Akiko Kagotani

Small cell carcinoma of the urinary bladder and prostate: Cytological analyses of four cases with emphasis on the usefulness of cytological examination.

The occurrence of small cell carcinoma in the urinary bladder and prostate is rare. Only a few reports on the cytological features of small cell carcinoma of the urinary bladder in the urine specimen have been documented and, moreover, the urinary cytological features of prostate small cell carcinoma have been rarely reported. In this study, we analyzed the cytological features of four cases of small cell carcinoma of the urinary bladder and prostate, and discussed the usefulness of cytological examination of urine specimen for this type of tumor. This study included two urinary bladder and two prostate small cell carcinoma cases. Analyses of the cytological features of these cases revealed the following: i) the background was mostly inflammatory and necrotic material was also occasionally observed; ii) numerous tumor cells were present in two cases, whereas only a few neoplastic cells were observed in the remaining cases; iii) the neoplastic cells were small in size, had scant cytoplasm and a high nuclear/cytoplasmic ratio, and were arranged in small clusters or occasionally as single cells; iv) the tumor cell clusters showed prominent nuclear moldings; and v) the nuclei of the neoplastic cells were round to oval in shape with finely granular chromatin containing inconspicuous nucleoli. The cytological features of small cell carcinoma in the urine specimen are characteristic. Therefore, careful observation of the urine specimen may lead to a correct diagnosis of small cell carcinoma of the urinary bladder and, moreover, cytodiagnosis of prostate small cell carcinoma may also be possible.

High‐grade urothelial carcinoma of the bladder with rhabdoid features: cytological and histological report of two cases

Dear Editor, Urothelial carcinoma (UC) occasionally shows a broad spectrum of histological features and has various histopathological variants. Among these, UC with rhabdoid features is an extremely rare variant, characterized by the presence of large, round to oval discohesive tumour cells with abundant cytoplasm containing an eosinophilic body, vesicular chromatin and conspicuous nucleoli. Only a limited number of cases have been described in the literature (Table 1). These tumours must be distinguished from rhabdoid tumours in childhood, which have a typical translocation that has not been described in UC with rhabdoid features. Herein, we report two cases of UC with rhabdoid features of the urinary bladder, and are the first to describe the cytological features of this rare variant. Case 1 A 75-year-old man presented with gross haematuria. Computed tomography (CT) demonstrated a sessile non-papillary tumour in the right bladder wall that had directly invaded outside of the bladder wall. Voided urine cytological examination was performed and, subsequently, the patient underwent transurethral resection of the bladder tumour. His post-operative course was uneventful and no metastasis was observed for 4 months by CT scan. Case 2 A 59-year-old man presented with gross haematuria. CT showed a papillary and sessile tumour in the bladder. Voided urine cytological examination was performed, and transurethral resection of the bladder tumour was subsequently conducted, followed by cystectomy with lymph node dissection. His post-operative course was uneventful and no recurrence or metastasis was observed during the following 21 months. Cytologically, abundant single discohesive tumour cells were present in a necrotic background in case 1 (Figure 1a). Tumour cells were large, round to oval and had a high nuclear/cytoplasmic ratio, enlarged centrally located round to oval nuclei containing coarse chromatin and occasional conspicuous nucleoli (Figure 1a). A few large atypical cells with enlarged eccentrically located nuclei with relatively rich cytoplasm containing an intracytoplasmic dense body were observed: these features were considered to be rhabdoid (Figure 1a, arrows). Similarly, in case 2, a small number of single discohesive tumour cells was observed in a haemorrhagic background. Tumour cells were medium to large and round to oval with a high nuclear/cytoplasmic ratio and enlarged round to oval nuclei. A few large atypical cells with large eccentrically located nuclei were noted, with relatively rich cytoplasm containing an intracytoplasmic dense body (Figure 1b, inset). Histologically, the tumour in case 1 was composed of discohesive cells with a relatively rich eosinophilic cytoplasm and large eccentrically located nuclei containing coarse chromatin and conspicuous nucleoli (Figure 1c). Large discohesive tumour cells with bright eosinophilic intracytoplasmic bodies were also observed (Figure 1c, arrows). Conventional highgrade invasive UC and flat in situ high-grade UC components were also present. The tumour had invaded into the submucosa. In case 2, the neoplastic cells of the invasive growth were discohesive and had a high nuclear/cytoplasmic ratio, large round to oval nuclei containing conspicuous nucleoli, and relatively rich eosinophilic cytoplasm (Figure 1d). The tumour had invaded into the muscularis propria of the bladder wall. Low-grade papillary UC component was also present (Figure 1d, inset). The cystectomy specimen revealed no residual carcinoma, and no lymph node metastasis was observed. Both cases showed fundamentally the same immunohistochemical characteristics. The tumour cells with rhabdoid features were diffusely positive for cytokeratin (AE1/AE3, CAM5.2) and cytokeratin 7 (CK7), but negative for CK20, a-smooth muscle actin, desmin and S-100 protein. Vimentin was negative in case 1, but focally positive in case 2. The intracytoplasmic bodies of the rhabdoid cells showed dot-positive immunoreactivity for cytokeratin (AE1/ AE3) in both cases (Figure 1c, inset, arrows) and vimentin in case 2. The clinicopathological features of UC with rhabdoid features are as follows: (1) this type of carcinoma commonly affects elderly men but can also occur in children; (2) the tumour may be seen in the bladder or renal pelvis; (3) conventional papillary UC or Correspondence: M. Ishida, Division of Diagnostic Pathology, Department of Clinical Laboratory Medicine, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu 520-2192, Japan Tel.: +81-77-548-2603; Fax: +81-77-548-2407; E-mail: mitsuaki@belle.shiga-med.ac.jp 1 These two authors contributed equally to this report. Correspondence 54

Signet‑ring cell melanoma with sentinel lymph node metastasis: A case report with immunohistochemical analysis and review of the clinicopathological features

Signet-ring cell melanoma is an extremely rare variant of malignant melanoma. A 68-year-old male presented with a black nodule on the left thigh. Histopathological examination revealed proliferation of sheet-like or variable-sized nests of atypical melanocytes. Neoplastic cells showing signet-ring cell appearance, characterized by the presence of eccentrically located enlarged nuclei and abundant pale cytoplasm, were also present. Immunohistochemically, the tumor cells were positive for S-100 protein, vimentin and Melan-A. Moreover, mammalian target of rapamycin (mTOR) pathway proteins were diffusely expressed. The current case report presents the 21st reported case of signet-ring cell melanoma. Analyses of the clinicopathological features revealed that this disease commonly affects middle-aged males and the presence of metastatic signet-ring cell melanoma with an unknown primary tumor. Immunohistochemical analyses of melanocytic markers have been useful for establishing the diagnosis of this type of disease, however, HMB-45 is occasionally found to be negative. In addition, the present case report is the first to analyze the expression of mTOR pathway proteins, which are central proteins involved in carcinogenesis and its inhibitor has been proposed as a therapeutic target for various types of tumor. Therefore, the mTOR inhibitor may also be a potential candidate for the treatment of this type of tumor.

Adenoid cystic carcinoma of the external auditory canal successfully diagnosed by fine-needle aspiration

Dear Dr. Bedrossian: Malignant tumor of the external auditory canal (EAC) is rare, and squamous cell carcinoma is the most common histopathological subtype. Moreover, glandular tumor of the EAC is also extremely rare, representing 0.00025% of all surgical pathology cases in one large series, and 2.4% of all ear neoplasms at one referral institution. Glandular tumor of the EAC is thought to arise from the ceruminous gland, which is a modified apocrine gland that is found deep within the dermis, usually bordering the cartilage in the outer one-third to one-half of the EAC. Adenoid cystic carcinoma (ACC) is the most common histopathological subtype of malignant glandular tumor of the EAC, second to ceruminous adenocarcinoma. Cytological diagnosis of EAC tumor is challenging because of the rarity of this tumor. Thus far, only two cytolǒgical reports on ACC of the EAC have been reported. Herein, we describe the cytological analysis of the third case of this tumor and discuss the usefulness of fine needle aspiration (FNA) in diagnosis of glandular tumor of the EAC. A 50-year-old Japanese male presented with a painful nodular lesion in his left EAC. Physical examination revealed a reddish hard nodule, measuring 15 mm, in his left posterior wall of the EAC. Magnetic resonance imaging demonstrated a relatively well-circumscribed tumor in his left posterior wall of the EAC invading into the adjacent cartilaginous tissue (Fig. 1). FNA of the EAC tumor was performed, followed subsequently by total resection of the tumor. Papanicolaou smear of the FNA specimen revealed cohesive aggregates of relatively uniform round to oval epithelial cells with scant cytoplasm, round nuclei, coarse chromatin, and inconspicuous nucleoli (Fig. 2). There were pale green spherical globules within the neoplastic nests (Fig. 2), which formed a dense purplish color by May–Grunwald–Giemsa stain and were surrounded by tumor cells (Fig. 2, inset). According to these findings, a cytodiagnosis of ACC of the EAC was made. Histopathological study of the resected EAC tumor demonstrated proliferation of basaloid cells arranged

Pigmented cervical intraepithelial neoplasia.

To the Editor: Squamous cell carcinoma (SCC) usually does not contain melanocytes within the tumor. Although a few reports on invasive SCC or SCC in situ with melanocytic hyperplasia within the tumor, namely pigmented SCC, have been reported in some organs, such as skin (1), oral mucosa (2), and nasal cavity (3), only 1 case of pigmented SCC of the uterine cervix has been reported in the English-language literature (4). Herein, we describe the first reported case of pigmented cervical intraepithelial neoplasia (CIN). A 37-yr-old Japanese female with Crohn disease entered the cervical screening program and was determined to have severely dysplastic squamous cells by Papanicolaou smear. Biopsy from the cervix revealed CIN III, and thus, conization of the uterine cervix was performed. Histopathologic study of the resected specimen demonstrated that proliferation of atypical squamous cells with large oval to round nuclei containing coarse chromatin and a single nucleolus was observed in almost the entire squamous epithelium (Figs. 1 and 2). Maturation of the squamous epithelium was confined to the superficial region (Fig. 1). Mitotic figures were frequently seen and found in the upper third of the epithelium. Moreover, atypical mitotic figures were also observed. Glandular involvement was present; however, no invasive growth was noted. These features are typical for CIN III. Dendritic cells containing dark brown pigments, which were considered as melanocytes because these pigments were bleached by the peroxide method and immunohistochemically positive for S-100 protein and Melan-A (Fig. 3), were scattered among the atypical squamous epithelium (Fig. 2). These cells were without atypia, and mitotic figures were not observed. Melanin pigments were also present in the cytoplasm of some atypical squamous cells (Fig. 2, inset). No S-100 protein and Melan A-positive melanocytes were present in the adjacent squamous and endocervical mucosae or in the stroma, although melanophages were scattered (Fig. 2). In addition, a few CD1a-positive dendritic cells were present within the CIN; however, the number of these cells in this region was low compared with that in adjacent normal squamous and endocervical mucosae. According to these findings, an ultimate diagnosis of pigmented CIN III was made. The uterine cervix is normally devoid of melanocytes; therefore, melanin-containing lesions such as melanosis, lentigo simplex, blue nevi, and malignant melanoma are extremely rare at this site (5). In addition, pigmented SCC is extremely rare in the uterine cervix; only 1 case of pigmented SCC has been reported (4), and the FIG. 1. Low-power view of cervical intraepithelial neoplasia III. Atypical squamous cell proliferation is observed almost entirely in the squamous epithelium. Melanophages are observed under the epithelium.

Pigmented median raphe cyst of the penis with consideration of the possible mechanism of melanocytic colonization: A case report

Median raphe cyst is a rare lesion located on the median raphe. The cyst wall is lined by cuboidal to columnar cells, transitional (urothelial) cells, stratified squamous cells or a mixture of these. The normal urethral mucosa and the median raphe cyst usually lack melanocytes and/or melanin pigment. However, albeit extremely rare, the presence of melanin pigment and/or melanocytes in median raphe cyst, namely pigmented median raphe cyst, has been previously reported. The current case report presents the sixth case of pigmented median raphe cyst and discusses the possible mechanism of melanocytic colonization in this tumor. A 48-year-old male presented with a nodule on the ventral surface of the penis. Histopathological study revealed that the cyst wall was covered by uniform bland cuboidal to urothelial cells. The peculiar observation was the presence of dendritic melanocytes among the epithelial cells. Therefore, a diagnosis of pigmented median raphe cyst was determined. Immunohistochemically, stem cell factor and endothelin-1 were not expressed in the epithelial cells of the cyst wall. It is well-known that melanocytes are rarely found in various non-melanocytic tumors, a phenomenon termed ‘colonization’. The mechanism by which melanocytes appear in median raphe cyst remains unclear. The present report is the first to demonstrate that melanocytic proliferation and differentiation factors, such as stem cell factor and endothelin-1, are not involved in the pigmentation of median raphe cyst. In addition, aberrant melanocytic migration may contribute to the development of this type of lesion.

Ascitic fluid due to type II herpes simplex virus infection: Report of a case with immunocytochemical confirmation

Herpes simplex virus (HSV) infection is usually observed in the oral cavity and external genitals, and HSV peritonitis is extremely rare. Herein, we report a case of type II HSV peritonitis successfully diagnosed by ascitic cytology. A 66‐year‐old Japanese man, who had been treated with steroid inhalation for 5 years due to chronic obstructive pulmonary disease, was suspected to have acute cholecystitis. Laparoscopic cholecystectomy and intraoperative cytological examination of ascitic fluid were performed. Cytological study of ascitic fluid revealed that abundant granular cell debris, degenerative cells and apoptotic bodies were present, as well as some single or multinucleated cells with ground glass nuclei. However, vivid mesothelial cells were rarely seen. Immunocytochemical staining for type II HSV was positive in single or multinucleated cells with ground glass nuclei. Therefore, a diagnosis of type II HSV peritonitis was made. This is the first reported case of type II HSV peritonitis successfully diagnosed by ascitic cytology. This report highlights that the presence of abundant cell debris, degenerative cells and apoptotic bodies, and the absence of vivid mesothelial cells are the key cytological findings to suspect HSV peritonitis, and the diagnosis can be confirmed by careful surveillance for characteristic nuclear findings of single or multinucleated cells. The frequency of opportunistic infection is increased because of the increased numbers of iatrogenic immunocompromised patients as seen in this case, therefore, cytological examination is a useful method for early detection of the causative agent of peritonitis including HSV. Diagn. Cytopathol. 2013;41:354–359.

Mediastinal seminoma: A case report with special emphasis on SALL4 as a new immunocytochemical marker

Cytological diagnosis is a valuable method for detection of mediastinal tumors, and recent reports have shown the usefulness of fine‐needle aspiration cytology for diagnosis of mediastinal tumors, including germ cell tumors. We report a case of mediastinal seminoma diagnosed intraoperatively by cytological examination of cystic fluid containing tumor cells.

Mucinous carcinoma occurring in the male breast

Male breast carcinoma is an uncommon neoplasm, accounting for 0.6% of all breast carcinomas. Invasive ductal carcinoma of no special type is the most common type of male breast carcinoma, and mucinous carcinoma occurring in the male breast is extremely rare. In the present study, we report a case of mucinous carcinoma of the male breast and discuss the clinicopathological features of this type of tumor. A 63-year-old Japanese male presented with a gradually enlarged nodule in the right breast. The resected breast specimen revealed pure mucinous carcinoma and immunohistochemical analyses demonstrated that tumor cells were positive for estrogen receptor (ER), but negative for progesterone receptor (PgR). In addition, HER2 expression was not amplified. Pure mucinous carcinoma is generally associated with a low incidence of lymph node or distant metastases, and excellent disease-free survival in females. However, certain cases of this type of tumor with axillary lymph node metastasis in the male breast have been reported. In addition, the immunoprofiles of mucinous carcinoma in males are fundamentally the same as those in females. More than 90% of cases show positive immunoreactivity for ER and/or PgR, and HER2 expression is not amplified. However, it has been reported that breast cancer in males is more frequently positive for ER than in females, and has less HER2 overexpression. The high rate of hormone receptor-positive breast cancer in males is considered to be due to similar conditions as those in breast cancer in postmenopausal women. The pathogenesis of male breast carcinoma, including mucinous carcinoma, remains unclear; therefore, additional clinicopathological studies are required.

Pigmented paget's disease: a diagnostic pitfall.

Paget’s disease (PD) of the breast is a rare manifestation of breast carcinoma, characterized by the presence of malignant glandular epithelial cells (Paget cells) within the squamous epithelium of the nipple and clinical manifestation of eczematous or erythematous changes of the nipple. PD is usually associated with underlying ductal carcinoma in situ or invasive ductal carcinoma, resulting from intraductal spread of carcinoma cells via lactiferous ducts into the skin of the nipple. Pigmented PD, characterized by the presence of melanin pigment in the Paget cells and/or dendritic melanocytes within the tumor nests, is a rare but distinct variant of PD. Herein, we describe the first cytological report on pigmented PD and discuss the differential diagnostic considerations. A 72-year-old Japanese female with a past history of brain infarction presented with an erosion of the right nipple. Physical examination revealed that an erythematous lesion accompanying focal erosion was present in the right nipple, however, no palpable tumor was present in her right breast. Mammography and computed tomography demonstrated no tumorous lesion in the right breast. PD was suspected clinically, thus, a scrape cytological examination was performed, and then total mastectomy was performed. Papanicolaou-stained scrape smear demonstrated that single or small clusters of atypical large cells were scattered in a background of abundant neutrophils and squamous cells without atypia. These atypical large cells had dense cytoplasm and large oval nuclei with coarse chromatin and conspicuous nucleoli. Molding of tumor cells was noted. A few atypical large cells had melanin pigment in the cytoplasm (Fig. 1). Immunocytochemical analysis revealed that these tumor cells showed positive immunoreactivity for cytokeratin (CK) 7 (Fig. 1, inset). Therefore, a cytodiagnosis of pigmented PD was made. Histopathological study of the mastectomy specimen showed that proliferation of atypical large epithelial cells with pale to slightly eosinophilic cytoplasm and large oval nuclei with conspicuous nucleoli (Paget cells) was observed within the epidermis of the nipple accompanied by focal erosion of the epidermis. Some Paget cells had melanin pigment in the cytoplasm, and dendritic melanocytes without atypia were observed within the tumor nests in the epidermis (Fig. 2). Intraductal proliferation of these carcinoma cells was also observed in the lactiferous ducts beneath the nipple (Fig. 2, inset). No invasive growth was noted. Immunohistochemically, tumor cells were positive for CK7, gross cystic disease fluid protein-15, and epithelial membrane antigen (EMA), but negative for S-100 protein, Melan A, HMB-45, and CK (34betaE12). Moreover, overexpression of HER2 protein was observed. Therefore, an ultimate diagnosis of pigmented PD was made. Scrape cytology has been recognized as a useful, easy, and non-invasive method for diagnosis of PD. Detection of cytological atypia of Paget cells can easily lead to a diagnosis of malignant tumor, however, differentiation from squamous cell carcinoma in situ of the skin (Bowen’s disease) and malignant melanoma may be difficult. Vohra et al. pointed out that long-standing lesions of PD frequently show epidermal hyperplasia with hyperparakeratosis and reactive atypia of keratinocytes, resulting in the presence of atypical keratinizing cells admixing with Paget cells. Therefore, differentiation from squamous cell Department of Clinical Laboratory Medicine and Division of Diagnostic Pathology, Shiga University of Medical Science, Shiga, Japan *Correspondence to: Mitsuaki Ishida, M.D., Ph.D., Department of Clinical Laboratory Medicine and Division of Diagnostic Pathology, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, E-mail: mitsuaki@belle.shiga-med.ac.jp Received 7 August 2012; Accepted 31 December 2012 DOI: 10.1002/dc.22977 Published online 1 March 2013 in Wiley Online Library (wileyonlinelibrary.com).