Shinichi Koba

Keratoacanthoma and other types of squamous cell carcinoma with crateriform architecture: Classification and identification

The terminology and classification of keratoacanthoma (KA) and other types of squamous cell carcinoma (SCC) with crateriform architecture have not been clarified. The study evaluated the clinicopathological features of 41 nodular (exo‐endophytic) SCC lesions with a central keratin‐filled crater, including KA (well‐developed stage). The lesions were histopathologically classified into six categories: (i) KA (well‐developed stage) (27 lesions); (ii) KA‐like SCC (three lesions); (iii) KA with malignant transformation (three lesions); (iv) infundibular SCC (crateriform) (four lesions); (v) crateriform SCC arisen from actinic keratosis (three lesions); and (vi) crateriform Bowens disease (one lesion). The true characteristics of KA‐like SCC remain unresolved, but there are three possibilities, namely, that it is one step in the evolution of KA, it is a borderline lesion between KA and invasive SCC, or it is one form of “KA with malignant transformation”. KA, KA‐like SCC, KA with malignant transformation and infundibular SCC (crater form) are considered to be hair follicle‐related neoplasms. In contrast, crateriform SCC arisen from actinic keratosis and crateriform Bowens disease are SCC, which are not related either to the hair follicles or KA. From an etiological standpoint, the presented lesions in these six categories are considered to be mixed up due to the similarity of crateriform architecture between the various types of lesions. However, the information provided in this report is intended to help physicians to make an accurate differential diagnosis of these conditions in clinical practice. The present study provides an opportunity to standardize the terminology for KA and related neoplasms.

Merkel cell carcinoma with cytokeratin 20-negative and thyroid transcription factor-1-positive immunostaining admixed with squamous cell carcinoma.

[2] Rathcke CN, Johansen JS, Vestergaard H. YKL-40, a biomarker of inflammation, is elevated in patients with type 2 diabetes and is related to insulin resistance. Inflamm Res 2006;55:53–9. [3] Lee CG, Hartl D, Lee GR, Koller B, Matsuura H, Da Silva CA, et al. Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13-induced tissue responses and apoptosis. J Exp Med 2009;206:1149–66. [4] Chupp GL, Lee CG, Jarjour N, Shim YM, Holm CT, He S, et al. A chitinase-like protein in the lung and circulation of patients with severe asthma. N Engl J Med 2007;357:2016–27. [5] Ober C, Tan Z, Sun Y, Possick JD, Pan L, Nicolae R, et al. Effect of variation in CHI3L1 on serum YKL-40 level, risk of asthma, and lung function. N Engl J Med 2008;358:1682–91. [6] Harvey S, Whaley J, Eberhardt K. The relationship between serum levels of YKL40 and disease progression in patients with early rheumatoid arthritis. Scand J Shizue Futatsugi-Yumikura Department of Immunology and Medical Zoology, Hyogo College of Medicine, Hyogo, Japan

Histogenesis of pure and combined Merkel cell carcinomas: An immunohistochemical study of 14 cases

The histogenesis of Merkel cell carcinoma (MCC) has remained unresolved. Moreover, one of the questions is whether pure MCC and combined MCC represent the same histogenesis and entity. The existence of combined MCC suggests that MCC likely arise from pluripotent stem cells. Merkel cells (MC) localize within the bulge area, which is populated by hair follicle stem cells. We used hair follicle stem cell markers to investigate whether MCC share certain characteristics of these stem cells. Fourteen MCC specimens were examined histologically and immunohistochemically. There were six pure MCC and eight combined MCC. In six combined MCC, both MCC components and squamous components at least focally shared the expression of one or more of cytokeratin (CK)15, CK19 and CD200, which are hair follicle stem cell markers. On the other hand, four cases of pure MCC showed partially distinct CK19 expression, but did not show CK15 and/or CD200 expression. There was a distinct difference between pure MCC and combined MCC on the expression of hair follicle stem cell markers. The normal skin expressed CK15, CK19 and CD200 in the bulge area, whereas CK15 and CD200 were absent in the MC‐rich glabrous skin and touch domes. The results led us to hypothesize that combined MCC originate from the hair follicle stem cells. We postulate that combined MCC undergo multidirectional differentiation into squamous, glandular, mesenchymal and Merkel cells. Further investigation is warranted to confirm the histogenesis of pure MCC and combined MCC.

Triphasic differentiations of Merkel cell carcinoma in primary and metastatic lesions

We present a rare case of Merkel cell carcinoma (MCC) with heterologous differentiation. The patient was an 86‐year‐old female patient with MCC who presented with a forearm skin tumor and left axillary lymph node swelling. Histopathologically, the malignant components of the primary and metastatic lesions showed the intermingled features of triphasic phenotype differentiation, which had distinct cell populations; MCC, sweat gland carcinoma (SGC) and malignant poorly differentiated spindle cells with myogenic differentiation were immunohistochemically showed. Moreover, an electron microscopic observation of the tumor cells revealed intracytoplasmic canaliculi and junctional structures that indicated ductal differentiation. To our knowledge, this is the first case of MCC admixed with SGC and sarcomatous components in both the primary and metastatic lesions. An immunohistochemical study, using several stem cell markers, indicated that the MCC arose from pluripotent epidermal stem cells.

Large-cell neuroendocrine carcinoma of the skin: ultrastructural and immunohistochemical findings.

Large‐cell neuroendocrine carcinoma (LCNEC) is an uncommon and aggressive neuroendocrine tumor, found mainly in the lung. Although LCNEC has been reported in various organs, LCNEC of the skin is extremely rare, poorly recognized and probably underestimated. Here we report a case of LCNEC of the skin, focusing on the histopathological and ultrastructural findings in detail. The patient was an 85‐year‐old Japanese woman presented with a mass on her right upper eyelid. Biopsy specimen showed an infiltrative mass with extension into the subcutis. Tumor cells were arranged in organoid and trabecular patterns with sheets, nests and trabecular cords. Extensive necrotic areas were observed. Most of the tumor cells were characterized by large cell size, polygonal shape, low nuclear‐cytoplasmic ratio, coarse nuclear chromatin and frequent nucleoli. They were positive for CD56, NSE, AE1/AE3, CK7, and negative for CK20, TTF‐1, synaptophysin and chromogranin A. A systematic radiographic examination revealed no additional neoplastic lesions other than the right upper eyelid mass. These findings suggest that the present case is a LCNEC of the skin. The existence of LCNEC in the skin should be recognized, as it is a rare variant of carcinoma that can potentially be misconstrued as a metastasis or as Merkel cell carcinoma.

The occurrence of two types of amyloid in the same patient

M. D’ INCAN J . JOUB ER T* J . KAN I TAK I S M. SALAV ERT O. TOURN I LHAC F . MA I TR E§ P . D É CHE LOTT E* P . SOUT EYRAND E . E S T È V E– L . MART IN– Departments of Dermatology, *Pathology and Haematology, CHU Clermont-Ferrand, Hôtel-Dieu, F-63058 Clermont-Ferrand, France Departments of Dermatology and Electron Microscopy, CHU Lyon, Edouard Herriot Hospital, F-69347 Lyon, France Departments of §Pathology and –Dermatology, CHG Orléans, La Source Hospital, F-45000 Orléans, France Correspondence: Michel D’Incan. E-mail: mdincan@chu-clermontferrand.fr

Angiolymphoid hyperplasia with eosinophilia associated with underlying arteriovenous hemangioma.

Figure 1. (a) An elastic, soft, domeshaped red nodule overlying a pulsatile nodule on the left posterior neck. (b) Angiolymphoid hyperplasia with eosinophilia (ALHE) with underlying subcutaneous arteriovenous hemangioma (AVH) (hematoxylin–eosin [HE], original magnification 91). (c) ALHE shows aberrant vessels lined by plump and epithelioid endothelial cells (HE, 920). (d) AVH shows a nonencapsulated proliferation of dilated blood vessels of various sizes (HE, 94). (e) Elastica van Gieson staining showed internal elastic lamina in very few vessels (910). (f) Diffuse cytoplasmic and moderate nuclear immunoreactivity of endothelial cells for hypoxia-inducible factor (HIF)-1a in ALHE (940). (g) Rare immunoreactivity of endothelial cells for HIF-1a in AVH (920).

Merkel cell carcinoma associated with stable chronic hemodialysis: A report of two cases.

Merkel cell carcinoma (MCC) is a rare but aggressive cutaneous malignancy associated with the Merkel cell polyomavirus (MCPyV). Multiple studies have shown that the incidence of MCC is higher among immunocompromised individuals than among the general population. In fact, immunosuppressed individuals account for approximately 10% of the MCC patient population. In this report, we describe two cases of MCPyV‐related MCC in Japanese patients on hemodialysis. In both the cases, MCC was present on the face. Both cellular and humoral immunities have been shown to be decreased in uremic patients, and dialysis patients have a high risk of viral‐mediated cancers, including human papillomavirus‐associated cancers. Immune dysfunction related to uremia and dialysis may be associated with a high risk of developing MCC.

Successful treatment of oral squamous cell carcinoma with intra‐arterial cisplatin and concurrent radiotherapy

yellowish plaque. A 1.3-cm red nodule with a hemorrhagic crust and 0.4-cm black papule arose within the plaque. Complete excision of the entire plaque was performed, and histopathology revealed NS in association with three distinct lesions: syringocystadenoma papilliferum, sebaceoma and trichoblastoma (Fig. 1a). Case 2 was a 61-year-old Japanese man who had a 2-year history of rapid growth in a previously asymptomatic plaque on his scalp since birth. There was no family history of malignancy. A physical examination of the left side of the scalp revealed a 1.0 cm 9 3.0 cm brown, verrucous plaque. A 3.0cm red nodule and 0.8-cm black papule arose within the plaque. Complete excision of the entire plaque was performed, and histopathology revealed NS in association with three distinct lesions: trichoblastoma, trichoepithelioma and squamous cell carcinoma (Fig. 1b). We performed an immunohistochemical study to elucidate bKlotho expression in NS. A paraffin-embedded tissue section was immunostained with 1:1000 diluted anti-bKlotho antibody (Aviva Systems Biology, San Diego, CA, USA). bKlotho was expressed in the epidermis of the NS lesion as well as in the normal epidermis (Fig. 1c). It was expressed in skin appendages of the NS lesion; the sebaceous duct (Fig. 1d), sebaceous cells (Fig. 1d) and most of the ectopic apocrine gland (Fig. 1e). In contrast, bKlotho expression was suppressed in the secondary tumors of NS; syringocystadenoma papilliferum (Fig. 1f), trichoblastoma (Fig. 1g), trichoepithelioma (Fig. 1h), sebaceoma (Fig. 1i) and squamous cell carcinoma (Fig. 1j). bKlotho regulates the function of FGF19 by forming a complex with fibroblast growth factor receptor (FGFR)4 to suppress the expression of the CYP7A1 gene, which encodes the ratelimiting enzyme for bile acid synthesis in hepatocytes. Additionally, anti-tumorigenic effects of bKlotho in hepatocellular carcinoma was reported. Although bKlotho and FGFR4 are expressed in skin, to our knowledge, there has been no report about the expression of bKlotho in skin diseases. A recent study reported postzygotic HRAS or KRAS mutations that resulted in constitutive activation of Ras–Raf–MAPK and PI3K–Akt signaling pathways in NS and its secondary tumors. Because the interaction of bKlotho with FGFR4 suppresses Akt signaling and proliferation of tumor cells, it is possible that the reduction of bKlotho expression synergistically enhances the HRASor KRAS-related Akt signaling in the epidermis of NS developing secondary tumors. However, further studies are required to clarify the roles of bKlotho in skin diseases including secondary tumors arising in NS.

Abstract 4220: Establishment of a rapid and automated detection system for BRAF mutations in malignant melanoma.

BRAF gene mutations have been observed in 30-70% of malignant melanoma patients. Recent development of therapeutic intervention using BRAF inhibitors requires an accurate and rapid detection system for BRAF mutations. In addition, there are only a few reports that investigated the clinical characteristics of the melanoma associated with BRAF mutations in Japanese patients on a large scale evaluation. We recently established quenching probe system (QP) for detection of an activating BRAF mutation, V600E and evaluated 113 melanoma samples diagnosed in Saga University Hospital from 1982 to 2011. The QP system includes fully automated genotyping, based on analysis of the probe DNA melting curve, which binds the target mutated site using a fluorescent guanine quenched probe. BRAF mutations were detected in 54 of 115 (47%) including 51 of V600E and 3 of V600K in Japanese melanoma cases. Among clinical subtypes of melanoma, nodular melanoma showed high frequency (12 of 15; 80%) of mutation followed by superficial spreading melanoma (13 of 26; 50%). The QP system is a simple and sensitive method to determine BRAF V600E mutation, and will be useful tool for patient-oriented therapy with BRAF inhibitors. Citation Format: Masaru Ide, Shinichi Koba, Yumi Nagano, Naoko Aragane-Sueoka, Akemi Sato, Takuya Inoue, Naomi Kobayashi, Noriyuki Misago, Yutaka Narisawa, Shinya Kimura, Eisaburo Sueoka. Establishment of a rapid and automated detection system for BRAF mutations in malignant melanoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4220. doi:10.1158/1538-7445.AM2013-4220