3.1.1. Giant CCA
The giant variety was the first deviation from the conventional form of CCA, reported in 1966 by Duperrat et al. [6
]. This lesion was twice the size of the largest lesion described until that point and measured 45 × 40 mm. Since then, the “giant” variant has been arbitrarily considered to be any CCA greater than 30 to 40 mm regardless of its morphologic appearance. The largest lesion was described by Grossin et al. [10
], which measured around 70 mm. The giant form can be solitary or multiple [11
] and can be exophytic [13
], plaque-like [14
], polypoid [15
] and cerebriform [16
]. The case of Arida et al. [15
] also showed a central endophytic component resembling keratoacanthoma, however, there was no significant cytologic atypia and therefore cannot be assigned to the atypical variant category.
3.1.2. Mucosal CCA
] described a CCA on the vermilion mucosa of the lower lip that was clinically thought to be leukoplakia. Two other cases from the lip area were reported earlier, but both were on the skin of the lip. There is only one other report of a mucosal variant, which was also pigmented [18
]. However, a similar phenomenon, known as glycogen acanthosis (GA), has been described in the esophagus, mouth and upper respiratory tract [19
]. Like the case of Weitzner, lesions on the tongue and larynx have also been reported to present as leukoplakia [19
]. These lesions show pale glycogen-containing keratinocytes without the involvement of the basal layer, analogous to cutaneous CCA. In the esophagus, these lesions are incidental findings and are often mistaken for a plaque of candidiasis. In Cowden syndrome, extensive involvement of the esophagus with GA is noted. Interestingly, a recent article has documented the association of Cowden syndrome and multiple CCAs [21
]. Turnbull et al. [22
] also noted CCA in one of the two sisters they reported with Cowden syndrome.
3.1.5. Atypical CCA
Clear cell acanthoma is a benign neoplasm or a reactive condition depending on the etiologic postulation. However, both benign neoplastic and reactive conditions have the biologic potential to progress to dysplasia or cancer. Grunwald et al. [32
] first reported two cases of CCA with cellular atypia and increased mitotic activity; although malignant degeneration was earlier suspected in two of over 100 cases reviewed by Degos and Civatte. Zak and Girerd [33
] reported one, and Degos referenced the other unpublished case. In both these cases, some of the rete ridges showed complex downward proliferation into the dermis associated with some dyskeratosis in Degos’s case. Parsons and Ratz [34
] reported squamous cell carcinoma in situ arising in CCA. Recently, Lin et al. [35
] described a case similar to those of Grunwald’s but preferred to call it malignant clear cell acanthoma.
Shirai et al. [36
] reported multiple CCA and multiple Bowen’s disease (BD) in a Japanese patient who had a questionable history of arsenic exposure. Although it was postulated by the authors that CCA may have progressed to BD due to the patient’s possible arsenic exposure, it appears that none of their CCAs had any atypical or dysplastic features. In their paper, they also referenced another case [37
] from the Japanese literature, where CCA from the cheek showed bowenoid transformation.
The above-described cases appear to be incidental and do not warrant labeling CCA a premalignant condition.
3.1.6. Pigmented CCA
The pigmented variant was first reported in the Spanish literature by Sanchez and Iglesias in 1975 [38
], while Langer et al. described the first reported case in the English literature [39
]. CCA is typically a hypomelanotic or amelanotic lesion due to a disturbance in melanin transfer from melanocytes to keratinocytes [39
]. Hollmann and Civatte [40
], upon electron microscopy, found intact melanocytes within CCA lacking in “melanin grains.” Later, in 1990, Fanti et al. [41
] also confirmed the presence of melanocytes within CCA. Several other pigmented variants [42
] have been reported, including one by Bugatti and Filosa [42
] which showed hemosiderin in the dermis and called it “hemosiderotic clear cell acanthoma”. Pigmented CCA has also been reported on the lower lip mucosa [18
] and on a finger which clinically resembled a melanocytic nevus [44
]. Multiple pigmented CCAs have also been reported in an African patient [45
It appears that, for CCA to be pigmented, melanocytic hyperplasia, with associated melanin-laden dendrites, is needed. Melanin transfer to keratinocytes is impeded possibly due to the latter being distended with glycogen, causing pressure blockage and resulting in the accumulation of melanin in melanocytic dendrites; however, the mechanism of melanin transfer from melanocytes to keratinocytes is more complex and the exact cause of impeded transfer in CCA is not known.
In contrast to healthy skin or pigmented seborrheic keratoses, pigmentation of the surface in pigmented CCA is not imparted by keratinocyte melanization but follows the pattern of melanocytic lesions.
3.1.7. Eruptive CCA
As discussed, CCA can be solitary or multiple, however, in some instances, the number of lesions ranges from a few lesions to a few hundred lesions. In such cases, the term “eruptive” has been applied by the authors. Several cases of the eruptive variant have been reported [46
]. The first of such cases was reported by Burg et al. [46
] as eruptive hamartomatous CCA in a 38-year-old female with over 100 lesions on her legs, arms, and trunk. Innocenzi et al. [47
] found approximately 400 papules of CCA in a 32-year-old female on the upper and lower extremities and reported it as “disseminated eruptive type”. Garcia-Gavin et al. [50
] defined the eruptive variant as having more than 30 lesions. Their case was unique in having a rapid onset within less than a month. Some of their cases regressed, leaving hyperpigmentation, which is interesting since CCA is typically hypo- or amelanotic compared to the adjacent healthy skin and allows for the speculation that some of these lesions may have been pigmented.
3.1.11. Trichilemmal CCA
The lesion described in our first case report demonstrates features of CCA including psoriasiform acanthosis, pale keratinocytes, PAS positivity, a diastase-labile staining pattern and sharp demarcation from the adjacent uninvolved epidermis. However, it differs from CCA in having no neutrophil exocytosis. Furthermore, in addition to pale cytoplasm, large clear perinuclear vacuoles were noted, reminiscent of outer sheath keratinocytes and keratinocytes of trichilemmoma. Peripheral palisading of basal keratinocytes was also identified.
One may argue that this case is merely a trichilemmoma which was also incidentally first described in 1962. Keratinocytes in trichilemmoma similarly contain cytoplasmic glycogen, and hence the demarcation between lesional and normal epidermis is also noted. The clinical and histological findings in our case, however, are not those of an exo-endophytic folliculocentric lesion located on the face. This lesion is a horizontally oriented papule on the neck, unlike trichilemmoma, which is vertically oriented. Thick eosinophilic basement membrane typical of trichilemmoma is also not seen in our case. Sharp demarcation accentuated by PAS staining in our case is tinctorial, similar to that seen in CCA. The demarcation in trichilemmoma is both tinctorial and architectural in the form of epithelial collarettes. We considered calling this lesion a “trichilemmal acanthoma”, however, due to the findings mentioned above, we prefer to document this case as a trichilemmal variant of CCA.
In the discussion of CCA versus trichilemmoma, an argument regarding the nomenclature of CCA is brought to light which is also reflected in the literature, which is whether to call these lesions “pale cell” or “clear cell” acanthoma. Keratinocyte cytoplasm in trichilemmoma is typically clear, while it is pale in keratinocytes of CCA. Perhaps the more appropriate term for CCA is pale cell acanthoma; however, this is not the objective of this paper. Another interesting fact is that CCA and GA, like trichilemmomas, are also reported to be associated with Cowden syndrome. Since all three of these lesions show cytoplasmic glycogen accumulation, there may be a disturbance of glycogen metabolisms in keratinocytes in patients with Cowden syndrome.
Based on immunohistochemical findings, Hashimoto et al. [53
] have suggested the outer root sheath derivation of CCA. However, this has not been the predominant thought of other authors. Zedek et al. [54
] reviewed fourteen CCAs, ten trichilemmomas and seven cases of psoriasis using conventional microscopy, PAS and immunohistochemistry and found that, immunohistochemically, CCA resembled psoriasis and not trichilemmoma. In our case, the CD34 stain was entirely negative while brightly highlighting the adjacent papillary vessels.
Dermoscopic examination in our case was not performed. Dermoscopy in CCA reveals a “string of pearls” appearance, dotted vessels arranged linearly in circular pattern [55
] (Figure 9
). This appearance, however, is not characteristic of CCA and can be seen in Bowen’s disease [56