Human Colorectal Cancer Stage-dependent Global DNA Hypomethylation of Cancer-associated Fibroblasts.

BACKGROUND/AIM: Cancer-associated fibroblasts (CAFs) play an important role in tumor development and progression. The prevailing consensus favors the view that a specific epigenetic signature underpins the stable CAF phenotype. The aim of the present study was to assess global DNA methylation in CAFs during the adenoma-carcinoma sequence in non-familial sporadic human colorectal cancer (CRC). PATIENTS AND METHODS: Immunohistochemical staining of nuclear 5-methylcytosine (5'-meCyt) was performed in matched samples of colonic tumor tissue and normal colonic mucosa excised from six patients with adenomas and four with adenocarcinomas. The staining intensity was expressed semi-quantitatively as the immunohistochemical staining score (ISS). RESULTS: ISS values of human colonic CAFs and adenomatous samples were 14.00±2.2 and 14.08±1.8, respectively, showing no statistically significant difference. In contrast, a marked trend was found towards global DNA hypomethylation in CAFs from adenocarcinomatous specimens compared to matched normal mucosa: ISS: 9.25±2.44 (range=6-11) vs. 16.17±0.75, respectively, p<0.03. CONCLUSION: Final stages of cancer development in CRC are associated with global DNA hypomethylation in stromal CAFs.

Multicenter study of 19 aortopulmonary window parathyroid tumors: the challenge of embryologic origin.

BACKGROUND: Ectopic abnormal parathyroid glands are relatively common in the superior mediastinum but are rarely situated in the aortopulmonary window (APW). The embryological origin of these abnormal parathyroid glands is controversial. The purpose of this investigation was to investigate the embryological origin and the surgical management of abnormal parathyroid glands situated in the APW. METHODS: The databases of patients operated on for primary, secondary, and tertiary hyperparathyroidism at eight European medical centers with a special interest in endocrine surgery were reviewed to identify those with APW adenomas. Demographic features, localization procedures, and perioperative and pathology findings were documented. The embryological origin was determined based on the number and position of identified parathyroid glands. RESULTS: Nineteen (0.24%) APW parathyroid tumors were identified in 7,869 patients who underwent an operation for hyperparathyroidism (HPT) and 181 patients (2.3%) with mediastinal abnormal parathyroid glands. Ten patients had primary, eight had secondary, and one had tertiary HPT. Sixteen patients had undergone previous unsuccessful cervical exploration. In three patients, an APW adenoma was suspected by preoperative localization studies and was cured at the initial operation. Sixteen patients had persistent HPT of whom 15 were reoperated, resulting in 6 failures. Evaluation of 17 patients who had bilateral neck exploration allowed us to determine the most probable origin of the APW parathyroid tumors: 12 were supernumerary, 4 appeared to originate from a superior, and 1 from an inferior gland. CONCLUSIONS: Abnormal parathyroid glands situated in the APW are rare and usually identified after an unsuccessful cervical exploration. Preoperative imaging of the mediastinum and neck are essential. The origin of these ectopically situated tumors is probably, as suggested by our data, from a supernumerary fifth parathyroid gland or from abnormal migration of a superior parathyroid gland during the embryologic development.

Facial metrics in children with corticotrophin-producing pituitary adenomas suggest abnormalities in midface development.

BACKGROUND: Tumors of the hypothalamic-pituitary unit have been linked to genetic syndromes that are associated with midfacial abnormalities. AIM: We hypothesized that mutations of genes that affect the development of the face (and consequently of the anterior pituitary) may be present in children with ACTH-producing pituitary adenomas, and if this is true then facial measurements would be different from those predicted by parental features. METHODS: We studied 20 children with corticotropinomas and a control group and their parents. All facial measurements were expressed according to standard deviation scores. RESULTS: Significant differences were seen between the children with pituitary adenomas and their parents for vertical facial height measures: nasal length (p < 0.001), lower facial height (p < 0.03) and overall facial height (p < 0.01). CONCLUSION: We conclude that some of the indices of midline craniofacial development, in particular those affecting the vertical axis, are different in children with corticotroph adenomas producing ACTH.

Tomoscintigraphy improves the determination of the embryologic origin of parathyroid adenomas, especially in apparently inferior glands: imaging features and surgical implications.

UNLABELLED: Identification of the embryologic origin of hyperfunctioning parathyroid adenomas in primary hyperparathyroidism (PHPT) could determine the most suitable approach for minimally invasive surgery. The aim of this study was to prospectively evaluate the reliability of a new, combined protocol for the preoperative localization and determination of the embryologic origin of parathyroid adenomas. METHODS: Anterior dual-isotope ((123)I/(99m)Tc-sestamibi) static planar imaging followed by tomoscintigraphy (SPECT acquisition) centered over the 140-keV photopeak (combined protocol) was performed on 35 consecutive patients with sporadic PHPT. On the basis of anatomic considerations, adenomas were classified as superior (P4 derived) if they were located above the isthmus or posterior to the thyroid on SPECT images, despite their apparently middle to inferior position, and as inferior (P3 derived) if the foci were located in inferior and anterior positions or along the thyrothymic tract. Parathyroid ultrasonography was performed on all patients. RESULTS: A total of 36 adenomas were removed: 34 solitary adenomas and 1 double adenoma (for totals of 19 P3-derived and 17 P4-derived adenomas). Pinhole subtraction imaging, SPECT, and ultrasonography sensitivities for detecting adenomas were 86%, 78%, and 77%, respectively. False-positive contralateral images were observed only with ultrasonography (3 cases). Positive SPECT results were associated with higher gland weights. Thirteen glands were identified by SPECT as posterior glands, despite their apparently inferior position, and were removed through an appropriate lateral endoscopic approach. Eleven (85%) of these glands had a P4 origin. Only 2 corresponded to large P3-derived adenomas (>2 g). CONCLUSION: By reclassifying apparently inferior adenomas as P4-derived adenomas prolapsed behind the thyroid gland, SPECT provides information about the most suitable surgical approach for avoiding recurrent laryngeal nerve injury. Additional pinhole images should increase the detection of small adenomas. The combined protocol offers both advantages.

Fetal gonadotrope cell origin of FSH-secreting pituitary adenoma - insight into human pituitary tumour pathogenesis.

OBJECTIVE: The pathogenesis of human pituitary adenomas remains unclear, but we report a case of FSH-secreting pituitary adenoma whose monohormonal phenotype suggests it was of fetal origin. PATIENTS: A 28-year-old woman presented with abdominal discomfort and irregular menses, enlarged multicystic ovaries and elevated serum oestradiol, with sustained high-normal FSH and low LH levels. MEASUREMENTS: Endocrine studies were performed before and after curative surgery, with assessment of tumour hormone secretion in vitro, and immunostaining of tumour tissue for a series of gonadotrope proteins. RESULTS: Immunocytochemistry showed that tumour cells were monohormonal for FSH. Normal components of gonadotrope signalling pathways were expressed, including oestrogen receptor-alpha, activin receptors, secretogranin-II and chromogranin-A. beta-glycan, the putative inhibin coreceptor, was absent. Tumour culture in vitro confirmed secretion of FSH with minimal LH, that was unsuppressed by oestradiol or inhibin-A. Human fetal pituitary tissue contained FSH-only cells at 18 weeks gestation, whereas normal adult pituitary tissue contained only bihormonal gonadotropes. CONCLUSIONS: We propose that this pituitary adenoma represents an indolent tumour of monohormonal fetal gonadotrope cells that originated early in gestation. Pituitary tumours may therefore arise from abnormal persistence of fetal cell types, with extremely slow growth over many years until reaching a size threshold to generate an endocrine syndrome. Understanding fetal pituitary architecture and function may be more informative for new insights into pituitary tumour pathogenesis than classical theories of cancer biology that invoke unrestrained cell proliferation.

Pharyngeal pituitary: development, malformation, and tumorigenesis.

The development of the pharyngeal pituitary (PhP) in the fetal period was morphologically and, for the first time, immunohistochemically examined. PhP, found in every individual, begins its hormone production at the 17-18th week of gestation, that is, 4-8 weeks later than that of sellar pituitary (SP). Only 1 of 25 examined fetuses without any stigmata of developmental anomalies showed a residual pituitary fragment in the craniopharyngeal canal (craniopharyngeal pituitary, CPhP). An adult case of a rare clivus pituitary adenoma that we examined is demonstrated in discussing its relationship to PhP. Extracranial ectopic pituitary adenomas in the literature describe an exclusively sphenoid sinus/nasopharyngeal/clivus location of the tumor. Their location corresponded exactly with that of PhP, so that the origin of the tumors can be reasonably speculated as PhP, although another origin, e.g., CPhP, can not be excluded. A variety of malformations of PhP, although very rare, have been described for the fist time during the systemic examination of 16 fetuses with different cranioneural malformations, such as agenesis, unseparated PhP from SP (pharyngosellar pituitary), fragmentation, and residual pituitary tissue in the open craniopharyngeal canal. However, developmental anomaly of PhP was not specifically associated with cranioneural malformations except in cases of chromosomal aberrations. The hormone production in PhP in malformation cases tended to be retarded. Absence of SP was recorded in 50% of anencephalics in the literature; however, PhP was identified in all anencephalics in our series, independent of the existence of SP. This supports the opinion that agenesis of SP in anencephalics seems to be false information.

Adenomatous lesions of the temporal bone immunohistochemical analysis and theories of histogenesis.

Adenomatous lesions of the temporal bone represent a diverse group of neoplasms. At least three histopathologic patterns have been described: glandular; ribbon-like, or "festooning;" and aggressive papillary. Combinations of glandular and ribbon-like histologies in the same lesion are not uncommon. The glandular and ribbon-like histologies have been associated with carcinoid tumors, and the aggressive papillary tumor has been considered a separate entity. Recently, the endolymphatic sac has been proposed as the site of origin of the aggressive papillary lesions. Previous reports have described neuroendocrine properties with characteristics embracing the three histologic types. The authors postulate that the neural crest is the site of origin of this unusual group of neoplasms. Immunohistochemical analysis on the pathologic specimens of patients with adenomatous lesions of the temporal bone was performed to test this hypothesis. From 1975 to 1992 seven patients were treated at the Cleveland Clinic Foundation with a diagnosis of middle ear adenoma. A panel of special stains for neuroectodermal markers, including synaptophysin, chromogranin, neuron specific enolase, calcitonin, and serotonin was used on the paraffin-embedded formalin-fixed specimens. Three lesions were also evaluated by electron microscopy, all demonstrating dense core, intracytoplasmic granules. Three ribbon-like tumors were positive for synaptophysin and chromogranin, and two of these were positive for serotonin. One glandular tumor was positive for synaptophysin, and an aggressive papillary tumor was positive for synaptophysin and neuron specific enolase. An additional papillary tumor was referred following a third recurrence without accompanying immunohistochemical data. Cholesteatoma-like material was identified with a few glandular cells interspersed, all negative by immunohistochemical evaluation. The seventh specimen, initially diagnosed as papillary adenoma on light microscopy, was not studied by the aforementioned stains, and was later identified as a papilloma of sinonasal origin. The neural crest gives rise to pluripotential stem cells with widespread anatomic distribution, including the temporal bone. Because immunomarkers used in this study are specific for neuroectodermal differentiation, results suggest that temporal bone adenomas have neuroendocrine characteristics and could be derived from the specialized neuroectoderm of the neural crest.

Pituitary tumors composed of adenohypophysial adenoma and Rathke's cleft cyst elements: a clinicopathological study.

Nine cases of pituitary tumors composed of mixed tissue elements of adenohypophysial adenoma and Rathke's cleft cyst are reported. All cases were associated with hyperprolactinemia and were managed by transsphenoidal adenomectomy with good results. The clinical and pathological features are presented, and embryological pathogenesis for the occurrence of this unique association is discussed in connection with the high incidence of immunoreactive S-100 protein cells identified in tumor tissues. Patients with this kind of pituitary tumor can be managed in the same fashion as patients with other types of pituitary adenoma.

A complex poroma-like adnexal adenoma.

Hidroacanthoma simplex, eccrine poroma, and dermal duct tumor are benign adenomas that develop from excretory ducts of eccrine glands and all three are variants of eccrine acrospiroma. To date, counterparts in apocrine or sebaceous glands have not been reported, but in this study we describe an adnexal, poroma-like adenoma that showed apocrine and sebaceous differentiations. Apocrine structures have the same embryonic origin as does the pilosebaceous system; both are derived from the primary epithelial germ. We suggest that the lesion we describe is truly a sebaceous and apocrine poroma. It must be distinguished from an infundibular adenoma whose pattern reproduces that of follicular poroma.

Neurocrest and colonic tumors: new clinical syndrome. Report of three cases.

This report describes three patients with both multiple intestinal polyps and tumors of neural crest origin. This combination of findings may represent a new clinical syndrome. The embryologic relationships between tumors derived from endoderm and tumors derived from neurocrest are described. An inherent defect in tissue proliferation or repair is postulated to explain the abnormal growth in these two different cell lines.

Functioning lipoadenoma of a supernumerary parathyroid gland in the mediastinum.

A patient underwent reexploration for a parathyroid adenoma; following identification of four normal glands in the cervical region, the mediastinum was entered, and an intrathymic lipoadenoma was excised. These very rare tumors have been associated with hypercalcemia in approximately half of the previously reported cases; however, none has previously been described as occurring entirely in the mediastinum.

[A case of mediastinal parathyroid adenoma visible on standard pulmonary radiography (author's transl)]. / Adénome parathyroïdien médiastinal, à propos d'un cas, visible sur les radiographies pulmonaires standards.

Mediastinal adenomas form about 10 % of all parathyroid adenomas, and are only very rarely visualized in standard pulmonary radiograms. This was the case however in a 54-year-old woman with hyperparathyroidism, chronic renal insufficiency, and an anterosuperior mediastinal tumor. After surgical excision by sternotomy the mass was found to be a large parathyroid adenoma weighing 105 g and measuring 8 cm in diameter. The authors discuss the problems raised by mediastinal adenomas and review the cases reported in the published literature.

[The role of organ cultures of mouse embryonal lung tissue in studying the transplacental blastomogenic effect of benz(alpha)pyrene]. / Rol' organnykh kul'tur émbrional'noi legochnoi tkani myshei v izuchenii transplatsentarnogo blastomogennogo deistviia benz(alpha)pirena

Under study was organ cultivation of embryonal pulmonary tissue in mice A and C57B1 given during the pregnancy period BP (4 and 12 mg), pyrene (12 mg) and a solvent (0.4 ml of sunflower oil). Only BP was found to produce marked hyperplastic changes in the pulmonary epithelium and adenomas in organ cultures of the lungs of line A, whereas in the lung cultures of line C57B1 the same dosage of BP resulted in the development of less pronounced hyperplastic changes in the epithelium. However, in both cases in the cultures the effect of BP was dependent on its dosage.

Ectopic apudocarcinomas and associated endocrine hyperplasias of the foregut.

Foregut endocrine polypeptide-secreting APUD cells (Amine-Precursor-Uptake and Decarboxylation), in their embryologic migration from neural crest to foregut may become "arrested" in the mesoderm or in other ectopic locations. They may become hyperplastic, adenomatous or malignant. Eight illustrative patients are reported. One patient had "pancreatic hyperparathyroidism" with hypercalcemic crises, pancreatic apudocarcinoma, normal parathyroids, biologically active parathormone, but inert immunochemically to the usual parathyroid antisera. Two had gastrin-secreting malignancies in the mesoderm. Remission after excision, but eventual recurrence of the syndrome due to islet cell hyperplasia required total gastrectomy. One patient had a gastric corpus apudocarcinoma found prospectively with hypergastrinemia which required excision of the tumor. One patient had acromegaly with hypergastrinemia and antral gastrinosis treated by pituitary irradiation, One patient had the antral or intermediary type of the Zollinger-Ellison syndrome with moderate hypergastrinemia, duodenal ulcer and antral gastrinosis, treated by vagotomy and antrectomy. One patient had hyperparathyroidism with antral gastrinosis, treated by parathyroidectomy. One patient had malignant Zollinger-Ellison syndrome and developed associated thyroid parafollicular cell hyperplasia and parathyroid chief cell hyperplasia, treated by total gastrectomy and multiple endocrine excisions. These investigative observations demonstrate ectopic loci and associated hyperplasias which support the concept of migration and bizarre potentiality of polypeptide-secreting cells of the foregut.