Highly sensitive fluorescence detection of metastatic lymph nodes of gastric cancer with photo-oxidation of protoporphyrin IX.

BACKGROUND: The establishment of a precise and rapid method to detect metastatic lymph nodes (LNs) is essential to perform less invasive surgery with reduced gastrectomy along with reduced lymph node dissection. We herein describe a novel imaging strategy to detect 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) fluorescence in excised LNs specifically with reduced effects of tissue autofluorescence based on photo-oxidation of PpIX. We applied the method in a clinical setting, and evaluated its feasibility. METHODS: To reduce the unfavorable effect of autofluorescence, we focused on photo-oxidation of PpIX: Following light irradiation, PpIX changes into another substance, photo-protoporphyrin, via an oxidative process, which has a different spectral peak, at 675 nm, whereas PpIX has its spectral peak at 635 nm. Based on the unique spectral alteration, fluorescence spectral imaging before and after light irradiation and subsequent originally-developed image processing was performed. Following in vitro study, we applied this method to a total of 662 excised LNs obtained from 30 gastric cancer patients administered 5-ALA preoperatively. RESULTS: Specific visualization of PpIX was achieved in in vitro study. The method allowed highly sensitive detection of metastatic LNs, with sensitivity of 91.9% and specificity of 90.8% in the in vivo clinical trial. Receiver operating characteristic analysis indicated high diagnostic accuracy, with the area under the curve of 0.926. CONCLUSIONS: We established a highly sensitive and specific 5-ALA-induced fluorescence imaging method applicable in clinical settings. The novel method has a potential to become a useful tool for intraoperative rapid diagnosis of LN metastasis.

Evaluation of PSF1 as a prognostic biomarker for prostate cancer.

BACKGROUND: Partner of SLD5 1 (PSF1) is an evolutionarily conserved DNA replication factor. Previous studies have suggested that transcriptional activity of the PSF1 gene correlated with malignancy of cancer cells. The objective of the current study was to evaluate the relationship between PSF1 expression and the clinical features of prostate cancer. METHODS: We determined the expression of PSF1 in 120 needle biopsy samples of prostate cancer by immunohistochemistry. We divided patients into PSF1-positive or -negative groups and analyzed the relationships between the expression of PSF1, the Gleason score, PSA level, TNM classification and prognosis. RESULTS: Our results showed that the PSF1 expression correlated significantly with PSA values at diagnosis (P=0.0028), with tumor grade (P<0.0001), and with clinical stage (P=0.0005). Moreover, the PSF1 expression correlated significantly with overall survival (hazard ratio (HR) 5.5; 95% confidence interval (CI) 2.17-15.8; P=0.003) and progression-free survival in 99 consecutive patients with prostate cancer. Noteworthy, the prognosis of PSF1-positive cases was also worse in patients with a Gleason score of 8-10 (HR 3.7; 95% CI 1.28-13.43; P=0.0143). Limitations include that this study had a retrospective design, that patients in the study were heterogeneous and included those with early and advanced cancer, and that small tumor fragments may not be representative of the entire carcinoma. CONCLUSIONS: PSF1 is expressed in high-grade prostate cancer and may be a useful biomarker to identify patients with a poor prognosis at the time of diagnosis.

Development of pancreatic cancers during long-term follow-up of side-branch intraductal papillary mucinous neoplasms.

BACKGROUND AND STUDY AIMS: Side-branch intraductal papillary mucinous neoplasms (SB-IPMNs), and associated synchronous and metachronous pancreatic cancers are increasingly detected as imaging modalities become more sensitive. We investigated the natural history of SB-IPMN, and the incidence and characteristics of pancreatic cancers among patients undergoing long-term follow-up. PATIENTS AND METHODS: We reviewed the clinical, imaging, and pathological features in 103 patients, diagnosed at the Aichi Cancer Center between September 1988 and September 2006 as having SB-IPMN, and conservatively followed up for ≥ 2 years (median 59 months) based on an endoscopic ultrasonography (EUS) database. RESULTS: 74 (71.8 %) patients had nonprogressive lesions. Overall, six patients (5.8 %) developed pancreatic cancers during follow-up, with intraductal papillary mucinous (IPM) carcinoma in four, and ductal carcinoma of pancreas that was not IPMN in two patients. Of the six pancreatic cancers, five were diagnosed at a resectable stage. The 5-year and 10-year actuarial rates of development of pancreatic cancer were 2.4 % and 20.0 %, respectively. Although, at the last follow-up, cyst size, main pancreatic duct (MPD) diameter, mural nodule size, and frequency of metachronous and/or synchronous cancers of other organs were significantly higher in patients who developed IPM carcinoma, resected SB-IPMNs without mural nodules and dilated MPDs had no IPM carcinomas. CONCLUSIONS: The frequency of pancreatic cancers is high on long-term follow-up of SB-IPMN. Although conservative management is appropriate for selected patients, regular and long-term imaging, especially by EUS is essential, even if SB-IPMN remains unchanged for 2 years. Presence of mural nodule and dilated MPD seem to be more appropriate indicators for resection than cyst size alone for SB-IPMNs.

Clinical impact of intraoperative histological examination of the ductal resection margin in extrahepatic cholangiocarcinoma.

BACKGROUND: Although ductal resection margin status in extrahepatic cholangiocarcinoma is evaluated by intraoperative histological examination of frozen sections, its clinical relevance remains controversial. METHODS: Material taken from patients who underwent R0 or R1 resection for extrahepatic cholangiocarcinoma with intraoperative histological examination of the final ductal resection margins between 1994 and 2003 were reviewed. The following histological classification was used: insufficient, negative for malignancy (NM), undetermined lesion (UDL) or positive for malignancy (PM). Multivariable analyses of overall survival and anastomotic recurrence in relation to ductal margin status were performed. RESULTS: Resection material from 363 patients was identified. For the proximal ductal margin, only PM in intramural lesions was significantly associated with poor survival (hazard ratio (HR) 1.72, 95 per cent confidence interval (c.i.) 1.06 to 2.74) and anastomotic recurrence (HR 6.39, 95 per cent c.i. 1.89 to 21.62) compared with NM. In analysis of overall survival according to distal ductal margin status, the HRs for UDL and PM lesions in comparison with NM were not significant. CONCLUSION: PM in intramural lesions found during intraoperative histological examination of the proximal ductal resection margin was related to clinical outcome. This finding favours additional resection of the bile duct. A similar association was not found for histology results of the distal resection margin.

Endoscopic submucosal dissection for colorectal tumors: technical difficulties and rate of perforation.

BACKGROUND AND STUDY AIM: Endoscopic submucosal dissection (ESD) for colorectal tumors is not generally recommended because of the technical difficulties and complications, including perforation. These aspects of ESD are thoroughly analyzed in our retrospective study. PATIENTS AND METHODS: We studied 105 colorectal tumors, from 100 patients, that were treated by ESD at the Kyoto Prefectural University of Medicine or Nara City Hospital between 2005 and 2008. We analyzed tumor size, operation time, rate of en bloc resection, and complications. In addition, we thoroughly investigated the cases of perforation. RESULTS: The average tumor size was 30.4 mm; average operation time, 102 min; and rate of en bloc resection, 88.5 %. Perforation occurred in 10.4 % of the ESD procedures. Of the 11 perforations, 8 were detected during ESD and treated by clip closure during endoscopy, while 3 were evident only on subsequent routine computed tomography (CT); these were also managed conservatively. A case of postoperative hemorrhage was also observed. CONCLUSIONS: ESD effectively achieved a high rate of en bloc resection. However, the perforation rate was substantial; hence, improvement in the ESD method is required. The outcomes of ESD, especially for early colorectal malignancies, need to be assessed further.

Continuous remission in an infant with chest wall malignant rhabdoid tumor after relapse.

Malignant rhabdoid tumor (MRT) is a highly aggressive tumor that occurs in infancy or childhood. The prognosis, especially in infants, is very poor. Here we report the long-term survival of a 5-month-old boy with MRT that arose from the chest wall. After total resection of the tumor, the patient was given 4 cycles of doxorubicin, vincristine, and cyclophosphamide, alternating with ifosfamide and etoposide. After 18 months off therapy, he had a local recurrence at the same site. After a second total resection, he was given additional chemotherapy with 30.6-Gy local irradiation. No further recurrence has been observed for 5 years since the second complete remission. Currently, he is alive and well at 7.5 years post-onset. Our experience in this case suggests a fundamental strategy of successful treatment of this highly malignant pediatric tumor: (1) complete resection of the localized tumor, (2) intensive multiagent chemotherapy for the minimal disseminated disease, and (3) radiotherapy for local control of the disease.

New POMT2 mutations causing congenital muscular dystrophy: identification of a founder mutation.

BACKGROUND: Dystroglycanopathies are a group of congenital muscular dystrophies (CMDs) with autosomal recessive inheritance, often associated with CNS and ocular involvement. They are characterized by the abnormal glycosylation of alpha-dystroglycan, and caused by mutations in at least six genes encoding enzymes: FKTN, POMGNT1, POMT1, POMT2, FKRP, and LARGE. POMT2 mutations have recently been identified in Walker-Warburg syndrome and in a milder muscle-eye-brain disease-like form. METHODS: We studied mentally retarded patients with CMD, analyzed POMT2 by sequencing the coding regions, and also performed a haplotype analysis in all patients and their family members carrying the new POMT2 mutation. RESULTS: We report three novel POMT2 mutations. One of these, p.Tyr666Cys, was homozygous in two unrelated patients and in a compound heterozygous state in others. All patients showed severe diffuse muscle weakness, microcephaly, severe mental retardation, and marked lordoscoliosis with hyperextended head. Elevated CK levels, cerebral cortical atrophy, and cerebellar vermis hypoplasia were constant findings. Mild cardiac abnormalities, focal white matter abnormalities, or partial corpus callosum hypoplasia were detected in single cases. Eye involvement was absent or mild. By genotype analysis, we defined a distinct 170kb haplotype encompassing POMT2 and shared by all the subjects harboring the mutation p.Tyr666Cys. CONCLUSIONS: Our results broaden the clinical spectrum associated with POMT2 mutations, which should be considered in patients with CMD associated with microcephaly, and severe mental retardation with or without ocular involvement.

Solitary myofibroma of the lumbar vertebra: adult case.

We present the first known adult case of solitary myofibroma of bone, which affected a lumbar vertebra in a 33-year-old male. Radiography identified a purely lytic lesion with a sclerotic rim in the right pedicle of L1. CT showed an expansile lytic lesion with a sclerotic rim. MRI of the lesion revealed an isointense signal on T1-weighted images, an inhomogeneously hyperintense signal on T2-weighted images, and marked enhancement with gadolinium. Pathological study showed a mixed picture of nodular proliferation of spindle-shaped myoid cells and hemangiopericytomatous proliferation of short spindle/small round cells. The tumor cells were immunoreactive for smooth muscle actin and immunonegative for desmin. This case of solitary myofibroma of bone is exceptionally rare because of its occurrence in an adult older than 20 years of age and its location at an extra-craniofacial site.

Frequent loss of RUNX3 gene expression in remnant stomach cancer and adjacent mucosa with special reference to topography.

Our previous studies suggest that a lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer. This study was conducted to determine whether alteration of RUNX3 gene expression could be detected in the normal-looking gastric remnant mucosa, and to ascertain any difference in the potential of gastric carcinogenesis between the anastomotic site and other areas in the remnant stomach after distal gastrectomy for peptic ulcer (RB group) or gastric cancer (RM group), by analysing RUNX3 expression with special reference to topography. A total of 89 patients underwent distal gastrectomy for gastric cancer from the intact stomach (GCI group) and 58 patients underwent resection of the remnant stomach for gastric cancer (RB group: 34 cases, RM group: 24 cases). We detected RUNX3 and gene promoter methylation by in situ hybridisation, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), and methylation-specific PCR. The interval between the initial surgery and surgery for remnant gastric cancer (interval time) was 10.4 years in the RM group, and 27.5 years in the RB group. Cancers in the RB group were significantly more predominant in the anastomosis area (P<0.05). Within the tumour, downregulation of RUNX3 expression ranged from 74.7 to 85.7% in the three groups. The rate of downregulation of RUNX3 of adjacent mucosa was 39.2% (11 in 28 cases) in RB and 47.6% (10 in 21 cases) in RM, which are significantly higher than that of the GCI group (19.5%, 17 in 87 cases). In noncancerous mucosa of the remnant stomach in the RB group, RUNX3 expression decreased more near the anastomosis area. In the RM group, however, there were no significant differences in RUNX3 expression by sampling location. Based on RUNX3 downregulation and clinical features, residual stomach mucosa of the RM group would have a higher potential of gastric carcinogenesis compared to the RB or GCI group. Gastric stump mucosa of the RB group has higher potential especially than other areas of residual stomach mucosa. Measurement of RUNX3 expression and detection of RUNX3 methylation in remnant gastric mucosa may estimate the forward risk of carcinogenesis in the remnant stomach.

Extended intestinal metaplasia. A survey of 1392 gastrectomies from dwellers of the Pacific basin.

BACKGROUND: To assess the extent of gastric intestinal metaplasia (IM) in gastrectomy specimens in populations of the Pacific basin having different incidence of gastric carcinoma. MATERIALS AND METHODS: One thousand three hundred and nine-two gastrectomies were investigated: 1088 had a gastric carcinoma and 304 miscellaneous gastric diseases. Twenty-one thousand three hundred and fourteen histological sections were reviewed under low-power (4X). IM was either spotty (SIM) or extended (EIM= encompassing one or more entire low-power fields/section). Widespread IM (WIM) was regarded as EIM if present in > or =5 histological sections. RESULTS AND CONCLUSION: The percent of gastrectomies harboring a carcinoma increased significantly with increasing age more notably in those with diffuse carcinomas (DC) than in those with intestinal carcinomas (IC). The percent of gastrectomies with EIM was significantly higher in specimens with IC than with DC, particularly among elderly patients, and in specimens from countries with a high cancer incidence. The percent of gastrectomies with WIM was higher in specimens having IC than in those having DC. Migration per se did not influence the frequency of specimens with EIM in elderly Japanese patients: Japanese migrants to Hawaii had a similarly high frequency of EIM as those dwelling in Japan. Japanese patients with a gastric carcinoma showed atypical mitoses in areas with EIM far from the tumor, suggesting that cellular mutation(s) play a role in the evolution of EIM towards gastric dysplasia and carcinoma in that ethnic group. The drawback of gastric biopsies in assessing the extent of gastric intestinal metaplasia and, thereby, estimating possible cancer risk in long-term studies has been stressed.

Proliferative activity of intrahepatic colorectal metastases after preoperative hemihepatic portal vein embolization.

Although hemihepatic portal vein embolization (PVE) has been used preoperatively to extend indications for hepatectomy in patients with colorectal metastases, the effects of this procedure on tumor growth and outcome remain controversial. To address this issue, we assessed the proliferative activity of intrahepatic metastases after PVE and the long-term outcome of this procedure. Eighteen patients with colorectal metastases underwent preoperative PVE between 1996 and 2000 (PVE group). Twenty-nine patients who underwent major hepatic resection without PVE served as control (non-PVE group). The hepatic parenchymal fraction of the left lobe had significantly increased from 38.1 +/- 3.2% to 45.9 +/- 2.9% 3 weeks after PVE (+20.5%, P <.0001). Tumor volume and percent tumor volume had also significantly increased from 223 +/- 89 mL to 270 +/- 97 mL (+20.8%, P =.016) and from 13.7 + 4.3% to 16.2 + 4.9% (+18.5%, P =.014), respectively. There was no apparent correlation between the increase in parenchymal volume and that in tumor volume. The Ki-67 labeling index of metastatic lesions was 46.6 +/- 7.2% in the PVE group and 35.4 +/- 12.6% in the non-PVE group (P =.013). Long-term survival was similar in the PVE and non-PVE groups, however, disease-free survival was significantly poorer in the PVE group than in the non-PVE group (P =.004). We conclude that PVE increases tumor growth and probably is associated with enhanced recurrence of disease. Although PVE is effective in extending indications for surgery, patient selection for PVE should be cautious.

Role of esophagectomy in treatment of esophageal carcinoma with clinical evidence of adjacent organ invasion.

With carcinoma of the thoracic esophagus, clinical evidence of invasion of adjacent organs (T4) indicates a highly advanced stage, and most surgeons avoid esophagectomy. Although the therapeutic strategy for such disease is generally selected based on preoperative evaluation and intraoperative inspection, their accuracy and the relation to survival outcomes after esophagectomy have seldom been analyzed on the basis of exact histopathologic evidence. We performed esophagectomy, with perioperative adjuvant therapy when possible, on patients with clinical-T4 tumors unless absolutely unresectable conditions were detected. Among the 500 patients who underwent esophagectomy, the 78 patients whose tumors were confirmed to be T4 pathologically were compared with patients whose tumors were assessed as T4 preoperatively or intraoperatively to evaluate the role of esophagectomy for clinical-T4 carcinoma. Esophagectomy was possible for 99% of the pathologic-T4 tumors preoperatively assessed as resectable, but the resection was grossly incomplete in 35%. The true-positive rates in tumors preoperatively and intraoperatively assessed as T4 were 51% and 84%, respectively. The hospital mortality rate in patients with pathologic-T4 tumors was 4%. The overall 5-year survival rate for patients with pathologic-T4 tumors was 14%, compared with 60% for those with tumors assessed as T4 intraoperatively but not pathologically. Esophagectomy with perioperative adjuvant therapy yielded occasional cure with an acceptable mortality rate for patients with pathologic-T4 tumors assessed as technically resectable. Preoperative assessment and intraoperative macroscopic inspection had limitations for predicting pathologic-T4 disease and incomplete resection. Only patients with definitive evidence of unresectability should be excluded from esophagectomy.

Prognostic factors and therapeutic strategy for anaplastic carcinoma of the thyroid.

Although anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, a few patients survive for a fairly long time after modern intensive treatment. We tried to identify prognostic factors of ATC to assist in deciding on the proper therapeutic strategy in individual patients. Of 47 patients with ATC (1976-1999), 3 patients with "incidental" ATC (largely differentiated thyroid carcinoma with a small region of ATC) were excluded because they had a favorable outcome. The 1-year survival rate of the remaining 44 patients with clinically distinct ATC was 16%. The presence of acute symptoms, large tumor (> 5 cm), distant metastasis, and leukocytosis (white blood cell count > or = 10,000/mm3) proved to be significant risk factors. Multivariate analysis by the Cox proportional hazard model showed that these four factors were independent factors for predicting death from ATC. We devised a novel prognostic index (PI) based on the number of these four unfavorable characteristics the patient possessed. Patients with a PI of < or =1 had a 62% survival rate at 6 months, whereas no patients with a PI of > or =3 survived longer than 6 months. All patients with a PI of 4 died from their disease within 3 months. Nine patients received multimodal treatment with a combination of surgery, external irradiation, and chemotherapy and had a long survival (mean 333 +/- 68 days; one patient is still alive and tumor-free), with a mean PI of 0.6. Our PI is useful as a means of selecting patients for aggressive therapy. When the PI is low, multimodal treatment should be attempted to obtain the best survival results; if it is high most patients are too seriously ill to tolerate intensive treatment and palliative therapy is recommended.

Genetic alterations and growth pattern in biliary duct carcinomas: loss of heterozygosity at chromosome 5q bears a close relation with polypoid growth.

Biliary duct carcinomas (BDCs) are relatively rare and the carcinogenic mechanisms underlying their induction are poorly understood. There are two growth patterns, polypoid and non-polypoid infiltrative type, but little information is available concerning the relation between growth pattern and genetic alterations. A comparative study was therefore conducted to clarify if differences in genetic changes, including loss of heterozygosity (LOH) at 5q, 9p, 17p, and 18q, and K-ras mutations exist between polypoid and non-polypoid infiltrative type BDCs. LOH analysis was performed using microsatellite markers and K-ras point mutations were analysed by dot blot hybridisation. The incidences of changes for polypoid and non-polypoid infiltrative types were 73% and 26% on 5q, 63% and 59% on 9p, 55% and 50% on 17p, and 20% and 18% on 18q, and 25% and 27% for K-ras mutations. Most importantly, we found the frequency of 5qLOH to be significantly higher with polypoid growth than in the non-polypoid infiltrative type (p<0.05), especially in extrahepatic duct carcinomas (p<0.05). The incidences of other genetic alterations (LOH at 9p, 17p, and 18q, and K-ras mutations) showed similar rates with both tumour types. The present data suggest that 5qLOH may have a close relation with polypoid growth in BDCs.

Thallium-201 single photon emission computed tomography (SPECT) in patients with duchenne's progressive muscular dystrophy: a histopathologic correlation study.

The pathomorphologic mechanism responsible for abnormal perfusion imaging during thallium-201 myocardial single photon emission computed tomography (201Tl-SPECT) in patients with Duchenne's progressive muscular dystrophy (DMD) was investigated. Hearts from 7 patients with DMD were evaluated histopathologically at autopsy and the results correlated with findings on initial and delayed resting 201Tl-SPECT images. The location of segments with perfusion defects correlated with the histopathologically abnormal segments in the hearts. Both the extent and degree of myocardial fibrosis were severe, especially in the posterolateral segment of the left ventricle. Severe transmural fibrosis and severe fatty infiltration were common in segments with perfusion defects. In areas of redistribution, the degree of fibrosis appeared to be greater than in areas of normal perfusion; and intermuscular edema was prominent. Thus, the degree and extent of perfusion defects detected by 201Tl-SPECT were compatible with the histopathology. The presence of the redistribution phenomenon may indicate ongoing fibrosis. Initial and delayed resting 201Tl-SPECT images can predict the site and progress of myocardial degeneration in patients with DMD.

Acute effects of cigarette smoking on platelet-dependent thrombin generation.

AIMS: Thrombin is an important factor in the pathogenesis of thrombotic diseases. To clarify whether smoking has an effect in platelet-dependent thrombogenesis, we studied the acute effects of smoking on platelet-dependent thrombin level in smokers. METHODS AND RESULTS: Subjects consisted of ten smokers and nine non-smokers. Platelet-dependent thrombin level measured after overnight fasting was greater in smokers than in non-smokers (smokers vs non-smokers, 121 +/- 47 vs 56 +/- 5 mIU. ml(-1), P < 0.01). When subjects in the smokers group smoked two cigarettes containing 0.9 mg of nicotine per cigarette, platelet-dependent thrombin levels showed a transient three-fold increase in blood samples obtained immediately after smoking (365+/-76 mIU. ml(-1), P < 0.001). Thrombin levels in the blood samples obtained 10 min and 30 min after smoking were less than that in the samples obtained immediately after smoking ceased, but were not significantly different from those in the samples obtained before smoking. Blood nicotine level increased significantly immediately after smoking (P < 0.001), and plasma protein C activity decreased significantly 30 min after smoking (P < 0.05). When nicotine or cotinine was added to the platelet-rich plasma of non-smokers ex vivo, the platelet-dependent thrombin level increased significantly (P < 0.002). CONCLUSION: Platelet-dependent thrombin level is enhanced in smokers, even when not smoking, when compared with non-smokers and increases immediately after smoking. Increases in nicotine and cotinine levels caused by smoking induced a prothrombotic state in smokers via increased platelet-dependent thrombogenesis.

[Discharge planning for home care].

The department of medical social work and discharge planning was established in the University of Tokyo hospital to ensure that patients would receive proper care at a right place. The discharge planning team consists of a physician, a medical social worker and a home care coordinator. The home care coordinator, who coordinates with the home nursing station and the primary care physician, is effective for advance of home care. The role of the home care coordinator is to relieve patients of their anxiety about home care. As a result, the number of home care patients has gradually increased.

Origin of giant cells in osteoclast-like giant cell tumors of the pancreas.

To clarify the origin of giant cells in osteoclast-like giant cell tumors (OGCTs) of the pancreas, we performed microscopical, immunohistochemical, and K-ras gene mutation analyses with a microdissection approach in 3 cases, featuring 4 cellular components (osteoclast-like giant cells [OGCs], pleomorphic large cells [PLCs], mononuclear cells, and ductal carcinoma cells). Two cases had abundant OGCs, and 1 case contained large number of both OGCs and PLCs. In each, none of the microdissected OGCs contained any K-ras gene mutation while they were positive for a histiocytic marker (CD-68). In contrast, PLCs, when present, frequently harbored K-ras gene mutations and were negative for CD-68. In all cases, mononuclear cells, a mixture of histiocyte-like and atypical, from microscopic and immunohistochemical viewpoints, also frequently showed K-ras alteration. Histiocyte-like mononuclear cell was equipped with a regular and oval nucleus similar to those in OGCs and was positive for CD-68. Atypical mononuclear cell showed an irregular, pleomorphic, or sometimes bizarre nucleus similar to those in PLCs and was negative for CD-68. All of the K-ras gene mutations found in PLCs and mononuclear cells were the same as in the ductal carcinoma cells within the same tumor. Thus, OGCs differ in origin from ductal cells and are strongly suggested to be nonneoplastic and of mesenchymal origin, whereas PLCs, which harbor K-ras gene mutations, are neoplastic and presumably derived from ductal carcinoma cells. Moreover, mononuclear cells may be classified into 2 types, histiocyte-like and atypical.