findings of previous studies in which SJS/TEN was characterized by a predominantly Th1 pattern of activation [8, 9]. Our results clearly showed slightly higher MIG and IP10 values in SJS/TEN than in DIHS/DRESS but statistical significance was not reached between these two groups, which indicated that DIHS/DRESS also exhibited a Th1 pattern of activation to some extent. The relatively small number of patients and the overlap in the range distribution in DIHS/DRESS vs SJS/TEN and DIHS/DRESS vs MPE imply that further extended studies are needed to reach a concrete conclusion. We then investigated whether the levels of the upregulated chemokines described above declined upon remission. Serum levels of MDC in DIHS/DRESS and MIG and IP-10 in SJS/TEN decreased in the remission stage (figure 1B), which was also observed in TARC in DIHS/DRESS (figure 1B) [3]. A recent study reported that biopsy specimens from SJS/TEN cutaneous lesions exhibited a mixed Th1/Th2 pattern [10]. The same group subsequently demonstrated that TARC levels were significantly higher in the sera of SJS/TEN patients than in the sera of healthy donors (HD) [9]. The median TARC levels reported were 580 pg/mL in SJS/TEN and 205.2 pg/mL in HD [9]. Our previous studies also showed elevated levels of TARC in SJS/TEN patients; average TARC levels were 2,198 pg/mL in one study [3] and 1,543 pg/mL in the other [4] (normal value of TARC: T)
11
A T C
A T
20
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A
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A
100 µ m
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100 µm
Figure 1. A) An erythematous lesion measuring 3.0 cm × 4.0 cm in size was observed on the patient’s scrotum. B) There were many small keratotic papules on the dorsal hands. C) Direct sequencing proved the proband to be heterozygous for c.16A>C, p.K6X. D) The histological examination obtained of the skin lesion obtained from the scrotum showed tumor nests composed of atypical tumor cells within the epidermis (H-E stain). The tissue sections of a skin lesion on the scrotum were doubly immunostained for CAM5.2 (green) and p-AKT (red). The tissue sections were also stained with 4’, 6-diamidine-2’phenylindole dihydrochloride (DAPI) to visualize the nuclei. E) Immunostaining for CAM5.2; F) immunostaining for pAKT; G) a merged picture.
patient might have CS; therefore, a PTEN gene analysis was performed after obtaining the patient’s informed consent. A heterozygous nonsense mutation (c.16A>C, p.K6X) at exon 1 was detected (figure 1C), which has not been previously reported. Accordingly, the patient was diagnosed as having CS. The histological examination of the skin lesion of the scrotum showed tumor nests composed of atypical cells within the epidermis (figure 1D). The tumor cells were immunohistochemically positive for carcinoembryonic antigen and CAM5.2 (figure 1E). These histological findings indicated a diagnosis of EMPD. No abnormalities were detected in the lymph nodes or internal organs on positron emission tomography and computed tomography of the entire body. The skin lesion was totally excised with a 1-cm surgical margin. The patient is now being carefully observed. We next examined the expression levels of human epidermal growth factor receptor 2 (HER2), PTEN and phosphorylated protein kinase B (p-AKT) in the tumor
90
cells to clarify the pathogenesis of EMPD in the present patient. Signals for p-AKT were clearly observed in the tumor cells, which were identified by CAM-5.2 staining (figures 1F,G); however, no HER-2 or PTEN signals were detected in the tumor cells (data not shown). PTEN is a lipid phosphatase that plays an important role as a negative regulator of the phosphoinositol-3kinase (PI3K)/AKT pathway [3, 4]. Hyperactivation of the PI3K/AKT pathway is associated with resistance to apoptosis, increased cell growth, cell proliferation and cellular energy metabolism. In addition, somatic alterations and biallelic mutations of the PTEN gene are common events in high-grade glioblastoma, melanoma and in cancers of the prostate and endometrium [5]. Therefore, the PTEN gene is considered to be a tumor-suppressor gene. Activation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway has been associated with the pathogenesis of sporadic EMPD [6]. HER2 can phosphorylate and activate the downstream PI3K/AKT signal and overexpression of HER2 is observed in about 88% of cases with sporadic mammary Paget’s disease (MPD). In contrast, HER2 expression has been detected in 35.7% of sporadic EMPD cases, although p-AKT was expressed in 87.5% of MPD and 92.9% of EMPD, respectively [7]. Therefore, AKT in tumor cells of EMPD may be phosphorylated and activated by another mechanism, such as phosphorylated-focal adhesion kinase (p-FAK), signal transducer and activator of transcription 3 (STAT3) and/or insulin-like growth factor-1 receptor (IGF-1R) [8-10]. A loss of PTEN function can also induce the activation of AKT via the constitutive synthesis of PIP3 [3]. In this patient, although the expression of p-FAK, STAT3 and IGF-1R were not examined, the loss or inactivation of the wild-type PTEN allele in the tumor may be associated with the development of EMPD, because PTEN immunostaining was proven to be negative in the Paget’s cells. No cases of EMPD arising in a CS patient have been reported; however, we speculate that the pathogenesis of EMPD in this patient is associated with CS, because CS patients have germline mutations of the PTEN gene in an allele and the PI3K/AKT pathway is known to play an important role in the development of sporadic EMPD. The exact correlation between CS and EMPD should be elucidated after the accumulation of more cases. However, this case will help to extend knowledge regarding CS. Disclosure. Financial support: none. Conflict of interest: none. 1
Department of Dermatology, Department of Pathology, Graduate School of Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan 3 Department of Dermatology, Shinseikai Toyama Hospital, Imizu, Japan 4 Department of Dermatology, Toyama Prefectural Central Hospital, Toyama, Japan 2
Kotaro MATSUI1 Teruhiko MAKINO1 Megumi MIZAWA1 Takeru HAMASHIMA2 Hironori HANAKAWA3 Naohito HATTA4 Masakiyo SASAHARA2 Tadamichi SHIMIZU1
EJD, vol. 25, n◦ 1, January-February 2015
1. Eng C. PTEN : one gene, many syndromes. Human Mutat 2003; 22: 183-98. 2. Liaw D, Marsh DJ, Li J, et al. Germline mutaion of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 1997; 16: 64-7. 3. Myers MP, Pass I, Batty IH, et al. The lipid phosphatase activity of PTEN is critical for its tumor suppressor function. Proc Natl Acad Sci USA 1998; 95: 13513-8. 4. Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1998; 273: 13375-8. 5. Bose S, Wang SI, Terry MB, Hibshoosh H, Parsons R. Allelic loss of chromosome 10q23 is associated with tumor progression in breast carcinomas. Oncogene 1998; 17: 123-7. 6. Chen S, Nakahara T, Uchi H, et al. Immunohistochemical analysis of the mammalian target of rapamycin signaling pathway in extramammary Paget’s disease. Br J Dermatol 2009; 161: 357-63. 7. Liu W, Iqbal J, Khoury T. Mammary Paget’s disease and extra-mammary Paget’s disease: two morphologically similar but biologically different diseases. J Cutan Pathol 2010; 37: 1145-9. 8. Chen SY, Moroi Y, Urabe K, et al. Concordant overexpression of pFAK and p-ERK1/2 in extramammary Paget’s disease. Arch Dermatol Res 2008; 300: 195-201. 9. Liu HJ, Moroi Y, Masuda T, et al. Expression of phosphorylated Stat3, cyclin D1 and Bcl-xL in extramammary Paget disease. Br J Dermatol 2006; 154: 926-32. 10. Liu H, Moroi Y, Yasumoto S, et al. Expression of insulin-like growth factor-1 receptor, p-AKT and p-ERK1/2 protein in extramammary Paget’s disease. Br J Dermatol 2006; 155: 586-91. doi:10.1684/ejd.2014.2475
Giant pedunculated pilomatrix carcinoma on the upper limb: A rare clinical appearance Pilomatricoma is a common benign skin tumor. The malignant counterpart of pilomatricoma, so-called pilomatrix carcinoma (PC), is rare and only approximately 100 cases of PC have been reported in the literature [1-3]. PC is a low-grade malignancy and is characterized by infiltrative growth and a tendency for local recurrence [4-6]. The most common clinical feature is a cyst-like appearance. Here we report a PC with the unusual clinical feature of a pedunculated appearance. A 36-year-old man presented with a pedunculated tumor on the left upper arm. He had noticed a small subcutaneous tumor on the left upper arm 10 years before, which had rapidly increased in size 6 months before presentation. Examination revealed a hemorrhagic, pedunculated, reddish tumor of 10.5 × 8.5 × 5.0 cm on the left upper arm. The tumor had ulceration, with yellowish necrotic tissue on its surface (figure 1A). The left axillary lymph node was not palpable. An incisional biopsy specimen showed proliferation of small basophilic cells with hyper-chromatic nuclei, scant cytoplasm and brisk mitotic activity. The edge of the tumor showed basophilic cells predominantly aligned at the periphery. Immunohistochemistry revealed that the tumor was positive for Ber-EP4, focally positive for CK5/6 and 34E12, and negative for CEA, CAM5.2, CK7/20, EMA, CD56, chromogranin and TTF-1. On the basis of these results, we suspected a malignant tumor with folEJD, vol. 25, n◦ 1, January-February 2015
A
B
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Figure 1. A) 10.5 × 8.5 × 5.0 cm pedunculated reddish tumor on the left arm. B) Histopathological section shows the islands of basophilic cells and eosinophilic shadow cells (hematoxylin eosin; original magnification: ×100). C) Dense lymphoid infiltration surrounding the tumor (hematoxylin eosin; original magnification: ×200). D) Basophilic cells with hyperchromatic nuclei showing pleomorphism and frequent mitoses (hematoxylin eosin; original magnification: ×400).
licular differentiation. Under general anesthesia, surgical excision was performed with 5-mm side margins. Histologically, the surgical specimen revealed an asymmetric, poorly circumscribed and lobulated neoplasm, penetrating into the deep dermis and the subcutaneous tissue without involvement of the overlying epidermis (figure 1B). The tumor was surrounded by a dense lymphocytic inflammatory infiltrate (figure 1C) and fibromyxoid stroma. Focally, multinucleated giant cells of the foreignbody type were present in the stroma. The tumor was composed of two cell types, basophilic cells and ghost cells (figure 1B). Most of the basophilic cells displayed hyperchromatic nuclei, cellular atypia and frequent mitoses (figure 1D). The ghost cells lacked nuclei and were characterized by a pale eosinophilic cytoplasm. The surgical margins were tumor-free and, 6 months after surgery, the patient remains free of disease. PC was initially described by Lopansri and Mihn in 1980 [7]. More than 60% of cases occur in the head and neck region [5]. The origin of PC is still controversial. The tumor mainly arises de novo as a solitary lesion. However, PC sometimes develops from a pilomatricoma after a latency that may last several decades [4]. PCs often present clinically as asymptomatic, slowly growing dermal and subcutaneous nodules. In a study by Cornejo et al., cases of PC were found to have been initially diagnosed as a cyst, basal cell carcinoma, squamous cell carcinoma, pilomatricoma and lipoma [1]. In the present case, the patient had an unusual-looking pedunculated tumor, and the clinical features differed from those described above; further, no case of PC with such characteristics has been reported to date, although Hague et al. reported a case of proliferating pilomatricoma, a variant of pilomatricoma, with a pedunculated appearance [8]. As far as we are aware, this is only the second case in the literature on pilomatricoma and PC of a tumor with a pedunculated appearance.
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11
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A T
20
A
A
G
A
100 µ m
D
100 µm
Figure 1. A) An erythematous lesion measuring 3.0 cm × 4.0 cm in size was observed on the patient’s scrotum. B) There were many small keratotic papules on the dorsal hands. C) Direct sequencing proved the proband to be heterozygous for c.16A>C, p.K6X. D) The histological examination obtained of the skin lesion obtained from the scrotum showed tumor nests composed of atypical tumor cells within the epidermis (H-E stain). The tissue sections of a skin lesion on the scrotum were doubly immunostained for CAM5.2 (green) and p-AKT (red). The tissue sections were also stained with 4’, 6-diamidine-2’phenylindole dihydrochloride (DAPI) to visualize the nuclei. E) Immunostaining for CAM5.2; F) immunostaining for pAKT; G) a merged picture.
patient might have CS; therefore, a PTEN gene analysis was performed after obtaining the patient’s informed consent. A heterozygous nonsense mutation (c.16A>C, p.K6X) at exon 1 was detected (figure 1C), which has not been previously reported. Accordingly, the patient was diagnosed as having CS. The histological examination of the skin lesion of the scrotum showed tumor nests composed of atypical cells within the epidermis (figure 1D). The tumor cells were immunohistochemically positive for carcinoembryonic antigen and CAM5.2 (figure 1E). These histological findings indicated a diagnosis of EMPD. No abnormalities were detected in the lymph nodes or internal organs on positron emission tomography and computed tomography of the entire body. The skin lesion was totally excised with a 1-cm surgical margin. The patient is now being carefully observed. We next examined the expression levels of human epidermal growth factor receptor 2 (HER2), PTEN and phosphorylated protein kinase B (p-AKT) in the tumor
90
cells to clarify the pathogenesis of EMPD in the present patient. Signals for p-AKT were clearly observed in the tumor cells, which were identified by CAM-5.2 staining (figures 1F,G); however, no HER-2 or PTEN signals were detected in the tumor cells (data not shown). PTEN is a lipid phosphatase that plays an important role as a negative regulator of the phosphoinositol-3kinase (PI3K)/AKT pathway [3, 4]. Hyperactivation of the PI3K/AKT pathway is associated with resistance to apoptosis, increased cell growth, cell proliferation and cellular energy metabolism. In addition, somatic alterations and biallelic mutations of the PTEN gene are common events in high-grade glioblastoma, melanoma and in cancers of the prostate and endometrium [5]. Therefore, the PTEN gene is considered to be a tumor-suppressor gene. Activation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway has been associated with the pathogenesis of sporadic EMPD [6]. HER2 can phosphorylate and activate the downstream PI3K/AKT signal and overexpression of HER2 is observed in about 88% of cases with sporadic mammary Paget’s disease (MPD). In contrast, HER2 expression has been detected in 35.7% of sporadic EMPD cases, although p-AKT was expressed in 87.5% of MPD and 92.9% of EMPD, respectively [7]. Therefore, AKT in tumor cells of EMPD may be phosphorylated and activated by another mechanism, such as phosphorylated-focal adhesion kinase (p-FAK), signal transducer and activator of transcription 3 (STAT3) and/or insulin-like growth factor-1 receptor (IGF-1R) [8-10]. A loss of PTEN function can also induce the activation of AKT via the constitutive synthesis of PIP3 [3]. In this patient, although the expression of p-FAK, STAT3 and IGF-1R were not examined, the loss or inactivation of the wild-type PTEN allele in the tumor may be associated with the development of EMPD, because PTEN immunostaining was proven to be negative in the Paget’s cells. No cases of EMPD arising in a CS patient have been reported; however, we speculate that the pathogenesis of EMPD in this patient is associated with CS, because CS patients have germline mutations of the PTEN gene in an allele and the PI3K/AKT pathway is known to play an important role in the development of sporadic EMPD. The exact correlation between CS and EMPD should be elucidated after the accumulation of more cases. However, this case will help to extend knowledge regarding CS. Disclosure. Financial support: none. Conflict of interest: none. 1
Department of Dermatology, Department of Pathology, Graduate School of Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan 3 Department of Dermatology, Shinseikai Toyama Hospital, Imizu, Japan 4 Department of Dermatology, Toyama Prefectural Central Hospital, Toyama, Japan 2
Kotaro MATSUI1 Teruhiko MAKINO1 Megumi MIZAWA1 Takeru HAMASHIMA2 Hironori HANAKAWA3 Naohito HATTA4 Masakiyo SASAHARA2 Tadamichi SHIMIZU1
EJD, vol. 25, n◦ 1, January-February 2015
1. Eng C. PTEN : one gene, many syndromes. Human Mutat 2003; 22: 183-98. 2. Liaw D, Marsh DJ, Li J, et al. Germline mutaion of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 1997; 16: 64-7. 3. Myers MP, Pass I, Batty IH, et al. The lipid phosphatase activity of PTEN is critical for its tumor suppressor function. Proc Natl Acad Sci USA 1998; 95: 13513-8. 4. Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1998; 273: 13375-8. 5. Bose S, Wang SI, Terry MB, Hibshoosh H, Parsons R. Allelic loss of chromosome 10q23 is associated with tumor progression in breast carcinomas. Oncogene 1998; 17: 123-7. 6. Chen S, Nakahara T, Uchi H, et al. Immunohistochemical analysis of the mammalian target of rapamycin signaling pathway in extramammary Paget’s disease. Br J Dermatol 2009; 161: 357-63. 7. Liu W, Iqbal J, Khoury T. Mammary Paget’s disease and extra-mammary Paget’s disease: two morphologically similar but biologically different diseases. J Cutan Pathol 2010; 37: 1145-9. 8. Chen SY, Moroi Y, Urabe K, et al. Concordant overexpression of pFAK and p-ERK1/2 in extramammary Paget’s disease. Arch Dermatol Res 2008; 300: 195-201. 9. Liu HJ, Moroi Y, Masuda T, et al. Expression of phosphorylated Stat3, cyclin D1 and Bcl-xL in extramammary Paget disease. Br J Dermatol 2006; 154: 926-32. 10. Liu H, Moroi Y, Yasumoto S, et al. Expression of insulin-like growth factor-1 receptor, p-AKT and p-ERK1/2 protein in extramammary Paget’s disease. Br J Dermatol 2006; 155: 586-91. doi:10.1684/ejd.2014.2475
Giant pedunculated pilomatrix carcinoma on the upper limb: A rare clinical appearance Pilomatricoma is a common benign skin tumor. The malignant counterpart of pilomatricoma, so-called pilomatrix carcinoma (PC), is rare and only approximately 100 cases of PC have been reported in the literature [1-3]. PC is a low-grade malignancy and is characterized by infiltrative growth and a tendency for local recurrence [4-6]. The most common clinical feature is a cyst-like appearance. Here we report a PC with the unusual clinical feature of a pedunculated appearance. A 36-year-old man presented with a pedunculated tumor on the left upper arm. He had noticed a small subcutaneous tumor on the left upper arm 10 years before, which had rapidly increased in size 6 months before presentation. Examination revealed a hemorrhagic, pedunculated, reddish tumor of 10.5 × 8.5 × 5.0 cm on the left upper arm. The tumor had ulceration, with yellowish necrotic tissue on its surface (figure 1A). The left axillary lymph node was not palpable. An incisional biopsy specimen showed proliferation of small basophilic cells with hyper-chromatic nuclei, scant cytoplasm and brisk mitotic activity. The edge of the tumor showed basophilic cells predominantly aligned at the periphery. Immunohistochemistry revealed that the tumor was positive for Ber-EP4, focally positive for CK5/6 and 34E12, and negative for CEA, CAM5.2, CK7/20, EMA, CD56, chromogranin and TTF-1. On the basis of these results, we suspected a malignant tumor with folEJD, vol. 25, n◦ 1, January-February 2015
A
B
C
D
Figure 1. A) 10.5 × 8.5 × 5.0 cm pedunculated reddish tumor on the left arm. B) Histopathological section shows the islands of basophilic cells and eosinophilic shadow cells (hematoxylin eosin; original magnification: ×100). C) Dense lymphoid infiltration surrounding the tumor (hematoxylin eosin; original magnification: ×200). D) Basophilic cells with hyperchromatic nuclei showing pleomorphism and frequent mitoses (hematoxylin eosin; original magnification: ×400).
licular differentiation. Under general anesthesia, surgical excision was performed with 5-mm side margins. Histologically, the surgical specimen revealed an asymmetric, poorly circumscribed and lobulated neoplasm, penetrating into the deep dermis and the subcutaneous tissue without involvement of the overlying epidermis (figure 1B). The tumor was surrounded by a dense lymphocytic inflammatory infiltrate (figure 1C) and fibromyxoid stroma. Focally, multinucleated giant cells of the foreignbody type were present in the stroma. The tumor was composed of two cell types, basophilic cells and ghost cells (figure 1B). Most of the basophilic cells displayed hyperchromatic nuclei, cellular atypia and frequent mitoses (figure 1D). The ghost cells lacked nuclei and were characterized by a pale eosinophilic cytoplasm. The surgical margins were tumor-free and, 6 months after surgery, the patient remains free of disease. PC was initially described by Lopansri and Mihn in 1980 [7]. More than 60% of cases occur in the head and neck region [5]. The origin of PC is still controversial. The tumor mainly arises de novo as a solitary lesion. However, PC sometimes develops from a pilomatricoma after a latency that may last several decades [4]. PCs often present clinically as asymptomatic, slowly growing dermal and subcutaneous nodules. In a study by Cornejo et al., cases of PC were found to have been initially diagnosed as a cyst, basal cell carcinoma, squamous cell carcinoma, pilomatricoma and lipoma [1]. In the present case, the patient had an unusual-looking pedunculated tumor, and the clinical features differed from those described above; further, no case of PC with such characteristics has been reported to date, although Hague et al. reported a case of proliferating pilomatricoma, a variant of pilomatricoma, with a pedunculated appearance [8]. As far as we are aware, this is only the second case in the literature on pilomatricoma and PC of a tumor with a pedunculated appearance.
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