1. York MR. Novel insights on the role of the innate immune system in systemic sclerosis. Expert Rev Clin Immunol 2011; 7: 481-9. 2. Worthley DL, Bardy PG, Mullighan CG. Mannose-binding lectin: biology and clinical implications. Intern Med J 2005; 35: 548-55. 3. Kilpatrick DC, Stewart K, Allan EK, McLintock LA, Holyoake TL, Turner ML. Successful haemopoietic stem cell transplantation does not correct mannan-binding lectin deficiency. Bone Marrow Transplant 2005; 35: 179-81. 4. Chalmers JD, Fleming GB, Hill AT, Kilpatrick DC. Impact of mannose-binding lectin insufficiency on the course of cystic fibrosis: A review and meta-analysis. Glycobiology 2011; 21: 271-82. 5. Clements PJ, Lachenbruch PA, Seibold JR, et al. Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol 1993; 20: 1892-6. 6. Steen VD, Medsger TA Jr.. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum 2000; 43: 2437-44. 7. Bhattacharyya S, Kelley K, Melichian DS, et al. Toll-Like Receptor 4 Signaling Augments Transforming Growth Factor- Responses: A Novel Mechanism for Maintaining and Amplifying Fibrosis in Scleroderma. Am J Pathol 2013; 182: 192-205. 8. Jiang D, Liang J, Fan J, et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med 2005; 11: 1173-9. 9. Yoshizaki A, Iwata Y, Komura K, et al. CD19 regulates skin and lung fibrosis via Toll-like receptor signaling in a model of bleomycin-induced scleroderma. Am J Pathol 2008; 172: 1650-63. 10. Wang M, Chen Y, Zhang Y, Zhang L, Lu X, Chen Z. Mannanbinding lectin directly interacts with Toll-like receptor 4 and suppresses lipopolysaccharide-induced inflammatory cytokine secretion from THP1 cells. Cell Mol Immunol 2011; 8: 265-75. doi:10.1684/ejd.2013.2245
Marked melanocyte colonization of pigmented Sister Mary Joseph’s nodule from intrahepatic cholangiocarcinoma Sister Mary Joseph’s nodule (SMJN) is a metastatic tumor deposit in the umbilicus; it often represents advanced malignancy with a dismal prognosis. SMJN can originate from various cancers but umbilical metastases from intrahepatic cholangiocarcinoma (ICC) are extremely rare. We present here the first case of pigmented SMJN from ICC and discuss the mechanisms of pigmentation. A 71-year-old Japanese woman presented with a 4-month history of a pigmented nodule in the umbilicus, 2 cm in diameter (figure 1A). Six months previously, the patient had undergone a left hepatectomy for ICC. A biopsy specimen from the umbilical nodule showed tumor cell nests with ductal structures showing similar pathological features to her ICC; the nests were located mainly in the dermis but had invaded the epidermis (figure 1B). Under higher magnification, the ductal structures consisted of atypical columnar cells and dendritic cells with numerous melanin granules. Fontana-Masson staining revealed intracellular melanin in the dendritic cells. The dendritic cells stained positively for tyrosinase (figure 1C), HMB-45, MART-1, MITF and c-kit (partly) but lacked CK-7, indicating that they were melanocytes, whereas the columnar cells had the opposite characteristics. In addition, perilesional and intralesional melanocytes were positive for basic fibroblast growth factor (bFGF) (figures 1D-F) but negative for stem cell factor and EJD, vol. 24, n◦ 1, January-February 2014
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Figure 1. A) Black and hyperpigmented umbilical nodule. B) Atypical cells with ductal structure in the dermis, invading the epidermis. C) The dendritic cells reacted to tyrosinase. D): Perilesional and intralesional melanocytes were positive for basic fibroblast growth factor (bFGF). E, F) The bFGF positive cell (arrow) was also immunolabeled with tyrosinase.
endothelin 1. On the basis of these findings a diagnosis of pigmented SMJN from ICC with melanocyte colonization was made. Cholangiocarcinoma is a heterogenous group of tumors that arises from cholangiocytes lining the biliary tree. ICC, a subtype of cholangiocarcinoma from the intrahepatic biliary tract, is the second most common primary liver cancer but accounts for less than 10% of cholangiocarcinomas [1]. The SMJN is most frequently found in patients with gastrointestinal cancer, followed by gynecological cancer [2, 3]; SMJN from ICC, as seen in our patient, is extremely rare. Azzapordi and Eusebe found that melanocytes in the epidermis gain the ability to migrate downwards into the tumor nests only when the tumors reach the epidermis-dermis interface [4]. In our patient the carcinoma nests had invaded the epidermis. Konomi et al. [5] obtained evidence that a chemotactic factor in the supernatant of a metastatic tumor culture attracts melanocytes. They concluded that melanocytes in the epidermis migrate to the tumor nest as a result of chemoattractant release by the tumor cells. To identify the chemoattractant that had promoted melanocyte colonization and proliferation in our patient, we immunostained for stem cell factor, endothelin 1 and bFGF, which are postulated to be melanocyte growth factors. Only bFGF was partly immunostained in the perilesional and intralesional melanocytes. As bFGF plays a critical role in melanocyte migration, survival and proliferation [6, 7], augmented autocrine expression of bFGF may explain the expansion of melanocytes within the infiltrated tumor milieu. We speculated that the mechanisms of pigmentation in our patient were as follows: firstly, tumor cell nests reached and invaded the epidermis and activated melanocytes in the basal layer, then these stimulated melanocytes started to produce bFGF, following which, the autocrine actions of bFGF promoted migration and proliferation of the melanocytes. In conclusion, we report a rare case of pigmented SMJN from ICC. Although further accumulation of similar cases is needed to elucidate the exact mechanisms of pigmentation, bFGF may be a crucial factor in pigmented ICC.
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Disclosure. Acknowledgment: We thank Dr. Ichiro Yamamoto, Division of Pathology, Nakatsu Municipal Hospital for his helpful advise. Financial support: This work was partly supported by grants from The Ministry of Health, Labour, and Welfare, The Ministry of Education, Culture, Sports, Science, and Technology, and the Environment Technology Development Fund of the Ministry of the Environment, Japan. Conflict of interest: none.
Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
Mutsumi HIGUCHI Satoko SHIBATA-KIKUCHI Takamichi ITO Chisato GONDO Masakazu TAKAHARA Yoichi MOROI Masutaka FURUE
1. Razumilava N, Gores GJ. Classification, diagnosis, and management of cholangiocarcinoma. Clin Gastroenterol Hepatol 2013; 11: 13-21. 2. Ullery BW, Wachtel H, Raper SE. Sister Mary Joseph’s nodule presenting as large bowel obstruction: A case report and brief review of the literature. J Gastrointest Surg 2013; 17: 1832-5. 3. Inadomi T. Sister Mary Joseph’s nodule: a clue to finding pancreatic cancer in a patient previously affected by gastric cancer. Eur J Dermatol 2005; 15: 492-4. 4. Azappordi JG, Eusebi V. Melanocyte colonization and pigmentation of breast carcinoma. Histopathology 1977; 1: 21-30. 5. Konomi K, Imayama S, Nagae S, Terasaki R, Chijiiwa K, Yashima Y. Melanocyte chemotactic factor produced by skin metastases of a breast carcinoma. J Surg Oncol 1992; 50: 62-6. 6. Wu CS, Lan CC, Chiou MH, Yu HS. Basic fibroblast growth factor promotes melanocyte migration via increased expression of p125(AK) on melanocytes. Acta Derm Venereol 2006; 86: 498-502. 7. Graeven U, Rodeck U, Karpinski S, Jost M, Philippou S, Schmiegel W. Modulation of angiogenesis and tumorigenicity of human melanocytic cells by vascular endothelial growth factor and basic fibroblast growth factor. Cancer Res 2001; 61: 7282-90.
A 23-year old healthy male presented with a one-year history of a gradually-growing subcutaneous tumour on his left buttock. On skin examination, there was a single, tender, non-fluctuant and skin-coloured, subcutaneous tumour on his buttock (figure 1A). We first diagnosed a benign tumour and resection biopsy was performed. Histopathological examination demonstrated that atypical, small, blue and round cells with round and vesicular nuclei densely proliferated both in the dermis and the subcutis (figures 1BC). Immunostaining of the biopsy specimen revealed that the tumour cells were diffusely immunoreactive only for MIC 2 protein (figure 1D). Tumour cells were all negative for other stains, i.e. CD45, cytokeratin, desmin, vimentin, CD56, myeloperoxidase, lysozyme, WT1, HMB45, CD68 and SMactin staining, so lymphoma or other diagnoses were considered less probable. Paraffin embedded sections of our patient were further analyzed for EWS gene rearrangement at chromosome 22q12, but were negative. After the diagnosis of CES, we confirmed he had no other lesions using magnetic resonance image (MRI), enhanced computed tomography (CT) and Positron Emission Tomography (PET)-CT. We performed radical resection with 3-cm margins two months after his first operation without chemotherapy and postoperative radiation. One and a half years after the initial diagnosis, no local recurrence and no remote metastasis have been detected. ES/PNET is the second most common primary bone and soft tissue tumour in children and adolescents [8] but the disease arising in skin is distinctly rare [2-6]. Delaplace et al demonstrated epidemiological and prognostic differences between ES of the bone and CES, and that CES had a better outcome [4]. The current survival rate of ES in the bone is estimated to be 41% [8], while the 10-year probability of survival in CES was estimated at 91% [4]. We investigated 15 case reports of Japanese primary CES between 1996 and 2012. At the time of tumour presentation, patient ages ranged from 1 month to 67 years (median 23 years). Nine of the 15 patients were female. The site of
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doi:10.1684/ejd.2013.2246
Primary cutaneous extraskeletal Ewing’s sarcoma/PNET: possibility of better prognosis than deep ES/PNET Extraskeletal Ewing sarcoma (ES) and Primitive Neuroectodermal Tumour (PNET) were first described by Angerval and Enzinger in 1975 [1]. Primary ES/PNET arising in skin is distinctly rare [2-6]. Unlike ES/PNET in deep soft tissue, which has a poor prognosis, cutaneous and subcutaneous ES seem to be associated with an indolent course and a favourable prognosis [3-5, 7]. We report a case of cutaneous ES (CES) in a young adult and additionally review the cases of CES which have been previously reported in Japan.
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Figure 1. A) Clinical appearance of subcutaneous tumour on his buttock. B) Low power image of primary cutaneous ES/PNET. The tumor was a multilocular, greyish-white, solid tumor. C) High Power image shows proliferation of atypical, small, blue and round cells with round and vesicular nuclei. D) Immunostaining revealed immunoreactivity only for MIC 2 protein. EJD, vol. 24, n◦ 1, January-February 2014
Marked melanocyte colonization of pigmented Sister Mary Joseph’s nodule from intrahepatic cholangiocarcinoma Sister Mary Joseph’s nodule (SMJN) is a metastatic tumor deposit in the umbilicus; it often represents advanced malignancy with a dismal prognosis. SMJN can originate from various cancers but umbilical metastases from intrahepatic cholangiocarcinoma (ICC) are extremely rare. We present here the first case of pigmented SMJN from ICC and discuss the mechanisms of pigmentation. A 71-year-old Japanese woman presented with a 4-month history of a pigmented nodule in the umbilicus, 2 cm in diameter (figure 1A). Six months previously, the patient had undergone a left hepatectomy for ICC. A biopsy specimen from the umbilical nodule showed tumor cell nests with ductal structures showing similar pathological features to her ICC; the nests were located mainly in the dermis but had invaded the epidermis (figure 1B). Under higher magnification, the ductal structures consisted of atypical columnar cells and dendritic cells with numerous melanin granules. Fontana-Masson staining revealed intracellular melanin in the dendritic cells. The dendritic cells stained positively for tyrosinase (figure 1C), HMB-45, MART-1, MITF and c-kit (partly) but lacked CK-7, indicating that they were melanocytes, whereas the columnar cells had the opposite characteristics. In addition, perilesional and intralesional melanocytes were positive for basic fibroblast growth factor (bFGF) (figures 1D-F) but negative for stem cell factor and EJD, vol. 24, n◦ 1, January-February 2014
A
C
B
C
D
E
Figure 1. A) Black and hyperpigmented umbilical nodule. B) Atypical cells with ductal structure in the dermis, invading the epidermis. C) The dendritic cells reacted to tyrosinase. D): Perilesional and intralesional melanocytes were positive for basic fibroblast growth factor (bFGF). E, F) The bFGF positive cell (arrow) was also immunolabeled with tyrosinase.
endothelin 1. On the basis of these findings a diagnosis of pigmented SMJN from ICC with melanocyte colonization was made. Cholangiocarcinoma is a heterogenous group of tumors that arises from cholangiocytes lining the biliary tree. ICC, a subtype of cholangiocarcinoma from the intrahepatic biliary tract, is the second most common primary liver cancer but accounts for less than 10% of cholangiocarcinomas [1]. The SMJN is most frequently found in patients with gastrointestinal cancer, followed by gynecological cancer [2, 3]; SMJN from ICC, as seen in our patient, is extremely rare. Azzapordi and Eusebe found that melanocytes in the epidermis gain the ability to migrate downwards into the tumor nests only when the tumors reach the epidermis-dermis interface [4]. In our patient the carcinoma nests had invaded the epidermis. Konomi et al. [5] obtained evidence that a chemotactic factor in the supernatant of a metastatic tumor culture attracts melanocytes. They concluded that melanocytes in the epidermis migrate to the tumor nest as a result of chemoattractant release by the tumor cells. To identify the chemoattractant that had promoted melanocyte colonization and proliferation in our patient, we immunostained for stem cell factor, endothelin 1 and bFGF, which are postulated to be melanocyte growth factors. Only bFGF was partly immunostained in the perilesional and intralesional melanocytes. As bFGF plays a critical role in melanocyte migration, survival and proliferation [6, 7], augmented autocrine expression of bFGF may explain the expansion of melanocytes within the infiltrated tumor milieu. We speculated that the mechanisms of pigmentation in our patient were as follows: firstly, tumor cell nests reached and invaded the epidermis and activated melanocytes in the basal layer, then these stimulated melanocytes started to produce bFGF, following which, the autocrine actions of bFGF promoted migration and proliferation of the melanocytes. In conclusion, we report a rare case of pigmented SMJN from ICC. Although further accumulation of similar cases is needed to elucidate the exact mechanisms of pigmentation, bFGF may be a crucial factor in pigmented ICC.
125
Disclosure. Acknowledgment: We thank Dr. Ichiro Yamamoto, Division of Pathology, Nakatsu Municipal Hospital for his helpful advise. Financial support: This work was partly supported by grants from The Ministry of Health, Labour, and Welfare, The Ministry of Education, Culture, Sports, Science, and Technology, and the Environment Technology Development Fund of the Ministry of the Environment, Japan. Conflict of interest: none.
Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
Mutsumi HIGUCHI Satoko SHIBATA-KIKUCHI Takamichi ITO Chisato GONDO Masakazu TAKAHARA Yoichi MOROI Masutaka FURUE
1. Razumilava N, Gores GJ. Classification, diagnosis, and management of cholangiocarcinoma. Clin Gastroenterol Hepatol 2013; 11: 13-21. 2. Ullery BW, Wachtel H, Raper SE. Sister Mary Joseph’s nodule presenting as large bowel obstruction: A case report and brief review of the literature. J Gastrointest Surg 2013; 17: 1832-5. 3. Inadomi T. Sister Mary Joseph’s nodule: a clue to finding pancreatic cancer in a patient previously affected by gastric cancer. Eur J Dermatol 2005; 15: 492-4. 4. Azappordi JG, Eusebi V. Melanocyte colonization and pigmentation of breast carcinoma. Histopathology 1977; 1: 21-30. 5. Konomi K, Imayama S, Nagae S, Terasaki R, Chijiiwa K, Yashima Y. Melanocyte chemotactic factor produced by skin metastases of a breast carcinoma. J Surg Oncol 1992; 50: 62-6. 6. Wu CS, Lan CC, Chiou MH, Yu HS. Basic fibroblast growth factor promotes melanocyte migration via increased expression of p125(AK) on melanocytes. Acta Derm Venereol 2006; 86: 498-502. 7. Graeven U, Rodeck U, Karpinski S, Jost M, Philippou S, Schmiegel W. Modulation of angiogenesis and tumorigenicity of human melanocytic cells by vascular endothelial growth factor and basic fibroblast growth factor. Cancer Res 2001; 61: 7282-90.
A 23-year old healthy male presented with a one-year history of a gradually-growing subcutaneous tumour on his left buttock. On skin examination, there was a single, tender, non-fluctuant and skin-coloured, subcutaneous tumour on his buttock (figure 1A). We first diagnosed a benign tumour and resection biopsy was performed. Histopathological examination demonstrated that atypical, small, blue and round cells with round and vesicular nuclei densely proliferated both in the dermis and the subcutis (figures 1BC). Immunostaining of the biopsy specimen revealed that the tumour cells were diffusely immunoreactive only for MIC 2 protein (figure 1D). Tumour cells were all negative for other stains, i.e. CD45, cytokeratin, desmin, vimentin, CD56, myeloperoxidase, lysozyme, WT1, HMB45, CD68 and SMactin staining, so lymphoma or other diagnoses were considered less probable. Paraffin embedded sections of our patient were further analyzed for EWS gene rearrangement at chromosome 22q12, but were negative. After the diagnosis of CES, we confirmed he had no other lesions using magnetic resonance image (MRI), enhanced computed tomography (CT) and Positron Emission Tomography (PET)-CT. We performed radical resection with 3-cm margins two months after his first operation without chemotherapy and postoperative radiation. One and a half years after the initial diagnosis, no local recurrence and no remote metastasis have been detected. ES/PNET is the second most common primary bone and soft tissue tumour in children and adolescents [8] but the disease arising in skin is distinctly rare [2-6]. Delaplace et al demonstrated epidemiological and prognostic differences between ES of the bone and CES, and that CES had a better outcome [4]. The current survival rate of ES in the bone is estimated to be 41% [8], while the 10-year probability of survival in CES was estimated at 91% [4]. We investigated 15 case reports of Japanese primary CES between 1996 and 2012. At the time of tumour presentation, patient ages ranged from 1 month to 67 years (median 23 years). Nine of the 15 patients were female. The site of
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doi:10.1684/ejd.2013.2246
Primary cutaneous extraskeletal Ewing’s sarcoma/PNET: possibility of better prognosis than deep ES/PNET Extraskeletal Ewing sarcoma (ES) and Primitive Neuroectodermal Tumour (PNET) were first described by Angerval and Enzinger in 1975 [1]. Primary ES/PNET arising in skin is distinctly rare [2-6]. Unlike ES/PNET in deep soft tissue, which has a poor prognosis, cutaneous and subcutaneous ES seem to be associated with an indolent course and a favourable prognosis [3-5, 7]. We report a case of cutaneous ES (CES) in a young adult and additionally review the cases of CES which have been previously reported in Japan.
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Figure 1. A) Clinical appearance of subcutaneous tumour on his buttock. B) Low power image of primary cutaneous ES/PNET. The tumor was a multilocular, greyish-white, solid tumor. C) High Power image shows proliferation of atypical, small, blue and round cells with round and vesicular nuclei. D) Immunostaining revealed immunoreactivity only for MIC 2 protein. EJD, vol. 24, n◦ 1, January-February 2014
![[Sister Mary Joseph' nodule].](/assets/img/hold.png)
