
  6. Clinical presentation and variants
  7. Histopathological and immunohistochemical characteristics
  8. Differential diagnosis
  9. Treatment
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

Learning objective

To show up-to-date knowledge of the characteristic histopathology, the clinical varieties, the differential diagnosis and clinical associations of clear cell acanthomas.

Question 1

What is true about clear cell acanthoma?

a) Aetiology is due to a reactive inflammatory dermatosis

b) Histopathology is required for definite diagnosis

c) The most common variant is the cystic type

d) The natural course is spontaneous recovery

e) Recurrence is common

Question 2

Which of the followings is not a characteristically histopathological feature of clear cell acanthoma?

a) Psoriasiform acanthosis

b) Pale keratinocytes

c) Intracellular glycogen

d) Epidermotropism

e) Positive for PAS stain

Question 3

What is (are) the variant type(s) of clear cell acanthoma?

a) Polypoid

b) Pigmented

c) Eruptive

d) Giant

e) All of the above

Question 4

Which of the followings is not included in the differential diagnosis of clear cell acanthoma?

a) Seborrhoeic keratosis

b) Squamous cell carcinoma

c) Dermatitis herpetiformis

d) Pyogenic granuloma

e) Dermatofibroma

Question 5

What is (are) the uncommon associated condition(s) concomitant with clear cell acanthoma?

a) Psoriatic plaque

b) Split-thickness skin graft

c) Wound healing

d) Melanocytic naevus

e) All of the above

Instructions for answering questions

  1. Top of page
  2. Summary
  3. Introduction
  4. Case report
  5. Pathogenesis and aetiology
  6. Clinical presentation and variants
  7. Histopathological and immunohistochemical characteristics
  8. Differential diagnosis
  9. Treatment
  10. Conclusion
  11. Learning points
  12. References
  13. CPD questions
  14. Instructions for answering questions

This learning activity is freely available online at https://www.wileyhealthlearning.com/ced

Users are encouraged to

  •  Read the article in print or online, paying particular attention to the learning points and any author conflict of interest disclosures
  •  Reflect on the article
  •  Register or login online at www.wileyhealthlearning.com/ced and answer the CPD questions
  •  Complete the required evaluation component of the activity

Once the test is passed, you will receive a certificate and the learning activity can be added to your RCP CPD diary as a self-certified entry.