Expression level of long noncoding RNA H19 of normotensive placentas in late pregnancy relates to the fetal growth restriction.

AIM: Infants with fetal growth restriction (FGR) are at an increased risk of perinatal morbidity and mortality. The long noncoding RNA H19 gene is expressed abundantly in placental villi and recent studies suggest that it regulates FGR. However, the role of H19 in the FGR placenta remains unclear. This study aimed to clarify the relationship between H19 expression and FGR using normotensive placentas after 34 weeks of gestation. METHODS: Formalin-fixed paraffin-embedded tissues from human placentas collected from pregnancies resulting in small for gestational age (SGA) and appropriate for gestational age (AGA) newborns were used. The histopathological features of placenta tissues, such as villous stromal fibrosis, the numbers of terminal villi, villous vessels and cytotrophoblasts were analyzed using hematoxylin and eosin, Masson's trichrome staining and immunostaining. The localization and expression of H19 in the placentas were demonstrated by in situ hybridization and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), respectively. Moreover, the expression levels of H19-regulated molecules such as IGF2 and decorin (DCN) were measured by RT-qPCR. RESULTS: Histopathological features of the placental villous were not different between placentas associated with SGA and AGA. H19 localized to the villous stroma, endothelial cells and cytotrophoblasts. Moreover, the expression level of H19 in SGA placentas was significantly lower than that in AGA placentas. The expression levels of IGF2 and DCN in SGA placentas tended to be lower than those in AGA placentas similarly to H19. CONCLUSION: This study highlights the potential importance of regulatory events mediated by H19 in SGA placentas without histopathological abnormalities in late pregnancy.

Farnesoid X receptor induces cell death and sensitizes to TRAIL-induced inhibition of growth in colorectal cancer cells through the up-regulation of death receptor 5.

Farnesoid X receptor (FXR) exhibits critical anti-cancer functions in several types of cancer, including colorectal cancer, in vitro and in vivo. However, the underlying mechanism remains unclear. We evaluated pharmacological activation of FXR with the synthetic agonist GW4064 using comprehensive proteomic analysis in colorectal cancer cell lines (HCT116, SW480, and DLD1). Among the commonly detected proteins in all three cell lines, death receptor 5 (DR5) was the most up-regulated protein, and key autophagy-related proteins, such as microtubule-associated protein 1 light chain 3 alpha/beta (MLP3A/3B) and p62 sequestosome-1 (SQSTM), were also differentially expressed. Western blot analysis showed that GW4064 stimulation induced activation of the extrinsic death signaling pathway in all cell lines and induced activation of the intrinsic death signaling pathway in DLD1 cells. Western blotting showed that DR5 up-regulation was associated with inhibition of autophagic activity. These results suggest that FXR activation induced DR5 up-regulation through inhibition of autophagic activity and the DR5-related death signaling pathway. In addition, DR5 selective ligand, also known as TRAIL, has been widely used for anti-cancer treatment in several clinical trials. Co-treatment of TRAIL with GW4064 synergistically inhibited colorectal cancer cell proliferation as compared with single treatments. To the best of our knowledge, our results provide novel insights into FXR function in cancer cell lines. These findings may contribute to a new therapeutic strategy for colorectal cancer.

Relationship between genetic alterations and clinicopathological characteristics of papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is characterized by proliferation of follicular cells with distinctive nuclear features such as ground glass appearance, nuclear groove and pseudoinclusion. From the proliferation pattern, PTC is divided into several histological subtypes; conventional histology is classified as papillary type, and there are also follicular and solid variants. PTC is heterogeneous in genetic alterations. PTC with BRAF mutation presents a histology of conventional PTC, and follows an aggressive clinical course. Most cases of PTC with RAS mutation show a follicular variant, and prognosis is favorable. RET/PTC1 is observed sporadically and in young cases, and prognosis is favorable. RET/PTC3 is associated with radiation exposure, and the solid variant is frequent. ETV6-NTRK3 may be associated with radiation exposure, and the clinical course is aggressive. Mutation in the telomerase reverse transcriptase promoter is observed in PTC cases involving elderly male patients. Tumor size is large, associated with distant metastasis and advanced stage. This mutation is found concomitantly with BRAF mutation, and the clinical course is aggressive. Genetic alterations form subsets of PTC with distinct clinicopathological features. Careful assessment of clinicopathological features is considered useful in predicting clinical course and when planning treatment.

2-Deoxy-d-glucose increases GFAT1 phosphorylation resulting in endoplasmic reticulum-related apoptosis via disruption of protein N-glycosylation in pancreatic cancer cells.

The glycolytic inhibitor 2-deoxy-d-glucose (2DG) causes energy starvation, affecting cell viability in a wide range of cancer cell lines. To determine the action of 2DG in pancreatic cancer, we performed proteomic analysis of pancreatic cancer cell line after 2DG treatment. Eighty proteins showed differential expression and among these, proteins involved in phosphohexose metabolism were upregulated. Up-regulation of glutamine: fructose 6-phosphate aminotransferase 1 (GFAT1), which belongs to the hexosamine biosynthesis pathway (HBP) that produces uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) to maintain glycoprotein, was validated by evaluation of mRNA and protein levels. Therefore, we assessed the amounts of total N-glycoproteins. Unexpectedly, we found a reduction of total N-glycoproteins and phosphorylation of GFAT1 by AMP-activated protein kinase (AMPK). These data may shed light on HBP dysfunction. Furthermore, we found endoplasmic reticulum (ER) stress accompanied by increased expression of ER stress markers, such as glucose response protein 78 (GRP78) and C/EBP-homologous protein (CHOP), in 2DG-treated cells. Moreover, the additive activation of AMPK by metformin (Met) synergistically enhanced the reduction of protein N-glycosylation and cell growth inhibition in the presence of 2DG. These results suggest that 2DG reduces N-glycosylation of proteins following the increase of phosphorylation of GFAT1 and results in the inhibition of cell growth mediated by ER stress in pancreatic cancer cells.

Prognostic utility of atypical mitoses in patients with breast cancer: A comparative study with Ki67 and phosphohistone H3.

BACKGROUND AND OBJECTIVES: Emerging evidence suggests that the presence of atypical mitoses is associated with poor prognosis in some types of cancer, but its clinical significance remains uncertain. Here, we investigated the occurrence of atypical mitoses in breast cancers. METHODS: Mitotic figures, including normal and atypical mitoses, were assessed in resected histological sections from 109 patients with invasive carcinoma of no special type (ICNST). Comparisons with clinicopathological features and biomarkers such as Ki67 and phosphohistone H3 (PHH3) were performed. RESULTS: The total number of mitotic figures, including atypical mitoses, was higher in situ and invasive ductal carcinoma components than in normal ducts. Morphological characteristics of atypical mitoses included multipolar, lagged, ring, asymmetrical mitoses, and anaphase bridge. Patients with higher total mitoses and PHH3, and the presence of atypical mitoses showed reduced overall survival (OS), compared to those with lower total mitoses and PHH3, and without atypical mitoses (P = 0.03, 0.02, and <0.001, respectively). In multivariate analysis, the presence of atypical mitoses alone attained significant correlation with shorter OS (P < 0.001). CONCLUSIONS: Atypical mitoses in routinely resected specimens have a robust prognostic value for ICNST of the breast, but its clinical utility remains to be validated in a multicenter large material.

Breast carcinoma with osteoclast-like giant cells: A cytological-pathological correlation with a literature review.

Breast carcinoma with osteoclast-like giant cells (OGCs) is a rare disease characterized by the infiltration of OGCs in the tumor; however, cytological aspects of this tumor type remain elusive. We examined the cytological features in fine needle aspiration (FNA) biopsy smears obtained from 5 patients who were histologically diagnosed with breast carcinoma with OGCs. We compared FNA and clinicopathological findings with results from the published literature. Histological assessment of the resected samples showed that all tumors exhibited a histological grade 1 phenotype with a predominant cribriform architecture. Four patients were estrogen receptor positive, and 1 patient showed a triple negative phenotype. All patients survived without tumor recurrence. In the FNA smears, tumor cells were arranged in loosely cohesive clusters, characterized by varying degrees of OGCs infiltration and rare formation of solid tumor nests. Occasionally, 2- or 3-dimensional clusters of tumor cells were found, accompanied by OGCs at the peripheral regions. In all patients, tumor cells were small without severe nuclear atypia. None of the patients showed significant background necrosis. In summary, cytological features of breast carcinoma with OGCs are characterized by loose aggregates of low grade tumor cells, the presence of OGCs, and the absence of necrosis, all of which were consistent with features reported previously. This peculiar form of breast tumors should be included in the differential diagnosis, when physicians encounter FNA findings including low grade ductal carcinoma with the admixture of multinucleated giant cells or OGCs.

Intramuscular Epithelioid Sarcoma Presenting as Extrinsic Flexor Tightness in the Forearm.

Epithelioid sarcoma is an uncommon soft tissue sarcoma involving predominantly the distal extremities of adolescents and young adults. Its rarity makes it difficult to diagnose accurately and treat properly in the early stages. We discuss the delayed diagnosis of a 37-year-old man who presented with extrinsic flexor tightness of the wrist and fingers. We initially thought that the lesion resulted from inflamed soft tissue of the flexor muscles causing contracture. However, histological examination of a biopsy specimen revealed nodular proliferation of epithelioid and spindle cells, which were immunoreactive to epithelial and nonepithelial markers, respectively, leading to the final diagnosis of epithelioid sarcoma.

Clinicopathological significance of a solid component in papillary thyroid carcinoma.

AIMS: Solid variant of papillary thyroid carcinoma (SVPTC) is characterized by a solid component (SC) involving more than 50% of the tumour with the preservation of the classical cytological features of papillary thyroid carcinoma (PTC). However, the clinical significance of SC in PTC has been rarely examined. Herein, we investigated retrospectively the clinicopathological features of PTC with various degrees (10-85%) of SC (PTCSC). METHODS AND RESULTS: Patients with PTCSC (n = 27) were stratified into SC-major (SC > 50% of the tumour) and SC-minor (SC < 49%) groups. The clinicopathological parameters were compared to the well-differentiated PTC (WPTC) group (n = 47). Both SC-minor (n = 18) and SC-major (n = 9) groups had increased incidence of a large-sized tumour, extracapsular extension and a high recurrence rate, compared to WPTC. Disease-free survival (DFS) of both SC-minor and SC-major was shorter than that of WPTC (P = 0.035 and P = 0.016, respectively). Overall survival was similar among all the groups. Univariate analysis revealed that SC was associated significantly with a recurrence rate (P = 0.018). Using multivariate analysis, SC appeared to be associated with a recurrence rate with borderline significance (P = 0.055). CONCLUSIONS: Our findings indicate that the presence of SC in PTC, regardless of the proportion, is associated with adverse clinical parameters and a shorter DFS.

A case of ulcerative colitis with squamous cell carcinomas and multiple foci of squamous dysplasia.

Squamous cell carcinoma (SqCC) in ulcerative colitis (UC) is rare. A 38 year-old Japanese woman, who suffered from left-sided UC for 18 years, underwent total colectomy due to SqCCs in the rectum and the sigmoid colon. They were well differentiated SqCC, and metastasis was found in the paracolic lymph nodes. Multiple small foci of squamous dysplasia (SD) were noted in the rectal mucosa. Glandular dysplasia was not found. TP53 was not detected in SD. Approximately 40% of cells were immunostained with TP53 in SqCC, however no mutation was found in TP53 gene. Human papilloma virus and Epstein Barr virus were negative in SD and SqCCs. The patient is free of the disease at one and half years after surgery and chemotherapy. SD may be a precursor of SqCC. It appeared that TP53 does not play a vital role in the development of SqCCs in the current case. Careful attention should be paid to SD in UC patients. Viral infection may need to be examined. The pathogenesis of SqCC in patients of UC needs to be elucidated.

IMP3 contributes to poor prognosis of patients with metaplastic breast carcinoma: A clinicopathological study.

Metaplastic breast carcinoma (MBC) is a rare type of tumor with heterogenous histological patterns. We investigated the immunohistochemical expression of IMP3, an oncofetal protein, in 31 MBC patients in association with histological subtypes and clinical outcomes. The cohort consisted of spindle cell carcinoma (SPC) (n=11), squamous cell carcinoma (SCC) (n=14), matrix-producing carcinoma (MPC) (n=4), carcinoma with osteocartilaginous elements (COC) (n=1), and low grade adenosquamous cell carcinoma (ASC) (n=1). IMP3 expression was identified in 7 cases of SPC (64%) and 6 patients of all the other subtypes (p=0.051). In comparison between IMP3 high (n=13) and low (n=18) groups, a large-sized tumor (≥4.0cm) was identified in 9 IMP3 high patients, and 14 IMP3 low patients had a small-sized tumor (p=0.01). High Ki67 positivity was detected in all of the IMP3 high patients and in 7 of the IMP3 low patients (p=0.002). During the follow-up period, 9 IMP3 high patients died, whereas 15 of the 18 IMP3 low patients remained alive (p=0.004). A univariate analysis revealed that IMP3 expression and tumor size were significantly associated with poor clinical outcomes (p=0.03 and <0.001, respectively). The IMP3 high group was likely to be associated with reduced overall survival compared to the IMP3 low group (p=0.06). These findings indicate that IMP3 may contribute to the aggressive behavior of MBC, and that this expression could potentially be a prognostic marker of MBC.

Histological analysis of hyalinised keloidal collagen formation in earlobe keloids over time: collagen hyalinisation starts in the perivascular area.

Keloids grow and do not regress. They are characterised histologically by hyalinised keloidal collagen (HKC). HKC amounts vary, and the mechanism by which they form is unclear. To clarify how HKCs form and whether their formation associates with specific clinical features, we studied the histological findings of earlobe keloids and compared them with respective clinical features. A total of 50 earlobe keloids from 43 patients were used for histological analysis of keloid size (mm2 ), HKC area (mm2 ) and HKC area ratio (%). As a result, keloid durations ranged from 3 months to >13 years. Early-stage keloids exhibited little HKC and a tendency for the HKCs to locate in perivascular regions. In later-stage keloids, the HKCs were extremely interconnected and formed a thick bitten donut-shaped region. HKC area ratios correlated positively with keloid duration (r2 = 0·58, P<0·05). HKC area ratios and keloid durations did not correlate with keloid sizes. These patterns of HKC formation and growth may explain why local therapies, which effectively remove fibroblasts and accumulated collagen but not HKCs, are ineffective in older keloids. Keloids should be promptly treated after diagnosis, and older keloids with extensive HKCs may require surgical excision followed by radiotherapy.

Identification of aldolase A as a potential diagnostic biomarker for colorectal cancer based on proteomic analysis using formalin-fixed paraffin-embedded tissue.

Colorectal cancer (CRC) is one of the most common cancers worldwide, and many patients are already at an advanced stage when they are diagnosed. Therefore, novel biomarkers for early detection of colorectal cancer are required. In this study, we performed a global shotgun proteomic analysis using formalin-fixed and paraffin-embedded (FFPE) CRC tissue. We identified 84 candidate proteins whose expression levels were differentially expressed in cancer and non-cancer regions. A label-free semiquantitative method based on spectral counting and gene ontology (GO) analysis led to a total of 21 candidate proteins that could potentially be detected in blood. Validation studies revealed cyclophilin A, annexin A2, and aldolase A mRNA and protein expression levels were significantly higher in cancer regions than in non-cancer regions. Moreover, an in vitro study showed that secretion of aldolase A into the culture medium was clearly suppressed in CRC cells compared to normal colon epithelium. These findings suggest that decreased aldolase A in blood may be a novel biomarker for the early detection of CRC.

Higher expression of EpCAM is associated with poor clinical and pathological responses in breast cancer patients undergoing neoadjuvant chemotherapy.

Neoadjuvant chemotherapy (NAC) is a standard regimen in treatment of breast cancer patients, but some are resistant to NAC. We hypothesized that breast cancer cells overexpressing epithelial cell adhesion molecule (EpCAM) could be resistant to NAC, contributing to a poor prognosis. Seventy patients with breast cancer were treated with NAC. Core needle biopsy (CNB) specimens and resected tumors before and after NAC, respectively, were examined for expression of EpCAM. In resected tumors, high EpCAM expression correlated with lymphovascular invasion status and nuclear grade (P = 0.01 and 0.008, respectively), and was associated with poor pathological and clinical responses (P < 0.001). High tumoral EpCAM expression in resected tumor was independently related to a poor pathological response. Patients with high EpCAM expression before and after NAC (high-to-high group) showed worse pathological and clinical responses (P = 0.008 and <0.001, respectively) than the patients with high and low EpCAM expression before and after NAC, respectively (high-to-low group). The overall survival rate of the high-to-high group appeared shorter compared with the high-to low-group (P = 0.049). Our findings imply that higher levels of EpCAM in breast cancer may be associated with poor response to NAC via a potential chemoresistant effect.

"Wild type" GIST: Clinicopathological features and clinical practice.

Gastrointestinal stromal tumor (GIST) is a mesenchymal tumor of the gastrointestinal tract. Mutation of KIT and PDGFRA genes is implicated in the tumorigenesis. Approximately 10% of GISTs do not harbor mutation of these genes, and they are designated as "wild type" GIST. They are classified into succinate dehydrogenase (SDH)-deficient and non-SDH-deficient groups. SDH-deficient group includes Carney triad and Carney Stratakis syndrome. The patients are young women. Tumors occur in the antrum of the stomach, and tumor cells are epithelioid. Lymph node metastasis is frequent. The non-SDH-deficient group includes neurofibromatosis (NF) type 1 and GISTs with mutations of BRAF, KRAS, and PIK3CA and with the ETV6-NTRK3 fusion gene. GIST in NF occurs in the small intestine, and tumor cells are spindle shaped. GIST with BRAF mutation arises in the small intestine. Attention to the age, gender, family history and other neoplasms may raise the prediction of syndromic disease. Location of the tumor, morphology, and pleomorphism of the tumor cells are further informative. Lymphovascular invasion should be carefully evaluated. The determination of KIT expression is essential for the diagnosis. When wild type GIST is suspected, intensive genetic analysis is required. Further, a careful and long-time observation is recommended.

A case of repeated small bowel perforations in a short period in a patient with cholesterol crystal embolism.

We report a case of jejunal perforation related to cholesterol crystal embolism (CCE) in a woman in her seventies. The jejunum was partially resected;histological examination of the resected tissue revealed that the perforation was caused by CCE. On postoperative day 12, computed tomography (CT) showed free air in the abdomen. We then performed a second operation to alleviate the anastomotic leakage. Subsequently, 26 days after the second surgery, CT again showed free air in the abdomen. A third operation was performed, and multiple perforations of the jejunum were detected. She died of multiple organ failure 43 days after the first surgery. The prognosis of CCE with gastrointestinal perforation is reported to beextremely poor, and there is a high rate of anastomotic leakage. Partial resection of the intestine and ileostomy might be useful for removing the intestinal perforations caused by a CCE. Steroid administration should be continued, however, because discontinuation may worsen the problem.

Nestin delineates pancreatic cancer stem cells in metastatic foci of NOD/Shi-scid IL2Rγ(null) (NOG) mice.

Pancreatic ductal adenocarcinoma (PDAC) is associated with a high incidence of hepatic metastases, as well as occasional pulmonary metastases. To delineate the potential role of cancer stem cells (CSCs) in PDAC metastasis, human PDAC cells were injected into the spleen of mice. The characteristics and expression of markers associated with CSC and epithelial-mesenchymal transition (EMT) of metastatic cells that developed in the liver and lung were then compared with parental cells. The metastatic cells were polygonal, and larger than parental cells. Metastatic cells also exhibited decreased proliferation and increased adhesion to extracellular matrices, as well as enhanced migration and invasion in vitro and increased metastatic capacity in vivo. The CSC markers ALDH1A1, ABCG2, and nestin were expressed at high levels in metastatic cells and exhibited changes consistent with EMT (eg, decreased E-cadherin expression). Moreover, metastatic cells readily formed spheres in culture and exhibited an increased side population by flow analysis. Nestin and ABCG2 were also expressed at high levels in metastatic lesions from PDAC patients, and silencing nestin with shRNA in PDAC cells derived from lung metastases resulted in a marked decrease in the capacity of the cells to form spheres and to yield pulmonary or hepatic metastases. Thus, the metastatic potential of human PDAC cells correlates with CSCs and with EMT characteristics and is dependent on nestin expression.

Inhibition of fibroblast growth factor receptor 2 attenuates proliferation and invasion of pancreatic cancer.

The alternative splicing of the extracellular domain of fibroblast growth factor receptor (FGFR)-2 generates the IIIb and IIIc isoforms. Expression of FGFR-2 IIIb correlates with vascular endothelial growth factor-A (VEGF-A) expression and venous invasion of pancreatic ductal adenocarcinoma (PDAC). By contrast, FGFR-2 IIIc expression correlates with faster development of liver metastasis after surgery, and increased proliferation rates and invasion of the cancer. In this study, we analyzed the expression and roles of total FGFR-2 (both isoforms) to determine the effectiveness of FGFR-2-targeting therapy for PDAC. Immunohistochemically, FGFR-2 was highly expressed in 25/48 (52.1%) PDAC cases, and correlated with advanced stage cancer. In FISH analysis, FGFR2 was amplified in 3/7 PDAC cell lines. We stably transfected an FGFR-2 shRNA targeting the IIIb and IIIc isoforms into FGFR2-amplified PDAC cells. The proliferation rates, migration, and invasion of FGFR-2-shRNA-transfected cells were lower than those of control cells in vitro. In response to FGF-2, FGFR-2-shRNA-transfected cells showed decreased phosphorylation of ERK compared with control cells. The FGFR-2-shRNA-transfected cells also expressed lower levels of vascular endothelial growth factor-A than control cells, and formed smaller s.c. tumors in nude mice. These findings suggest that FGFR-2 is a therapeutic target for inhibition in PDAC.

Morphological spectrum of renal pathology and its correlation to clinical features in patients with disseminated intravascular coagulation: a study involving a series of 21 autopsy cases.

Disseminated intravascular coagulation (DIC), a thrombohemorrhagic disorder, occurs as a secondary complication in many diseases, but the histopathological features of kidneys in DIC have not been extensively characterized thus far. We reviewed 21 autopsy cases of patients with a clinical diagnosis of DIC and studied the repertoire of renal pathology. Eighteen patients had elevated serum creatinine levels and 15 patients had a variable degree of proteinuria. Underlying disorders included malignant neoplasms in 12 patients, and abdominal aortic aneurysm, acute myocardial infarction, and systemic infections in other patients. Coexistent glomerular pathology, such as focal segmental glomerulosclerosis (FSGS) with different morphological variants, and microthrombi formation, was present in many patients. The microthrombi were histologically similar to that seen in thrombotic microangiopathy, but characteristics associated with DIC were detected by special staining. The presence of FSGS correlated with the degree of urinary protein (P = 0.0044), and the presence of acute tubular injury (ATI) and the extent of global glomerulosclerosis both correlated with serum creatinine levels (P = 0.019 and 0.0003, respectively). FSGS was probably due to endothelial cell damage, another potential etiology for FSGS. Global glomerulosclerosis, a result of previous renal injury, can be a determinant of renal function during the acute phase of DIC.

Aortic squamous metaplasia in a patient with aortoesophageal fistula secondary to thoracic aortic aneurysm: an autopsy case.

Aortoesophageal fistula (AEF) is highly lethal. A 74-year-old man presented with hematemesis and consciousness loss. He had a long-term history of hypertension and gout. Computed tomography revealed an aneurysm of the distal descending thoracic aorta, which was treated by insertion of an aortic stent graft. After 24 days of stenting, endoscopic examination revealed an AEF. After 6 months of stenting, he died owing to mediastinitis. On autopsy, macroscopically, we found a 4 × 2.5-cm, oval, well-circumscribed AEF. We identified squamous epithelium in the area surrounding the AEF that covered the thoracic aorta inner cavity. Immunohistochemical analysis revealed that the squamous epithelium in the thoracic aorta was positive for p63 and 34ßE12. In conclusion, we encountered a long-term AEF case with aortic squamous metaplasia. To the best of our knowledge, human aortic metaplasia has never been reported. In the present case, aortic squamous metaplasia retained continuity with the esophageal squamous epithelium; therefore, the migration of the squamous epithelium through the AEF may have been induced by aortic erosion.

Expression of lumican in hidroacanthoma simplex and clonal-type seborrheic keratosis as a potent differential diagnostic marker.

Lumican, a member of the small leucine-rich proteoglycan family, regulates the assembly and diameter of collagen fibers in the extracellular matrix of various tissues. The lumican expression correlates with pathological conditions and the growth and metastasis of various malignancies. In cutaneous neoplasms, the lumican expression is lower in advanced-stage malignant melanomas that invade the dermis than in early-stage melanomas. Furthermore, we have recently reported that the expression pattern of lumican is different from that of actinic keratosis and the Bowen disease. Lumican is positive in the poroid cells of intraepidermal sweat ducts; therefore, we examined the expression patterns of lumican in acanthotic-type seborrheic keratosis and Pinkus-type poroma followed by clonal-type seborrheic keratosis and hidroacanthoma simplex. The neoplastic cells of acanthotic-type seborrheic keratosis exhibited positive immunostaining in only 1 of 31 cases (3.23%), whereas the poroid cells of Pinkus-type poroma exhibited positive immunoreactivity in 26 of 28 patients (92.8%). In the hidroacanthoma simplex cases, lumican was expressed in poroid cells forming intraepidermal nests in 22 of 28 patients (78.6%), whereas the neoplastic cells in most cases of clonal-type seborrheic keratosis were negative for lumican. In some seborrheic keratosis cases that were positive for lumican in neoplastic cells, lumican was observed in squamoid cells but not in basaloid cells. Therefore, it is necessary to evaluate the immunoreactivity of lumican in seborrheic keratosis and in basaloid cells. These findings suggest that lumican is a potent differential diagnostic marker that distinguishes hidroacanthoma simplex from clonal-type seborrheic keratosis.