doi: 10.1111/1346-8138.12840
Journal of Dermatology 2015; 42: 616–620
CONCISE COMMUNICATION
Sebaceous carcinoma in association with actinic keratosis: A report of two cases with an immunohistochemical study Noriyuki MISAGO, Maki KUWASHIRO, Noriko TSURUTA, Yutaka NARISAWA Division of Dermatology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
ABSTRACT We report two cases of sebaceous carcinoma associated with actinic keratosis (AK) with an immunohistochemical study, which suggests the possibility that sebaceous carcinoma really does develop within AK. Case 1 had sebaceous carcinoma arising within the atrophic type AK and case 2 had sebaceous carcinoma associated with bowenoid AK in the periphery and some parts of the overlying epidermis of the lesion.
Key words: adipophilin, atrophic type actinic keratosis, bowenoid type actinic keratosis, cytokeratin 1, sebaceous carcinoma.
INTRODUCTION Actinic keratosis (AK) has recently received attention as a source of extraocular sebaceous carcinoma (including in situ sebaceous carcinoma).1–4 However, it has been debated whether the AK is really the origin of the sebaceous carcinoma. Some authors have suggested that the neoplastic cells of AK could differentiate toward sebocytes.2,3 However, other authors have claimed that the “AK” in this setting is not AK, but rather the undifferentiated sebaceous carcinoma in situ, which represents the AK-like area composed of immature, unlipidized neoplastic cells.4 We herein report two cases of extraocular sebaceous carcinoma arising on AK with an immunohistochemical study, which suggests the possibility that sebaceous carcinoma really does develop within AK.
CASE REPORTS Case 1 involved an 85-year-old woman with a slowly growing, scaly, erythematous plaque measuring 2.2 cm 9 1.5 cm in size, on her right cheek (Fig. 1a). The entire lesion was removed under a clinical diagnosis of AK. Scanning magnification of the lesion histopathologically showed the downward proliferation of several neoplastic aggregations from the overlying atrophic epidermis (Fig. 1b). Most of the neoplastic aggregations were located in the papillary and upper reticular dermis, although one aggregation invaded into the middle reticular dermis. Pronounced solar degeneration was seen in the upper to middle dermis. The atypical basal cells (including some atypical suprabasal cells) with large hyperchromatic nuclei were located close together, and were found throughout the basal layer of the atrophic epidermis within the lesion. The downwardly proliferating, neoplastic aggregations were
composed of basaloid and vacuolated cells with nuclear atypia (Fig. 1c), and some of the vacuolated cells had a bubbly cytoplasm and scalloped nuclei, which showed differentiation toward sebocytes. A few, small-sized neoplastic aggregations with basaloid and vacuolated cells budded from the atrophic epidermis (Fig. 1d). These histopathological features were consistent with the diagnosis of sebaceous carcinoma arising within AK (atrophic type). Several step sections revealed an association of a few foci of bowenoid AK in the atrophic type lesion; however, no sebaceous carcinoma lesion was seen in this bowenoid AK area. Case 2 involved an 82-year-old woman with a slowly growing, scaly and crusted, erythematous plaque measuring 2.0 cm 9 1.8 cm in size on her left cheek (Fig. 2a). The entire lesion was removed under a clinical diagnosis of AK. Scanning magnification of the lesion histopathologically showed that many neoplastic aggregations downwardly proliferated into the deep dermis from the crusted epidermis (Fig. 2b). Pronounced solar degeneration was seen even in the deep dermis. The neoplastic aggregations were composed of basaloid and vacuolated cells with nuclear atypia (Fig. 2c), and most of the vacuolated cells had bubbly cytoplasm and scalloped nuclei, which showed their differentiation toward sebocytes. The overlying epidermis with parakeratosis was occupied by these proliferated basaloid and vacuolated cells in some parts, and it was fully replaced by the atypical keratinocytes with bowenoid features in other parts. The findings of squamous cell carcinoma (SCC) in situ with bowenoid features were also seen in the periphery of the lesion (Fig. 2d). These histopathological features were consistent with the diagnosis of sebaceous carcinoma arising on bowenoid AK. Neither recurrence nor metastasis has been seen in either case 1 or 2 during the follow up of 2 years and 1 year, respectively.
Correspondence: Noriyuki Misago, M.D., Division of Dermatology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan. Email: [email protected] Received 19 November 2014; accepted 2 February 2015.
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© 2015 Japanese Dermatological Association
Sebaceous carcinoma with actinic keratosis
(a)
(b)
(c)
(d)
Figure 1. Clinicopathological features of case 1. (a) A scaly, erythematous plaque on the right cheek. (b) Scanning magnification showed the downward proliferation of several neoplastic aggregations from the overlying atrophic epidermis. Atypical basal cells (including some atypical suprabasal cells) were found throughout the basal layer of the atrophic epidermis, which generally preserved the orthokeratosis (inset). (c) The proliferated, neoplastic aggregation was composed of basaloid and vacuolated cells with nuclear atypia, and some of the vacuolated cells had bubbly cytoplasm and scalloped nuclei (inset). (d) A small budding of sebaceous carcinoma focus was also seen within the atrophic type actinic keratosis (hematoxylin–eosin, original magnifications: [b] 930, [inset] 9280; [c] 9180, [inset] 9500; [d] 9270).
(a)
(b)
(c)
(d)
Figure 2. Clinicopathological features of case 2. (a) A scaly and crusted, erythematous plaque on the left. (b) Scanning magnification showed that many neoplastic aggregations downwardly proliferated into the deep dermis from the crusted epidermis. (c) The neoplastic aggregations were composed of basaloid and vacuolated cells with nuclear atypia, and most of the vacuolated cells had a bubbly cytoplasm and scalloped nuclei (inset). A part of the overlying epidermis was fully replaced by the atypical keratinocytes with bowenoid features (encompassed by the dotted square). (d) The bowenoid type actinic keratosis area was seen in the periphery of the lesion (hematoxylin–eosin, original magnifications: [b] 925; [c] 9120, [inset] 9500; [d] 9150).
© 2015 Japanese Dermatological Association
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(a)
(b)
(d)
(e)
(f)
(g)
(c)
(h)
Figure 3. Immunohistochemical features of the lesions. (a) In case 1, adipophilin was positively stained in most of the vacuolated and basaloid cells in the sebaceous carcinoma area, (b) including a small budding area, whereas it was negative in the neoplastic cells of the overlying atrophic type actinic keratosis (AK). The insets in both figures indicate the membranous vesicular staining pattern. (d) In case 1, cytokeratin (CK)1 was negative in the sebaceous carcinoma area, (c) including a small budding area, whereas it was positive in the suprabasal cells of the overlying atrophic type AK. (e) In case 2, the adipophilin expression in the border between the sebaceous carcinoma area and bowenoid type AK area was negative in the latter and showed gradual positivity in the former. The inset indicates the membranous vesicular staining pattern. (f) In case 2, the CK1 expression in the border part clearly demonstrated its positivity in the suprabasal cells in the AK area and the negativity in the sebaceous carcinoma area. (g,h) In part of the main lesion of case 2, a combination of an adipophilin /CK1+ staining pattern in the overlying bowenoid AK area, and an adipophilin+/CK1 staining pattern in the downwardly proliferated sebaceous carcinoma area, was also seen. Panel (g) shows the adipophilin staining and (h) shows CK1 staining (original magnifications: [a] 9150, [inset] 9500; [b] 9300, [inset] 9500; [c] 9280; [d] 9110; [e] 9150, [inset] 9500; [f] 9120; [g] 9160; [h] 9100).
IMMUNOHISTOCHEMICAL FINDINGS Immunohistochemical staining was performed using antibodies against adipophilin (1:10; AP125; Progen Biotechnik, Heidelberg, Germany) and cytokeratin (CK)1 (1:20; 34bB4; Novocastra, Newcastle, UK). In case 1, adipophilin was positively stained in most of the vacuolated and basaloid cells in the sebaceous carcinoma area, whereas it was negative in the overlying atrophic type AK (Fig. 3a,b). CK1 was negative in the sebaceous carcinoma area, whereas it was positive in the suprabasal cells of the overlying atrophic type AK (Fig. 3c,d). In case 2, adipophilin was also positively stained in most of the vacuolated and basaloid cells in the sebaceous
618
carcinoma area. The adipophilin expression in the border part between sebaceous carcinoma area and bowenoid AK area demonstrated negativity in the AK area and gradual positivity in the sebaceous carcinoma area (Fig. 3e). The CK1 expression in this border part clearly demonstrated positivity in the suprabasal cells in the AK area and negativity in the sebaceous carcinoma area (Fig. 3f). This type of contrasting staining pattern of adipophilin and CK1 was also observed in some lesional parts, which were composed of the overlying epidermis with bowenoid features (adipophilin /CK1+) and downwardly proliferated sebaceous carcinoma (adipophilin+/ CK1 ) (Fig. 3g,h).
© 2015 Japanese Dermatological Association
Sebaceous carcinoma with actinic keratosis
DISCUSSION In 2000, Ansai and Mihara1 first reported two cases of sebaceous carcinoma arising on AK. They considered three possibilities as the disease situation for these two cases: (i) the combination of sebaceous carcinoma and AK might have been accidental; (ii) the neoplastic cells of AK may differentiate towards sebocytes; and (iii) “AK” was merely in situ sebaceous carcinoma without sebocytes, which represented an AK-like lesion.1 After this report, additional cases of sebaceous carcinoma which arose within AK or were associated with AK in the periphery of the sebaceous carcinoma lesion, have recently been reported.2–4 Although the first possibility has not yet been completely ruled out, the remaining two possibilities have been discussed in recent reports regarding the disease situation of these cases.2–4 In most of the reported cases of sebaceous carcinoma associated with AK,1,3,4 the AK lesions were generally bowenoid AK, except for one case, in which a small focus of atrophic type AK was seen in the periphery of sebaceous carcinoma.2 The idea that the “AK” is merely in situ sebaceous carcinoma in these cases has been based on the fact that the histopathological features of bowenoid AK or Bowen’s disease are indistinguishable from those of in situ (intraepithelial) sebaceous carcinoma without sebocytes.4,5 We herein reported two cases, the first of which showed sebaceous carcinoma arising within the atrophic type AK, and the second of which showed sebaceous carcinoma associated with bowenoid AK in the periphery and some overlying epidermis of the lesion. The histopathological features of the atrophic type AK are considered to be specific for AK, and there have been no previous reports of in situ sebaceous carcinoma, which histopathologically presented as an atrophic type AK-like lesion. It has also been generally accepted that, in in situ (intraepithelial) sebaceous carcinomas in ocular regions, there are two main histopathological patterns; pagetoid and bowenoid, and an atypical basal layer (atrophic type AK-like) pattern has not been described.5,6 Therefore, the presented case 1 suggests that the neoplastic basal cells of atrophic type AK have the potential to spawn different types of neoplastic cells which differentiate towards sebocytes. It is therefore possible that pluripotent cancer stem cells, which show sebaceous differentiation, can occur within the neoplastic basal cells of atrophic type AK.2 In order to distinguish the two types of lesions, bowenoid AK and in situ sebaceous carcinoma without sebocytes, we performed immunostaining of adipophilin and CK1 in both of our cases, which was useful for this distinction, especially in case 2. There is a general agreement that adipophilin is one of the most useful markers to diagnose sebaceous neoplasms, and adipophilin is positively stained in sebaceous carcinomas and is negative in SCC.7–9 Adipophilin detects the lipid droplets,7 and was expressed even in the basaloid cells in our two sebaceous carcinoma lesions. However, there may be a possibility that immature sebaceous carcinoma cells without lipid droplets do not express adipophilin. Cytokeratin 1 is one of the markers of differentiation of epidermal keratinocytes, and it is expressed in the supraba-
© 2015 Japanese Dermatological Association
sal cells of the normal epidermis.10 CK1 expression is also seen in suprabasal cells in AK, Bowen’s disease and the proliferating cells in well-differentiated SCC,11–13 although this expression is diminished in the immature neoplastic cells of SCC.12 CK1 is generally negative in sebaceous carcinomas, which are composed of neoplastic sebaceous germinative cells and sebocytes.14 It is unlikely that undifferentiated sebaceous carcinomas (both in situ and invasive carcinomas) without sebocytes would initiate the expression of CK1. Considering these general staining patterns of adipophilin and CK1, the contrasting staining patterns observed in case 2, namely, the “adipophilin+/CK1 ” pattern in the sebaceous carcinoma area and the “adipophilin /CK1+” pattern in the bowenoid AK area supported our diagnosis and the idea that sebaceous carcinoma developed on the bowenoid AK in case 2. In summary, based on the histopathological and immunohistochemical findings of these two cases, we consider that sebaceous carcinoma really does arise within the lesion of AK, even though the accidental association of these two conditions may be possible. The overlying epidermal lesions in these two cases are not in situ sebaceous carcinomas without sebocytes, which represent the AK-like area, but they are considered to truly be AK. Sebaceous carcinoma and AK may have a common carcinogenic factor, such as ultraviolet radiation exposure.
CONFLICT OF INTEREST:
None declared.
REFERENCES 1 Ansai S, Mihara I. Sebaceous carcinoma arising on actinic keratosis. Eur J Dermatol 2000; 10: 385–388. 2 Nakashima K, Adachi K, Yamasaki A, Yamada N, Yoshida Y, Yamamoto O. Sebaceous carcinoma with actinic keratosis. Acta Derm Venereol 2010; 90: 196–198. 3 Ishida M, Okabe H. Intraepidermal sebaceous carcinoma occurring concurrently with actinic keratosis. J Cutan Pathol 2012; 39: 731– 732. 4 Aung PP, Batrani M, Mirzabeigi M, Goldberg LJ. Extraocular sebaceous carcinoma in situ: report of three cases and review of the literature. J Cutan Pathol 2014; 41: 592–596. 5 Leibovitch I, Selva D, Huilgol S, Davis G, Dodd T, James CL. Intraepithelial sebaceous carcinoma of the eyelid misdiagnosed as Bowen’s disease. J Cutan Pathol 2006; 33: 303–308. 6 Currie GP, Plaza JA, Harris GJ. Intraepithelial sebaceous carcinoma: a case report of an unusual occurrence. Am J Dermatopathol 2014; 36: 673–676. 7 Muthusamy K, Halbert G, Roberts F. Immunohistochemical staining for adipophilin, perilipin and TIP47. J Clin Pathol 2006; 59: 1166– 1170. 8 Ostler DA, Prieto VG, Reed JA, Deavers MT, Lazar AJ, Ivan D. Adipophilin expression in sebaceous tumors and other cutaneous lesions with clear cell histology: an immunohistochemical study of 117 cases. Mod Pathol 2010; 23: 567–573. 9 Ansai S, Takeichi H, Arase S, Kawana S, Kimura T. Sebaceous carcinoma: an immunohistochemical reappraisal. Am J Dermatopathol 2011; 33: 579–587. 10 Heid HW, Moll I, Franke WW. Patterns of expression of trichocytic and epithelial cytokeratins in mammalian tissues. I. Human and bovine hair follicles. Differentiation 1988; 37: 137–157.
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11 Ichikawa E, Watanabe S, Otsuka F. Immunohistochemical localization of keratins and involucrin in solar keratosis and Bowen’s disease. Am J Dermatopathol 1995; 17: 151–157. 12 Watanabe S, Ichikawa E, Takahashi H, Otsuka F. Changes of cytokeratin and involucrin expression in squamous cell carcinomas of the skin during progression to malignancy. Br J Dermatol 1995; 132: 730–739.
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13 Takayama A, Ochiai T, Hara H, Morishima T. Immunohistochemical study of cytokeratins and proliferative activity in Bowen disease and Bowen carcinoma. Jpn J Dermatol 1997; 107: 851–860. (In Japanese.) 14 Ansai S, Arase S, Kawana S, Kimura T. Immunohistochemical findings of sebaceous carcinoma and sebaceoma: retrieval of cytokeratin expression by a panel of anti-cytokeratin monoclonal antibodies. J Dermatol 2011; 38: 951–958.
© 2015 Japanese Dermatological Association
Journal of Dermatology 2015; 42: 616–620
CONCISE COMMUNICATION
Sebaceous carcinoma in association with actinic keratosis: A report of two cases with an immunohistochemical study Noriyuki MISAGO, Maki KUWASHIRO, Noriko TSURUTA, Yutaka NARISAWA Division of Dermatology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan
ABSTRACT We report two cases of sebaceous carcinoma associated with actinic keratosis (AK) with an immunohistochemical study, which suggests the possibility that sebaceous carcinoma really does develop within AK. Case 1 had sebaceous carcinoma arising within the atrophic type AK and case 2 had sebaceous carcinoma associated with bowenoid AK in the periphery and some parts of the overlying epidermis of the lesion.
Key words: adipophilin, atrophic type actinic keratosis, bowenoid type actinic keratosis, cytokeratin 1, sebaceous carcinoma.
INTRODUCTION Actinic keratosis (AK) has recently received attention as a source of extraocular sebaceous carcinoma (including in situ sebaceous carcinoma).1–4 However, it has been debated whether the AK is really the origin of the sebaceous carcinoma. Some authors have suggested that the neoplastic cells of AK could differentiate toward sebocytes.2,3 However, other authors have claimed that the “AK” in this setting is not AK, but rather the undifferentiated sebaceous carcinoma in situ, which represents the AK-like area composed of immature, unlipidized neoplastic cells.4 We herein report two cases of extraocular sebaceous carcinoma arising on AK with an immunohistochemical study, which suggests the possibility that sebaceous carcinoma really does develop within AK.
CASE REPORTS Case 1 involved an 85-year-old woman with a slowly growing, scaly, erythematous plaque measuring 2.2 cm 9 1.5 cm in size, on her right cheek (Fig. 1a). The entire lesion was removed under a clinical diagnosis of AK. Scanning magnification of the lesion histopathologically showed the downward proliferation of several neoplastic aggregations from the overlying atrophic epidermis (Fig. 1b). Most of the neoplastic aggregations were located in the papillary and upper reticular dermis, although one aggregation invaded into the middle reticular dermis. Pronounced solar degeneration was seen in the upper to middle dermis. The atypical basal cells (including some atypical suprabasal cells) with large hyperchromatic nuclei were located close together, and were found throughout the basal layer of the atrophic epidermis within the lesion. The downwardly proliferating, neoplastic aggregations were
composed of basaloid and vacuolated cells with nuclear atypia (Fig. 1c), and some of the vacuolated cells had a bubbly cytoplasm and scalloped nuclei, which showed differentiation toward sebocytes. A few, small-sized neoplastic aggregations with basaloid and vacuolated cells budded from the atrophic epidermis (Fig. 1d). These histopathological features were consistent with the diagnosis of sebaceous carcinoma arising within AK (atrophic type). Several step sections revealed an association of a few foci of bowenoid AK in the atrophic type lesion; however, no sebaceous carcinoma lesion was seen in this bowenoid AK area. Case 2 involved an 82-year-old woman with a slowly growing, scaly and crusted, erythematous plaque measuring 2.0 cm 9 1.8 cm in size on her left cheek (Fig. 2a). The entire lesion was removed under a clinical diagnosis of AK. Scanning magnification of the lesion histopathologically showed that many neoplastic aggregations downwardly proliferated into the deep dermis from the crusted epidermis (Fig. 2b). Pronounced solar degeneration was seen even in the deep dermis. The neoplastic aggregations were composed of basaloid and vacuolated cells with nuclear atypia (Fig. 2c), and most of the vacuolated cells had bubbly cytoplasm and scalloped nuclei, which showed their differentiation toward sebocytes. The overlying epidermis with parakeratosis was occupied by these proliferated basaloid and vacuolated cells in some parts, and it was fully replaced by the atypical keratinocytes with bowenoid features in other parts. The findings of squamous cell carcinoma (SCC) in situ with bowenoid features were also seen in the periphery of the lesion (Fig. 2d). These histopathological features were consistent with the diagnosis of sebaceous carcinoma arising on bowenoid AK. Neither recurrence nor metastasis has been seen in either case 1 or 2 during the follow up of 2 years and 1 year, respectively.
Correspondence: Noriyuki Misago, M.D., Division of Dermatology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan. Email: [email protected] Received 19 November 2014; accepted 2 February 2015.
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© 2015 Japanese Dermatological Association
Sebaceous carcinoma with actinic keratosis
(a)
(b)
(c)
(d)
Figure 1. Clinicopathological features of case 1. (a) A scaly, erythematous plaque on the right cheek. (b) Scanning magnification showed the downward proliferation of several neoplastic aggregations from the overlying atrophic epidermis. Atypical basal cells (including some atypical suprabasal cells) were found throughout the basal layer of the atrophic epidermis, which generally preserved the orthokeratosis (inset). (c) The proliferated, neoplastic aggregation was composed of basaloid and vacuolated cells with nuclear atypia, and some of the vacuolated cells had bubbly cytoplasm and scalloped nuclei (inset). (d) A small budding of sebaceous carcinoma focus was also seen within the atrophic type actinic keratosis (hematoxylin–eosin, original magnifications: [b] 930, [inset] 9280; [c] 9180, [inset] 9500; [d] 9270).
(a)
(b)
(c)
(d)
Figure 2. Clinicopathological features of case 2. (a) A scaly and crusted, erythematous plaque on the left. (b) Scanning magnification showed that many neoplastic aggregations downwardly proliferated into the deep dermis from the crusted epidermis. (c) The neoplastic aggregations were composed of basaloid and vacuolated cells with nuclear atypia, and most of the vacuolated cells had a bubbly cytoplasm and scalloped nuclei (inset). A part of the overlying epidermis was fully replaced by the atypical keratinocytes with bowenoid features (encompassed by the dotted square). (d) The bowenoid type actinic keratosis area was seen in the periphery of the lesion (hematoxylin–eosin, original magnifications: [b] 925; [c] 9120, [inset] 9500; [d] 9150).
© 2015 Japanese Dermatological Association
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(a)
(b)
(d)
(e)
(f)
(g)
(c)
(h)
Figure 3. Immunohistochemical features of the lesions. (a) In case 1, adipophilin was positively stained in most of the vacuolated and basaloid cells in the sebaceous carcinoma area, (b) including a small budding area, whereas it was negative in the neoplastic cells of the overlying atrophic type actinic keratosis (AK). The insets in both figures indicate the membranous vesicular staining pattern. (d) In case 1, cytokeratin (CK)1 was negative in the sebaceous carcinoma area, (c) including a small budding area, whereas it was positive in the suprabasal cells of the overlying atrophic type AK. (e) In case 2, the adipophilin expression in the border between the sebaceous carcinoma area and bowenoid type AK area was negative in the latter and showed gradual positivity in the former. The inset indicates the membranous vesicular staining pattern. (f) In case 2, the CK1 expression in the border part clearly demonstrated its positivity in the suprabasal cells in the AK area and the negativity in the sebaceous carcinoma area. (g,h) In part of the main lesion of case 2, a combination of an adipophilin /CK1+ staining pattern in the overlying bowenoid AK area, and an adipophilin+/CK1 staining pattern in the downwardly proliferated sebaceous carcinoma area, was also seen. Panel (g) shows the adipophilin staining and (h) shows CK1 staining (original magnifications: [a] 9150, [inset] 9500; [b] 9300, [inset] 9500; [c] 9280; [d] 9110; [e] 9150, [inset] 9500; [f] 9120; [g] 9160; [h] 9100).
IMMUNOHISTOCHEMICAL FINDINGS Immunohistochemical staining was performed using antibodies against adipophilin (1:10; AP125; Progen Biotechnik, Heidelberg, Germany) and cytokeratin (CK)1 (1:20; 34bB4; Novocastra, Newcastle, UK). In case 1, adipophilin was positively stained in most of the vacuolated and basaloid cells in the sebaceous carcinoma area, whereas it was negative in the overlying atrophic type AK (Fig. 3a,b). CK1 was negative in the sebaceous carcinoma area, whereas it was positive in the suprabasal cells of the overlying atrophic type AK (Fig. 3c,d). In case 2, adipophilin was also positively stained in most of the vacuolated and basaloid cells in the sebaceous
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carcinoma area. The adipophilin expression in the border part between sebaceous carcinoma area and bowenoid AK area demonstrated negativity in the AK area and gradual positivity in the sebaceous carcinoma area (Fig. 3e). The CK1 expression in this border part clearly demonstrated positivity in the suprabasal cells in the AK area and negativity in the sebaceous carcinoma area (Fig. 3f). This type of contrasting staining pattern of adipophilin and CK1 was also observed in some lesional parts, which were composed of the overlying epidermis with bowenoid features (adipophilin /CK1+) and downwardly proliferated sebaceous carcinoma (adipophilin+/ CK1 ) (Fig. 3g,h).
© 2015 Japanese Dermatological Association
Sebaceous carcinoma with actinic keratosis
DISCUSSION In 2000, Ansai and Mihara1 first reported two cases of sebaceous carcinoma arising on AK. They considered three possibilities as the disease situation for these two cases: (i) the combination of sebaceous carcinoma and AK might have been accidental; (ii) the neoplastic cells of AK may differentiate towards sebocytes; and (iii) “AK” was merely in situ sebaceous carcinoma without sebocytes, which represented an AK-like lesion.1 After this report, additional cases of sebaceous carcinoma which arose within AK or were associated with AK in the periphery of the sebaceous carcinoma lesion, have recently been reported.2–4 Although the first possibility has not yet been completely ruled out, the remaining two possibilities have been discussed in recent reports regarding the disease situation of these cases.2–4 In most of the reported cases of sebaceous carcinoma associated with AK,1,3,4 the AK lesions were generally bowenoid AK, except for one case, in which a small focus of atrophic type AK was seen in the periphery of sebaceous carcinoma.2 The idea that the “AK” is merely in situ sebaceous carcinoma in these cases has been based on the fact that the histopathological features of bowenoid AK or Bowen’s disease are indistinguishable from those of in situ (intraepithelial) sebaceous carcinoma without sebocytes.4,5 We herein reported two cases, the first of which showed sebaceous carcinoma arising within the atrophic type AK, and the second of which showed sebaceous carcinoma associated with bowenoid AK in the periphery and some overlying epidermis of the lesion. The histopathological features of the atrophic type AK are considered to be specific for AK, and there have been no previous reports of in situ sebaceous carcinoma, which histopathologically presented as an atrophic type AK-like lesion. It has also been generally accepted that, in in situ (intraepithelial) sebaceous carcinomas in ocular regions, there are two main histopathological patterns; pagetoid and bowenoid, and an atypical basal layer (atrophic type AK-like) pattern has not been described.5,6 Therefore, the presented case 1 suggests that the neoplastic basal cells of atrophic type AK have the potential to spawn different types of neoplastic cells which differentiate towards sebocytes. It is therefore possible that pluripotent cancer stem cells, which show sebaceous differentiation, can occur within the neoplastic basal cells of atrophic type AK.2 In order to distinguish the two types of lesions, bowenoid AK and in situ sebaceous carcinoma without sebocytes, we performed immunostaining of adipophilin and CK1 in both of our cases, which was useful for this distinction, especially in case 2. There is a general agreement that adipophilin is one of the most useful markers to diagnose sebaceous neoplasms, and adipophilin is positively stained in sebaceous carcinomas and is negative in SCC.7–9 Adipophilin detects the lipid droplets,7 and was expressed even in the basaloid cells in our two sebaceous carcinoma lesions. However, there may be a possibility that immature sebaceous carcinoma cells without lipid droplets do not express adipophilin. Cytokeratin 1 is one of the markers of differentiation of epidermal keratinocytes, and it is expressed in the supraba-
© 2015 Japanese Dermatological Association
sal cells of the normal epidermis.10 CK1 expression is also seen in suprabasal cells in AK, Bowen’s disease and the proliferating cells in well-differentiated SCC,11–13 although this expression is diminished in the immature neoplastic cells of SCC.12 CK1 is generally negative in sebaceous carcinomas, which are composed of neoplastic sebaceous germinative cells and sebocytes.14 It is unlikely that undifferentiated sebaceous carcinomas (both in situ and invasive carcinomas) without sebocytes would initiate the expression of CK1. Considering these general staining patterns of adipophilin and CK1, the contrasting staining patterns observed in case 2, namely, the “adipophilin+/CK1 ” pattern in the sebaceous carcinoma area and the “adipophilin /CK1+” pattern in the bowenoid AK area supported our diagnosis and the idea that sebaceous carcinoma developed on the bowenoid AK in case 2. In summary, based on the histopathological and immunohistochemical findings of these two cases, we consider that sebaceous carcinoma really does arise within the lesion of AK, even though the accidental association of these two conditions may be possible. The overlying epidermal lesions in these two cases are not in situ sebaceous carcinomas without sebocytes, which represent the AK-like area, but they are considered to truly be AK. Sebaceous carcinoma and AK may have a common carcinogenic factor, such as ultraviolet radiation exposure.
CONFLICT OF INTEREST:
None declared.
REFERENCES 1 Ansai S, Mihara I. Sebaceous carcinoma arising on actinic keratosis. Eur J Dermatol 2000; 10: 385–388. 2 Nakashima K, Adachi K, Yamasaki A, Yamada N, Yoshida Y, Yamamoto O. Sebaceous carcinoma with actinic keratosis. Acta Derm Venereol 2010; 90: 196–198. 3 Ishida M, Okabe H. Intraepidermal sebaceous carcinoma occurring concurrently with actinic keratosis. J Cutan Pathol 2012; 39: 731– 732. 4 Aung PP, Batrani M, Mirzabeigi M, Goldberg LJ. Extraocular sebaceous carcinoma in situ: report of three cases and review of the literature. J Cutan Pathol 2014; 41: 592–596. 5 Leibovitch I, Selva D, Huilgol S, Davis G, Dodd T, James CL. Intraepithelial sebaceous carcinoma of the eyelid misdiagnosed as Bowen’s disease. J Cutan Pathol 2006; 33: 303–308. 6 Currie GP, Plaza JA, Harris GJ. Intraepithelial sebaceous carcinoma: a case report of an unusual occurrence. Am J Dermatopathol 2014; 36: 673–676. 7 Muthusamy K, Halbert G, Roberts F. Immunohistochemical staining for adipophilin, perilipin and TIP47. J Clin Pathol 2006; 59: 1166– 1170. 8 Ostler DA, Prieto VG, Reed JA, Deavers MT, Lazar AJ, Ivan D. Adipophilin expression in sebaceous tumors and other cutaneous lesions with clear cell histology: an immunohistochemical study of 117 cases. Mod Pathol 2010; 23: 567–573. 9 Ansai S, Takeichi H, Arase S, Kawana S, Kimura T. Sebaceous carcinoma: an immunohistochemical reappraisal. Am J Dermatopathol 2011; 33: 579–587. 10 Heid HW, Moll I, Franke WW. Patterns of expression of trichocytic and epithelial cytokeratins in mammalian tissues. I. Human and bovine hair follicles. Differentiation 1988; 37: 137–157.
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11 Ichikawa E, Watanabe S, Otsuka F. Immunohistochemical localization of keratins and involucrin in solar keratosis and Bowen’s disease. Am J Dermatopathol 1995; 17: 151–157. 12 Watanabe S, Ichikawa E, Takahashi H, Otsuka F. Changes of cytokeratin and involucrin expression in squamous cell carcinomas of the skin during progression to malignancy. Br J Dermatol 1995; 132: 730–739.
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13 Takayama A, Ochiai T, Hara H, Morishima T. Immunohistochemical study of cytokeratins and proliferative activity in Bowen disease and Bowen carcinoma. Jpn J Dermatol 1997; 107: 851–860. (In Japanese.) 14 Ansai S, Arase S, Kawana S, Kimura T. Immunohistochemical findings of sebaceous carcinoma and sebaceoma: retrieval of cytokeratin expression by a panel of anti-cytokeratin monoclonal antibodies. J Dermatol 2011; 38: 951–958.
© 2015 Japanese Dermatological Association
