Cytoarchitectural Features Research Articles

Trichilemmal carcinoma with neuroendocrine differentiation

We report a 12-mm nodular, cream-coloured skin lesion that appeared on the left nasal ala in an 81-year-old man. This trabecular infiltrative tumour showed keratin microcysts, stromal hyalization, cytoarchitectural malignancy features, colonizing melanocytes, and immunoexpression of epithelial membrane antigen, cytokeratin 15/20, chromogranin, synaptophysin and CD56. To our knowledge, this is the first documented case of a trichilemmal carcinoma with neuroendocrine differentiation and melanocyte colonization, which is suggested by the trabecular growth pattern and requires immunohistochemical confirmation. The colonization of the epithelial nests by nonatypical dendritic or spindle melanocytes is a clue to morphological recognition of pilar neoplasms, along with the presence of stromal induction (CD34-positive peritumoral spindle cells), catagen-like apoptotic bodies, calcifications, keratin microcysts and cell balls.

Hepatocellular dysplastic nodules

The multistep process of hepatic carcinogenesis is mirrored by the morphologic classification of lesions detectable in cirrhosis, which include large regenerative nodules (LRN), low grade dysplastic nodules (LGDN), and high grade dysplastic nodules (HGDN). The latter belong to the "bordeline malignancy" category requiring accurate distinction from well-differentiated and early hepatocellular carcinoma (HCC). Nodules in cirrhosis are usually detected by non-invasive imaging techniques, which are unable to discriminate malignant from non-malignant forms, particularly in the 1-2-cm sized group. Liver biopsy is essential in providing practical diagnostic information to hepathologists in the management of cirrhotic patients with ultrasound (US)-detectable nodules. Histologic diagnosis on liver samples is based on the accurate search of a set of cyto-architectural features (e.g. cell atypia, cell crowding, trabecular thickness, microacini) and by a supplement of histochemical (Gomori staining) and immunocytochemical stainings. The latter rely upon the search of both well established and novel markers, targeted to evaluate stromal invasion (CK7/19), the vascular pattern (ASMA and CD34), or tumor markers (including HSP70 and glipican-3). Still, the diagnostic sensitivity is limited by the type and size of sampling and by its representativity of the entire lesion. Thus, the best diagnostic approach requires the integration ofclinical, morphological, and immunocytochemical information with imaging data (i.e. US pattern, perfusional pattern, helical computed tomography/magnetic resonance pattern). Molecular data are still under evaluation as to their diagnostic efficacy in this controversial field. Discrepancies have emerged recently between Eastern and Western interpretation of these lesions, particularly in the category of "borderline" nodules that are mostly labelled as early, well differentiated HCC by Eastern pathologists and as HGDN by Western pathologsts. Novel and more objective phenotypical and molecular markers are needed to discriminate within the grey area of borderline lesions that, epidemiologically, are likely distinct between Eastern and Western geographic areas. These tools might allow a better understanding of the boundaries of the process going from high grade dysplasia to in situ HCC and from the latter to microinvasive HCC and advanced HCC, for proper clinical management and optimal therapy.

The Controversial Nosology of Benign Nerve Sheath Tumors: Neurofilament Protein Staining Demonstrates Intratumoral Axons in Many Sporadic Schwannomas

Schwannomas are benign peripheral nerve sheath tumors believed to be composed purely of cells with ultrastructural features of Schwann cells; these tumors are believed to develop eccentrically from the surface of nerves and not to contain axons, other than immediately beneath the capsule. This concept has recently been disputed in cases associated with neurofibromatosis type 2. The usual presence of intratumoral axons in neurofibromas is said to allow easy distinction from schwannomas. Eighty sporadic schwannomas (20 conventional, 20 cellular, 20 ancient, 10 gastric, and 10 plexiform) were retrieved from the authors' files. Hematoxylin-and-eosin stained slides were reviewed, diagnoses were confirmed and all tumors were stained for S-100 protein and neurofilament protein (NFP). The amount (rare, focal, multifocal, and diffuse) and distribution (central and/or peripheral) of axons within the tumors were analyzed. All tumors were strongly and diffusely positive for S-100 protein (nuclear and cytoplasmic staining). NFP-positive axons were identified in 11 of 20 (55%) conventional schwannomas (2 rare, 4 focal, 3 multifocal, and 2 diffuse; 5 central, 4 peripheral, and 2 central and peripheral) and in 15 of 20 (75%) cellular schwannomas (3 rare, 6 focal, and 6 multifocal; 12 central, 1 peripheral, and 2 central and peripheral). Of the 20 ancient schwannomas, 7 cases (35%) showed intratumoral axons, highlighted by NFP immunostaining (1 rare, 4 focal, 1 multifocal, and 1 diffuse; 4 peripheral, 2 central, and 1 central and peripheral). Most cases of gastric schwannoma showed no evidence of intratumoral axons; 9 cases (90%) were negative for NFP and only 1 case (10%) was positive (focal and central). Seven of 10 cases (70%) of plexiform schwannomas were negative for NFP, whereas only 3 cases (30%) showed positive axons (2 multifocal and 1 focal; 3 central). The unexpected but quite frequent presence of intratumoral axons in schwannomas argues against conventional views of these lesions' pathogenesis as an eccentric encapsulated lesion and raises the possibility that a more diverse cell population, perhaps more closely resembling neurofibromas, may constitute these neoplasms. Although NFP-positive axons were most often present in the conventional and cellular variants of schwannoma, their presence was also observed in a minority of ancient, gastric and plexiform schwannomas. Differentiation between neurofibroma and schwannoma in cases with overlapping cytoarchitectural features should not be based solely on the presence or absence of NFP-positive axons within a given tumor.

O-13 Differential expression of ER and Ki67 in normal breast tissue and proliferating breast disease: further support of the progenitor cell concept?

Evaluation of the surgical margins of excision specimens for ductal carcinoma in situ (DCIS) of breast is challenging due to cautery artifact introduced in the specimen at the time of surgery. Cautery destroys the cytoarchitectural features at the tissue margins and makes the distinction between usual ductal hyperplasia (UDH) and DCIS difficult. Previous studies have shown the value of immunohistochemical staining for cytokeratin 5/6 (CK5/6) and high-molecular-weight keratin (HMWK) in distinguishing UDH from DCIS. We hypothesized that staining for CK5/6 and HMWK (34bE12) may be helpful in evaluating the cauterized surgical margins, given the 2 antibodies follow the same pattern as described in the preserved foci of the 2 entities. Forty-three excised breast specimens were stained for CK5/6 and HMWK (34bE12). Study material was divided into 5 groups: DCIS without cautery artifact, UDH without cautery artifact, UDH with cautery artifact, DCIS with mild-to-moderate cautery artifact morphologically recognizable as involving the surgical margin on hematoxylin and eosin stain, and DCIS with severe cautery artifacts precluding the evaluation of surgical margins on hematoxylin and eosin stain. A comparative evaluation of pattern, extent, and intensity of the 2 immunostains was done. Our results strongly suggest that antibodies for CK5/6 and HMWK (34bE12) may be useful in determining the presence of DCIS at surgical margins even in the event of severe cautery artifact.

Atypical mucinous metaplasia and intraepithelial neoplasia of the female genital tract—a case report and review of the literature

Müllerian metaplasia of the female genital tract is usually of limited extent and subtype. We describe the replacement of the lining of the entire genital tract and much of the overlying pelvic serosa by metaplastic müllerian epithelium, in a nulliparous 65-year-old woman with cervical agenesis. She did not have Peutz-Jeghers syndrome and had not had any form of prior hormonal treatment. The metaplastic epithelium extended from the vagina to the serosal surface of the pelvic organs. Mucinous epithelium predominated. In addition, there was multifocal dysplasia of the metaplastic epithelium; this was most prominent in the fallopian tubes where there was marked papillation with cytoarchitectural features reminiscent of a borderline mucinous ovarian tumor. Although müllerian metaplasia is well recognized at different sites within the female genital tract, this highly unusual finding of multiple metaplastic epithelial subtypes and dysplasia involving the mucinous metaplastic epithelium along the entire genital tract and pelvic serosal surface has not, to the best of our knowledge, been reported previously in the absence of Peutz-Jeghers syndrome.

Apocrine Mixed Tumors of the Skin With Architectural and/or Cytologic Atypia: A Retrospective Clinicopathologic Study of 18 Cases

We present a series of 18 atypical apocrine mixed tumors of the skin characterized by architectural and/or cytologic atypia but which nevertheless do not qualify these lesions as carcinomas. There were 15 males and 3 females, and all but 1 presented with solitary nodules ranging in size from 4 to 20 mm; 1 female had a large tumor of 12 cm. The tumors were preferentially located on the head area, especially the face (13 cases). Other locations included the lower extremities (3) and inguinal area (2). In all patients, surgical excision of the tumors was performed. Clinical follow-up was available in 11 cases and ranged from 1 to 24 years (mean 9.6 y; median 5 y). No recurrences or metastases were documented. Overall, the lesions manifested a rather benign architecture, usually with good circumscription, lack of capsular breach or hypercellularity; however, some asymmetry, focally irregular infiltrationlike or pushing tumorous borders were seen. Microscopically, 17 cases conformed to the so-called hyaline cell-rich variant and showed multinucleated, bizarre, hyperchromatic cells in hyaline cell areas that had a myoepithelial immunophenotype; in 1 case, atypical mitotic figures were noted. One case showed mild nuclear pleomorphism in the ductal component. Tumors were negative for p53, including bizarre giant cells that did not label with Ki-67. Ultrastructurally, hyaline cells exhibited features consistent with myoepithelial differentiation. Seven cases studied by immunohistochemistry proved negative for HER-2/neu (c-erbB-2) protein expression, and the HER-2/neu gene was not amplified by fluorescence in situ hybridization analysis in 5 cases tested. As controls, 4 authentic malignant mixed tumors were studied, but these likewise tested negative for HER-2/neu protein expression and showed no gene amplification; 1 malignant mixed tumor had polysomy 17. We conclude that some atypical cytoarchitectural features in apocrine mixed tumors, albeit worrisome, do not indicate a malignant change.

The Immunological Milieu of the Liver

From the immunology standpoint, the liver is a peculiar organ for several reasons that range from its anatomical location to its cytoarchitecture and its variety of specific functions. Receiving blood directly from the digestive system, the liver is the crossroad at which the majority of antigens enter the organism. Hence, the milieu of the liver must provide a finely tuned balance between generating tolerance to self as well as to nonpathogenic molecules and microorganisms and producing an appropriate immune response to pathogens. Knowledge of the mechanisms that effectively maintain this balance is critical to the understanding of the pathogenesis of chronic inflammatory liver diseases, infectious, autoimmune, and others. Several theories have been proposed to explain what causes one or another response to take precedence. Although no definitive answer is yet available, the critical elements include, for tolerance, the particular cytoarchitectural features and the intrahepatic existence of antigen-presenting cells and, for immunity, inflammatory expressions including type 1 cytokines and chemokines, notably CCR5. Herein we review the available data on immune responses in the liver with particular emphasis on the unique structural and functional features of this "lymphoid" organ.

Cytoarchitectural and kinetic features in the histological evaluation of follicular thyroid neoplasms

The diagnosis of follicular thyroid carcinomas is mainly based on capsular and vascular invasion. The aim of this study was to determine the diagnostic relevance of nuclear features, inflammation and stromal changes. Anisokaryosis, chromatin pattern, nucleolus, nuclear pleomorphism, nuclear/cytoplasmic ratio, necrosis, stromal changes and tumour interstitial lymphocytes (TIL) were analysed in adenomatous hyperplastic nodules (39), adenomas (43) and carcinomas (28 minimally invasive, 48 widely invasive and 27 anaplastic). Ki67 immunostaining, in situ end labelling (ISEL) for apoptosis and the Ki67/ISEL index were analysed by topographical compartments. Variables were compared by histological diagnosis using Fisher's exact test, analysis of variance and Student's t-tests and considered significant if P < 0.05. TIL were absent in 96% of neoplasms and 54% of adenomatous hyperplastic nodules. Conspicuous nucleoli, increased nuclear-cytoplasmic ratio and coexistent apoptosis-myxoid changes distinguished minimally invasive carcinomas from adenomas. The most specific variables of high-grade carcinoma were vasculonecrotic patterns, nuclear hyperchromatism and pleomorphism. A kinetic advantage predominated in the internal compartments of benign lesions and in the peripheral compartments of malignant lesions. Follicular carcinomas show up-regulation of proliferation markers and the distinctive topographical kinetic profiles provide a basis for the distinction between benign and malignant and an explanation for the circumscription and encapsulation of benign lesions.

Primary splenic marginal zone lymphoma with florid granulomatous reaction—A case report and review of literature

Splenic marginal zone lymphomas (SMZL) constitute about 20% of primary splenic NHLs. We report a case of primary SMZL with a florid granulomatous reaction which obscured the underlying lymphoma. Although granulomas have been described in splenic non-Hodgkin lymphoma, it can be extensive and mask the underlying lymphoma. A careful search for the cytoarchitectural features of SMZL is warranted in such a case.

Pseudosarcomatous and sarcomatous proliferations of the bladder

Pseudosarcomatous fibromyxoid tumor (PFT), postoperative spindle cell nodule (PSN), sarcoma, and sarcomatoid carcinoma of the bladder are frequently difficult to distinguish histopathologically with significant differences in disease-related outcomes. A retrospective review of our pathology registry over the last 25 years identified 7 PFT, 10 PSN, 18 primary bladder sarcomas, and 17 sarcomatoid carcinomas. Most patients with PFT, PSN, sarcoma, and sarcomatoid carcinoma were diagnosed between the ages of 50 to 60 years with PFT and PSN most commonly detected in women. A previous history of urological instrumentation and bladder cancer was present in all patients with PSN but none of the patients with PFT. Pseudosarcomatous fibromyxoid tumors were characterized by a tissue culture-like proliferation of myofibroblastic cells with focal atypia and overall cytoarchitectural features mimicking nodular fasciitis. Sarcomas and sarcomatoid carcinomas exhibited cellular atypia, mitotic activity with atypical mitosis, and the presence of necrosis. Transurethral resection was sufficient to control all PFT and PSN with no evidence of distant metastatic spread. In contrast, local recurrences and distant metastases frequently occurred in patients with primary sarcoma and sarcomatoid carcinoma despite aggressive surgical management, which was often combined with neoadjuvant chemotherapy (50% and 65% disease-specific mortality, respectively). Pseudosarcomatous fibromyxoid tumor and PSN have unique clinical and pathologic features that allow their distinction from primary bladder sarcoma and sarcomatoid carcinoma.

Differences in chemo‐ and cytoarchitectural features within pars principalis of the rat anterior olfactory nucleus suggest functional specialization

The anterior olfactory nucleus (AON) lies between the olfactory bulb and piriform cortex and is the first bilaterally innervated structure in the olfactory system. It is typically divided into two subregions: pars externa and pars principalis. We examined the cytoarchitecture of pars principalis, the largest cellular area of the region, to determine whether it is homogeneously organized. Quantitative Nissl studies indicated that large cells (cell body area >2 standard deviations (SD) larger than the mean cell size) are densest in lateral and dorsolateral regions, while small cells (>1 SD smaller than the mean) are more numerous in medial and ventral areas. Further evidence for regional differences in the organization of the AON were obtained with immunohistochemistry for calbindin (CALB), parvalbumin (PARV), glutamic acid decarboxylase (GAD), and choline transporter (CHT). Cells immunopositive for CALB (CALB+) were denser in the deep portion of Layer II, although homogeneously dispersed throughout the circumference of the AON. PARV+ cells were located in the superficial half of Layer II and were sparse in ventral and medial regions. CHT+ and GAD+ fibers were denser in lateral versus medial regions. No regional differences were found in GAD+ somata, or in norepinephrine transporter or serotonin transporter immunoreactivity. The observed regional differences in cyto- and chemoarchitectural features may reflect functional heterogeneity within the AON.

Subtle Changes in the Ageing Human Brain

Subtle changes in the human brain constitute a third element in addition to plaques and tangles as markers of vulnerability to Alzheimer's disease (AD). Neurofibrillary tangle (NFT) distribution shows the closest relationship to the severity of dementia. Two features of the distribution (regional selectivity and columnar clustering) provide clues about the structural changes due to normal ageing that may precede tangle formation. It is hypothesized that the columnar organization of the cortex, determines the pattern of pathological spread in AD and, consequently, the pattern of function loss. Minicolum thinning occurs in normal ageing and echoes the selective regional distribution of NFT formation in AD. NFT vulnerability appears to emerge from hierarchical variation in neural plasticity associated with the hierarchical variation in size and spacing of mini and macro-columns in the cortex. Regional differences may involve regional variation in gene expression. Dietary Omega 3 fatty acid intake has been shown to have neuroprotective effects on the cytoarchitectural features that contribute to this cortical hierarchy.

Detection of entorhinal layer II using Tesla magnetic resonance imaging

The entorhinal cortex lies in the mediotemporal lobe and has major functional, structural, and clinical significance. The entorhinal cortex has a unique cytoarchitecture with large stellate neurons in layer II that form clusters. The entorhinal cortex receives vast sensory association input, and its major output arises from the layer II and III neurons that form the perforant pathway. Clinically, the neurons in layer II are affected with neurofibrillary tangles, one of the two pathological hallmarks of Alzheimer's disease. We describe detection of the entorhinal layer II islands using magnetic resonance imaging. We scanned human autopsied temporal lobe blocks in a 7T human scanner using a solenoid coil. In 70 and 100 microm isotropic data, the entorhinal islands were clearly visible throughout the anterior-posterior extent of entorhinal cortex. Layer II islands were prominent in both the magnetic resonance imaging and corresponding histological sections, showing similar size and shape in two types of data. Area borders and island location based on cytoarchitectural features in the mediotemporal lobe were robustly detected using the magnetic resonance images. Our ex vivo results could break ground for high-resolution in vivo scanning that could ultimately benefit early diagnosis and treatment of neurodegenerative disease.

An immunohistochemical approach to the differential diagnosis of renal tumors

Renal neoplasms comprise several distinct clinicopathologic entities with potential prognostic and the rapeutic differences. Although careful morphologic examination using sections stained with hematoxylin and eosin will allow for the correct diagnosis in the majority of cases, there is sufficient overlap between several entities such that ancillary techniques may be necessary to arrive at the correct diagnosis. In routine diagnostic surgical pathology practice of renal tumors, immunohistochemistry is the foremost ancillary technique. Using an approach based on common histologic patterns (tumors with clear cytoplasm, granular cytoplasm, tubulopapillary architecture, spindle cell morphology, small round-cell morphology, and infiltrating poorly differentiated carcinoma), we will discuss the utility of immunohistochemistry in the differential diagnosis of renal neoplasms. In recent years, needle biopsies from renal masses are being increasingly performed. In these small biopsies, the entire range of cytoarchitectural features that are generally necessary to make a diagnosis may not be fully appreciated. Immunohistochemistry may be helpful in this setting to narrow the differential diagnosis or to arrive at a definitive diagnosis. Finally, the use of immunohistochemistry for the confirmation of metastatic renal cell carcinoma presenting at distant sites will be discussed. Panels of immunohistochemical stains are proposed for different settings, including renal cell carcinoma (RCC) marker, CD10, and vimentin to suggest renal origin of a metastatic tumor, and markers to aid in subclassification of RCC, including parvalbumin and c-kit for chromophobe RCC, and cytokeratin 7 and alpha-methyl-acyl-CoA racemase for papillary RCC.

Three-dimensional chemoarchitecture of the basal forebrain: Spatially specific association of cholinergic and calcium binding protein-containing neurons

The basal forebrain refers to heterogeneous structures located close to the medial and ventral surfaces of the cerebral hemispheres. It contains diverse populations of neurons, including the cholinergic cortically projecting cells that show severe loss in Alzheimer’s and related neurodegenerative diseases. The basal forebrain does not display any cytoarchitectural or other structural features that make it easy to demarcate functional boundaries, a problem that allowed different investigators to propose different organizational schemes. The present paper uses novel three-dimensional reconstructions and numerical analyses for studying the spatial organization of four major basal forebrain cell populations, the cholinergic, parvalbumin, calbindin and calretinin containing neurons in the rat. Our analyses suggest that the distribution of these four cell populations is not random but displays a general pattern of association. Within the cholinergic space (i.e. the volume occupied by the cortically projecting cholinergic cell bodies) the three other cell types form twisted bands along the longitudinal axis of a central dense core of cholinergic cells traversing the traditionally defined basal forebrain regions, (i.e. the medial septum, diagonal bands, the substantia innominata, pallidal regions and the bed nucleus of the stria terminalis). At a smaller scale, the different cell types within the cholinergic space occupy overlapping high-density cell clusters that are either chemically uniform or mixed. However, the cell composition of these high-density clusters is regionally specific. The proposed scheme of basal forebrain organization, using cell density or density relations as criteria, offers a new perspective on structure–function relationship, unconstrained by traditional region boundaries.

Amygdaloid inputs define a caudal component of the ventral striatum in primates.

The ventral striatum mediates goal-directed behavior through limbic afferents. One well-established afferent to the ventral striatum is the amygdaloid complex, which projects throughout the shell and core of the nucleus accumbens, the rostral ventromedial caudate nucleus, and rostral ventromedial putamen. However, striatal regions caudal to the anterior commissure also receive inputs from the amygdala. These caudal areas contain histochemical and cytoarchitectural features that resemble the shell and core, based on our recent studies. Specifically, there is a calcium binding protein (CaBP)-poor region in the lateral amygdalostriatal area that resembles the "shell." To examine the idea that the caudal ventral striatum is part of the "classic" ventral striatum, we placed small injections of retrograde tracers throughout the caudal ventral striatum/amygdalostriatal area and charted the distribution of specific amygdaloid inputs. Amygdaloid inputs to the CaBP-poor zone in the lateral amygdalostriatal area arise from the basal nucleus, the magnocellular subdivision of the accessory basal nucleus, the periamygdaloid cortex, and the medial subdivision of the central nucleus, resembling that of the shell of the ventral striatum found in our previous studies. There are also amygdaloid inputs to CaBP-positive areas outside the shell, which originate mainly in the basal nucleus. Taken together, the "limbic-related" striatum forms a continuum from the rostral ventral striatum through the caudal ventral striatum/lateral amygdalostriatal area based on histochemical and cellular similarities, as well as inputs from the amygdala.

Pelvic washing cytology in serous borderline tumors of the ovary using ThinPrep: are there cytologic clues to detecting tumor cells?

The detection of tumor cells in pelvic washings of patients with serous borderline tumors of the ovary (SBT) remains a diagnostic challenge. Accurate diagnosis of pelvic washings is important in determining therapeutic regimens and assessing patient prognosis. No study has exclusively examined pelvic washing cytology of patients with SBT using only ThinPrep methodology. The purpose of this study is to examine whether cytologic clues exist in detecting tumor cells of SBT in pelvic washings processed with ThinPrep. Using previously established criteria, we reviewed the pelvic washes of 37 patients with SBT and correlated them with the histologic findings in the omentum. We also compared their cytoarchitectural features with pelvic washes in patients with benign ovarian disease and serous carcinoma. Cytoarchitectural features that achieved statistical significance in distinguishing cells of a SBT from reactive mesothelial cells include the following findings: presence of a two-cell population (P = 0.001), psammoma bodies (P = 0.001), cytoplasmic vacuolization (P = 0.001), smooth group contours (P = 0.004), nuclear size >2x neutrophils (P = 0.004), high nuclear-to-cytoplasmic (N/C) ratio (P = 0.004), absent intercellular windows (P = 0.007), and course nuclear chromatin (P = 0.032). Psammoma bodies were the only statistically significant feature distinguishing SBT from serous carcinoma, being more common in SBT than serous carcinoma (P = 0.035). The prominent number of associated psammoma bodies seen in the SBT group was a notable finding that may aid as a valuable cytologic clue in detecting tumor cells. Overall cellularity remains a source of false-negative diagnosis. Correlation with histologic findings remains crucial given our inability to reliably distinguish tumor cells of SBT from endosalpingiosis or serous adenocarcinoma.

Neuroendocrine Carcinomas of the Colon and Rectum

This study was designed to review experience with neuroendocrine carcinomas of the colon and rectum at a single institution, with emphasis on the pathology and clinical characteristics of this uncommon malignancy. A study group of patients was identified from a prospective colorectal service database. Pathology was reviewed and neuroendocrine tumors were classified by a single pathologist. Medical records were retrospectively reviewed. From March 1975 to September 1998, 38 patients with neuroendocrine carcinomas were identified from the colorectal service database comprising 6495 patients (0.6 percent). These neuroendocrine carcinomas did not include carcinoid tumors. Average patient age was 57 years (range, 29-86 years). There were 17 males (44.7 percent) and 21 females (55.3 percent). Tumors were located as follows: 17 colon, 14 rectum, 6 anal canal, and 1 appendix. The diagnosis of neuroendocrine carcinoma was suggested preoperatively from tissue biopsy in 59.3 percent (16/27) of patients evaluable. Pathology was reviewed and tumors were categorized as small cell carcinoma (n = 22) or large cell neuroendocrine carcinoma (n = 16). Most tumors (20/25 evaluable, 80 percent) stained positive by means of immunohistochemistry for neuroendocrine markers, including chromogranin (18/19), synaptophysin (10/15), and/or neuron-specific enolase (14/15). Metastatic disease was detected at the time of diagnosis in 69.4 percent of the patients (25/36). Tumors were advanced at the time of diagnosis, with American Joint Committee on Cancer (AJCC) Stage I (n = 6), Stage III (n = 7), and Stage IV (n = 25) tumors. As a group, these tumors had a poor prognosis, with a median survival of 10.4 months. One-year, two-year, and three-year survival was 46 percent, 26 percent, and 13 percent, respectively. There was no significant difference in survival based on pathologic subtypes. Median follow-up time was 9.4 months (range, 0.6-263.7 months). Neuroendocrine carcinomas of the colon and rectum are uncommon, comprising less than 1 percent of colon and rectal cancers. Pathologically, these tumors are poorly differentiated carcinomas with distinctive cytoarchitectural features and are often immunoreactive for markers of neuroendocrine differentiation. The prognosis for high-grade neuroendocrine carcinomas is poor, as most patients have metastatic disease at the time of diagnosis.

Cyto- and chemoarchitecture of the hypothalamus of a wallaby ( Macropus eugenii) with special emphasis on oxytocin and vasopressinergic neurons.

We have studied the organization of the hypothalamus in an Australian diprotodontid metatherian mammal, the wallaby ( Macropus eugenii), using cytoarchitectural, histochemical and immunohistochemical techniques. Coronal sections of adult brains were processed for Nissl staining, histochemical reactivity (cytochrome oxidase, nicotinamide adenine dinucleotide phosphate diaphorase and acetylcholinesterase) and immunohistochemistry (antibodies to tyrosine hydroxylase, calbindin, calretinin, non-phosphorylated neurofilament protein, oxytocin and vasopressin). The distribution of immunoreactive neurons for these substances was mapped with the aid of a computer-linked microscope. In general, the wallaby hypothalamus showed a similar nuclear organization to that seen in rodents. The paraventricular nucleus could be divided into several subdivisions based on the different cellular parcellation, similar to that described in rodents. The ventromedial hypothalamic nucleus had cell-sparse dorsomedial and cell-dense ventrolateral subdivisions as seen in eutheria, suggesting a similar functional compartmentalization in all theria. The positions of tyrosine hydroxylase-positive neurons in the wallaby hypothalamus were also similar to those in eutheria. Oxytocin and vasopressinergic neurons were found in all the same major nuclear groups as seen in eutheria, although a nucleus circularis could not be identified. The general similarities between wallaby and eutherian hypothalamus indicate that the basic chemo- and cytoarchitectural features of the hypothalamus are common to eutheria and metatheria and validate the use of the wallaby as a mammalian model of wide applicability in investigations of hypothalamic functional development.

The genesis of epileptogenic cerebral heterotopia: clues from experimental models

The pre‐natal administration of methylazoxymethanol acetate (MAM) in rats is able to induce cerebral heterotopia that share striking similarities with those observed in human periventricular nodular heterotopia, a cerebral dysgenesis frequently associated with drug‐resistant focal seizures. In the present study, we investigated the mode of neurogenesis in cerebral heterotopia of MAM‐treated rats, by analyzing post‐natal cytoarchitectural features and time of neurogenesis using bromodeoxyuridine immunocytochemistry. The cytoarchitectural analysis demonstrated the existence, in the early post‐natal period, of white matter cellular bands in close anatomical relationship with the heterotopia, which most likely serve as a reservoir of young, migrating neurons for the newly forming heterotopia. The birth dating analysis demonstrated that the period of generation of neurons within the heterotopia and adjacent white matter bands, was extended in comparison to corticogenesis in normal rat brains. In addition, it demonstrated that the heterotopia were formed through a rather precise outside‐in (for cortical and periventricular heterotopia) and dorso‐ventral (for intra‐hippocampal heterotopia) neurogenetic pattern. We hypothesize that the MAM‐induced ablation of an early wave of cortical neurons is sufficient to alter per se the migration and differentiation of subsequently generated neurons, which in turn set the base for the formation of the different types of heterotopia. On this basis, we suggest a neurogenetic scheme for MAM‐induced heterotopia that can also explain the origin and intrinsic epileptogenicity of periventricular nodular heterotopia in humans.