Hulin Han

The Glycolytic Phenotype is Correlated with Aggressiveness and Poor Prognosis in Invasive Ductal Carcinomas

Purpose Glucose uptake and glycolytic metabolism are enhanced in cancer cells, and increased expression of glucose transporter 1 (GLUT1) has also been reported. The aim of this study was to investigate GLUT1 expression in human breast tissues and invasive ductal carcinomas. Methods We used tissue microarrays consisting of normal breast tissue, ductal hyperplasia, ductal carcinoma in situ, invasive ductal carcinoma, and lymph node metastases. We examined GLUT1 expression in the microarrays by immunohistochemistry, reviewed the medical records and performed a clinicopathological analysis. Results Membranous GLUT1 expression was observed in normal and tumor cells. GLUT1 expression was higher in ductal carcinoma in situ, invasive ductal carcinoma, and lymph node metastasis than in normal tissue and ductal hyperplasia (p=0.002). Of 276 invasive ductal carcinomas, 106 (38.4%) showed GLUT1 expression. GLUT1 expression was correlated with higher histologic grade (p<0.001), larger tumor size (p=0.025), absence of estrogen receptor (p<0.001), absence of progesterone receptor (p<0.001), and triple-negative phenotype (p<0.001). In univariate survival analysis, patients with GLUT1 expression had poorer overall survival and disease-free survival (p=0.017 and p=0.021, respectively, log-rank test). In multivariate survival analysis with the Cox proportional hazards model, GLUT1 expression was an independent prognostic factor of poorer overall survival and disease-free survival (p=0.017 and p=0.019, respectively). Conclusion GLUT1 expression seems to play an important role in malignant transformation, and the glycolytic phenotype in invasive ductal carcinoma may indicate aggressive biological behavior and a worse prognosis.

Clinicopathological significance of CADM4 expression, and its correlation with expression of E-cadherin and Ki-67 in colorectal adenocarcinomas

Aims Cell adhesion molecule 4 (CADM4) is a novel tumour suppressor. The purpose of this study was to investigate the correlation between its expression and the expression of E-cadherin and Ki-67 in colorectal adenocarcinomas, as well as its effect on patient survival. Methods We evaluated CADM4 expression in tissue microarrays of 513 colorectal adenocarcinomas by immunohistochemistry. Results CADM4 was highly expressed in 210 of the 513 colorectal adenocarcinomas; expression was reduced in 185 cases and absent in the remaining cases. Loss of CADM4 expression was correlated with larger tumour size (6.2±2.1 cm vs 5.3±2.0 cm, p<0.001), mucinous tumour type (61.5% vs 20.9%, p<0.001), lymph node metastasis (31.4% vs 20.9%, p=0.022), higher Dukes stage (25.5% vs 19.6%, p=0.044), poorer differentiation (38.5% vs 18.8%, p<0.001), absence of E-cadherin expression (28.5% vs 16.0%, p=0.007) and presence of Ki-67 expression (27.3% vs 12.3%, p<0.001). In univariable Cox regression analysis, absence of CADM4 expression was associated with poorer overall survival (HR 0.712; 95% CI 0.512 to 0.989, p=0.042) and disease-free survival (HR 0.732; 95% CI 0.546 to 0.981, p=0.037). In multivariate analysis with the Cox proportional hazards model, CADM4 expression was not an independent prognostic factor of overall survival (HR 0.726; 95% CI 0.516 to 1.021, p=0.066) and disease-free survival (HR 0.762; 95% CI 0.563 to 1.033, p=0.080). Conclusions Loss of CADM4 expression is relatively frequent in colorectal adenocarcinomas and may play an important role in cancer progression and patient survival.

Clinicopathological significance of dual-specificity protein phosphatase 4 expression in invasive ductal carcinoma of the breast.

Purpose Dual-specificity protein phosphatase 4 (DUSP4), also known as mitogen-activated protein kinase phosphatase (MKP) 2 is a member of the inducible nuclear MKP group. The role of DUSP4 in cancer development and progression appears to vary with the type of malignancy. The purpose of this study was to investigate DUSP4 expression in a case series of invasive ductal carcinoma of the breast. Methods We constructed tissue microarrays consisting of 16, 14, 47, and 266 cases of normal breast tissue, usual ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma, respectively. DUSP4 expression was investigated by immunohistochemistry. Results Cytoplasmic DUSP4 expression was observed. DUSP4 was more frequently expressed in malignant than in benign cases (p=0.024). The mean DUSP4 expression score was significantly higher in malignant tumors than in benign lesions (p=0.019). DUSP4 expression was significantly correlated with a larger tumor size (>2 cm, p=0.015). There was no significant correlation between overall survival or disease-free survival and DUSP4 expression in all 266 patients. We evaluated the impact of DUSP4 expression on the survival of 120 patients with T1-stage tumors. Interestingly, Kaplan-Meier survival curves revealed that DUSP4 expression had a significant effect on both overall patient survival (p=0.034, log-rank test) and disease-free survival (p=0.045, log-rank test). In early T-stage breast cancer, DUSP4 expression was associated with a worse prognosis. Conclusion DUSP4 is frequently upregulated in breast malignancy, and may play an important role in cancer development and progression. In addition, it may be a marker of adverse prognosis, especially in patients with early T1-stage cancer.

Appendiceal Crohn’s disease clinically presenting as acute appendicitis

AIM To determine the incidence of appendiceal Crohns disease (CD) and to summarize the characteristic histologic features of appendiceal CD. METHODS We reviewed the pathology files of 2179 appendectomy specimens from January 2007 to May 2013. The computer-assisted retrieval search facility was utilized to collect specimens. We selected those cases that were diagnosed as CD or chronic granulomatous inflammation and defined the final diagnosis according to the histologic findings of CD, including transmural lymphocytic inflammation, non-caseating epithelioid granulomas, thickening of the appendiceal wall secondary to hypertrophy of muscularis mucosa, mucosal ulceration with crypt abscesses, mucosal fissures, and fistula formation. RESULTS We found 12 cases (7 male and 5 female patients, with an average age of 29.8 years) of appendiceal CD. The incidence of appendiceal CD was 0.55%. The chief complaints were right lower quadrant pain, abdominal pain, lower abdominal pain, and diarrhea. The duration of symptom varied from 2 d to 5 mo. The histologic review revealed appendiceal wall thickening in 11 cases (92%), transmural inflammation in all cases (100%), lymphoid aggregates in all cases (100%), epithelioid granulomas in all cases (100%), mucosal ulceration in 11 cases (92%), crypt abscesses in 5 cases (42%), perforation in 2 cases (17%), muscular hypertrophy in 1 case (8%), neural hyperplasia in 5 cases (42%), and perpendicular serosal fibrosis in 8 cases (67%). CONCLUSION A typical and protracted clinical course, unusual gross features of the appendix and the characteristic histologic features are a clue in the diagnosis of appendiceal CD.

Clinicopathological significance of CADM4 expression in invasive ductal carcinoma of the breast

Aims Cell adhesion molecule 4 (CADM4) is a novel tumour suppressor involved in cell adhesion. Loss or decreased expression of CADM4 has been associated with the development and progression of some cancers. The purpose of this study was to investigate the clinicopathological significance of CADM4 expression in breast cancer. Methods We constructed tissue microarrays to evaluate the immunohistochemical expression of CADM4 in 256 cases of invasive ductal carcinoma (IDC) and 45 cases of ductal carcinoma in situ (DCIS). Results CADM4 was expressed in 37 (82.2%) DCIS cases, and in 173 (67.6%) IDC cases. CADM4 expression was higher in DCIS than in IDC (p=0.049). Loss or decrease of CADM4 expression was significantly correlated with higher histological grade (p=0.020), absence of oestrogen receptors (p<0.001), absence of progesterone receptors (p=0.024), and overexpression of c-erbB-2 (p=0.018). In univariable and multivariable Cox regression analyses of all 256 IDC cases, CADM4 expression was not significantly associated with overall and disease-free survival. However, it showed a significant positive association with longer disease-free survival in 187 stages I and II IDC cases (p=0.039, log-rank test). Conclusions Loss or decrease of CADM4 expression seems to play an important role in breast cancer invasiveness, and it is associated with poorer biological parameters. CADM4 can be used as a novel marker predicting risk of recurrence and disease outcomes in stages I and II IDC.

Fine needle aspiration cytology of a granular cell tumour arising in the thyroid gland.

Dear Editor, Granular cell tumours (GCTs) were considered to be of myogenic origin by Abrikosoff in 1926 but are now regarded as tumours associated with nerve sheath differentiation. GCTs can occur at any age and the male to female ratio is about 1 : 3. The tumours are mainly subcutaneous, but are occasionally found in muscle and skin, and more rarely in internal organs. Approximately 70% of cases occur in the head and neck region, of which 30% are in the tongue. They also arise in the breast, oesophagus, tracheobronchial tree, gastrointestinal tract and urinary bladder. GCTs are almost always benign; recurrence is infrequent (less than 5%) and results from incomplete excision. To our knowledge, eight primary GCTs of the thyroid gland have been previously reported; only two of the reports described cytological findings obtained by fine needle aspiration (FNA). We describe a case of thyroid GCT together with its radiological [computed tomography (CT) and sonography] and cytopathological characteristics. A 24-year-old woman presented with a painless neck mass that had been growing gradually over the previous 3 years. Multiple nodules without tenderness were noted in both lobes of the thyroid gland. Thyroid function tests were within normal limits. Thyroid sonography revealed a markedly hypoechoic nodule, measuring 1.8 cm diameter, on the medial side of the right mid-zone and multiple isoechoic masses, ranging from 0.5 to 2.1 cm in both thyroid lobes. CT revealed a non-enhancing mass, identical to the hypoechoic nodule of the sonogram, and multiple enhancing lesions (Figure 1a). The haematoxylin and eosinand Papanicolaoustained conventional FNA smears of the right mid-zone showed benign follicular cells and large granular cells, which were present as single cells and in syncytial clusters (Figure 1b). These cells had finely granular abundant cytoplasm with ill-defined cellular borders and small round to oval nuclei (Figure 1c). The chromatin pattern was uniformly regular and the nucleoli were small or inconspicuous. Intranuclear inclusions were not noted. Some naked nuclei were present with granular debris due to disruption of cell membranes. No mitotic figures, inflammation or necrosis were evident. The FNA smears were initially interpreted as Benign, consistent with a benign follicular nodule according to the Bethesda system, and we added a comment for the presence of Hürthle cell change. Total thyroidectomy was performed for a presumed follicular neoplasm. Grossly, the surgical specimen consisted of a thyroid gland measuring 9.8 · 5.3 · 2 cm containing six well-demarcated yellowish white nodules ranging from 0.3 to 2.8 cm. Microscopically, the tumour in the mid-zone of the right lobe contained confluent sheets of uniform polygonal to slightly spindle-shaped cells with central or eccentric nuclei surrounded by abundant uniform granular cytoplasm (Figure 1d). On special staining, there were prominent periodic acid Schiff (PAS)-positive fine granules in their cytoplasm. Immunohistochemical stains were positive for S-100, NSE and CD68 and negative for GFAP and TTF-1. The pathological diagnosis was thus confirmed as GCT. The other five nodules showed nodular hyperplasia. The tumour was encapsulated, but in some places the capsule was incomplete and tumour cells mingled with adjacent thyroid follicles. There are suggested criteria of malignant GCT, such as the presence of necrosis and mitoses, high nuclear to cytoplasmic ratio, nuclear pleomorphism, vesicular nuclei with prominent nucleoli, and high Ki-67 expression. In our case, the tumour cells were benign-looking and uniform in appearance and their nuclei had finely dispersed chromatin with inconspicuous nucleoli and no mitotic figures. The Ki-67 labelling index was less than 1%. The partial incomplete capsulation was noted, but we Correspondence: K.-S. Jang, MD, Department of Pathology, College of Medicine, Hanyang University, 17 Haengdang-Dong, SeongdongGu, Seoul 133-792, Korea Tel.: +82-2-2290-8960; Fax: +82-2-2296-7502; E-mail: medartisan@hanyang.ac.kr

Splenic hamartoma: A case report and review of the literature

Splenic hamartoma is a rare benign malformation, composed of an anomalous mixture of normal splenic elements, often found incidentally while working up other complaints or at autopsy. A splenic mass was incidentally found while evaluating the effects of a traffic accident in a 63-year-old woman. Abdominal computed tomography revealed a well-defined splenic mass with rim enhancement. The patient underwent splenectomy. The resected spleen contained a well-defined mass lesion measuring 3.5 cm × 3.0 cm. Microscopic examination revealed disorganized slit-like vascular channels lined by plump endothelial cells without atypia. The cells lining the vascular channels were positive for CD8, CD31, CD34 and vimentin. Endothelial cells that are positive for CD8 are a key feature that differentiates hamartoma from other vascular lesions of the spleen. Although this tumor is very rare, it must be included in the differential diagnosis of splenic mass-forming lesions.

Hepatobiliary and Pancreatic: Hepatic actinomycosis

A 72-year-old man was investigated because of a 1-week history of fever, headache and myalgia. Seven years previously, he had been diagnosed with gastric adenocarcinoma and treated with a subtotal gastrectomy. On admission to hospital, his temperature was elevated (38.3°C) but no other abnormalities were detected on physical examination. Laboratory tests revealed mild anemia (hemoglobin 114 g/l), an elevated white cell count (12.6x10/l) and a mild elevation of C-reactive protein (13.6 mg/l), aspartate aminotransferase (53 u/l), alanine aminotransferase (65 u/l), alkaline phosphatase (222 u/l) and g-glutamyl transferase (264 u/l). His serum glucose was also elevated. A contrast-enhanced computed tomography (CT) scan showed several lesions of low-attenuation in both lobes of the liver (Figure 1). The differential diagnosis included liver abscesses and liver metastases. A percutaneous aspirate was obtained under ultrasound guidance and yielded thick brown turbid fluid. In wet-fixed smears, blue colonies of actinomycosis with “bales of wool” appearance were seen on a background of mixed inflammatory cells (Figure 2). In cell-block sections, there were many irregularly lobulated or scalloped basophilic granules termed “sulphur granules” that are characteristic of Actinomyces. There was no evidence of metastatic adenocarcinoma. Gram staining revealed positive filamentous bacilli (Figure 2 inset, white arrow). The patient was treated with percutaneous drainage for 2 weeks and with high-dose penicillin-G given intravenously. His fever subsided after 2 weeks and laboratory tests gradually returned to normal. The abscesses had resolved on repeat CT scan after 2 months. Hepatic actinomycosis is a rare disease. Although cases of primary hepatic actinomycosis have been described, actinomycosis appears to spread to the liver from other abdominal sites in the majority of cases. Symptoms are often non-specific with weight loss and fever. However, most patients with hepatic actinomycosis have an elevated serum alkaline phosphatase level in addition to a leucocytosis and elevated erythrocyte sedimentation rate. The typical radiological feature is that of multiple liver abscesses but multiple small lesions may be difficult to characterize. Percutaneous aspirates can be diagnostic when they contain “sulphur granules” with gram-positive bacilli. Cultures are positive in some but not all patients. Larger abscesses can be treated by percutaneous drainage but eradication of the infection usually requires prolonged courses of intravenous penicillin. The evolution of hepatic abscesses caused by actinomycosis is usually more insidious than that associated with pyogenic abscesses.

Lymphoepithelioma-like Carcinoma of the Renal Pelvis: A Case Report and Review of the Literature

Lymphoepithelioma is an undifferentiated epithelial tumor primarily described in the nasopharynx and characterized by syncytial nests of malignant epithelial cells with a prominent reactive lymphoid infiltrate [1]. A carcinoma that shows similar histological features but arises outside the nasopharynx is called lymphoepithelioma-like carcinoma (LELC). LELC has been described in a variety of organs including salivary glands, thymus, lungs, stomach, skin, uterine cervix, breast, prostate, and the urinary tract [2]. The renal pelvis is an extremely rare site for this tumor. To the best of our knowledge, only eight cases have been reported in the English literature and one case has been reported in the Korean literature [1-8]. We recently experienced a case of LELC arising in the right renal pelvis in a 65-year-old woman.

Tumour-to-tumour metastasis of lung adenocarcinoma to ovarian serous cystadenoma

Introduction Tumour-to-tumour metastasis is a rare phenomenon, although double primary neoplasms are fairly common. Since it was fi rst described by Berent in 1902, fewer than 200 cases have been reported in the English-language literature (Berent 1902). Th e most frequent donor tumour is lung cancer, followed by breast, prostate and thyroid carcinoma (Ro et al. 1990). Renal cell carcinomas are the most common recipients of metastases in the case of malignant tumours, while meningioma appears to be the most common recipient of benign tumours (Honma et al. 1989; Sella and Ro 1987). Metastasis to the ovary is more common in younger women, which suggests that the abundant vascularity and local hormonal eff ects may be important. Tumours that are known to secondarily involve the ovary typically include carcinomas of the breast and the gastrointestinal tract. We describe the fi rst case of lung adenocarcinoma that metastasised into a large ovarian serous cystadenoma.