Expression of erythropoietin receptor in human Merkel cell carcinoma of the eyelid.

BACKGROUND: Merkel cell carcinoma (MCC) of the eyelid is a rare malignant solid tumor of the elderly, which demonstrates a large, firm, reddish nodule mimicking an angiomatous lesion. The expression of erythropoietin (Epo) and Epo receptor (EpoR), as well as vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR) and basic fibroblast growth factor (bFGF) were examined in human MCC tissues. MATERIALS AND METHODS: Three patients diagnosed with MCC of the eyelid underwent surgical excision. Isolated tissues were fixed by 4% paraformaldehyde and then were examined using immunohistochemistry. RESULTS: The carcinoma cells consisted of irregular tumor nests with linear stroma and showed hypercellularity indicated by small round nuclei with several mitoses. While immunoreactivity of Epo was undetectable, an increased expression of EpoR was noted in the carcinoma cells. Cytoplasmic immunoreactivity for EpoR was detected in a variety of carcinoma cells, including mitotic cells. VEGF, VEGFR, and bFGF, other angiogenic factors were not expressed in the MCC tissues. CONCLUSION: EpoR was highly expressed in MCC of the eyelid, suggesting that the Epo-EpoR pathway plays an important role in the formation of MCC.

Expression of thymidine phosphorylase in choroidal malignant melanoma associated with neovascular glaucoma.

Reported herein is a case of 62-year-old man who complained of blurred vision and ocular pain in his right eye. The patient was diagnosed with choroidal melanoma complicated by neovascular glaucoma (NVG) and total retinal detachment, and he underwent enucleation of the eye. The isolated tumor was 2.5 x 2.5 cm in size. It was accompanied by intratumoral calcification, and consisted of epithelioid and spindle melanoma cells. There were a variety of microvessels in the stroma of the iris. The expression of thymidine phosphorylase (dThdPase), an angiogenic factor, was examined immunohistochemically. Cytoplasmic immunoreactivity for dThdPase was more prominent in the epithelioid cells than in spindle tumor cells. Another case of choroidal melanoma without NVG had less marked immunoreactivity. These results suggest that the production of dThdPase by melanoma cells correlates with the pathogenesis of NVG.

Cyclo-oxygenase-1 and -2 expression in human oral mucosa, dysplasias and squamous cell carcinomas and their pathological significance.

Cyclo-oxygenase (COX) is a key enzyme in the conversion of arachidonic acid to prostanoids. The expression of its isoforms, COX-1 and -2 is found in many human malignancies. This study analyzed the correlation between COX expression and the pathobiological nature of human oral mucosa, dysplasias and squamous cell carcinomas (SCCs). We examined 9 specimens of normal oral epithelia, 65 lesions with dysplasias and 50 SCCs. Labeling indices (LIs) for COX-1, COX-2, Ki-67 and P53, microvessel density (MVD) and apoptotic index (AI) were evaluated using immunohistochemistry and TUNEL methods. Western blot analysis of COX-1 and -2 was performed on four human oral SCC cell lines, all of which showed expression. The LIs for COX-1 and -2 were higher for the dysplasias than the SCCs. LIs of COX-2 but not COX-1 correlated with the histological grade of dysplasia, being highest for the severe dysplasias (p < 0.05). In contrast, the COX-2 LIs as well as COX-1 were significantly (p < 0.05) inversely correlated with the histological differentiation of the SCCs. COX-2 expression was significantly correlated with LIs of COX-1 for dysplasia (p < 0.05), but not for the SCCs. In addition no significant relationship was noted between COX-2 expression and the Lis of Ki-67, P53, AI as well as MVD for the dysplasias and SCCs. The expression of COX-1 and -2 is correlated with early stage tumorigenesis and cellular differentiation of SCCs in the oral dysplasia-carcinoma sequence.

Epstein-Barr virus-infected malignant T/NK-cell lymphoma in a patient with hypersensitivity to mosquito bites.

We report an autopsy case of Epstein-Barr virus (EBV)-infected malignant lymphoma in a young male who had hypersensitivity to mosquito bites. The autopsy revealed multiple confluent lymphoma lesions in the lungs, and on the right leg irregular-shaped skin ulcers were seen. The left pleural effusion also contained a large number of lymphoma cells. The lymphoma cells were determined as T/NK-cell type cells by immunohistochemistry. EBV DNA was detected most intensively in the lungs and EBV-encoded small RNAs-positive lymphoma cells were also observed in the lungs at a high frequency. EBV latent membrane protein-1 expression and a high Ki-67 labeling indices were noted in the lymphoma cells of the lung lesions. These findings indicate that the development of the malignant lymphoma was associated with the proliferation of EBV-infected lymphoma cells, and the cells that infiltrated the whole the body, especially the lungs, caused the patient's death.

Cardiac chondrosarcoma producing parathyroid hormone-related protein.

Chondrosarcoma is a malignant tumor characterized by the formation of cartilage. A case of primary cardiac chondrosarcoma of the left atrium developed in a middle-aged male. The preoperative serum concentrations of C-parathyroid hormone-related protein (PTHrP) and calcium were high (413.2 pmol/L and 12.2 mg/dl, respectively), but normalized after resection of the tumor, which measured 7 x 5 x 3.5 cm. The tumor was histopathologically diagnosed as chondrosarcoma, composed of outer atypical chondroid cells and inner pleomorphic and spindle mesenchymal cells mimicking malignant fibrous histiocytoma. Half of the cartilaginous tumor cells and a few pleomorphic cells showed cytoplasmic immunoreactivity for PTHrP. The tumor is a possible example of the functional pleiotropy of chondrosarcoma.

Expression of cyclooxygenase-1 and cyclooxygenase-2 in human esophageal mucosa, dysplasia and carcinoma.

OBJECTIVE: COX (cyclooxygenase), a prostaglandin H synthase, catalyzes the rate-limiting step in prostaglandin biosynthesis. Two isoforms of COX have been identified: COX-1 and COX-2. We examined the expression of COX-1 and COX-2 in esophageal normal mucosa, dysplasia and squamous cell carcinoma (SCC). METHODS: The expression of COX-1 and COX-2 in 80 surgically removed esophagi due to SCC, as well as in 5 human esophageal SCC cell lines was analyzed, using immunohistochemistry and Western blot analyses. RESULTS: COX-1 and COX-2 were variably expressed in the SCC cell lines. Higher COX-1 expression was noted in 31 (41.9%) of the 74 specimens of normal mucosa, in none of the 40 specimens of dysplastic mucosa and in 15 (18.8%) of the 80 specimens of SCC, the frequency being significantly higher in normal mucosa than in dysplasia or SCC (p < 0.0001, p = 0.0018, respectively). COX-1 expression was significantly higher in well-differentiated SCC than in moderately or poorly differentiated SCC (p < 0.01). Higher COX-2 expression was noted in none (0.0%) of the specimens of normal mucosa, in 12 (30%) of the specimens of dysplastic mucosa, and in 41 (51.3%) of the speciments of SCC, the frequency being significantly higher in SCC than in normal mucosa or dysplasia (p < 0.0001, p = 0.0278, respectively). CONCLUSIONS: COX-1 is expressed in normal esophageal mucosa and is occasionally induced in well-differentiated SCC, whereas COX-2 expression is more characteristic of dysplasia and carcinoma than of normal mucosa, implying a possible association with cell differentiation in the former, and esophageal tumorigenesis in the latter.

Tubular adenoma and intramucosal intestinal-type adenocarcinoma of the stomach: what are the pathobiological differences?

BACKGROUND: The concept of human early gastric cancer has discrepancies among pathologists worldwide. Recently, a novel morphological classification of gastrointestinal intramucosal neoplasias was proposed and conceptual differences have gradually decreased. However, there are few studies on the differences of pathobiological properties among the intraepithelial neoplasms. The aim of the present study was to clarify the clinicopathological significance of gastric intramucosal tumors from the pathobiological viewpoint. METHODS: This study analyzed 70 tubular adenomas (TAs) with mild or moderate atypia and 52 intramucosal intestinal-type adenocarcinomas (IMACs) of the stomach from the viewpoint of the apoptotic index (AI), Ki-67 labeling index (KI), and intratumoral microvessel density (IMVD), using immunohistochemistry and the terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick-end labeling (TUNEL) method. We also examined the expression of P53 and thymidine phosphorylase (dThdPase). RESULTS: The mean AI was significantly higher and the mean KI and IMVD were significantly lower in the TAs than in the IMACs (P < 0.05, P < 0.001, and P < 0.01, respectively). AI and IMVD showed a negative correlation in TAs and IMACs (TAs; P = 0.015; r = 0.28; IMACs; P = 0.006; r = 0.41). dThdPase and nuclear P53 expression were significantly higher in the IMACs than in the TAs (P < 0.05, P < 0.01). Mean IMVD was significantly higher in dThdPase-positive tumors than in the negative ones (P < 0.01, P < 0.01) in both TAs and IMACs. CONCLUSION: IMACs possess higher proliferative activity of tumor cells, with a vascular-rich microenvironment, than TAs. This might reflect the pathobiological differences between gastric IMACs and TAs, and could also provide useful information on indications for gastric endoscopic mucosal resection for IMACs as has been recommended by the Japanese Gastric Cancer Association.

Prostatic stromal sarcoma: case report and review of the literature.

We report a case of a 65-year-old man with rare prostatic stromal sarcoma in which suprapubital radical prostatectomy was performed, but neither chemotherapy nor radiation therapy were administered before or after the operation. The well-circumscribed tumor, measuring 5 cm in diameter, showed a homogeneous white grayish cut surface with a hard consistency. Histopathologically, the tumor consisted mainly of medium-sized rounded cells with a sarcomatous and epithelioid appearance intermingled with collagen fiber. Hyalinized foci were also noted in the tumor. Immunohistochemistry revealed that the tumor cells were diffusely positive for vimentin and focally positive for progesterone receptor and CD34, but not for EMA, cytokeratin or estrogen receptor. No recurrence or distant metastasis of the tumor has occurred in 8 years of follow up. The tumor was diagnosed as prostatic stromal sarcoma (PSS) showing epithelioid differentiation and of a progesterone-dependent nature. Possible favorable nature of the PSS might be expected after complete resection.

Expression of cyclo-oxygenase-2 is correlated with high intratumoral microvessel density and low apoptotic index in human esophageal squamous cell carcinomas.

Cyclo-oxygenase (COX) is a key enzyme in the conversion of arachidonic acid to prostanoids. COX-2 expression has been found in many malignancies. This study analyzed the correlation between COX-2 expression and angiogenesis or apoptosis in human esophageal carcinomas. The study examined the expression of COX-2 in six esophageal carcinoma cell lines and in 100 esophageal squamous cell carcinomas, comparing intratumoral microvessel density (IMVD) and apoptotic index (AI) by immunohistochemistry and TUNEL methods. COX-2 was variably expressed in all the cell lines examined. COX-2 immunoreactivity was observed mainly in the cytoplasm of carcinoma cells. Significantly higher mean IMVD and lower AI were noted in the 51 strong COX-2 expressing cases than in the 49 weak cases. IMVD and AI were negatively correlated. COX-2 expression was higher in the tumors with lymphatic invasion than in the others. These data indicate that COX-2 expression is associated with increased intratumoral microvessels and suppression of tumor cell apoptosis. Thus COX-2 might play an important role in the angiogenesis and regulation of apoptosis in esophageal squamous cell carcinomas.

Mast cells in human allografted kidney: correlation with interstitial fibrosis.

INTRODUCTION: Chronic allograft nephropathy is the major cause of long-term graft failure in human allografted kidney transplantation. In addition to macrophages and T lymphocytes, mast cells have been shown to increase in chronic allograft nephropathy. The present study examined tryptase-positive mast cells and microvessels in the allografted kidney. MATERIALS AND METHODS: We selected 131 biopsy specimens obtained from 100 allografted, 14 non-grafted renal biopsy specimens and nine nephrectomy specimens due to renal cell carcinomas. Formalin-fixed, paraffin- embedded specimens were immunostained using primary antibodies for mast cell tryptase, mast cell chymase and CD34. The number of the mast cells and microvessels was counted in at least 20 high-power fields (10 x 40). RESULTS: Tryptase-positive mast cells outnumbered chymase, toluidine blue or naphthol-AS-D choloacetate-positive mast cells. The mean number of the tryptase-positive mast cells was significantly higher in the 36 specimens with chronic allograft nephropathy (5.1 +/- 3.5) among the grafted kidneys with other disease categories (P < 0.001). In the chronic allograft nephropathy, the mean numbers of mast cells was significantly higher in Ci 2 + Ci 3 (n = 20; 6.4 +/- 3.89) than in Ci 1 (n = 16; 3.6 +/- 2.65) (P < 0.01). In the non-grafted kidney, the number of mast cells was highest in the four specimens with diabetic nephropathy. Mast cells and microvessels were analysed in the two representative cases, which subsequently developed chronic allograft nephropathy. Both of the cases showed the highest number of mast cells in chronic allograft nephropathy. In contrast, the mean number of microvessels tended to decrease along with interstitial fibrosis. CONCLUSIONS: This study demonstrated clearly a close association between renal interstitial fibrosis and mast cells, which might play an important role in the development of chronic allograft nephropathy.

Paradoxical effects by preoperative oral low-dose tegafur administration in human gastric carcinomas: enhanced apoptosis and increased intratumoral microvessel density.

This study examined the effect of preoperative low-dose tegafur treatment in human gastric carcinomas. Among 55 patients with gastric carcinoma, 33 received an oral administration of tegafur 600 mg/body/day for 7 days before. Formalin-fixed, paraffin-embedded specimens were immunostained for Ki-67, P53, P21, CD34, Bax, VEGF, and dThdPase and also examined by the terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling procedure. The apoptotic index (AI), Ki-67 labeling index (KI) and intratumoral microvessel density (IMVD) were counted. Mean AI and IMVD were 3.4+/-1.60 and 126.1+/-36.56 in the treated carcinomas, and 2.3+/-0.88 and 98.0+/-44.40 in the non-treated carcinomas, both values being significantly higher in the former (P<0.05). The treatment resulted in a significant increase of mean AI in the intestinal type, in the early, and in the P53-positive carcinomas (P<0.05), while the treatment brought a significant increase of IMVD in the diffuse type, in the early and in the P53-negative carcinomas (P<0.05, respectively). No significant difference was noted on the frequency of P53, P21, BAX, VEGF and dThdPase expressions between the two groups. Ki-67 expression did not correlate with any factors. Preoperative low-dose tegafur treatment resulted in a paradoxical effect; enhanced apoptosis and increased IMVD in human gastric carcinomas.

Expression of Fas and Fas ligand in esophageal tissue mucosa and carcinomas.

The Fas ligand (FasL) and its receptor Fas play a key role in the initiation of an apoptotic pathway. We describe the expression of Fas receptor and ligand pair antigens in surgical samples collected from a cohot of 89 patients compared with 89 squamous cell carcinomas (SCCs), 45 dysplasias and 42 normal mucosae of the esophagus. TUNEL method was performed in 89 SCCs. Evaluation of FasL on normal mucosae displayed a heterogeneous immunoreaction in a minority of specimens, whereas SCCs exhibited a more extended and homogeneous reactivity. Fas-positive carcinoma cells revealed frequent apoptosis. Furthermore, a significantly longer disease-free survival can be observed in patients with Fas-positive tumors than in Fas-negative carcinomas and in patients with FasL-negative tumors than in FasL-positive carcinomas. In conclusion, FasL expression may play an important role in tumor progression. On the other hand, Fas-expressing carcinoma cells were associated with frequent apoptosis. Both FasL and Fas expressions correlate with prognostic significance in esophageal SCCs.

Detection of mycobacterial DNA in formalin-fixed, paraffin-embedded tissue specimens by duplex polymerase chain reaction: application to histopathologic diagnosis

Granuloma is a chronic inflammatory process associated with noninfectious agents or infectious diseases such as tuberculosis. Determination of the causative agent might be occasionally difficult in histopathologic sections. In this study, we examined 60 specimens of granuloma or inflammatory lesions that were originally diagnosed as 51 cases of granulomatous inflammation, 6 of leprosy, and 3 of atypical mycobacteriosis. The diagnoses in the last two categories were made both histologically and clinically. All of the sections and DNA were prepared from formalin-fixed, paraffin-embedded blocks. Histopathologic and immunohistochemical findings were compared with the results of duplex polymerase chain reaction (PCR) using two primers to amplify mycobacterial-common 383-base pair (bp) DNA and Mycobacterium tuberculosis-complex-specific 240-bp DNA. Six samples of leprosy and three of atypical mycobacteriosis showed the 383-bp but not the 240-bp band. Among the 51 specimens of granulomatous inflammations, nine showed no band of even the beta-globin, the cases being excluded from this analysis. The 42 specimens of granulomatous inflammation were subdivided into three categories by PCR: (1) 383- and 240-bp positive; (2) 383-bp positive and 240-bp negative; and (3) both negative. Category 1 included 32 specimens (76.2%), being considered as tuberculosis. One specimen was classified into Category 2, indicating possible atypical mycobacterium. Category 3 included nine specimens, composed of five of sarcoidosis and four other agent-induced granulomas, when compared with histologic and clinical findings. These findings indicate that the PCR assay using DNA extracted from paraffin-embedded materials provides useful information to differentiate tuberculosis from other type of granulomas.