Ductal Differentiation Research Articles

Intraductal and Papillary Variants of Acinar Cell Carcinomas

The recognition and differential diagnosis of pancreatic intraductal neoplasms (IN) have gained importance in the past few years, as the incidence of these tumors (especially intraductal papillary mucinous neoplasms-IPMNs) have risen to >10% of pancreatic resections, and their significance as precursors of invasive cancer is better appreciated. Acinar cell carcinomas (ACCs) are typically solid tumors; however, we have recently encountered 7 ACCs with either intraductal growth and/or a papillary/papillocystic pattern that could be mistaken for IN. The clinicopathologic features of these cases were studied. Four patients were male and 3 female, with a mean age of 59 and mean tumor size of 4.9 cm (as compared with 10 cm in conventional ACCs). Only 1 patient had metastasis at the time of diagnosis (as opposed to 50% in usual ACCs). In 5 cases, the tumors had nodular growth of sheet-forming acinar cells, some of which were within ducts, as evidenced by the polypoid nature of the process, partial ductal lining, and presence of small tributary ducts in the walls. In 3 cases, the tumor had papillary and/or papillocystic growth, at least focally. All cases had cystic areas. No mucin was identified. All expressed trypsin. Markers of ductal differentiation were either absent or focal. A minor endocrine component was present in 3. The main histologic findings that distinguished these tumors from IPMNs were the more sheetlike nature of the nodules (rather than villous or arborizing papillae), cuboidal cells, overall basophilia of the cytoplasm, prominent nucleoli, apical granules, intraluminal crystals or pale, acidophilic secretions (enzymatic condensations), and lack of mucin. In conclusion, some ACCs show intraductal growth or exhibit papillary patterns, which can mimic IN, especially IPMNs. In such cases, attention to morphologic details described above, and immunohistochemistry are helpful. The clinical significance of this variant is difficult to determine; however, it appears that the tumors are relatively small and metastasis at presentation is less common than typically seen in ACCs (1/7 vs. 50%).

Esophageal Gland Duct Adenoma: Immunohistochemical Comparison With the Normal Esophageal Gland and Ultrastractural Analysis

Esophageal gland duct adenomas are extremely rare tumors. Here, we report the case of a 75-year-old Japanese man who had undergone total gastrectomy for advanced gastric cancer. Esophageal gland duct adenoma was incidentally found in the lower esophagus. It appeared to be detached from the site of gastric cancer and was well demarcated without a capsule. Histologic analysis revealed papillary and cystic structures mainly comprising eosinophilic cells with minimum nuclear atypia. Immunohistochemical analysis revealed that the tumor were diffusely positive for the S100 protein with preserved alpha-SMA-positive myoepithelial cell layers and a characteristic cytokeratin expression pattern similar to that in normal esophageal gland ducts (CK5/6+++, CK7+++, CK17+, CK18+, CK19+++, CK20-, HMWCK+++). In addition, differentiation into the terminal duct was confirmed by a combination of mucin staining and immunohistochemical and ultrastructural examinations. This is the first report that refers to the ultrastructural findings of an esophageal gland duct adenoma and describes terminal duct differentiation. We believe that the possibility of an esophageal gland duct adenoma should be considered when diagnosing a ductal or glandular lesion of the esophagus.

Nonductal neoplasms of the pancreas

Although the majority of pancreatic neoplasms are infiltrating ductal adenocarcinomas or other neoplasms with ductal differentiation, neoplasms with acinar, endocrine, mixed, or uncertain differentiation constitute a diverse and distinctive group. The most common and best-characterized nonductal neoplasms are pancreatic endocrine neoplasm, acinar cell carcinoma, pancreatoblastoma, and solid pseudopapillary neoplasm. This review details the clinical and pathologic features of these nonductal neoplasms, highlighting diagnostic criteria including the use of specific immunohistochemical stains to define the cellular differentiation of the neoplasms.

Small Cell Carcinoma of the Breast

Small cell carcinoma of the breast (SCCB) is an uncommon neoplasm that accounts for less than 1% of primary breast cancers. Histologically, these tumors have striking similarities to small call carcinoma of the lung, usually with evidence of associated ductal carcinoma-in-situ (DCIS) with areas of ductal, lobular, or papillary differentiation. Immunoreactivity for neuroendocrine markers is documented in two thirds of cases, while 33% to 50% are positive for estrogen receptor (ER) or progesterone receptor (PR). Her2/neu expression has not been reported in SCCB. Treatment, which may include surgery, radiotherapy, and combination chemotherapy, is based on clinical stage and the presence of metastases. Prognosis is variable and is dependent on the initial stage of disease.

Fgf10 regulates hepatopancreatic ductal system patterning and differentiation

During organogenesis, the foregut endoderm gives rise to the many different cell types that comprise the hepatopancreatic system, including hepatic, pancreatic and gallbladder cells, as well as the epithelial cells of the hepatopancreatic ductal system that connects these organs together and with the intestine. However, the mechanisms responsible for demarcating ducts versus organs are poorly understood. Here, we show that Fgf10 signaling from the adjacent mesenchyme is responsible for refining the boundaries between the hepatopancreatic duct and organs. In zebrafish fgf10 mutants, the hepatopancreatic ductal epithelium is severely dysmorphic, and cells of the hepatopancreatic ductal system and adjacent intestine misdifferentiate toward hepatic and pancreatic fates. Furthermore, Fgf10 also functions to prevent the differentiation of the proximal pancreas and liver into hepatic and pancreatic cells, respectively. These data shed light onto how the multipotent cells of the foregut endoderm, and subsequently those of the hepatopancreatic duct, are directed toward different organ fates.

Paucicellular infiltrating ductal carcinoma of pancreas: an unusual variant

A 65-year-old man presented with obstructive jaundice from a 3-cm mass in the head of the pancreas. A Whipple resection was performed. Histologic examination of the tumor showed scanty tumor cells arranged in a single-file manner set within a desmoplastic sclerotic stroma. In other areas, the tumor was arranged around preexisting ducts in a targetoid fashion. Very focal ductal and signet-ring cell differentiation was noted. This unusual variant of pancreatic cancer was characterized by paucicellularity and a pattern of invasion resembling lobular carcinoma of breast.

Solitary eccrine syringofibroadenoma with prominent plasma cell infiltration

Eccrine syringofibroadenoma (ESFA) is a rare, benign, adnexal neoplasm thought to be eccrine ductal differentiation displaying variable clinical findings and characteristic histological features. It usually occurs as a solitary nodule on the extremities of an elderly person. Histological findings typically show a proliferation of anastomosing strands, cords, and columns of monomorphous epithelial cells that harbor eccrine duct formations embedded in a fibrovascular stroma. Acrosyringial nevus, though usually regarded as an identical lesion, is sometimes regarded as a different entity showing prominent plasma cell infiltration. We report two cases of solitary ESFA with prominent plasma cell infiltration. Clinicopathological features of both cases suggest that acrosyringeal nevus and ESFA may be of the same disease entity. Prominent plasma cell infiltration may be just one of the common histological features of ESFA.

Diagnosis and Treatment of Pancreatoblastoma in China

Pancreatoblastoma is an extremely rare pancreatic neoplasm. The aims of the current study were to analyze the clinical, pathological, and immunohistochemical features of pancreatoblastoma and to discuss its management. The clinical data of 30 Chinese pancreatoblastoma patients (among them, 1 case was treated by authors, and the other 29 cases were reported in Chinese literature from January 1981 to December 2005) were reviewed and analyzed. Patients with pancreatoblastoma had an age range of 5 months to 42 years. There were 24 children and 6 adult cases, with a male-female ratio of 2:1 (20/10). The tumor size ranged from 2 to 20 cm in diameter. Metastases were found during the operation in 8 cases (26.7%) (among them, 66% with liver invasion and 50% with multiple metastases including spleen, kidney, and bone). Pancreatoduodenectomy was performed in 5 cases (16.7%). Nine cases (30%) received chemotherapy with vincristine, cyclophosphamide, and adriamycin. By immunohistochemistry, the tumors exhibited acinar, endocrine, and ductal differentiation. The mean time of survival was 25.5 months. These results suggest that the diagnosis of pancreatoblastoma mainly depends on the pathological findings, surgical resection is the most effective way for cure, and adjuvant chemotherapy could be a good palliative method in certain patients.

A Histopathological and Immunohistochemical Study of High-Molecular-Weight Cytokeratin, Mitochondrial Protein and Gross Cystic Disease Fluid Protein-15 in Pleomorphic Adenomas-With Special Reference to Epithelial Metaplastic Changes-

Pleomorphic adenoma, which is the major histopathological type of salivary gland tumor, shows polymorphous features including proliferating epithelial components with tubulo-ducatal and/or solid nests and mesenchyme-like components with myxomatous, myxo-chondromatous, and/or fibrohyalinized tissues. The process of metaplasia, which involves progressive changes in tissues, results in the transformation of fully differentiated cells of one type into differentiated cells of another type in various organs and diseases. Therefore, metaplastic change is an important morphological factor that determines the individual characteristics and typical histogenesis of various lesions. The purpose of the present study was to investigate metaplastic changes histopathologically and immunohistochemically using antibodies against high-molecular-weight keratin (34βE12), mitochondrial protein (MIT) and gross cystic disease fluid protein-15 (BRST-2) in order to clarify the morphological nature and mechanism of the metaplastic change in pleomorphic adenomas. These antibodies are known to be useful markers of squamous, oncocytic and apocrine-like metaplasia, respectively. Histopathologically, the parenchyma of pleomorphic adenoma consisted of double-layered epithelial elements showing luminal and abluminal arrangements, continuously adjacent to mesenchyme-like elements with myxomatous, myxochondromatous and/or hyalinized tissues. The epithelial parenchyma contained squamous eddies with polygonal cells and/or horny keratin pearls (10/10 cases), eosinophilic cuboidal and/or columnar oncocytic cells (8/10 cases), and also apocrine-like features (3/10 cases). Immunohistochemically, 34βE12-positive cells corresponded to the squamous eddies, whereas MIT- and BRST-2-positive cells corresponded to the eosinophilic, oncocytic cells and apocrine-like cells, respectively. In addition, positive immunoreactivity for 34βE12, MIT and BRST-2 was evident at luminal sites, and 34βE12 was expressed at abluminal sites in this tumor. These results suggest that metaplasia of squamous epithelium is associated with both ductal or luminal differentiation and abluminal differentiation of basal and myoepithelial cells, whereas, metaplastic changes of oncocytes and apocrine cells are related to ductal, luminal proliferation, comprising the typical polymorphous features of pleomorphic adenoma.

Activin A and Glucose Derived Human Pancreatic Ductal Cells into Insulin-producing Cells

- Abstract - - Abstract - - Abstract - - Abstract - Background: Cellular replacement therapy holds promise for the treatment of diabetes mellitus but donor tissue is severely limited. Human postnatal pancreatic ductal cells are a potential source of new beta cells. Therefore, we investigated the potential of human pancreatic ductal cells could be differentiated into endocrine cells that would be capable of secreting insulin in response to glucose. Methods: Cell fractions enriched with pancreatic ductal cells after human islet isolation were treated with streptozotocin to remove residual beta cells, grown in monolayer culture, changed the media for differentiation in the presence of activin A and glucose, supplemented with 10% FCS. The differentiation markers, insulin secretion and cell proliferation were examined. Result: No insulin was detectable in cell preparations after 5 days of treatment with streptozotocin. In monolayer culture, 80% of the streptozotocin-treated pancreatic ductal cells expressed cytokeratin-19. Cell cultures with a high proportion of cytokeratin-19 cells had greater plasticity for differentiation into cells with phenotypic and functional markers of beta cells. This property were significantly enhanced by treatment of activin A and glucose. The differentiated human pancreatic ductal cells secreted insulin sensitively responded with high glucose. Conclusion: Human pancreatic ductal cells are a potential source of new glucose -induced insulin producing cells that may be developed further for clinical use. Therefore, the present data support a possible role for human adult pancreatic ductal cells, following expansion and differentiation, as a source of insulin by transplantation cells to type I diabetes patients. (J Kor Diabetes Assoc 31:44~50, 2007)

Maturation of in vitro-generated human islets after transplantation in nude mice

The long-term function of human pancreatic islet grafts may depend on the neogenesis of beta cells from epithelial precursors within the grafted tissue. We have developed an in vitro model for human islet neogenesis. In this study, we have investigated the morphological signs of maturation in cultivated human islet buds (CHIBs) before and after transplantation. Clusterin is a molecule associated with beta-cell differentiation in rodents. In adult human islets, clusterin expression was located only in alpha- and PP-cells, but in CHIBs and human fetal islets, it was distributed in all four types of endocrine cells. Some immature endocrine cells in the CHIBs co-expressed insulin and glucagon. After transplantation, CHIBs became mature with one type of hormone per endocrine cell, and clusterin expression became restricted in alpha-cells. Cells co-expressing endocrine markers and cytokeratin 19, as a sign of ductal to endocrine cell transition, were frequently detected in both fresh islets and CHIBs after transplantation. We conclude that clusterin may be involved in the development of islets, and the in vitro-derived islets become mature after transplantation into nude mice. Ductal cell differentiation into endocrine cells may be an important factor in sustaining the long-term function of islet transplants.

Reduced lecithin:retinol acyltransferase expression in human breast cancer

Retinoids, vitamin A (retinol) and related metabolites, have been shown to be important in regulating cell growth and differentiation. We have shown that expression of the enzyme lecithin:retinol acyltransferase (LRAT), which converts retinol to retinyl esters, is reduced in several human carcinomas as compared with adjacent normal tissue from the same organs. The purpose of this research was to determine if aspects of retinoid signaling are impaired in human breast cancer. We evaluated LRAT protein expression in neoplastic and adjacent, non-neoplastic glandular breast tissue specimens from human patients. We evaluated 26 specimens from patients diagnosed with breast cancer between 2003 and 2005. Representative paraffin-embedded tissue blocks from each tumor, with each containing adjacent non-neoplastic glandular breast tissue, were examined by immunohistochemistry with affinity purified antibodies to human LRAT protein. LRAT protein was prominently detected throughout the non-neoplastic glandular breast tissue in all of the specimens. Areas of ductal carcinoma in situ and well-differentiated invasive breast carcinomas showed an intensity of staining with the LRAT antibody which was similar to that of the adjacent normal tissue. Expression of LRAT protein progressively decreased with a reduction in the degree of tumor differentiation in invasive breast carcinomas. LRAT protein levels correlate better with the degree of ductal tumor differentiation than does estrogen receptor status in this study. Furthermore, normal human breast epithelium exhibits intense LRAT staining, indicating a major role for LRAT in human breast physiology.

The PDX1 Homeodomain Transcription Factor Negatively Regulates the Pancreatic Ductal Cell-specific Keratin 19 Promoter

Keratin 19 is a member of the cytokeratin family that is critical for maintenance of cellular architecture and organization, especially of epithelia. The pancreas has three distinct cell types, ductal, acinar, and islet, each with different functions. Embryologically, the pancreatic and duodenal homeobox 1 (PDX1) homeodomain protein is critical for the initiation of all pancreatic lineages; however, the later differentiation of the endocrine pancreas is uniquely dependent upon high PDX1 expression, whereas PDX1 is down-regulated in the ductal and acinar cell lineages. We find that this down-regulation may be required for normal ductal expression of cytokeratin K19. The K19 promoter-reporter gene assay demonstrates that ectopic PDX1 inhibits K19 reporter gene activity in primary pancreatic ductal cells. This is reinforced by our findings that retrovirally mediated stable transduction of PDX1 in primary pancreatic ductal cells suppresses K19 expression, and short interfering RNA to PDX1 in Min6 insulinoma cells results in the induction of normally undetectable K19. Complementary functional and biochemical approaches led to the unexpected finding that a multimeric complex of PDX1 and two members of the TALE homeodomain factor family, MEIS1a and PBX1b, regulates K19 gene transcription through a specific cis-regulatory element (-341 to -325) upstream of the K19 transcription start site. These data suggest a unifying mechanism whereby PDX1, myeloid ecotropic viral insertion site (MEIS), and pre-B-cell leukemia transcription factor 1 (PBX) may regulate ductal and acinar lineage specification during pancreatic development. Specifically, concomitant PDX1 suppression and MEIS isoform expression result in proper ductal and acinar lineage specification. Furthermore, PDX1 may inhibit the ductal differentiation program in the pancreatic endocrine compartment, particularly beta cells.

Sarcomatoid eccrine porocarcinoma: report of two cases and a review of the literature

Eccrine porocarcinoma is an uncommon sweat gland malignancy. To the best of our knowledge, there has been no report in the English literature of porocarcinoma with predominantly undifferentiated sarcomatous change. We present two cases of sarcomatoid eccrine porocarcinoma associated with a benign poroma. Case 1 pertained to an 82-year-old woman with an ulcerated chest wall tumor, and Case 2 was that of a 74-year-old woman who presented with an ulcerated plaque in the lower leg. Case 1 showed an unusual pseudo-angiosarcomatous morphology with spindle cells dissecting through collagen bundles and forming vascular like channels. Case 2 revealed high-grade malignant spindle cells with focal evidence of ductal differentiation. In both the cases, benign poromatous elements were histologically evident. Immunohistochemistry performed showed pancytokeratin positivity in spindle cells of both lesions. Epithelial membrane antigen and carcino-embryonic antigen positivity in the malignant ductal elements and focal smooth muscle actin staining of the spindle cells were demonstrated in Case 2. A brief review of relevant literature is presented.

Eccrine ductal and acrosyringeal differentiation of the breast epithelium—a lesion associated with some metaplastic breast carcinomas

Two cases of metaplastic breast carcinoma associated with eccrine ductal metaplasia in the surrounding breast tissue are reported. The metaplastic epithelium deviated from the normal in its immunophenotype not expressing glandular cytokeratins (Cam 5.2) and estrogen receptors, being maspin-positive, and resembling morphologically different segments of dermal eccrine duct and acrosyringium. In addition, in one of the cases, basalioma-like intraductal cell proliferation was observed, also showing focal acrosyringeal differentiation. The invasive carcinomas, one of them representing "syringomatous squamous tumor of the breast" while the other diagnosed as high-grade metaplastic carcinoma, also showed focal eccrine and acrosyringeal differentiation and intensive diffuse maspin expression. These previously unrecognized metaplastic changes of the breast epithelium may represent precursor lesions of certain types of metaplastic breast carcinomas.

Pleomorphic Giant Cell Adenocarcinoma of the Prostate

Pleomorphic tumors with giant cells have been described in a variety of primary sites. However, only a few cases have been described among prostatic carcinomas with only 1 on diagnostic biopsy material. Five cases were retrieved from the consultation files of one of the authors. One of the cases was retrieved from the surgical pathology files at our institute. Patient ranged in age from 59 to 76 years (mean=65.8 y). The diagnosis was made on needle biopsy (n=3), urethral biopsy (n=1), transurethral resection (n=1), or radical prostatectomy (n=1). In all cases, giant, bizarre, anaplastic cells were present. In 4 of the cases, marked pleomorphism occupied 5% of the specimen, with 20% and 70% bizarre giant cells in the other 2 cases. In one case, the bizarre cells had atypical mitotic figures, with other cases showing no mitoses in the markedly pleomorphic cells. In addition to the pleomorphic giant cell component, multiple coexistent histologic components were seen including Gleason score 9 conventional prostate cancer (n=6), small cell carcinoma (n=1), squamous carcinoma (n=1), and prominent ductal adenocarcinoma differentiation with intraductal spread (n=1). Immunohistochemically, 4 cases were for negative for prostate-specific antigen in the giant cells, 1 had 5% staining, and the other had 50% positivity in the giant cells. Staining for prostate-specific antigen in the conventional prostate carcinoma component was 1%, 5%, 20%, 50%, 100%, and 100%. The bizarre giant cells were strongly positive for cytokeratins AE1/AE3 and/or Cam 5.2 (n=3). Two cases had a history of conventional prostate cancer 4 years before the giant cell component, 1 treated with Lupron and the other with radiation. Follow-up after diagnosis of the giant cell component: Case 1: dead in 1 year of disease; Case 2: progressive metastases in 2 years; Case 3: alive at 1 year with disease; Case 4: large perineal recurrence after brachytherapy at 3 years; Case 5: radical prostatectomy with extraprostatic extension and seminal vesicle invasion; and Case 6: alive at 3 months, free of disease. Conventional prostate cancer, even when very high grade, typically consists of cells with relatively uniform nuclei. Our study expands the histology described in prostate cancer to include in very rare cases with prominent pleomorphism and bizarre giant cells. This giant cell component heralds a particularly aggressive clinical outcome.

Imatinib-induced eccrine squamous syringometaplasia

To the Editor: Eccrine squamous syringometaplasia (ESS) is a peculiar benign entity, defined as a squamous metaplasia of the cuboidal epithelial cells of the eccrine sweat ducts. The clinical presentation is not distinctive and consists of erythematous papules, vesicles, and/or erythematous plaques. In chronic myeloid leukemia (CML) the bcr-abl (Philadelphia) hybrid gene encodes a tyrosine kinase, which is selectively inhibited by imatinib mesylate (Gleevec, formerly STI571). The use of imatinib is associated with a high rate of adverse cutaneous reactions in patients with Philadelphia chromosome–positive CML. Rash and edema are the most common adverse effects.1Valeyrie L. Bastuji-Garin S. Adverse cutaneous reactions to imatinib (STI571) in Philadelphia chromosome-positive leukemias: a prospective study of 54 patients.J Am Acad Dermatol. 2003; 48: 201-206Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar We report the first case of squamous syringometaplasia of which we are aware in a patient treated with imatinib for CML. A 51-year-old Caucasian woman with Philadelphia chromosome–positive CML presented with multiple asymptomatic papules on the face and upper chest of 1 week's duration. The lesions appeared a few days after she had started induction therapy with imatinib, 400 mg daily. Her medical history and medications were otherwise stable and unremarkable. Physical examination revealed numerous 5-mm erythematous papules on the lower eyelids, cheeks, and upper chest (Fig 1). Further physical examination was unremarkable. A biopsy specimen taken from a papule on the lower eyelid revealed a dermal infiltrate of irregular epithelial nests resembling invasive squamous cell carcinoma. However, the epithelial cells did not display atypia, and there was no stromal desmoplasia (Fig 2). Immunohistochemistry was positive for carcinoembryonic antigen, indicating ductal differentiation, while Ki-67 staining confirmed low mitotic activity. Clinically, the papules began to disappear within 72 hours after brief discontinuation of imatinib. The rash reappeared with rechallenge 1 week later. Two subsequent biopsy specimens on the right cheek and upper chest showed histologic features similar to those of the first biopsy. The diagnosis of ESS was made.Fig 2Histopathology of biopsy specimen shows a dermal infiltrate of irregular epithelial nests. (Hematoxylin-eosin stain; original magnification: ×200.)View Large Image Figure ViewerDownload (PPT) ESS has been reported in cancer patients receiving various chemotherapeutic regimens and in association with tetrachlorodibenzodioxin, chronic ulcers and scars, squamous cell carcinoma, keratoacanthoma, lobular panniculitis, and pyoderma gangrenosum.2Susser W.S. Whitaker-Worth D.L. Mucocutaneous reactions to chemotherapy.J Am Acad Dermatol. 1999; 40: 367-398Abstract Full Text Full Text PDF PubMed Scopus (258) Google Scholar The stimulus for eccrine ductal squamous metaplasia is not known. The numerous associations suggest that ESS represents a nonspecific reactive change to damaged eccrine ductal epithelium. Metcalf and Maize3Metcalf J. Maize J. Squamous syringometaplasia in lobular panniculitis and pyoderma gangrenosum.Am J Dermatopathol. 1990; 12: 141-149Crossref PubMed Scopus (33) Google Scholar suggest that inflammation induces ductal necrosis, in turn triggering squamous metaplasia. Others argue that ESS and neutrophilic eccrine hidradenitis are all in the spectrum of chemotherapy-associated eccrine changes, with ESS at the noninflammatory end and neutrophilic eccrine hidadenitis at the inflammatory end.4Hurt M.A. Halvorson R.D. Eccrine squamous syringometaplasia.Arch Dermatol. 1990; 126: 73-77Crossref PubMed Scopus (74) Google Scholar Imatinib is 95% bound to human plasmaproteins and eliminated predominantly via the bile. It is not known whether imatinib is secreted in sweat. An alternative (and yet-unproven) theory of ESS involves direct medication toxicity to sweat glands due to concentration and secretion in the eccrine unit.5Peng B. Lloyd P. Clinical pharmacokinetics of imatinib.Clin Pharmacokinet. 2005; 44: 879-894Crossref PubMed Scopus (484) Google Scholar In ESS, however, histopathology shows unaffected eccrine coils with a sparse lymphoid infiltrate, features that distinguish it from neutrophilic eccrine hidadenitis. The ducts appear as infiltrative nests of squamous epithelium mimicking invasive squamous cell carcinoma. The retained lobular configuration, absence of squamous atypia and stromal desmoplasia, and immunohistochemical demonstration of ductal differentiation may aid in the differential diagnosis.6Serrano T. Saez A. Eccrine squamous syringometaplasia. A prospective clinicopathologic study.J Cutan Pathol. 1993; 20: 61-65Crossref PubMed Scopus (39) Google Scholar We report the association of imatinib therapy with ESS. The ability to distinguish ESS from squamous cell carcinoma is important to avoid misdiagnosis and inappropriate treatment.

Role of HOXA7 to HOXA13 and PBX1 genes in various forms of MRKH syndrome (congenital absence of uterus and vagina)

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome refers to the congenital absence or severe hypoplasia of the female genital tract, often described as uterovaginal aplasia which is the prime feature of the syndrome. It is the second cause of primary amenorrhea after gonadal dysgenesis and occurs in ~1 in 4500 women. Aetiology of this syndrome remains poorly understood. Frequent association of other malformations with the MRKH syndrome, involving kidneys, skeleton and ears, suggests the involvement of major developmental genes such as those of the HOX family. Indeed mammalian HOX genes are well known for their crucial role during embryogenesis, particularly in axial skeleton, hindbrain and limb development. More recently, their involvement in organogenesis has been demonstrated notably during urogenital differentiation. Although null mutations of HOX genes in animal models do not lead to MRKH-like phenotypes, dominant mutations in their coding sequences or aberrant expression due to mutated regulatory regions could well account for it. Sequence analysis of coding regions of HOX candidate genes and of PBX1, a likely HOX cofactor during Müllerian duct differentiation and kidney morphogenesis, did not reveal any mutation in patients showing various forms of MRKH syndrome. This tends to show that HOX genes are not involved in MRKH syndrome. However it does not exclude that other mechanisms leading to HOX dysfunction may account for the syndrome.

FGF10 regulates hepatopancreatic ductal system differentiation

The hepatopancreatic ductal system, which consists of the common bile, cystic, extra hepatic and extra pancreatic ducts, joins the liver, pancreas, and gallbladder together into the intestine through the hepatopancreatic ampulla. Differentiation of the hepatopancreatic ductal system occurs concurrently with liver and pancreas differentiation. However unlike the liver and pancreas, the genetic mechanisms regulating hepatopancreatic ductal system development is largely unknown. Here, we show that mesenchymal cells, marked by the expression of the LIM homeodomain protein, ISL1, surround the developing hepatopancreatic ductal system and intestine but are absent around the pancreas and liver. Therefore, we hypothesized that these surrounding ISL1+ mesenchymal cells may be signaling to the presumptive hepatopancreatic duct to regulate its development. We show that the genes encoding FGF10 ligand and its high affinity receptor, FGFR2, are expressed in the mesenchyme and endoderm, respectively. In fgf10 null embryos, expression of the fgf target gene, dusp6, is lost from the organ-forming region of the endoderm, suggesting that the endoderm receives fgf10 signaling from the mesenchyme. We also find that the hepatopancreatic ductal epithelium of fgf10 null embryos is dysmorphic and expanded. Gene expression analyses of fgf10 null embryos indicate that the hepatopancreatic ductal system and adjacent intestinal cells mis-differentiate into hepatic cells and pancreatic endocrine and exocrine cells. Our findings demonstrate that cells of the presumptive hepatopancreatic ductal system and adjacent intestine are multipotent and poised to become pancreatic and hepatic tissues in absence of fgf10 signaling from the mesenchyme.

Mesenchymal epimorphin is important for pancreatic duct morphogenesis

Epithelial-mesenchymal interactions are crucial for the proper development of many organs, including the pancreas. Within the pancreas, the ducts are thought to harbor stem/progenitor cells, and possibly to give rise to pancreatic ductal carcinoma. Little is known about the mechanism of formation of pancreatic ducts in the embryo. Pancreatic mesenchyme contains numerous soluble factors which help to sustain the growth and differentiation of exocrine and endocrine structures. Here, we report that one such morphoregulatory mesenchymal protein, epimorphin, plays an important role during pancreatic ductal proliferation and differentiation. We found that epimorphin is expressed in pancreatic mesenchyme during early stages of development, and at mesenchymal-epithelial interfaces surrounding the ducts at later stages. Strong upregulation of epimorphin expression was seen during in vitro pancreatic duct differentiation. Similarly, in vitro pancreatic duct formation was inhibited by a neutralizing antibody against epimorphin, whereas addition of recombinant epimorphin partially rescued duct formation. Together, our study demonstrates the role of epimorphin in pancreatic ductal morphogenesis.