Motoki Arakane

KIT (CD117) Expression in Benign and Malignant Sweat Gland Tumors.

Abstract:KIT (CD117, c-kit) is a receptor tyrosine kinase involved in the tumorigenesis of several neoplasms. KIT is expressed by the secretory cells of normal sweat glands. We studied the KIT expression and KIT mutational status in various benign and malignant tumors of eccrine and apocrine glands. We included a total of 108 cases comprising 10 benign and 6 malignant sweat gland tumors, and KIT expression was immunohistochemically detected (positive rate): 10 syringomas (0%), 8 poromas (25%), 20 mixed tumors (40%), 21 spiradenomas (43%), 1 cylindroma (0%), 5 hidradenomas (40%), 7 syringocystadenoma papilliferum cases (0%), 1 papillary hidradenoma (100%), 2 tubulopapillary hidradenomas (50%), 8 hidrocystomas (29%), 2 adenoid cystic carcinomas (100%), 5 porocarcinomas (20%), 6 apocrine carcinomas (33%), 10 extramammary Paget diseases (30%), 1 spiradenocarcinoma (100%), and 1 syringocystadenocarcinoma papilliferum (0%). Most KIT-positive cells were luminal cells, arising from glandular structures. We performed polymerase chain reaction–single-strand conformation polymorphism for detecting KIT mutational status. All cases showed no mutations at hot spots for KIT (exons 9, 11, 13, and 17). KIT mutation does not seem to be mechanism for KIT expression, but the expression may be from native sweat glands.

Gastric lanthanosis (lanthanum deposition) in dialysis patients treated with lanthanum carbonate.

Lanthanum carbonate (LaC) is used to prevent hyperphosphatemia in dialysis patients. It is commonly believed that there is little LaC absorption from the intestines. However, La deposition in the gastric mucosa, which we coined “gastric lanthanosis”, was recently reported. We describe here the clinicopathological features of and a possible mechanism for gastric lanthanosis. This study included 23 patients with definite gastric lanthanosis. We extracted characteristic clinicopathological features of gastric lanthanosis by computed tomography (CT) imaging and endoscopic, histologic, electron‐microscopic, and element analysis examinations. The Helicobacter pylori infection rate in the lanthanosis group was much lower than that among the general population. The clinicopathological features characteristic of gastric lanthanosis were mucosal high‐density linear appearance by CT, reflective bright‐white spots (BWS) by gastroscopy, eosinophilic histiocytes occasionally phagocytizing foreign materials by histology, and numerous electron‐dense particles in the histiocytes. The particles had burr‐like skeletons resembling La crystals. Gastric lanthanosis is an under‐reported, but not a rare lesion. It is characterized by endoscopic BWS and histologic eosinophilic histiocytes in dialysis patients treated with LaC. The proposed mechanism for gastric lanthanosis is that LaC is dissolved by gastric juice, crystallized within the mucosa and is phagocytized by histiocytes.

Pigmented median raphe cyst of the penis.

To the Editor, Median raphe cyst represents a relatively rare cystic lesion on the median raphe, which extends from the urethral meatus to the anus. Since the first report by Mermet in 1895,1 several terminologies, including median raphe cyst, ‘mucoid cyst of penile skin’ and ‘genitoperineal cyst of the medium raphe’ have been used.2 There is a general agreement that median raphe cyst is derived from the urethral mucosa or urethral gland (Littre’s gland).3 It appears commonly in children or adolescents with a mean size of less than 20 mm.4 Rarely, median raphe cyst contains melanin and melanocytes and clinically has a pigmented appearance. Such a cyst is called pigmented median raphe cyst.5 We report herein a case of pigmented median raphe cyst with a review of the literature. A 6-year-old boy presented with a brownish nodule on the ventral aspect of the penis, which had been noticed 5 years previously and increased in size with body growth. On physical examination, the nodule was slightly elevated with a smooth surface and was elliptical in shape, elastic soft and movable, measuring 2 × 8 mm on the median raphe of the penis (Fig. 1). The nodule was resected, and no local recurrence was noted 10 months postoperatively. Microscopic examination of the resected specimen showed a unilocular cyst in the dermis (Fig. 2A). The inner surface of the cyst was smooth and lined by one to several layers of uniform bland cuboidal cells with abundant brown pigment (Fig. 2B). No cells showed decapitation secretion reminiscent of apocrine origin. The brown pigment was melanin, as it stained black by the Fontana–Masson method and bleached by potassium permanganate–oxalic acid solution. Although it was difficult to detect melanocytes with hematoxylin–eosin staining, immunostaining for Melan A/MART-1 by alkaline phosphatase and fast-red highlighted them at the basal layer (Fig. 2C). Fig. 1. A brownish elliptic-shaped nodule on the median raphe (arrows) of the penis.

Intravenous leiomyomatosis treated with radical hysterectomy and adjuvant aromatase inhibitor therapy

Intravenous leiomyomatosis (IVL), a rare disease that is histologically benign but clinically aggressive, is characterized by the intraluminal growth of benign leiomyoma in the intrauterine and systemic veins. Preoperative diagnosis of IVL is difficult, because the symptoms of early stage IVL are similar to those of uterine leiomyoma. The efficacy of adjuvant hormone therapy after surgical resection of IVL remains unclear. Herein is described a case of IVL that was diagnosed preoperatively, in which successful total resection of the tumor was achieved by radical hysterectomy. The patient, a 50‐year‐old premenopausal Japanese woman, also underwent aromatase inhibitor treatment and was free of disease at 36 months after surgery. Contrast‐enhanced computed tomography is suggested as the best assessment for identifying and diagnosing IVL. Radical hysterectomy can be considered a successful therapy for total resection. Aromatase inhibitor treatment may be effective, especially when the patient has not yet entered menopause.

Significant expression of thyroid transcription factor-1 in pulmonary squamous cell carcinoma detected by SPT24 monoclonal antibody and CSA-II system.

In contrast to the usefulness of thyroid transcription factor-1 (TTF-1) in distinguishing primary adenocarcinoma of the lung from metastatic lesions, TTF-1 expression in pulmonary squamous cell carcinoma is reported to be at low level and not a suitable immunohistochemical marker. We hypothesized that the highly sensitive detection system, CSA-II, can visualize even faint expression of TTF-1 in pulmonary squamous cell carcinoma. In this study, 2 commercially available clones of TTF-1 monoclonal antibody, 8G7G3/1 and SPT24, were used for staining 38 cases of pulmonary squamous cell carcinoma, in combination with the CSA-II and the conventional detection system, EnVision. The combined use of the 8G7G3/1 clone with EnVision and CSA-II showed a positive reaction in only 1 and 4 cases, respectively. The use of SPT24 clone showed positive staining in 5 cases with EnVision and in 20 of 38 cases (52.6%) with the CSA-II. Interestingly, positive staining by the SPT24-CSA-II technique of samples from tissue blocks preserved for <2 years was 73.6% compared with only 31.5% in those preserved for >2 years. In addition, a 6-month preservation of the cut sections resulted in stain fading and decreased positivity (50%), compared with freshly cut sections. We conclude that the use of the SPT24 monoclonal antibody with the CSA-II system can detect even weak expression of TTF-1 in pulmonary squamous cell carcinoma. This staining technique can potentially allow the discrimination of primary squamous cell carcinoma of the lung from metastatic lesions, especially in freshly prepared paraffin sections.

Cutaneous horn malignant melanoma

A 73-year-old Japanese woman presented with cutaneous horn on the right cheek. The resected tumor was 9 mm in diameter, with 14 mm protrusion, and showed exophytic growth with marked papillomatosis. Histopathology showed proliferation of atypical melanocytes with melanin pigments in the epidermis and dermis under the cutaneous horn. These cells were confined to the base of the cutaneous horn, and did not spread to the surrounding epidermis. The final diagnosis was cutaneous horn malignant melanoma. This pathological entity is considered a specific form of verrucous melanoma, and might be added to the list of cutaneous horn-forming lesions.

Case of malignant melanoma that developed the ability to secrete granulocyte colony-stimulating factor.

tory of erosion on her left nipple. Physical examination revealed a reddish nodule measuring 10.7 mm 9 9.8 mm 9 8.0 mm with an erosive surface on her left nipple (Fig. 1a). Breast palpation failed to reveal any masses except for the nodule on her nipple. However, magnetic resonance imaging revealed limited dilation of lactiferous ducts in the upper medial part of her left breast, which was separated from her nipple. A biopsied specimen from her nipple revealed an ill-defined dermal tumor composed of a collection of ductal structures of varying shapes and sizes (Fig. 1b,c). These structures were lined with two distinct types of epithelial cells: myoepithelial cells lining the outer edge of the ductal structure, and cuboidal cells facing the lumen with frequent apocrine snouts. Mild atypia, with variation in size and shape, and hyperchromatic nuclei with prominent nucleoli were observed (Fig. 1c). Immunohistochemically, more than half the tumor cells were positive for 5-hmC (73.0 3.9%) (Fig. 1d). We diagnosed it as EAN and performed a tumor resection with preservation of her left nipple. Mild atypicality was also found in a vacuum-assisted biopsy specimen from the dilated lactiferous ducts. Wide local excision was performed. Histopathologically, mildly atypical epithelial cells formed a cribriform architecture within the ductal structure (Fig. 1e). The ratio of 5-hmC-positive cells was less than 10% (Fig. 1f). We diagnosed it as ductal carcinoma in situ (DCIS). In case 2, a 44-year-old Japanese woman had a 4-month history of bloody discharge from her left nipple. Physical examination revealed a well-defined erosion without induration (Fig. 1g). A biopsied specimen showed ductal structures consisting of two cell types: myoepithelial cells and epithelial luminal cells (Fig. 1h). Immunohistochemically, more than the tumor cells were positive for 5-hmC (83.5 2.9%). We diagnosed it as EAN and performed a tumor resection with preservation of her left nipple. Erosive adenomatosis of the nipple is a benign mammary proliferation that may be misdiagnosed as breast cancer, especially DCIS. DCIS is a malignant proliferation of cells within the basement membrane-bound structures. Immunostaining of several proteins, including carcinoembryonic antigen, vimentin and muscle-specific actin, has been used to aid diagnosis. The results of this staining are reliable, but not absolute. Levels of 5-hmC are dramatically reduced in a broad spectrum of human cancers. Immunohistochemically, fewer than 10% of tumor cells in breast cancer are 5-hmC-positive (Prof. Ken-ichi Ito, 2015, unpubl. data). We noted a clear difference in the proportion of 5-hmC-positive tumor cells between EAN and DCIS, implying that the presence of 5-hmC will be useful for the diagnosis of EAN.

Difference in transducin-like enhancer of split 1 protein expression between basal cell adenomas and basal cell adenocarcinomas - an immunohistochemical study

BackgroundBasal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) are benign and malignant, basaloid salivary gland neoplasms, respectively. These tumors show a dual-cell proliferation of inner luminal/ductal cells and outer abluminal/myoepithelial or basal cells. The only difference between them is defined as a malignant morphology such as invasion. Recently, the nuclear expression of β-catenin and a catenin beta-1 (CTNNB1) mutation were found in BCA. Transducin-like enhancer of split 1 (TLE1) belongs to the Groucho/TLE family, and it functions in the “off” state in the Wnt/β-catenin signaling pathway. We hypothesized that if the dysregulation of the Wnt/β-catenin signaling pathway could be attributed to the tumorigenesis of BCA/BCAC, there might be differences in TLE1 expression between BCA and BCAC.MethodThe study included 35 BCA and 4 BCAC cases. We performed immunohistochemistry to detect TLE1 and β-catenin and investigated the catenin beta-1 (CTNNB1) mutational profile among BCA and BCAC cases.ResultsIn BCA, the expression of TLE1 was confined to luminal cells of glandular structures, in contrast to the expression of β-catenin in abluminal cells. The BCA cases harbored CTNNB1 gene mutations (12/35). In BCAC, luminal cell staining of TLE1 was identical to BCA in non-invasive areas (4/4) but indistinct in invasive areas (3/4). The BCAC cases were β-catenin positive for abluminal cells in both areas. The BCAC cases had CTNNB1 mutation (2/4) and the laser-captured microdissection allowed the separate collection of infiltrative and non-infiltrative areas to detect the same mutation.ConclusionsImmunohistochemical analysis for TLE1 can identify BCA and BCAC by luminal cell staining difference, especially indistinct luminal cell expression for TLE1 in invasive areas of BCAC. Moreover, TLE1 can be luminal/ductal cell markers.

A case of anaplastic lymphoma kinase-positive renal cell carcinoma coincident with Hodgkin lymphoma

We report a case of ALK‐positive renal cell carcinoma coincident with Hodgkin lymphoma. The patient was a 19 year‐old‐girl without sickle cell trait. The right renal tumor was discovered concomitantly with Hodgkin lymphoma (HL). After chemotherapy for HL, right nephrectomy was performed. Microscopically, the tumor showed a solid and focally pseudo‐papillary growth pattern studded with tubular structures. Most tumor cells were small bland eosinophilic cells, but rhabdoid cells, vacuolated cells, pleomorphic multinucleated giant cells were also admixed. The variety of growth patterns and cell features led us to speculate a possibility of ALK‐positive renal cell carcinoma (ALK + RCC). ALK was immunohistochemically positive, and fluorescence in situ hybridization analysis detected a split signal of the ALK gene. We examined previously reported partner genes (STRN, TPM3, VCL and EML4) by RT‐PCR, but fusion gene was not detected. RCC showing solid or cribriform growth patterns with vacuolated cells with intracytoplamic lumina, rhabdoid cells, and mucus production indicates the possibility of ALK + RCC.

Peutz–Jeghers-type polyp with malignant transformation arising in the ileal conduit

To the Editor: Peutz–Jeghers syndrome (PJS) is a hereditary gastrointestinal polyposis characterized by mucocutaneous pigmentation. The gastrointestinal polyps in PJS have a distinct histological appearance with a branching pattern of smooth muscle. A solitary hamartomatous polyp with similar histology but without mucocutaneous pigmentation or a family history of PJS is diagnosed as a Peutz–Jeghers-type polyp. The ileum is the most frequent part of the gastrointestinal tract that is incorporated into the urinary tract. Although the incorporation of the bowel segment into the urinary tract has several advantages, the potential long-term sequelae of this procedure, particularly the late development of cancer, are of prime concern. To the best of our knowledge, ours is the first case of a solitary Peutz–Jeghers-type polyp with a focus on adenocarcinoma arising in the ileal conduit. A 53-year-old female patient had an ileal conduit constructed 30 years prior, as a surgical intervention for nephrogenic diabetes insipidus. Twenty-three years after the surgery, she was placed on hemodialysis due to diabetic nephropathy. The patient came to our hospital with the chief complaint of lower abdominal pain and gross hematuria from her urostomy. The patient had neither mucocutaneous pigmentation nor a family history of gastrointestinal polyposis that would suggest PJS. No physical abnormalities were observed. Her tumor marker laboratory tests were normal. Endoscopic examination revealed a mutilobulated polyp measuring approximately 20 mm in diameter, 10 cm from the ileal conduit opening (Fig. 1). We subsequently performed a mucosal resection because the hematuria was considered to be caused by this polyp. A gastrointestinal and colonic endoscopy showed no other polyps. On macroscopic observation, the polyp was pedunculated and multilobulated, measuring 24 × 10 mm in diameter. Histological examination showed branching bundles of smooth muscle and hyperplastic ileal mucosa (Fig. 2, top), which were suggestive of a Peutz–Jeghers-type polyp. The background ileal mucosa showed the non-tumoral small intestinal mucosa with Paneth cells and mild chronic inflammation in the lamina propria. Glandular cells lacked nuclear atypia for the most part, but atypical cells corresponding to well-differentiated adenocarcinoma were focally observed (Fig. 2, bottom). The adenocarcinoma component was about 5%. Immunohistochemical studies revealed MUC2 was focal positive, MUC4 and CDX2 were positive diffusely. The mucin phenotypes corresponded to the intestinal phenotype. These results were similar to the background ileal mucosa. Ki-67/MIB-1 overexpression was observed in the adenocarcinoma cells. Therefore, the tumor was diagnosed as well-differentiated tubular adenocarcinoma in a Peutz–Jeghers-type polyp. The patient’s postoperative course has been unremarkable with no further bleeding. Endoscopic examination was performed at regular intervals, and there has been no recurrence during the 44-month follow-up period. Peutz–Jeghers syndrome is an autosomal dominant hamartomatous polyposis syndrome that is associated with mucocutaneous hyperpigmentation; the majority of patients with PJS have been diagnosed with a mutation in the STK11 gene, which is located at 19p13.3. PJS polyps are histologically characterized by smooth muscle showing a typical branching pattern. Our patient did not exhibit mucocutaneous hyperpigmentation and did not have family history of gastrointestinal polyposis. However, several patients with a solitary hamartomatous polyp without familial history and mucocutaneous pigmentation have been previously described and such lesions are called Peutz–Jeghers-type polyps. A search of case reports on the MEDLINE database up to 2013 using the terms ‘Peutz–Jeghers-type polyp’ revealed 24 publications, all of which describe polyps in gastrointestinal tract, including the duodenum (36%), small intestine (24%), and large intestine (24%). Among them, only four cases were associated with malignant transformation. Sekino et al. reported that the malignant transformation rate of duodenal Peutz-Jeghers-type polyps was 14.8% (4 of 27 cases). Previous reports demonstrate that 3%–6% of PJS polyps undergo neoplastic change, such as adenomas or adenocarcinomas. Peutz–Jeghers-type polyps should be treated with endoscopic or surgical resection because of their malignant potential. The ileum is the most frequent part of the gastrointestinal tract that is incorporated into the urinary tract. It is estimated that more than 10 000 patients who undergo cystectomy for bladder cancer in the USA each year receive a conventional ileal conduit and that more than 2000 of them receive a continent urinary diversion. Metabolism disorders, renal dysfunction, stenosis of anastomosis and ileus, particularly the development of cancer are long-term sequelae that cause major concern. Certain reports of late malignancy were documented following augmentation cystoplasty or urinary conduit. Adenocarcinoma and urothelial carcinoma are the most frequently reported urointestinal cancers, whereas squamous cell carcinoma has rarely been reported. Ali-El-Dein et al. investigated late urointestinal malignancy in patients who underwent ileal incorporation in the urinary Pathology International 2015; 65: 106–107 doi:10.1111/pin.12233 bs_bs_banner