Lipid-rich and clear cell neuroendocrine tumors ("carcinoids") of the appendix: potential confusion with goblet cell carcinoid.

The so-called clear cell change has been described in neuroendocrine tumors at several locations. Those associated with von Hippel Lindau disease are pathognomonically "clear" and the cytoplasmic appearance has been ascribed to intracytoplasmic lipid. However, lipid has not been demonstrated in all cases of clear cell carcinoid tumors. Such variants have not been described in carcinoid tumors of the appendix and cases with a prominent proportion of clear or more correctly, lipid-rich cytoplasm may bear a superficial resemblance to goblet cell carcinoid and/or signet ring adenocarcinoma. Seven cases, in 5 females and 2 males ranging in age from 22 to 65 years, were noted to have a population of lipid-rich and vacuolated clear cells accounting for 25% or more of the tumor population. The carcinoid tumors were incidental in all cases with 4 of patients presenting with appendicitis, 2 with concomitant mucinous cystadenocarcinomas of the appendix and 1 with an adenocarcinoma of the ascending colon. Morphologically, the tumors had a nested and trabecular pattern and were composed of an admixture of microvesicular and clear lipid-rich cells. There were no mitoses, areas of necrosis of lymphovascular invasion and all cases extended to the mesoappendix. All cases were positive for synaptophysin, chromogranin, and serotonin but negative for inhibin. Three cases were examined ultrastructurally, and showed the presence of intracytoplasmic lipid and neurosecretory granules. None of the patients have shown evidence of recurrent disease. The importance of recognizing this variant of carcinoid tumor in the appendix is to avoid confusion with goblet cell carcinoid tumors with or without a signet ring adenocarcinoma. The presence of multi-vacuolated, foamy and clear cells, some resembling signet ring or goblet cells, in otherwise classic carcinoid tumors is rare but should be considered in this context in the appendix.

Application of light microscopical and ultrastructural immunohistochemistry in the study of goblet cell carcinoid in the appendix.

BACKGROUND: Goblet cell carcinoids appear less frequently in the appendix than do other carcinoids. In the presented work a case with a goblet cell carcinoid of the appendix is described. METHODS: Routine histological and histochemical methods were employed, with a combination of histochemistry and immunohistochemistry on one section and light and electron microscopical immunohistochemisty on paraffin-embedded material, were applied to identify the type of the carcinoid and to reveal the fine structure of cell types in the tumour nests of the appendix. RESULTS: During the biopsy of a patient who had undergone appendectomy, an infiltration with clusters of goblet cells in the submucosa of the appendix was found. After a second operation of right-sided hemicolectomy, similar clusters of goblet cells were detected in the muscle layers of the caecum. After 18 months the patient died from cirrhosis and had not developed metastases or any recurrence. Immunohistochemically the serotonin-, somatostatin-, chromogranin A- and synaptophysin-positive endocrine cells were basally attached to mucin-secreting cells. The combined staining revealed simultaneously present endocrine cells (chromogranin-A-positive) and mucin-secreting cells (PAS- or alcian blue-positive). The ultrastructural immunohistochemistry showed that chromogranin A-positive cells had discoid and pleomorphic granules and were located in tumour nests or as single cells in the appendiceal wall. CONCLUSION: The combined histochemical and immunohistochemical procedure and the ultrastructural immunohistochemistry on archival material could contribute in clarifying the diagnosis of goblet cell carcinoid.

As you like it, Part 3: A critique and historical review of calcification as seen with the electron microscope.

As You Like It, Part 3, is a continuation of the lectures given by the author (Ultra Path VIII and Ultra Path IX). It is a critical historical review of topics of interest to electron microscopists, attempting to show what went wrong and perhaps also why. The topics chosen this time demonstrate the prominent role electron microscopy has played in elucidating the diverse ways in which calcification can occur. The classic concept of dystropic and metastatic calcification is now inadequate to explain all observed phenomena. The electron microscope shows that calcification occurs in many different intracellular and extracellular sites and that each has its own morphology and etiology. Thus, a new classification based on ultrastructural morphology is born, but few seem to be aware of it. The author examines the ubiquitous but not too well-known phenomenon of cell remodeling, which often, but not always, leads to calcification. Topics are presented under the following headings: (1) matrical lipidic debris, (2) spherical microparticles, (3) matrix vesicles, (4) intramitochondrial calcification, (5) intralysosomal calcification, (6) calcification of collagen, (7) calcification of elastic fibers, and (8) calcification of secretory products.

Goblet cell carcinoids of the appendix: immunophenotype and ultrastructural study.

BACKGROUND: Goblet cell carcinoids of the appendix are rare neoplasms with uncertain biological behavior. OBJECTIVE: The aims of our study were to evaluate the immunophenotype of this neoplasm with cell cycle/cell proliferation markers and to understand their histogenesis with ultrastructural analysis using conventional carcinoids as a frame of reference. METHODS: Clinical data and archival pathologic material of all goblet cell carcinoids of the appendix recorded by the Saskatchewan Cancer Registry between 1970 and 1998 were reviewed and evaluated by light microscopy, histochemistry, immunohistochemistry, and electron microscopy. RESULTS: Seven cases of goblet cell carcinoids were identified among 110 cases of conventional carcinoids of the appendix. Histopathology revealed widespread infiltration of the periappendiceal fat in all cases, with extensive perineural invasion. The cells stained strongly positive for mucicarmine, periodic acid-Schiff, periodic acid-Schiff diastase, Alcian blue, cytokeratin, and carcinoembryonic antigen. Most cases were positive for synaptophysin. Increased expression of cell proliferation markers and cell cycle markers was observed. Expression of p53 was strong in one case. Electron microscopy demonstrated the presence of mucinous vacuoles of varying sizes and occasional membrane-bound neuroendocrine granules. CONCLUSIONS: Goblet cell carcinoids of the appendix arise from a pluripotent cell with divergent neuroendocrine and mucinous differentiation. These neoplasms are widely invasive; they demonstrate a high cellular proliferation rate and dysregulation of the cell cycle with up-regulation of cyclin D1 and p21, and down-regulation of p16. Complete removal of the tumor is recommended because of the unpredictable biological behavior of this tumor, which includes delayed local recurrences and lung metastases.

Multiple ileal carcinoids and appendiceal endocrine carcinoma in association with Meckel's diverticulum. A histochemical and immunohistochemical study.

An unusual case of multicentric ileal carcinoids and appendiceal endocrine carcinoma in association with Meckel's diverticulum was studied, with special attention given to the histogenesis of these neoplasms. A total of six ileal carcinoids, the largest of which was located in the wall of Meckel's diverticulum, were macroscopically and microscopically confirmed to be multicentric and revealed no visceral metastases. The histochemical and immunohistochemical profiles of the ileal carcinoids and the appendiceal carcinoma differed considerably: the former resembled subepithelial neuroendocrine cells and the latter resembled epithelial nonmucous cells and Paneth cells. The appendiceal carcinoma exhibited signs of endocrine differentiation, expressing somatostatin and vasoactive intestinal polypeptide, and secreted mucus. The tumor had metastasized to various organs. The carcinoids exhibited signs of neuroendocrine and glandular differentiation, expressing neuron-specific enolase, serotonin, chromogranin A, and endocrine granule constituent, and secreted little mucus. The data suggest different tumor cell origins or different grades of differentiation of the two types of intestinal endocrine cell tumor.

Distant metastasis from a carcinoid tumor of the appendix less than one centimeter in size.

The presentation and management of a patient with liver metastasis from a 0.6 cm carcinoid tumor of the appendix is presented. This is the first documented case of distant metastasis from a carcinoid of the appendix less than 1 cm in size. Histopathologic, immunohistochemical, and electron microscopic studies support the appendiceal carcinoid as being the primary neoplasm. Invasion of the mesoappendix was the only finding to suggest potentially aggressive behavior. We reviewed the literature and found 414 previously reported cases that provided complete information regarding tumor size, mesoappendiceal invasion, and presence of metastasis. For the entire group the frequency of metastasis was related to tumor size greater than 2 cm (p less than 0.0001) and invasion of the mesoappendix (p less than 0.0001). After dividing the group based on size, mesoappendiceal invasion was related to metastasis in those tumors less than 2 cm in size (p less than 0.0001) but not in tumors larger than 2 cm (p = 0.1538).

Immunohistochemical and ultrastructural studies of twelve argentaffin and six argyrophil carcinoids of the appendix vermiformis.

Endocrine cell types in 12 argentaffin and six argyrophil carcinoids and in nonneoplastic epithelia of the appendix vermiformis were investigated histochemically, immunohistochemically, and ultrastructurally. The nonneoplastic epithelia contained serotonin (Ser), peptide YY (PYY), glicentin (Gli), neurotensin (Neu), and somatostatin (So) cells in decreasing frequency. Out of 30 nonneoplastic Ser cells examined ultrastructurally, 28 cells were EC1 cells and two were non-EC cells. Eleven of 12 argentaffin carcinoids could be immunostained with anti-Ser serum and all of those 11 were composed almost totally of Ser cells. One of the 11 contained a small number of Neu cells. Ultrastructurally, 11 argentaffin carcinoids were composed predominantly of EC1 and/or ECn cells, and one was composed primarily of non-EC cells. Out of the six argyrophil carcinoids, five were argyrophil, non-argentaffin carcinoids; three consisted almost totally of PYY cells; one consisted of 60% PYY cells, 40% So cells and a few Gli cells; and one consisted of Ser cells alone. Ultrastructurally, the first four of those tumors were composed of D1 and/or L cells and the latter tumor was composed of ECn cells. The remaining one argyrophil carcinoid contained a few Ser-positive argentaffin cells and consisted almost totally of ECn cells which were found in both parts, with and without argentaffinity. It is concluded that the appendiceal carcinoids comprise two distinct groups on the basis of the main constituting cell type: Ser-positive, argentaffin carcinoids, composed of EC cells and peptide (especially of PYY)-positive, and Ser-negative, argyrophil non-argentaffin carcinoids of D1 and/or L cells.

Argyrophil, non-argentaffin carcinoids of the appendix vermiformis. Immunohistochemical and ultrastructural studies.

Five argyrophil, non-argentaffin classical carcinoids of the appendix were found in 19 appendiceal classical carcinoids and were investigated histochemically, immunohistochemically and ultrastructurally. All tumors consisted entirely of argyrophil cells. Three of the five carcinoids were composed almost totally of peptide YY cells and were negative for serotonin. One of them consisted of peptide YY cells (60%), somatostatin cells (40%), and a few cells with glucagon-like immunoreactivity (GLI). The remaining one without peptides was homogeneously immunoreactive for serotonin alone. Ultrastructurally, each of the four peptide-positive carcinoids was composed of one kind of endocrine cell type with round secretory granules. Average diameter of granules were 150, 160, 190, and 210 nm, respectively. The non-argentaffin, serotonin-positive carcinoid showed predominant round secretory granules and a few irregular ones, both being 150 nm in largest diameter. It is suggested that the argyrophil, non-argentaffin carcinoids of the appendix are subdivided into two groups; carcinoids composed mainly of peptide (especially, peptide YY)-positive cells with round granules of D1 and/or L cell type and those of serotonin-positive cells with pleomorphic granules of ECn cell type.

Adenocarcinoma primitivo del apéndice / Primitive adenocarcinoma of the appendix

Se presentan cuatro casos de adenocarcinoma apendicular diagnosticados y tratados en el Hospital Clínico de la Pontificia Universidad Católica de Chile. En esta rara entidad todos nuestros pacientes fueron mujeres sobre los 50 años. No tiene cuadro clínico propio. Con frecuencia aparece como hallazgo intraoperatorio y/o histopatológico, en pacientes intervenidos por apendicitis aguda simple o complicada, por lo que todo apéndice extirpado sebe ser sometido a biopsia diferida. El adenocarcinoma apendicular debe considerarse en el diagnóstico diferencial de la peritonitis apendicular localizada en todo paciente mayor de 50 años. En los tumores apendiculares se sigue la clasificación de Morson y Dawson (16). Se destaca la importancia de las técnicas de inmunoperoxidasas en el diagnóstico diferencial con el carcinoide. Cuando la afección está localizada, se recomienda la apendicectomía seguida de hemicolectomía derecha y linfadenectomía regional, la cual puede ser complementada con quimioprofilaxis con 5-FU y control periódico incluyendo CEA

Ultrastructural study on an appendiceal carcinoid tumor showing intra-nerve fiber growth.

Ultrastructural and immunohistochemical studies on an appendiceal carcinoid tumor in a 53-year-old man disclosed an intimate association of nerves and tumor cells. Electron microscopy revealed that the tumor nests were composed of neurosecretory cells containing neurosecretory granules and peripherally-located Schwann cells encasing axons. Some tumor nests were continuous with nerve fibers invested in the common basal lamina. These findings suggest that at least some carcinoid tumors of the appendix show intra-nerve fiber growth, and that the neurosecretory cells might be present in the nerve fibers from the beginning or infiltrated into the nerve fibers at a very early stage of neoplastic transformation.

[Electron microscopic characteristics of carcinoid tumors of varying localization and degree of differentiation]. / Elektronno-mikroskopicheskaia kharakteristika kartsinoidnykh opukholei razlichnoi lokalizatsii i stepeni differentsirovki.

Results of an electron-microscopic study of 15 carcinoid tumours of different sites were compared to those of histological and histochemical investigation. Highly differentiated tumours (6 observation had pronounced tissue and organ-specific features, contained a high number of argentaffin and/or argyrophilic endocrine granules in all cells. Moderately differentiated tumours (3 observations) showed a typical structure and abundance of secretory granules in the cytoplasm; when the chromatin of their nuclei became coarse, consisting of large clumps, karyolemma invaginations and bulging appeared, this being a sign of malignization. These nuclei changes progressed in the poorly differentiated tumours, number of secretory granules decreased (they were absent in 50% of cells). Argentaffin carcinoid of the appendix, intestine and cecum contained mainly serotonin granules (diameter 200-350 nm) and small number of polypeptide hormones granules (diameter less than 200 nm). The inverse correlation between the granules was observed in the bronchial carcinoid.

Adenocarcinoid of the appendix presenting as bilateral Krukenberg's tumor of the ovaries. Immunohistochemical and ultrastructural studies and literature review.

A patient with an adenocarcinoid of the appendix presented with bilateral Krukenberg's tumors of the ovaries. Immunohistochemical and ultrastructural studies revealed a selective ability of the mucinous (goblet cell) component of the appendiceal neoplasm to metastasize. A review of the literature has revealed nine previously published cases of appendiceal adenocarcinoid metastatic to the ovaries. All showed involvement of both ovaries, but none provided unequivocal evidence of a metastatic proliferating carcinoid element. As the appendiceal lesion is often grossly inconspicuous, it may be overlooked in cases presenting initially with ovarian tumors. Routine appendectomy is therefore recommended in such patients where no grossly obvious primary tumor is evident.

Combined production of mucus, amines and peptides by goblet-cell carcinoids of the appendix and ileum.

Goblet-cell carcinoids are particular mucus-producing tumors combining features of typical carcinoids and adenocarcinomas. The immunoreactivity of five goblet-cell carcinoids of the appendix and one tumor of the ileum for 5-hydroxytryptamine (5-HT, serotonin), glucagon, somatostatin, substance P (SP), neuron-specific enolase (NSE), lysozyme, secretory component (SC) and carcino-embryonic antigen (CEA) was compared with that of the mucosa of the appendix (n = 24) and ileum (n = 12), and of typical carcinoids (appendix: n = 10; ileum: n = 3). The goblet-cell carcinoids were consistently lysozyme-, SC- and CEA-reactive and contained weakly NSE reactive endocrine cells, while typical carcinoids were lysozyme-, SC- and CEA-negative, but strongly NSE- reactive. Two goblet-cell carcinoids were glucagon-reactive, one displayed SP-reactivity, one malignant tumor was reactive to the alpha-chain of glycoprotein hormones; six of ten typical appendix carcinoids were SP reactive, as were the three typical ileum carcinoids. Using the immunogold technique combined with the alcian-blue reaction, the presence of 5-hydroxytryptamine (5-HT) and mucus was demonstrated within the same cell. These findings suggest histogenetic differences between goblet-cell carcinoids and typical carcinoids; the former are possibly derived from undifferentiated stem cells, whereas the latter probably arise from endocrine cells in the mucosal stroma.

Extraepithelial intraneural endocrine cells as starting-points for gastrointestinal carcinoids.

Endocrine cells can be demonstrated by light- and electron microscopy in the lamina propria of the mucosa of the appendix. They are always in direct contact with a nerve fibre. The endocrine cell (type EC1 and EC2 cell) and the polyaxonal non-myelinated nerve fibre are separated from the interstitial connective tissue by a common continuous basal lamina. The term "ECC-NF complex" ("EC cell-nerve fibre complex") is suggested by the authors to describe this morphological unit. The intraneural endocrine cells may be derived from neuroendocrine-programmed ectoblasts (Pearse, 1977). The electron microscopic demonstration of these "ECC-NF complexes" in carcinoid tumours of the appendix and of similarly structured "eC-NF complexes" ("endocrine cell-nerve fibre complexes") in carcinoids of the rectum allows us, following the demonstration of small nerve fibres within carcinoids of the appendix, caecum and rectum (and bronchus) to propose a hypothetical pathogenesis of gastrointestinal carcinoid tumours from these intraneural endocrine cells. Carcinoid tumours may develop by proliferation of the intraneural endocrine cells with microcarcinoids as intermediate stages. In this way the histogenesis of the carcinoids is located a priori in the subepithelial stroma. Nerve fibres are morphological markers of this proposed mechanism. Assuming a neuroectodermal cytogenesis for the intraneural endocrine cells we therefore also postulate a histogenesis of the carcinoids from the neuroectoderm.

Malignant carcinoid tumors in children.

The clinical, light microscopic, and ultrastructural features of four malignant carcinoid tumors in children, three boys and one girl ages 8--14 years, are described. Extensive metastases to multiple organs were present in three, and in the fourth child there was diffuse local infiltration of the bowel wall, which resembled a lymphoma. The primary tumor arose in the ileum in one child and in the transverse colon in another. In two children, the primary sites could not be determined; one patient is still alive and in the other, permission for autopsy was refused. Electron microscopy showed moderate numbers of neurosecretory granules in some cells in all cases. One patient with extensive metastases showed repeated partial response to radiotherapy and chemotherapy. Eight benign appendiceal carcinoids were seen at the same hospital over the same period, suggesting malignant carcinoids may be more common in children than often assumed.

The amphicrine (endo-exocrine) cells in the human gut, with a short reference to amphicrine neoplasias.

In the human gastrointestinal tract the amphicrine cells are described as a special form of endocrine cells. Depending on their behaviour under silver impregnation, they are divided into three subgroups: the mucoargentaffine, the mucoargyrophilic and the mucoargyrophobic cells. They were detected electron microscopically in 1969, but they were histologically verified and identified as mucus-excreting endocrine elements only in 1977. Since 1969 such cells have also been observed in normal and regenerating rat and mouse stomachs. Our own human material includes stomach (3 cases), appendix (12 cases), colon (1) and a series of amphicrine proliferations and tumours. Two cases of chronic gastritis and one chronic peptic ulcer with metaplastic and regenerating epithelium contained mucoargyrophilic cells with mucus below the nucleus in the atypical glands. The possibility of endocrine granules being sluiced out in the mucous grains is discussed. Of the appendices only two were normal (ages 6 and 7 years), 10 showed pathological changes: there were seven neurogenic appendicopathies (14-58 years), one lymphatic hyperplasia, and one hyperplasia of mucoargyrophobic cells with mucostasis. Mucoargentaffine cells far outnumbered the mucoargyrophilic and mucoargyrophobic cells. The mucus may have either an apical or basal location; in the latter case, paracrine secretion into the subepithelial lamina propria was seen. As neoplastic cells, the amphicrine cells form the rare amphicrine tumours (goblet-cell and muco-adenoid carcinoids) of the appendix and colon. They are also found in mucinous cystadenomas of the ovary [26], in the enteral type of a nasal carcinoma [27,28], and in a 5-HT-carcinoid of the ovary [15]. They are therefore to be regarded as a differentiation disorder of the endocrine cells under the pathological conditions of appendicopathy, hyperplasia, metaplasia and true neoplasias.

Goblet cell carcinoid of appendix: ultrastructural features and histogenetic aspects.

Light and electron microscopic examination of a goblet cell carcinoid revealed cells with pleomorphic neurosecretory-type granules, cells containing mucin some of which also contained these granules and less differentiated cells lacking the aforementioned features. Recent embryologic and anatomic studies of developing avian and mammalian gut, respectively, show that intestinal APUD cells are probably of endodermal origin. Therefore, mixed carcinoid tumors such as the goblet cell variant could arise in crypt base stem cells.