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1.  Appendiceal Diverticulitis Clinically Masquerading as an Appendiceal Carcinoma 
Appendiceal diverticulosis is a rare condition. Herein reported is a case of appendiceal diverticulosis and diverticulitis clinically masquerading as appendiceal carcinoma. A 62-year-old woman presented with abdominal pain. US and CT showed a tumor measuring 5 × 4 × 4 cm in vermiform appendix. Colon endoscopy showed mucosal elevation and irregularity in the orifice of vermiform appendix. A biopsy of the appendiceal mucosa showed no significant changes. Clinical diagnosis was appendiceal carcinoma and wide excision of terminal ileum, appendix, cecum, and ascending colon was performed. Grossly, the appendix showed a tumor measuring 5 × 3 × 4 cm. The appendiceal lumen was opened, and the appendiceal mucosa was elevated and irregular. The periappendiceal tissue showed thickening. Microscopically, the lesion was multiple appendiceal diverticula. The diverticula were penetrating the muscle layer. The mucosa showed erosions in places. Much fibrosis, abscess formations, and lymphocytic infiltration were seen in the subserosa. Abscesses were also seen in the diverticular lumens. Some diverticula penetrated into the subserosa. The pathologic diagnosis was appendiceal diverticulitis. When they encounter an appendiceal mass, clinicians should consider appendiceal diverticulitis as a differential diagnosis.
PMCID: PMC4273474  PMID: 25544908
2.  Inflammatory Pseudotumor Containing Necrotizing Granulomatous Lesions of Kidney: A Hitherto Undescribed Entity 
Case Reports in Urology  2014;2014:263859.
Herein reported is a case of inflammatory pseudotumor (IPT) of kidney. It is not described in WHO, AFIP, and other books. A review of the literature revealed about 35 cases. A 76-year-old man underwent nephrectomy under clinical diagnosis of renal pelvic carcinoma. Grossly, a solid tumor was seen in renal parenchyma. Microscopically, it was composed of spindle cell tissue with inflammation and many necrotizing granulomas. Epithelioid histiocytes were abundant but giant cells were few. Lymphocytes and plasma cells were also seen. The features suggested tuberculosis (TB), but Ziehl-Neelsen stains and PCR revealed no TB bacillus. Immunohistochemistry showed that the tumor spindle cells were positive for vimentin, CD68, CD45, and Ki-67 (labeling = 18%), α-smooth muscle antigen, and NSE. Focal staining of KIT (mast cells), S100 protein (Langerhans cells), and CD10 (spindle cells) was present. IgG4 was negative. The tumor spindle cells were negative for other antigens examined.
PMCID: PMC4212631  PMID: 25379319
3.  Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT lymphoma) in Ulcerative Colitis 
Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) occurring in inflammatory bowel diseases, including ulcerative colitis (UC) and Crohn's disease, has been reported, although it is extremely rare. An 18-year-old man with a two-years history of UC underwent colon endoscopy, and was found to have active total UC ranging from anus to cecum. Six biopsies were obtained. The microscopic examinations showed severe infiltrations of atypical small lymphocytes. They showed hyperchromatic nuclei and increased nucleocytoplasmic ratio and scattered immunoblastic cells. Centrocyte-like atypical lymphocytes, monocytoid cells, and plasma cells were seen in some places. Vague germinal centers were present, and apparent lymphoepithelial lesions were seen. No crypt abscesses were seen, and there were few neutrophils. No apparent other findings of UC were seen. Immunohistochemically, the atypical lymphocytes were positive for vimentin, CD45, CD20, CD79α, CD138, κ-chain, λ-chain, and p53 and Ki-67 antigen (labeling index = 63%). They were also positive for CD45RO, CD3, and CD15, but these positive cells were very scant compared with CD20 and CD79α. They were negative for CD10, CD30, CD56, cytokeratin (CK) AE1/3, CK CAM5.2, CK34BE12, CK5, CK6, CK7, CK8, CK14, CK18, CK19, CK20, EMA, chromogranin, synaptophysin, NSE, S100 protein, CEA, CA19-9, p63, and HMB45. Without clinical information, the appearances are those of MALT lymphoma. However, with clinical information, making the diagnosis of MALT lymphoma was hesitated. It is only mentioned herein that atypical lymphocytic infiltrations indistinguishable from MALT lymphoma occurred in an 18-year-old male patient with a two-year history of UC.
PMCID: PMC4196349  PMID: 25253369
Histopathology; immunohistochemistry; MALT lymphoma; Ulcerative colitis
4.  Smooth muscles and stem cells of embryonic guts express KIT, PDGFRRA, CD34 and many other stem cell antigens: suggestion that GIST arise from smooth muscles and gut stem cells 
Gastrointestinal stromal tumor (GIST) is believed to original from interstitial cells of (ICC) present in Auerbach’s nerve plexus. GIST frequently shows gain-of-function mutations of KIT and PDGFRA. In practical pathology, GIST is diagnosed by positive immunostaining or KIT and/or CD34. The author herein demonstrates that human embryonic gastrointestinal tract smooth muscles (HEGITSM) and human embryonic stem gastrointestinal cells (HEGISC) consistently express KIT, CD34, NCAM, PDGFRA and other stem cell (SC) antigens NSE, synaptophysin, chromogranin, bcl-2, ErbB, and MET throughout the embryonic development of 7-40 gestational week (GW). CK14 was negative. The author examines 42 cases (7-40 GW) of embryonic GI tract (EGI). The HEGISM, HEGIST, and gall bladder smooth muscles (SM) were consistently positive for KIT, CD34, NCAM, PDGFRA, synaptophysin, chromogranin, NSE, bcl-2, ErbB2, and MET in foregut, stomach, GB, midgut, and hindgut throughout the fetal life (7-40 GW). The stem cells (SC) were seen to create the SM, nerves, ICC, and other all structures of GI tract. In adult gastrointestinal walls (n=30), KIT, CD34, PDGFRA, and S100 proteins were expressed in Auerbach’s nerve plexus and ICC. The bronchial and vascular SM of embryos did not express these molecules. In GIST, frequent expressions of KIT (100%, 30/30), CD34 (90%, 27/30), and PDGFRA (83%, 25/30) were seen. In general, characteristics of tumors recapitulate their embryonic life. Therefore, it is strongly suggested that GIST may be originated from GI SM and/or GI SC in addition to ICC.
PMCID: PMC3657355  PMID: 23696920
GI tract; GIST; smooth muscles; stem cells; stem cell antigens
5.  Autopsy findings of fatal cryptogenic organizing pneumonia 
Autopsy cases of cryptogenic organizing pneumonia (COP) have been rarely reported. A 73-year-old Japanese man consulted to a hospital because of flu-like sickness. He was diagnosed as pneumonia, and treated by antibiotics. He was referred to our hospital for further treatment. Chest X-P showed pneumonia involving the whole lungs. Blood laboratory test showed leukocytosis, increased CRP, and decreased PaO2. Despite of steroid therapy, he showed a downhill course and died one month after the first manifestation. The clinical diagnosis was acute pneumonia or ARDS. At autopsy, the both lungs were voluminous. The weight of lungs was 1050 g in the left lung and 1300 g in the right lung. The both lungs were entirely affected. The lungs were hard and little air was recognized. Microscopically, almost all alveolar spaces contained Masson’s bodies. Bronchiolitis obliterans was not recognized. The alveolar walls were not affected. The Masson’s bodies showed collagenization with lymphocytic infiltration. Hyalinization of Masson’s bodies with little inflammatory infiltration was frequently seen. Cartilagenous metaplasia and ossification of Masson’s bodies were seen in some places. The pulmonary arteries were affected by fibrosis, and occasionally showed thrombosis. The pathological diagnosis was COP. The heart weighted 500 g, and showed right ventricular hypertrophy (cor pulmonale). Other pathologic changes were pleural effusion (left, 800 ml: right, 1200 ml), acute liver congestion, prostatic hypertrophy, colon adenoma, and hypercellular bone marrow. The cause of death was respiratory failure due to COP and pleural effusion. In conclusion, the author reported an autopsy case of fatal COP.
PMCID: PMC3657366  PMID: 23696931
Lung; cryptogenic organizing pneumonia; histopathology
6.  Primary pure signet-ring cell carcinoma of the extrapulmonary left main bronchus: a case report with an immunohistochemical study 
Although several case reports and series of primary signet-ring cell adenocarcinoma (SRCA) of the lung have been reported, primary SRCA of the extrapulmonary main bronchus has not been reported. A 61-year-old man was found to have a tumor of the mediastinum of the left pulmonary hilus on routine chest X-ray examination. A transbronchial endoscopy revealed an elevated tumor in the extrapulmonary left bronchus near the tracheal bifurcation. Biopsy was taken from the bronchial lesion. It revealed pure typical SRCA. Histochemically, Alcian-blue/PAS stain showed intracytoplasmic mucins. Immunohistochemically, the tumor cells were positive for cytokeratin (CK) AE1/3, CK CAM5.2, CK7, CK18, CEA, EMA, CA19-9, Ki-67 (labeling=20%), p53, and MUC1. They were negative for CK34BE12, CK5/6, CK8, CK14, CK19, CK20, p63, vimentin, TTF-1, CDX-2, MUC2, MUC5AC and MUC6. The pathological diagnosis of primary SRCA of the left main bronchus was made. The patient died of carcinomatosis 18 months after the first presentation. In conclusion, the author reported the first case of primary SRCA of the extrapulmonary left main bronchus near the tracheal bifurcation with an extensive immunohistochemical study.
PMCID: PMC3657368  PMID: 23696933
Bronchus; signet ring cell adenocarcinoma; histopathology; immunohistochemistry
7.  Urinary bladder urothelial carcinoma with expression of KIT and PDGFRA and showing diverse differentiations into plasmacytoid, clear cell, acantholytic, nested, and spindle variants, and into adenocarcinoma, signet-ring cell carcinoma, small cell carcinoma, large cell carcinoma, and pleomorphic carcinoma 
Various tumors can arise in the urinary bladder (UB); most common is urothelial carcinoma (UC). UC of the UB have many variants. Other types of carcinomas such as adenocarcinoma (AC) and small cell carcinoma (SmCC) can occur in UB carcinomas. Expression of KIT and PDGFRA has not been reported. A 66-year-old man admitted to our hospital because of hematuria. Cystoscopy revealed papillary invasive tumor and a transurethral bladder tumorectomy (TUR-BT) was performed. The TUR-BT showed UC, AC, SmCC, large cell carcinoma (LCC), and pleomorphic carcinoma (PC). The UC component showed plasmacytoid, spindle, nested, clear cell, acantholytic variants. The AC element showed tubular adenocarcinoma and signet-ring cell carcinoma (Sig). Immunohistochemically, all of these subtypes were positive for cytokeratin (CK) AE1/3, CK CAM5.2, CK34BE12, CK5, CK6, CK7, CK8, CK18, CK19, CK20, EMA, CEA, p63, CA19-9, p53 (positive 45%), MUC1, NSE, NCAM, KIT, PDGFRA, and Ki-67 (87%). They were negative for vimentin, chromogranin, synaptophysin, S100 protein, CD34, CD14, α-smooth muscle actin, CD31, caldesmon, CD138, CD45, κ-chain, λ-chain, MUC2, MUC5AC and MUC6. Mucin histochemistry revealed mucins in AC element including Sig. A molecular genetic analysis using PCR-direct sequencing method identified no mutations of KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12 and 18) genes. The carcinoma was highly aggressive and invaded into muscular layer. The nuclear grade was very high, and there were numerous lymphovascular permeations were seen. The surface showed carcinoma in situ involving von-Brunn’s nests. This case shows that carcinoma of UB can show diverse differentiations into numerous histological types and variants, and can express KIT and PDGFRA. The both genes showed no mutations in the present case.
PMCID: PMC3657370  PMID: 23696935
Urinary bladder; urothelial carcinoma; small cell carcinoma; adenocarcinoma; KIT; PDGFRA
8.  Primary cutaneous small cell carcinoma; a case report with differential diagnosis 
Primary cutaneous small cell carcinoma (PC-SmCC) is extremely rare; only two cases have been reported in the world literatures. A 79-year-old woman presented a small cutaneous tumor in the face. Physical examination showed a tumor measuring 1.0x.08x0.6 cm in the shallow skin of the face. Excisional skin biopsy was performed. The biopsy showed complete excision of the tumor. The tumor was located in the shallow dermis and no connections to epidermis were seen. The tumor was invasive into subcutaneous tissue and surrounding dermis. The tumor was very hypercellular tumor composed of small cells with scant cytoplasm, hyperchromatic nu lei, negative nucleoli, and molded nuclei. The shapes of tumor cells are round, ovoid or spindle. The histological appearances fulfilled the criteria of SmCC of WHO. Immunohistochemically, the tumor cells were positive for cytokeratin (CK) AE1/3, CK CAM5.2, CK34BE12, CD5, CD6, CK8, p63, NSE, NCAM, synaptophysin (focal), chromogranin (focal), p53, KIT, PDGFRA and Ki-67 (labeling index (LI)=86%). They were negative for CK7, CK19, CK20, EMA, vimentin, CEA, S100 protein, CA19-9, TTF-1, MUC1, MUC2, MUC5AC and MUC6. Mucin histochemistry revealed no mucins. A molecular genetic analysis of PCR-direct sequencing identified no mutations of KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12 and 18) genes. The author diagnosed this cutaneous tumor as SmCC. Post-diagnosis whole body examination using various imaging and endoscopic techniques revealed no tumors. This may confirm that the skin tumor was primary. The cutaneous tumor was completely resected with wide margins. The patient is now followed up without therapy 8 months after the diagnosis. No recurrence or metastasis is seen. The differential diagnosis from Merkel cell carcinoma and basal cell carcinoma is very difficult and herein discussed.
PMCID: PMC3657372  PMID: 23696937
Skin; small cell carcinoma; basal cell carcinoma; Merkel cell carcinoma
9.  Pseudomyxoma cutis; a new entity 
Pseudomyxoma (PM) implies an accumulation of a large amount of mucins which show myxomatous appearances. PM Peritonei (PMP) is famous and the only example of PM. PMP means excessive accumulation of mucins and mucin-secreting cells in the peritoneal cavity. The causes of PMP are mostly mucinous tumors, both benign and malignant, of ovaries and vermiform appendix. The author experienced excessive accumulation of mucins and mucin-producing cells in the subcutis and deep soft tissue. This situation very resembled PMP. Thus, the author termed the lesion as PM cutis (PMC). A 57-year-old man admitted to our hospital because of multiple subcutaneous large tumors in the perianal skin. The tumors were deeply seated and soft. No biopsy was performed. Very large skin and subcutis resection of the perianal region was done. Grossly, the material was skin and sot tissue flap measuring 25x25x5cm. The subcutis and deep soft tissue were resected. On cut surface, the tumor was slimy liquid. Microscopical examination revealed a large amount of mucins pools and mucin-producing intestinal epithelium with mild atypia. The author diagnosed it metastatic extremely well differentiated adenocarcinoma producing mucins, and pointed out anorectal primary. Thus, Miles operation was performed, which showed tumor formation in the anus. The tumor was located from the submucosa to adventitia, and composed of mucin pools and mucins producing intestinal-type epithelium with atypia. Mucins histochemistry showed that the mucin pools and epithelial cytoplasm contained neutral, carboxylated, and sulfated mucins. Immunohistochemically, the tumor cells were positive for CKAE1/3, CKCAM5.2, CK7, CK8, CK19, CK20, CEA, CA19-9,CD68, MET, p53, MUC2, MUC5AC, KIT, PDGFRA, chromogranin, and Ki-67 (76%). They were negative for CK34BE12, CK5/6, CK14, CK18, EMA, vimentin, desmin, smooth muscle actin, p63, CD34, ER, PgR, CA125, MUC1, MUC6, CD45, CD10, synaptophysin, surfactant Apo-A, TTF-1, NCAM, bcl-2, CDX-2. Although the atypia is mild, the author diagnosed primary anorectal extremely well differentiated adenocarcinoma with excessive production of mucins. The author considers the cutaneous mucins and tumor cells are metastatic or directly invading lesions of the anal tumor. Thus, the author termed pseudomyxoma cutis (PMC) for the cutaneous lesion.
PMCID: PMC3657373  PMID: 23696938
Pseudomyxoma; skin; anal; mucins; mucin producing tumor; immunohistochemistry
10.  Pathologic diagnosis of large cell neuroendocrine carcinoma of the lung in an axillary lymph node: a case report with immunohistochemical and molecular genetic studies 
The author herein reports a large cell neuroendocrine carcinoma (LCNEC) of the lung diagnosed in an axillary lymph node without clinical data, with an emphasis of KIT and PDGFRA. A 64-year-old woman presented with axillary and cervical lymph nodes swelling. An excisional biopsy of an axillary lymph node was performed under the clinical diagnosis of malignant lymphoma. The HE section showed a presence of large malignant cells arranged in a medullary pattern. The tumor cells had nucleoli. The HE diagnosis was large cell lymphoma or metastatic undifferentiated carcinoma, in particular large cell carcinoma of the lung. The tumor cells were positive for cytokeratins, p53 protein, thyroid transcriptional factor-1, neuron-specific enolase, synaptophysin, CD56, KIT, and PDGFRA. In contrast, they were negative for CD3, CD15, CD30, CD45, CD20, CD45RO, CEA, CA19-9, and chromogranin (Dako). Ki-67 labeling (Dako) was 100%. Therefore, a diagnosis of LCNEC of the lung was made. A molecular genetic analysis for KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12 and 18) identified no mutations. Later, a lung tumor and pleural effusion were detected, and the cytology of the effusion and sputum revealed carcinoma cells compatible with LCNEC. The patient was diagnosed as lung LCNEC, and treated by chemotherapy (cisplatin) and radiation (45 Gray). The present report is the first one with an examination of protein expression and gene mutations of KIT and PDGFRA in a metastatic focus of LCNEC of the lung.
PMCID: PMC3657374  PMID: 23696939
LCNEC; KIT; PDGFRA; metastasis
11.  Cutaneous hybrid tumor composed of epidermal cyst and cystic pilomatricoma expressing p53 and high Ki-67 labeling 
Hybrid tumor composed of epidermal cyst and pilomatricoma has been reported in only four times in the English literature. Herein, a cutaneous hybrid tumor composed of epidermal cyst and cystic pilomatricoma in a 58-year-old woman was presented. The tumor was located in the scalp, and measured 1 x 1 x 1 cm. The tumor was cystic and contained atheromatous materials. Histologically, the cyst was composed of epidermal cyst (50% in area) and pilomatricoma (50% in area). The pilomatricoma was composed mostly of basophilic cells. Interestingly, the pilomatricoma element of the cyst showed immunoreactive p53 and Ki-67 (labeling=40%). In conclusion, the fifth case of hybrid tumor composed of epidermal cyst and pilomatricoma was presented.
PMCID: PMC3657376  PMID: 23696941
12.  Retroperitoneal fibrosis associated with renal cel carcinoma 
PMCID: PMC3657378  PMID: 23696943
Retroperitoneal fibrosis; tumor-associated fibrosis; renal cell carcinoma
14.  Epstein-Barr virus associated lymphoepithelial carcinoma of the esophagus 
Lymphoepithelial carcinoma (LEC), also called lymphoepithelioma-like carcinoma, is defined as an undifferentiated carcinoma or poorly differentiated squamous cell carcinoma, accompanied by a prominent reactive lymphoplasmacytic infiltrate. LEC can occur in many organs, but is most common in head and neck regions including pharynx. LEC may be associated with Epstein-Barr virus (EBV) infection. LEC of the esophagus is extremely rare; only nine cases have been reported. A 79-year-old man presented epigastralgia and dysphagia. A blood laboratory test showed no significant findings. He was a hepatitis C virus healthy carrier. Tumor markers of CEA and SCC were normal. Upper gastrointestinal endoscopy showed a tumor in the lower esophagus. Biopsies were taken, and they identified malignant epithelioid cells and heavy infiltration of mature lymphocytes. The epithelioid cells showed large size, nuclear atypia, mitotic figure, hyperchromasia, and increased nucleo-cytoplasmic ratio. The lymphocytes were free from atypia. Immunohistochemically, the epithelioid cells were positive for cytokeratin (CK) AE1/3, CK CAM5.2, CK WSS, CK MNF16, CK KL1, CK5/6, CK7, CK8, CK14, CK18, CK19, p53, and Ki-67 (labeling=27%). They were negative for CK34BE12, CK20, p63, CEA, CA19-9, NSE, synaptophysin, CD56, chromogranin, KIT (CD117), desmin, vimentin, MUC apomucins, and several leukocytic markers. The epithelioid cells were positive for EBV associated molecules including EBV-encoded nuclear antigen2 (EBNA2), EBV latent membrane protein-1 (LMP-1), and EBV early RNAs (EBER). The lymphocytes were positive for CD45 and vimentin, and were composed of B-cells positive for CD20, CD79α, bcl-2, and CD10, T-cells positive for CD3 and CD45RO, NK-cells positive for CD56, and plasma cells positive for CD38, CD138, CD79α, κ-chain, and λ-chain. No light chain restriction was seen. Most of the lymphocytes were B and T-cells, and NK-cells and plasma cells were very scant. The lymphoplasma cells were reactive cells, because of no atypia and also because no p53 and very low Ki-67 labeling (3%). The lymphocytes were negative for CD21 and other antigens such as CKs and EMA. The pathological diagnosis was primary LEC of the esophagus. Imaging techniques revealed lymph nodes metastasis of the perigastric and periaortic regions, but identified no other tumors in the body. The patient was inoperative, and was treated by chemoradiation. The esophageal LEC and lymph nodes metastases were markedly reduced in size.
PMCID: PMC3609699  PMID: 23573354
Esophagus; lymphoepithelial carcinoma; immunohistochemistry; Epstein-Barr virus
15.  Human fetal ductal plate revisited: II. MUC1, MUC5AC, and MUC6 are expressed in human fetal ductal plate and MUC1 is expressed also in remodeling ductal plate, remodeled ductal plate and mature bile ducts of human fetal livers 
Mucins are high-molecular-weight glycoproteins, which are heavily decorated with a large number of O-linked oligosaccharides and a few N-glycan chains, linked to a protein backbone. The protein backbone is called mucin core protein or MUC apomucins. MUC expression is down-regulated or up-regulated in malignant neoplasms. These alterations of MUC apomucins, which are regulated by MUC genes, are associated with carcinogenesis and malignant potentials of cancers. MUC expression during human fetal intrahepatic bile duct (IBD) development has been studied only once, and there has been only one histochemical study of mucins in human fetal IBD development. The author herein immunohistochemically investigated the expression of MUC1, MUC2, MUC5AC, and MUC6, and histochemically investigated carbohydrate component of mucins in human fetal cholangiocytes with the use of 32 human fetal livers of various gestational ages. MUC1 is a transmembranous apomucin, while MUC2, MUC5AC and MUC6 are secretory apomucins. Under normal conditions, MUC1 (polymorphic epithelial mucin) is present mainly in the pancreatic epithelium. MUC2 (goblet cell mucin) is mainly located in goblet cells. MUC5AC (gastric foveolar mucin) and MUC6 (pyloric gland-type mucin) are located in the stomach. In the present study, the processes of the human IBD development could be categorized into four stages; ductal plate (DP), remodeling DP, remodeled DP, and mature IBDs. The author identified that MUC1 was present in ductal plate (DP), remodeling DP, remodeled DP, and mature IBD in human fetal livers. MUC5AC and MUC6 were present only in the DP. MUC5AC and MUC6 were absent in remodeling DP, remodeled DP, and mature IBD in human fetal livers. No expression of MUC2 was seen throughout the fetal IBD development. Histochemically, no carbohydrate component of mucins were seen in the remodeling DP and remodeled DP, while neutral and acidic mucins (carboxylated and sulfated mucins) were seen in mature IBD in human fetal livers. The DP showed frequently neutral mucins and less frequently acidic mucins (carboxylated and sulfated mucins residues). These findings suggest that the DP cells have MUC1, MUC5AC and MUC6, and that remodeling DP, remodeled DP, and mature IBDs have MUC1, but not MUC5AC and MUC6. The presence of neutral and acidic carbohydrates in DP suggests that these carbohydrates of mucin are attached to the MUC5AC and MUC6 mucin core proteins. Although the implications are unclear, the expression of these MUC apomucins and their carbohydrate residues are associated with normal development of IBDs in human fetal livers.
PMCID: PMC3606847  PMID: 23573304
Ductal plate; human fetal liver; intrahepatic bile duct development; mucins; MUC apomucins; histochemistry; immunohistochemistry
16.  An immunohistochemical study of primary signet-ring cell carcinoma of the stomach and colorectum: II. expression of MUC1, MUC2, MUC5AC, and MUC6 in normal mucosa and in 42 cases 
Expression of MUC apomucins has rarely been investigated in the signet-ring cell carcinoma (SRCC) of the stomach and colorectum. The author examined immunohistochemically the expression status of MUC1, MUC2, MUC5AC, and MUC6 in 30 cases of gastric SRCC and 12 cases of colorectal SRCC. The normal distribution of these MUC apomucins was also examined in the non-tumorous parts of the stomach and colorectum. In normal tissues, the stomach epithelial cells consistently expressed MUC2, MUC5AC, MUC6, but consistently not MUC1. In colorectum, cryptal epithelial cells consistently expressed MUC2, but consistently not MUC1, MUC5AC, and MUC6. The expression pattern of the gastric SRCC was as follows: MUC1, 3/30 (10%); MUC2, 4/30 (13%); MUC5AC, 20/30 (67%), and MUC6 21/30 (70%). The expression pattern of the colorectal SRCC was as follows: MUC1, 5/12 (42%); MUC2, 11/12 (92%); MUC5AC, 4/12 (33%); and MUC6, 0/12 (0%). Significant differences (p<0.05) were found in the expression of MUC1 (stomach SRCC 10% vs colorectal SRCC 42%), MUC2 (13% vs 92%), MUC5AC (67% vs 33%), and MUC6 (70% vs 0%). Thus, there was a significant tendency that primary gastric SRCC express MUC5AC and MUC6 but not MUC1 and MUC2, while primary colorectal SRCC express MUC1, MUC2 and MUC5A, but not MUC6. These different expressions of these MUC apomucins in gastric and colorectal SRCC seem useful to determine the primary site of metastatic SRCC and for differential diagnosis of SRCC of other sites. In the gastric SRCC, the up-regulation of MUC1 and the down-regulation of MUC2, MUC5AC and MUC6 appear to be associated with carcinogenesis, malignant potential, progression, and clinical behaviors in gastric SRCC. In the colorectal SRCC, the up-regulation of MUC1 and MUC5AC may be associated with carcinogenesis, malignant potential, progression, and clinical behaviors in colorectal SRCC. A comparative review of the present SRCC and presently reported ordinary adenocarcinoma and SRCC cases of the stomach and colorectum was performed.
PMCID: PMC3606850  PMID: 23573307
Signet-ring cell carcinoma; MUC; mucins; stomach; colorectum; histopathology; immunohistochemistry
17.  An immunohistochemical study of primary signet-ring cell carcinoma of the stomach and colorectum: III. expressions of EMA, CEA, CA19-9, CDX-2, p53, Ki-67 antigen, TTF-1, vimentin, and p63 in normal mucosa and in 42 cases 
There have no comprehensive immunohistochemical studies of primary signet ring cell carcinoma (SRCC) in the stomach and colorectum. The author examined the expression of nine common antigens (EMA, CEA, CA19-9, CDX-2, p53, Ki-67 antigen, TTF-1, vimentin, and p63) in the non-tumorous normal epithelium of the stomach and colorectum and in 42 cases of primary SRCC of the stomach (30 cases) and colorectum (12 cases). The normal epithelium of the stomach and colon consistently (100%) expressed EMA, CEA, CA19-9, CDX-2, and Ki-67 (labeling <15%). Normal epithelium of these locations never expressed p53, TTF-1, vimentin, and p63. In the primary gastric SRCC, the expression percentage of EMA was 57% (17/30), CEA 100% (30/30), CA19-9 100% (30/30), CDX-2 43% (13/30), p53 83% (25/30), Ki-67 100% (30/30) (labeling index= 36 ± 23 %), TTF-1 0% (0/30), vimentin 0% (0/30), and p63 0% (0/30). In primary colorectal SRCC, the expression percentage of EMA was 25% (3/12), CEA 100% (12/12), CA19-9 100% (12/12), CDX-2 93% (28/30), p53 75% (9/12), Ki-67 100% (30/30) (labeling index= 47% ± 26 %), TTF-1 0% (0/12), vimentin 0% (0/12), and p63 0% (0/12). A comparative statistical analysis showed significant difference in EMA (gastric SRCC 57% vs colorectal SRCC 25%) and CDX-2 (43% vs 93%). There were no significant differences in the other seven antigens’ expression between primary gastric SRCC and primary colorectal SRCC. These findings provide much knowledge of primary SRCC of the stomach and colorectum. The data indicated primary gastric SRCC frequently express EMA but not CDX-2 whereas primary colorectal SRCC frequently express CDX-2 but not EMA. These findings also suggest that EMA and CDX-2 are down-regulated during the gastric SRCC carcinogenesis. This down regulations may be associated with the malignant transformation of gastric SRCC. The data of colorectal SRCC suggest EMA is markedly down-regulated and also suggest that this EMA down-regulation may be associated with the carcinogenesis of colorectal SRCC. The expression pattern of EMA and CDX-2 may be useful in differential diagnosis between primary gastric SRCC and primary colorectal SRCC in the metastatic sites of SRCC.
PMCID: PMC3606852  PMID: 23573309
Signet-ring cell carcinoma; common antigens; EMA; CDX-2; stomach; colorectum; histopathology; immunohistochemistry
18.  An immunohistochemical study of primary signet-ring cell carcinoma of the stomach and colorectum: I. cytokeratin profile in 42 cases 
Expression of cytokeratin (CK) profiles in primary signet-ring cell carcinoma (SRCC) of the stomach and colorectum have rarely reported; only two such studies are present in the world literature. Herein, an immunohistochemical study on cytokeratin (CK) expression was performed in 42 cases of primary SRCC of the stomach (30 cases) and colorectum (12 cases). SRCC was defined as an adenocarcinoma in which more than 50% adenocarcinoma cells showed SRCC phenotype with prominent intracytoplasmic mucins. In the gastric SRCC, the expression of CK was as follows; CK AE1/3 (30/30, 100%) CK CAM5.2 (30/30, 100%), CK 34BE12 (0/30, 0%), CK5/6 (2/30, 7%), CK7 (26/30, 89%), CK8 (12/30, 40%), CK14 (0/30, 0%), CK18 (30/30, 100%), CK19 (2/30, 7%), and CK20 (3/30, 10%). In the colorectal SRCC, the expression of CK was as follows; CK AE1/3 (12/12, 100%) CK CAM5.2 (12/12, 100%), CK 34BE12 (0/12, 0%), CK5/6 (0/12, 10%), CK7 (2/12, 17%), CK8 (3/12, 25%), CK14 (0/12, 0%), CK18 (12/12, 100%), CK19 (7/12, 58%), and CK20 (8/12, 67%). A statistical analysis showed that significant differences of CK expression between the gastric SRCC and colorectal SRCC were observed in CK7 (stomach 67% vs. colorectum 17%), CK19 (7% vs. 42%) and CK20 (13% vs. 67%); gastric SRCC tended to express CK7, but not CK19 and CK20, while colorectal SRCC tended to express CK19 and CK20, but not CK7. In gastric SRCC, CK7+/CK20- pattern was as follows: CK7+/CK20- (24/30, 81%), CK7+/CK20+ (2/30, 6%), CK7-/CK20+ (1/30, 3%), and CK7-/CK20- (3/30, 10%). CK7/CK19 patterns in gastric SRCC were as follows; CK7+/CK19- (25/30, 83%) CK7+/CK19+ (1/30, 3%), CK7-/CK19+ (1/30, 3%), CK7-/CK19- (3/30, 10%). In colorectal SRCC, the CK7/CK20 patterns were as follows: CK7+/CK20- (2/12, 17%), CK7+/CK20+ (0/12, 0%), CK7-/CK20+ (8/12, 66%), and CK7-/CK20- (2/12, 17%). The CK7/CK19 pattern in colorectal SRCC was as follows; CK7+/CK19- (1/12, 8%), CK7+/CK19+ (1/12, 8%), CK7-/CK19+ (6/12, 50%), and CK7-/CK19- (4/12, 34%). Statistical data indicated that CK7+/CK20- and CK7+/CK19- patterns were significantly prevalent in gastric SRCC, and CK7-/CK20+, CK7-/CK19+ and CK7-/CK20- patterns dominated significantly in colorectal SRCC. CK expression has been studied largely in terms of CD7/CK20 expression pattern in various carcinomas. The present study provided possible usefulness of CK7/19 expression status in various carcinomas including SRCC.
PMCID: PMC3606860  PMID: 23573317
Signet-ring cell carcinoma; cytokeratin; stomach; colorectum; histopathology; immunohistochemistry
19.  Multiple cytokeratin-negative malignant tumors composed only of rhabdoid cells in the renal pelvis: a sarcomatoid urothelial carcinoma? 
The author presents a unique case of multiple cytokeratin-negative malignant tumors consisting only of rhabdoid cells in the renal pelvis. A 54-year-old man complained of hematuria. A transurethral endoscopic examination revealed multiple papillary tumors, and transurethral resection of the bladder tumors was performed. Pathologically, they were ordinary papillary urothelial transitional cell carcinomas. Imaging modalities revealed multiple tumors of the right renal pelvis, and nephrectomy was performed. Grossly, three polypoid tumors measuring 2-4 cm were present in the pelvis. Histologically, they were composed only of malignant cells with rhabdoid features. There were no elements of transitional cell carcinoma. Immunohistochemically, the pelvic tumors were positive for vimentin and Ki-67 antigen (labeling=40%). They were negative for pancytokeratins (AE1/3, CAM5.2, KL-1 and polyclonal wide), 34βE12, cytokeratin (CK) 5/6, CK7, CK8, CK14, CK18, CK19, CK20, melanosome, EMA, CEA, desmin, S100 protein, α-smooth muscle actin, myoglobin, myogenin, CD34, p53 protein, p63, CD3, CD20, CD30, CD45, CD45RO, chromograin, synaptophysin, CD56, CD68, and KIT. NSE and PDGFRA were focally present, but this appeared nonspecific. Namely, the pelvic tumors expressed only vimentin. The author speculates that the pelvic multiple malignant “rhabdoid” tumors are not sarcomas but urothelial “rhabdoid” carcinoma with complete loss of CKs.
PMCID: PMC3606863  PMID: 23573320
Rhabdoid tumor; urothelial carcinoma; renal pelvis; immunohistochemistry
20.  Combined hepatocellular-cholangiocarcinoma with stem cell features, ductal plate malformation subtype: a case report and proposal of a new subtype 
In the current WHO blue book, combined hepatocellular-cholangiocarcinoma (C-HCC-CC) was classified into two types; classical type and type with stem cell features. The latter is extremely rare, and is subcategorized into the following three subtypes; typical subtype, intermediate cell subtype, and cholangiocellular subtype. Recently, intrahepatic cholangiocarcinoma (ICC) with features of ductal plate malformations (DPM) have been reported, and the ICC with DPM was proposed as a subtype of ICC. The author herein reports a case of C-HCC-CC with stem cell features. Characteristically, the CC element showed features of DPM. A 51-year-old man of HBV carrier was found to have high AFP. A laboratory test showed an elevated AFP (395 ng/ml, normal 9-10) and hepatitis B virus-related antigens and antibodies. Liver and ductal enzymes and PIVKAII were within normal ranges. Imaging modalities including CT identified a small liver tumor. Hepatocellular carcinoma (HCC) was suspected, and the resection of the hepatic tumor was performed. Grossly, the liver tumor is well-defined white solid tumor measuring 22x16x23 mm. Microscopically, the tumor was a C-HCC-CC, and was composed of following three elements: well differentiated HCC, well differentiated cholangiocarcinoma (CC), and intermediate tumor element. Characteristically, the CC cells formed tortuous markedly irregular tubules with intraluminal cell projections, bridge formations, intraluminal tumor biliary cells; such features very resembled the ductal plate (DP) and DPM. Immunohistochemically, the cells of CC element were positive for stem cell antigens (KIT (CD117), CD56, EMA, CD34), HepPar1, EpCAM, cytokeratin (CK) CAM5.2, AE1/3, CK34BE12 (focal), CK7, CK8, CK18, CK19, CA19-9, p53, MUC1, MUC2, MUC5AC, MUC6, and Ki-67 (labeling=25%). They were negative for CEA, CK5/6, CK20, NSE, chromogranin, synaptophysin, and p63. No mucins were found by histochemically. The background liver showed chronic hepatitis B (a1, f3). Very interestingly, many DPMs were scattered in the non-tumorous parenchyma. This type of C-HCC-CC with DPM features has not been reported. The author herein proposes that this tumor should be included or added in the C-HCC-CC subtype as C-HCC-CC with stem cell features, DMP subtype.
PMCID: PMC3606865  PMID: 23573322
Combined hepatocellular cholangiocarcinoma; liver stem cells; ductal plate; ductal plate malformation; histopathology; immunohistochemistry
21.  Mycosis fungoides in plaque stage with pronounced eosinophilic infiltration, folliculotropism, and concomitant invasive squamous cell carcinoma 
Mycosis fungoides (MF) is a relatively rare cutaneous T-cell malignancy. Only two cases of MF with marked eosinophilia have been reported. In addition, MF with concomitant squamous cell carcinoma (SCC) occurring in the site of MF has not been reported. The author reports herein a very rare case of MF in the plaque stage showing pronounced eosinophilic infiltration, folliculotropic pattern, and in situ development of poorly differentiated squamous cell carcinoma (SCC). A 75-year-old man was found to show high prostate specific antigen (PSA, 13 hg/ml) and prostatic biopsy showed well differentiated prostatic adenocarcinoma of Gleason score 6. Imaging techniques showed no metastatic lesions. He was treated by estrogen therapy. At 80 years, he consulted our hospital because of erythematous patch in the trunk. Biopsy showed mild infiltrations of lymphocyte and eosinophils. The lesion disappeared spontaneously. At 82 years, he consulted our hospital of because of erythematous patch at the back, and biopsy showed mildly atypical lymphocytes positive for CD20 and CD45, but negative for CD30, CD45RO, S100 protein, and cytokeratin (CK). Lymphoma was suspected but not definite. The lesions spontaneously disappeared. At 86 ages, he also consulted our hospital because of plaques in the face. Biopsy showed proliferation of atypical lymphocytes, marked infiltration of mature eosinophils, marked infiltration of these cells in the fair follicles (folliculotropism), and poorly differentiated invasive SCC arising from follicular cells. An immunohistochemical analysis showed that the atypical lymphocytes are T-lymphoma cells with T-cell markers, cyclinD1, p53, and high Ki67 labeling (50%) but without B-cell markers, NK-cell markers and plasma cell markers. The eosinophils were mature, and lacked p53 and showed low Ki67 labeling (4%). The carcinoma was positive for CK, p53, cyclinD1, and high Ki67 labeling (35%). A diagnosis of MF in the plaque stage with marked non-neoplastic eosinophilic infiltration, marked folliculotropism, and coexistent poorly differentiated invasive SCC was made by the author. Post-biopsy imaging techniques showed no metastasis or lymphadenopathy in the body. The patient was now treated by chemotherapy.
PMCID: PMC3606866  PMID: 23573323
Mycosis fungoides; eosinophils; squamous cell carcinoma
22.  Inverted variant of urothelial carcinoma of the urinary bladder: a report of three cases and a proposal for a new clinicopathologic entity 
Inverted urothelial carcinoma (UC) without papillary areas is very rare; only 31 cases of three papers have been reported. The author herein reports three additional cases, and proposes the term “inverted variant” (IV) of UC. The materials were 3 cases of IV of UC, 5 cases of inverted papilloma (IP), and two cases of nested variant (NV) of UC. The three cases of IV of UC consisted of 56-year-old woman, 63-year-old man, and 78-year-old man. Presenting symptoms were hematuria in all cases. The cystoscopic findings were elevated tumors without papillary proliferations in all cases. The treatment was transurethral tumor resection (TUR-BT) in all cases. The sizes was 0.6 cm, 0.5 cm, and 3 cm. Microscopically, IV of UC showed inverted growth of atypical cells without papillary proliferations. Compared to IP, the inverted growth pattern was similar, but cytological atypia and thick trabeculae were noted in IV of UP while they were absent in IP. Compared to NV of UC, the growth pattern is different; NV of UC showed nested and vague tubular pattern. The cellular atypia is more pronounced in IV of UC than NV of UC. Immunohistochemically, p53 expression was seen in all the cases of IV of UC and in all the cases of NV of UC, while p53 expression was negative in all the cases of IP. Ki-67 labeling index was 25, 30 and 40% in IV of UC, 15 and 30% in NV of UC, and 3, 5, 6, 7, 9% in IP. Invasive features were seen in 1 case of IV of UC and 2 cases of NV of UC. In all cases of IV of UC, IP, and NV of UC, the TUR-BT, but one case of IV of UC, showed no recurrence after TUR-BT, while one case of IV of UC showed a recurrence. In conclusion, the IV and UC were structurally and cytologically very different from the NV of UC. The IV of UC was structurally similar to IP, but cellular atypia and thickened trabeculae were seen in IV and UC. p53 expression and Ki-67 labeling status were entirely different between in IV of UC and IP. The author proposes the term of IV of UC as a new clinicopathological entity.
PMCID: PMC3606868  PMID: 23573325
Urothelial carcinoma; inverted type; inverted papilloma; urinary bladder; immunohistochemistry
23.  Small cell carcinoma of the oral cavity (cheek mucosa): a case report with an immunohistochemical and molecular genetic analysis 
Small cell carcinoma (SCC) of the oral cavity is extremely rare; only one case has been reported in the English Literature. The author herein reports the second case of SCC of the oral cavity. A 59-year-old man presented with oral tumor (5 cm) in the right cheek mucosa. A biopsy was taken. The HE histology was typical SCC consisting of small epithelial cells with hyperchromatic nuclei, molded nuclei, scant nucleocytoplasmic ratio, and negative nucleoli. Immunohistochemically, the tumor cells are positive for pancytokeratin (PCK) WSS, PCK MNF-116, cytokeratin (CK) 34BE12, CK5/6, CK14, vimentin, KIT (CD117), CD56, synaptophysin, p53 protein, and Ki67 antigen (Ki-67 labeling = 70%). The tumor cells are negative for PCK AE1/3, PSK CAM5.2, CK7, CK8, CK18, CK19, CK20, EMA, NSE, chromogranin, platelet-derived growth factor-α (PDGFRA), CD45, CD45RO, CD3, CD20, CD30, CD79a, and bcl-2. A retrospective genetic analysis using PCR-direct sequencing method in paraffin sections identified no mutations of KIT (exons 9, 11, 13 and 17) and PDGFRA (exons 12 and 18) genes. Various imaging modalities including CT and MRI and upper and lower gastrointestinal endoscopy did not identified no tumors other than the oral tumor. Thus, the oral tumor was thought primary. The oral tumor rapidly enlarged, and distant metastases to cervical lymph nodes, ribs and iliac bones emerged. The patient is now treated by cisplatin-based chemotherapy 16 months after the first manifestation.
PMCID: PMC3606870  PMID: 23573327
Oral cavity; cheek mucosa; small cell carcinoma; histopathology; immunohistochemistry; molecular biopsy of KIT and PDGFRA
24.  Sarcomatoid carcinoma in the pelvic cavity 
Sarcomatoid carcinoma in the pelvic cavity is very rare. A 58-year-old Japanese man was admitted to our hospital because of lower abdominal fullness. CT and MRI revealed a large mass in the left pelvic cavity. Transurethral bladder endoscopy showed tumor invasion, and large biopsies were obtained from the bladder lesion. Histologically, the tumor was composed of malignant round cells with hyperchromatic nuclei. Many intracytoplasmic vacuoles were present. No carcinomatous areas were seen. Immunohistochemically, the tumor cells were positive for cytokeratin (CK) 18, vimentin, p53 and Ki-67 (labeling 80%). The tumor cells were negative for panCK AE1/3, CD5/6, CK7, CK8, CK14, CK19, CK20, CK 34BE12, EMA, desmin, calretinin, WT-1, S100 protein, α-smooth muscle actin, CEA, CD34, CD45, CD20, factor VIII-related antigen, synaptophysin, p63, CDX2, and myoglobin. Because the CK18 was diffusely expressed, the pathological diagnosis was sarcomatoid carcinoma.
PMCID: PMC3606872  PMID: 23573329
Sarcomatoid carcinoma; pelvic cavity; urinary bladder
25.  Primary cutaneous neuroendocrine tumor (atypical carcinoid) expressing KIT and PDGFRA with myoepithelial differentiation: a case report with immunohistochemical and molecular genetic studies 
Primary cutaneous neuroendocrine tumors (NET) except for Merkel cell carcinoma have rarely been reported. Herein reported is a very unique case of primary cutaneous NET with immunohistochemical markers of myoepitheliomas. A 47-year-old woman presented a tumor measuring 0.8x0.9x0.6 cm of the face. The tumor was excised completely with wide margins. Morphologically, the tumor was located in the dermis, and the tumor was composed of epithelioid cells arranged in trabecular, sinusoidal, rosette, ribbon-like, and cord-like patterns. Focal areas show tubular formations. The tumor cells were homogenous, and their nuclei showed hyperchromasia but no apparent histological features of malignancy were seen. The stroma was very scant. No invasive features were seen. Immunohistochemically, the tumor cells were strongly positive for cytokeratin (CK) 34BE12, CD5/6, CK14, NCAM (CD56), p63, and KIT (CD117), and moderately positive for CK AE1/3, p53, chromogranin, synaptophysin, neuron-specific enolase (NSE), PDGFRA, CA19-9, and Ki-67 antigen (labeling index=23%). The tumor cells were negative for CK CAM5.2, CK7, CK8, CK18,CK19,CK20, EMA, vimentin, CEA, HMB45, S100 protein, α-smooth muscle antigen, desmin, CD34, GFAP, neurofilaments, CD99 (MIC2), CD45, CD57, ErbB2, TTF-1, MUC1, MUC2, MUC5AC, and MUC6. Mucins examined by d-PAS and Alcian blue techniques were negative. A genetic analysis using PCR-direct sequencing method in paraffin sections identified no mutations of KIT (exons 9, 11, 13 and 17) and PDGFRA (exons 12 and 18) genes. Imaging modalities including CT and MRI identified no tumor in the body. The clinicians thought that the tumor was cured. She was a sailor and immediately visited other countries; therefore the follow-up could not be done.
PMCID: PMC3606874  PMID: 23573331
Skin; NET; carcinoid; neuroendocrine; myoepithelioma; immunohistochemistry; KIT; PDGFRA

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