Akiko Kanzaki

Insulin-like growth factor 2 mRNA-binding protein-3 as a marker for distinguishing between cutaneous squamous cell carcinoma and keratoacanthoma

In the histopathological diagnosis of cutaneous tumors, the differential diagnosis of squamous cell carcinoma (SCC) with crateriform architecture and keratoacanthoma (KA) is often difficult so an accurate understanding of the biological features and the identification of reliable markers of SCC and KA are crucial issues. Insulin-like growth factor 2 mRNA-binding protein-3 (IGF2BP3, also known as IMP3) is thought of as a bona fide oncofetal protein, which is overexpressed and is involved in cell proliferation, migration, and invasion in several kinds of tumors. However, the role of IMP3 in cutaneous SCC and KA has not been well studied. Therefore, we focused on studying the biological functions of IMP3 in SCC and KA. In human skin SCC cell lines, HSC-1 and HSC-5, and the human keratinocyte cell line, HaCaT, IMP3 mRNA levels were significantly higher than that of normal human skin. The knockdown of IMP3 expression reduced the proliferation of HSC-1, and significantly reduced invasion by HSC-1 and HSC-5. In contrast, the knockdown of IMP3 did not significantly affect invasion by HaCaT cells. In immunohistochemical studies of SCC and KA tissues, the Ki-67 labeling index (LI) of the suprabasal cell layer was significantly higher in SCC, compared with KA tissues and the tumor-free margin (TFM) adjacent to SCC and KA. Most SCC tissues stained strongly positive for IMP3, but KA tissues and TFM were mostly negative for IMP3. The Ki-67 LI of the IMP3-positive group was significantly higher than that of the IMP3-negative group in the suprabasal cell layer of SCC. These results suggest that IMP3 plays an important role in proliferation and, more significantly, in the invasion of SCC, and may be a suitable marker for the histopathological diagnosis of SCC with a crateriform architecture and KA. Furthermore, IMP3 may potentially be a new therapeutic target for SCC.

Association of psoriasis with Hashimoto's thyroiditis, Sjögren's syndrome and dermatomyositis.

Dear Editor, Psoriasis is an autoimmune chronic inflammatory skin disease and has been reported to coexist with other autoimmune diseases such as Hashimoto’s thyroiditis, Sj€ ogren’s syndrome and dermatomyositis. We describe here the first case of a combination of these four autoimmune diseases. A 52-year-old Japanese woman with Hashimoto’s thyroiditis for 6 years visited our department in October 2006. Physical examination revealed edematous erythema on her face, neck, upper back and extremities. Her upper back was covered with itching edematous erythema suggesting shawl sign (Fig. 1a). She had a heliotrope rash on the upper eyelids (Fig. 1b) and Gottron’s sign on the knuckles (Fig. 1c) with proximal muscle weakness. Abnormal laboratory findings were as follows: creatinine kinase, 187 IU/L (normal range, 50–170); myoglobin, 95 ng/mL (normal range, 0–65); thyroid-stimulating hormone, 7.1 lU/mL (normal, <5); antinuclear antibody, positive with a titer of 1:320; anti-SSA, more than 500 (normal, <7); and antithyroglobulin more than 100 (normal, <0.3). The skin biopsy from a forearm showed subtle vacuolar interface dermatitis with sparse superficial perivascular inflammation with increased mucin (Fig. 1d). The muscle biopsy from the left vastus lateralis muscle did not reveal an apparent muscle degeneration but lymphocyte infiltration of perimysium was found. The labial gland biopsy disclosed tightly aggregated lymphocytes surrounding a duct (>50 in 4 mm). From these findings, the diagnoses of Hashimoto’s thyroiditis, Sj€ ogren’s syndrome and dermatomyositis were made. She was treated with 60 mg prednisolone together with levothyroxine sodium hydrate with remarkable effect and gradually tapered off prednisolone. In July 2014, she visited us complaining of erythematic plaques with silvery scales on the face, neck, upper back (Fig. 1e), upper extremities and elbows of 2 months’ duration without treatment by prednisolone. The skin biopsy from an elbow showed marked acanthosis of the epidermal ridges with parakeratosis, dilated capillaries and lymphocytic perivascular infiltration in the dermis (Fig. 1f). From the clinical and histological findings, the diagnosis of psoriasis was made. She was treated with topical corticosteroid and vitamin D3 with remarkable effect. In November 2014, she visited us complaining of myalgia and symmetrical, proximal muscle weakness with a heliotrope rash, elevated creatinine kinase (226 IU/L) and positivity of anti-TIF-1 antibody, whereas psoriasis is well controlled. Being suspected of the recurrence of dermatomyositis, she was treated with 20 mg prednisolone. She is now being tapered off prednisolone together with the addition of 6 mg methotrexate and remains in clinically good condition both for dermatomyositis and psoriasis. Although there have been three reports of the association of psoriasis with Hashimoto’s thyroiditis and Sj€ ogren’s syndrome, there has been no report of the coexistence of these three diseases plus dermatomyositis. Furthermore, relatively few cases of patients with coexistent dermatomyositis and psoriasis have been reported. It is intriguing that T-helper 17 cells play an important role in both dermatomyositis and psoriasis. Dermatomyositis requires treatment with oral corticosteroids which are implicated in the exacerbation of psoriasis, (a) (b)

Successful multitarget therapy using prednisolone, mizoribine and tacrolimus for Henoch–Schönlein purpura nephritis in children

Figure 1. Clinical, endoscopic, histopathological and electron micrography of skin, alimentary tracts and/or kidney, and mutations in CYP3A5 and MDR1. (a) Clinical images of lower limbs. (b) Histopathological observations of a skin biopsy showing hematoxylin–eosin (H-E) staining and direct fluorescent stainings with antiimmunoglobulin (Ig)A and -C3 antibodies (scale bar, 100 lm). (c) Endoscopic and histopathological findings of Henoch– Sch€ onlein purpura (HSP)-affected alimentary tracts (scale bar, 100 lm). (d) Histopathological and electron micrography observations of a renal biopsy. Arrows in periodic acid methenamine silver (PAM) and Masson-trichrome stainings indicate fibrin deposition. Direct fluorescent stainings with anti-IgA1, -IgA2 and C3 antibodies are also shown. Arrowheads and an arrow in the electron micrograph demonstrate mesangial deposits and infiltration of a macrophage, respectively. (e) DNA sequencing showing the single nucleotide polymorphisms in CYP3A5 and MDR1, whose products are involved in the metabolism of tacrolimus. The DNA analyses were conducted after obtaining written informed consent according to the guidelines of the institutional review board of Nippon Medical School Hospital in accordance with the Declaration of Helsinki guidelines.

Case of lupus miliaris disseminatus faciei associated with marked formation of cysts, successfully treated with intralesional injections of triamcinolone acetonide

Dear Editor, Lupus miliaris disseminatus faciei (LMDF), a granulomatous inflammatory disorder, is characterized by red or white-yellowish papules typically on the eyelids, nose and around the lips. The condition is seen from adolescence to middle age. The lesions often regress spontaneously in 1–2 years, sometimes leaving scars. The etiopathogenesis is unknown. Currently, it is hypothesized that LMDF is an immune response to pilosebaceous units. Here, we report a patient with LMDF associated with marked formation of cysts that was resistant to various treatments but responded well to intralesional injections of triamcinolone acetonide. A 57-year-old woman developed erythematous papules on her eyelids and cheeks 5 months before referral. The condition improved slightly with oral minocycline and sulfur and camphor lotion ointment. The patient did not respond to 20 mg prednisolone per day for 2 weeks, so she was referred to our department. Numerous clusters of erythematous nodules, papules and cysts were present on the patient’s face (Fig. 1a) without flushing. Multiple cysts contained a yellow, translucent,

Dermoscopy of pigmented papillated Bowen disease: A report of two cases

(g) (h) Figure 1. (a) A 5 mm 9 3 mm brown keratotic plaque behind the left ear of the patient (case 1). (b) Dermoscopic findings showing whitish scaly fissures and bluegray to brown ridges surrounded by irregularly shaded brown areas. White arrows indicate fissures and a white arrowhead indicates ridges (case 1). (c) Histopathology showing a hyperkeratotic lesion with papillomatosis (case 1) (hematoxylin–eosin [HE], original magnification 920). (d) Atypical keratinocytes were hyperchromatic (case 1) (HE, 9400). (e) A 5 mm 9 3 mm dark brown keratotic nodule on the left knee of the patient (case 2). (f) Dermoscopic findings showing a blue-gray to brown cobblestone appearance with dark brown or whitish fissures and a continuing brown structureless area. White arrows indicate fissures and white arrowheads indicate ridges (case 2). (g) Histopathology showing hyperkeratosis, parakeratosis and papillary upward projections of the epidermis (case 2) (HE, 920). (h) Atypical keratinocytes were seen in the entire epidermis (case 2) (HE, 9200).

A Case of Metastatic Basal Cell Carcinoma Treated with Cisplatin and Adriamycin

A 72-year-old man was referred to our hospital for treatment of an ulcer that had been growing on his back for 10 years. Physical examination showed an ulcerated tumor from the neck to the back and swollen cervical lymph nodes. The tumor size was 12×9 cm. Histology of the biopsy showed a nodular and morpheic basal cell carcinoma (BCC). A chest computed tomography (CT) scan showed multiple lung tumors. CT-guided biopsy of the lung and the cervical lymph node revealed metastatic basal cell carcinoma (MBCC). The primary skin tumor was resected and a total of 10 courses of cisplatin (25 mg/m2/day×75%) and adriamycin (50 mg/m2×75%) were administered for metastatic basal cell carcinoma (MBCC). The patient died 5 years and 3 months after his first visit. Autopsy revealed MBCC in the lung, kidney, pancreas, several lymph nodes, liver and bone. A portion of the tumor cells were composed of squamoid cells with eosinophilic cytoplasm, large nuclei, lack of the characteristic peripheral palisading and retraction artifacts, and variable cytoplasmic keratinization. These pathological findings were compatible with basosquamous cell carcinoma. Chemotherapy was effective for MBCC in this patient.

Follicular lymphoma presenting follicular papules in the skin: A case report

ularly shaped blood vessels proliferating mainly in the dermis, with an infiltrate of lymphocytes and eosinophils in the dermal stroma (Fig. 1b). A high-power view revealed the aberrant vessels lined by plump, epithelioid endothelial cells (Fig. 1c). The deep subcutaneous nodule consisted of a well-circumscribed but non-encapsulated proliferation of dilated blood vessels of various sizes (Fig. 1b). These proliferating blood vessels consisted of intermingled thick-walled and thin-walled vessels (Fig. 1d). Elastica van Gieson staining showed internal elastic lamina in very few vessels, indicating that most of the blood vessels were veins (Fig. 1e). An obvious arteriovenous shunt was not identified. These clinical and histopathological findings led to the diagnosis of angiolymphoid hyperplasia with eosinophilia (ALHE) associated with underlying arteriovenous hemangioma (AVH). The endothelial cells in ALHE were immunoreactive to hypoxia-inducible factor (HIF)-1a, and rarely in AVH (Figs 1f,g). No recurrence was seen during a 3-year follow up. Angiolymphoid hyperplasia with eosinophilia, also known as epithelioid hemangioma, is an uncommon benign vascular lesion with distinct clinicopathological characteristics. Its etiology and pathogenesis are still uncertain. There is considerable controversy whether ALHE is a reactive lesion or a true neoplasm. Olsen and Helwig found arteriovenous malformation (AVM) in 42% of ALHE, and regard AVM as a possible cause of ALHE. Other authors also reported cases associated with arteritis, thrombus and AVM, mentioning the causal relationship of arterial lesions to ALHE. Sun et al. postulated that local hypoxia may play a role in the pathogenesis of ALHE. Our patient had underlying AVH in combination with ALHE. AVH is a rare, benign, acquired vascular lesion of unknown pathogenesis. To our knowledge, AVH, which is a type of hemangioma, not malformation, has never been described as a comorbidity of ALHE. We hypothesized that our patient had local hypoxia due to underlying AVH and the hypoxic condition led to endothelial cell proliferation, causing ALHE. In this case, diffuse cytoplasmic and moderate nuclear immunoreactivity of the endothelial cells for HIF-1a was observed in ALHE. HIF-1 is an oxygen-dependent transcription factor, which plays a crucial role in the angiogenesis of tumors. If hypoxia occurs, the HIF-1a subunit becomes stable and interacts with co-activators to modulate its transcriptional activity. Overexpression of HIF-1a can lead to the production of various hypoxia-inducible mRNA, including the mRNA encoding vascular endothelial growth factor, platelet-derived growth factor B, erythropoietin, galectin-3, WT-1 protein and transforming growth factor-a, which are confirmed stimulators of endothelial cell proliferation. Hypoxia may also promote endothelial cell proliferation though the renin–angiotensin–aldosterone system. Coexistence of ALHE with underlying deep type AVH and the immunohistochemical results in our case favor the hypothesis that ALHE is a reactive lesion triggered by hypoxia.

Intralymphatic Histiocytosis with Massive Interstitial Granulomatous Foci in a Patient with Rheumatoid Arthritis

Vol. 29, No. 2, 2017 237 Received January 11, 2016, Revised March 30, 2016, Accepted for publication April 7, 2016 Corresponding author: Hidehisa Saeki, Department of Dermatology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Tel: 81-3-5814-6254, Fax: 81-3-3823-6731, E-mail: h-saeki@nms.ac.jp This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright

Platelet-Rich Plasma Injection and Cutaneous Sarcoidal Granulomas

Corresponding author: Hidehisa Saeki, Department of Dermatology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. Tel: 81-3-5814-6254, Fax: 81-3-3823-6731, E-mail: h-saeki@nms.ac.jp This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright

Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type, with Primary Manifestation as an Upper Eyelid Swelling.

Extranodal natural killer/T-cell lymphoma (ENK/TCL) is most often in the nose or the nasopharynx but can present elsewhere. We report a rare case of ENK/TCL that presented as swelling of an upper eyelid without ocular involvement. A 76-year-old man visited our hospital with a swollen lesion of the left upper eyelid which had appeared 2 months earlier. A biopsy of the upper eyelid revealed slight perivascular and periadnexal infiltration of mononuclear cells with dermal edema. Treatment with oral prednisolone at a dosage of 20 mg/day decreased the eyelid swelling. However, 5 months later, exacerbation of the swelling and nasal congestion were observed. A second biopsy of the upper eyelid revealed a diffuse dermal infiltrate composed of mononuclear cells with an angiocentic growth pattern. Immunohistochemical studies and in situ hybridization showed natural killer-lineage antigens (CD56, granzyme B, and T-cell intracellular antigen 1) with expression of Epstein-Barr virus. These findings lead to the diagnosis of ENK/TCL. We treated the patient with radiation therapy (50 Gy) and 3 courses of a regimen including dexamethasone, carboplatin, etoposide, and ifosphamide. This case suggests that ENK/TCL can present with swelling of an upper eyelid as the primary sign of the skin lesion. Swelling of an upper eyelid should be considered in the differential diagnosis of ENK/TCL.