Pituitary Adenoma in Carney Complex: An Immunohistochemical,Ultrastructural, and Immunoelectron Microscopic Study

First described in 1985, Carney complex is a rare, heritable disorder featuring abnormal skin pigmentation, cardiac and cutaneous myxoma, melanotic schwannoma of psammomatous type, and endocrine abnormalities, including pituitary adenomas. Patients with the latter present with elevated growth hormone (GH) levels and acromegaly or gigantism. Prolactin (PRL) elevation may also be seen. The authors have investigated 2 resected pituitary adenomas from patients with Carney complex. One, a 19-year-old female acromegalic with elevated GH, IgF-1, and PRL levels, had a mammosomatotroph adenoma immunoreactive for GH and PRL. Ultrastructurally, GH and PRL were present in the same secretory granules. The second patient, a 27-year-old acromegalic, had a sparsely granulated GH cell adenoma that by immuno-electron microscopy revealed GH immunoreactivity only. The lack of morphologic similarity between the 2 adenomas indicates that pituitary tumors in patients with Carney complex may not exhibit the same phenotype.     

Pituitary adenoma in Carney complex: an immunohistochemical,ultrastructural, and immunoelectron microscopic study

First described in 1985, Carney complex is a rare, heritable disorder featuring abnormal skin pigmentation, cardiac and cutaneous myxoma, melanotic schwannoma of psammomatous type, and endocrine abnormalities, including pituitary adenomas. Patients with the latter present with elevated growth hormone (GH) levels and acromegaly or gigantism. Prolactin (PRL) elevation may also be seen. The authors have investigated 2 resected pituitary adenomas from patients with Carney complex. One, a 19-year-old female acromegalic with elevated GH, IgF-1, and PRL levels, had a mammosomatotroph adenoma immunoreactive for GH and PRL. Ultrastructurally, GH and PRL were present in the same secretory granules. The second patient, a 27-year-old acromegalic, had a sparsely granulated GH cell adenoma that by immuno-electron microscopy revealed GH immunoreactivity only. The lack of morphologic similarity between the 2 adenomas indicates that pituitary tumors in patients with Carney complex may not exhibit the same phenotype.     

Ultrastructural Features of Apoptosis in Human Pituitary Adenomas

Although several recent studies deal with various molecular aspects of apoptosis, or programmed cell death, very little information is available on the ultrastructural changes associated with apoptosis in the adenohypophysis and its role in the regulation of pituitary adenoma growth and progression. This paper describes the distinct ultrastructural sequences that develop during the various phases of the apoptotic process. The study is based on the ultrastructural investigation of more than 8,000 surgically removed pituitary biopsies, which were examined by histology and immunocytochemistry for diagnostic purposes. No apoptosis was found in normal adenohypophysis and it is also a rare event in pituitary adenomas. When present, adenomatous adenohypophysial cells exhibit common and characteristic apoptotic changes. The ultrastructural alterations of membraneous organelles associated with apoptosis are similar to those previously reported in other tissues. It is noteworthy that apoptosis is clearly distinguishable from the ubiquitous dark cells denoting the common way of cell death. The findings suggest that apoptosis in pituitary adenomas is not a random event. Practically every specimen containing multiple apoptotic cells represents corticotroph adenoma. Occasional examples occur in lactotroph or gonadotroph adenomas. Although electron microscopic specimens are admittedly small, the large number of investigated cases gives credence to the observations.     

Ultrastructural Features of Apoptosis in Human Pituitary Adenomas

Although several recent studies deal with various molecular aspects of apoptosis, or programmed cell death, very little information is available on the ultrastructural changes associated with apoptosis in the adenohypophysis and its role in the regulation of pituitary adenoma growth and progression. This paper describes the distinct ultrastructural sequences that develop during the various phases of the apoptotic process. The study is based on the ultrastructural investigation of more than 8,000 surgically removed pituitary biopsies, which were examined by histology and immunocytochemistry for diagnostic purposes. No apoptosis was found in normal adenohypophysis and it is also a rare event in pituitary adenomas. When present, adenomatous adenohypophysial cells exhibit common and characteristic apoptotic changes. The ultrastructural alterations of membraneous organelles associated with apoptosis are similar to those previously reported in other tissues. It is noteworthy that apoptosis is clearly distinguishable from the ubiquitous dark cells denoting the common way of cell death. The findings suggest that apoptosis in pituitary adenomas is not a random event. Practically every specimen containing multiple apoptotic cells represents corticotroph adenoma. Occasional examples occur in lactotroph or gonadotroph adenomas. Although electron microscopic specimens are admittedly small, the large number of investigated cases gives credence to the observations.     

Pituitary Corticotroph Adenoma Containing Many Apoptotic Cells: A Histologic,Immunohistochemical, Ultrastructural and Molecular Study

Apoptosis regulates cell turnover in normal tissues and occurs during the neoplastic process. Owing to difficulties in recognizing apoptotic cells by histology alone, several complementary approaches have been introduced, which disclosed the presence of cells with typical nuclear and cytoplasmic changes characteristic of apoptosis. Electron microscopy remains the most conclusive method to reveal the structural changes. Identification of caspase cleaved keratin 18 intermediate filament rearrangements can contribute to the identification of early apoptotic changes. The authors present here an unusual case of a pituitary corticotroph adenoma removed surgically from a young woman with Cushing disease. The tumor contained many apoptotic cells identified by histology. In addition, the apoptotic events were investigated using various morphologic techniques, including electron microscopy, the in situ end-labeling technique, and immunohistochemistry to confirm the caspase-cleaved keratin 18 rearrangements.     

Pituitary Carcinoma: An Ultrastructural Study of Eleven Cases

Pituitary carcinomas are very rare. Defined as adenohypophysial tumors that undergo craniospinal and/or systemic metastasis, most are PRL- or ACTH-producing. Their ultrastructural features, particularly relative to benign adenomas of similar functional type, have not been sufficiently explored. Eleven cases of immunohistochemically characterized pituitary carcinoma with documented cerebrospinal and/or systemic metastases were collected from various institutions and studied by transmission electron microscopy. The tumors were surgically removed from 7 women and 4 men ranging in age between 28 and 74 years (mean, 50 years). All were endocrinologically functioning. Six tumors secreted PRL; three were ACTH-producing; one each was GH/PRL- and TSH-producing. The patients with the ACTH-producing tumors had all presented with Cushing's disease and two of them had undergone adrenalectomy (Nelson syndrome). In most cases significant cellular atypia and mitotic activity were observed. In terms of morphologic features of functional differentiation, electron microscopy revealed that in 9 cases the tumor cells maintained at least some ultrastructural markers of their basic phenotype. A unique feature in 2 ACTH carcinomas was the variable admixture of smooth endoplasmic reticulum with intermediate (cytokeratin) filaments. In 2 cases, both PRL-producing carcinomas, the cell type comprising the tumor could not be identified on an ultrastructural basis alone. Ultrastructural investigation of pituitary carcinomas confirms their endocrine nature and, in most but not all cases, reveals their functional differentiation. Despite the diagnostic utility of electron microscopy in the assessment of theserare tumors, the distinction of pituitary carcinoma from pituitary adenoma cannot be firmly made on ultrastructural grounds alone.     

Pituitary chromophobe adenomas consisting of prolactin cells

Summary Morphologic studies of pituitary neoplasms removed by surgery from 36 human patients revealed 8 chromophobe adenomas which differed clearly from the remaining tumors. The cytoplasm of the adenoma cells failed to stain with PAS, aniline blue, aldehyde fuchsin, aldehyde thionin, orange G or light green, but positively stained granules were found by using erythrosine or carmoisine. Immunoperoxidase technique disclosed the presence of prolactin in the cytoplasm of some adenoma cells. The adenoma cells exhibited distinct ultrastructural features such as well developed rough surfaced endoplasmic reticulum with Nebenkern formation, prominence of Golgi apparatus, presence of misplaced exocytosis as well as pleomorphism of secretory granules with a considerable variation of size ranging from 130 to 500 nm in diameter. Thus, by electron microscopy the adenoma cells showed a close resemblance to prolactin cells of the non-tumorous pituitary glands except for the reduced size and number of secretory granules.These chromophobe adenomas are regarded as representing a distinct pathological entity clearly distinguishable from other forms of pituitary neoplasms. In view of the morphologic findings and the elevation of blood prolactin level (measured in 3 patients) the term, sparsely granulated prolactin producing pituitary adenoma, appears to be the most appropriate one to designate these tumors.The authors wish to thank Dr. H. Friesen for providing the anti-human prolactin and Dr. L. A. Sternberger for the peroxidase-anti-peroxidase complex. The excellent technical assistance of Mrs. Gezina Ilse and Miss Nancy Macphail and the valuable secretarial help of Mrs. Maureen Rowling are appreciated.The work was supported in part by MA-552 grant of the Medical Research Council of Canada and by the St. Michael's Hospital Research Society.     

Pituitary adenomas with hyperfunction of TSH

Summary In a collection of 564 surgically removed pituitary adenomas, 4 cases were found to have had elevated TSH plasma levels. One of these tumors (case 1) could be classified as a highly differentiated mucoid TSH cell adenoma presenting histochemical reactions typical of, as well as electron microscopical features identical to, normal TSH cells. Immunoenzymatic studies failed to demonstrate TSH in the tumor cells. Two further adenomas (case 2 and 3) were similarly structured in many areas, but showed regions of poorer differentiation in which cells with distinct pleomorphism, irregular secretory granules, increased numbers of ribosomes and a well developed rough endoplasmic reticulum were present. In 10% of the tumor cells GH could be demonstrated immunoenzymatically, but there was no TSH. The fourth adenoma was an undifferentiated acidophilic adenoma showing pleomorphic cells having slight acidophil and partly mucoid granulations. The ultrastructure showed convoluted nuclei, increased numbers of free ribosomes as well as abundant rough endoplasmic reticulum and secretory granules which were different in size and number but distinctly of the TSH cell type. Immunoenzymatically, TSH was found in some cells, with GH in more cells. Endocrinologically, elevated levels of GH were measured in cases 2, 3 and 4 with LH being increased in case 1. Clinical and morphological correlations are discussed.Supported by the Sonderforschungsbereich 34 (Endocrinology) of the Deutsche ForschungsgemeinschaftDedicated to Professor Dr. Gerhard Seifert on the occasion of his 60th birthday     

Myofilament Localization and Immunoelectron Microscopic Detection of Muscle-Specific Actin in Neoplastic Myoepithelial Cells in Pleomorphic Adenomas and Myoepitheliomas

Elucidating the cellular characteristics of the nonluminal or myoepithelial cells of pleomorphic adenomas is one approach to establishing the diagnostic criteria for myoepitheliomas. Ultrastructural features of nonluminal tumor cells in 22 pleomorphic adenomas and of tumor cells in 9 myoepitheliomas were assessed from micrographs of routinely fixed and epoxy resin-embedded samples. Recognizable myofilaments were only moderately prominent in 1 myoepithelioma. In the rest of the cases, irrespective of whether nonluminal cells of pleomorphic adenomas or tumor cells of myoepitheliomas were spindle, angular, round, or plasmacytoid in form, myofilaments were noted only in one third of the cases and were present even in these in a small proportion of the tumor cells. Intermediate filament accumulations and basal lamina were more frequent findings associated with nonluminal tumor cells. Six pleomorphic adenomas and 2 myoepitheliomas had been fixed in half-strength glutaraldehyde and embedded in LR White resin for immunoelectron microscopic detection of muscle-specific actin. In 3 (2 pleomorphic adenomas and myoepitheliomas) of these 8 cases, readily visualized bands of filaments in many tumor cells were strongly labeled by the colloidal gold probe detecting muscle-specific actin even when myofilaments were minimal and infrequent in 2 cases and undetectable in the third by routine transmission electron microscopy. Lack of myofilament detection by immunocyto-chemistry or routine electron microscopy does not exclude a diagnosis of pleomorphic adenoma or myoepithelioma when growth patterns and cytology indicate such diagnoses. Immunoelectron microscopy, in fact, shows that muscle-specific actin can be detected even when myofilaments or muscle actin are apparently absent or minimal by routine electron microscopy or immunohistochemistry, respectively. Because examples of pleomorphic adenoma and myoepithelioma each with similar histologic and cytologic features of the myoepithelio-matous cells can have variable degrees or complete absence of expression of myofilaments or muscle-specific actin, the time-honored term myoepithelial for the nonluminal cells of pleomorphic adenomas and the term myoepithelioma are legitimate even in the absence of those markers that are specific for normal myoepithelial cells.     

Myofilament Localization and Immunoelectron Microscopic Detection of Muscle-Specific Actin in Neoplastic Myoepithelial Cells in Pleomorphic Adenomas and Myoepitheliomas

Elucidating the cellular characteristics of the nonluminal or myoepithelial cells of pleomorphic adenomas is one approach to establishing the diagnostic criteria for myoepitheliomas. Ultrastructural features of nonluminal tumor cells in 22 pleomorphic adenomas and of tumor cells in 9 myoepitheliomas were assessed from micrographs of routinely fixed and epoxy resin-embedded samples. Recognizable myofilaments were only moderately prominent in 1 myoepithelioma. In the rest of the cases, irrespective of whether nonluminal cells of pleomorphic adenomas or tumor cells of myoepitheliomas were spindle, angular, round, or plasmacytoid in form, myofilaments were noted only in one third of the cases and were present even in these in a small proportion of the tumor cells. Intermediate filament accumulations and basal lamina were more frequent findings associated with nonluminal tumor cells. Six pleomorphic adenomas and 2 myoepitheliomas had been fixed in half-strength glutaraldehyde and embedded in LR White resin for immunoelectron microscopic detection of muscle-specific actin. In 3 (2 pleomorphic adenomas and myoepitheliomas) of these 8 cases, readily visualized bands of filaments in many tumor cells were strongly labeled by the colloidal gold probe detecting muscle-specific actin even when myofilaments were minimal and infrequent in 2 cases and undetectable in the third by routine transmission electron microscopy. Lack of myofilament detection by immunocyto-chemistry or routine electron microscopy does not exclude a diagnosis of pleomorphic adenoma or myoepithelioma when growth patterns and cytology indicate such diagnoses. Immunoelectron microscopy, in fact, shows that muscle-specific actin can be detected even when myofilaments or muscle actin are apparently absent or minimal by routine electron microscopy or immunohistochemistry, respectively. Because examples of pleomorphic adenoma and myoepithelioma each with similar histologic and cytologic features of the myoepithelio-matous cells can have variable degrees or complete absence of expression of myofilaments or muscle-specific actin, the time-honored term myoepithelial for the nonluminal cells of pleomorphic adenomas and the term myoepithelioma are legitimate even in the absence of those markers that are specific for normal myoepithelial cells.     

The Immunophenotype of Pituitary Adenomas

Although the production of pituitary hormones by adenohypophysial tumors has been studied extensively, an examination of the immunophenotype of pituitary adenomas using a broad spectrum of antibodies has not been previously investigated. We studied 23 pituitary adenomas using a large panel of antibodies to determine if these tumors exhibited a common immunophenotype. Various neuroendocrine markers, synaptophysin, neuron-specific enolase (NSE), and the intermediate filament protein, low-mol-wt keratin were expressed in most examples. There was, however, differential expression of chromogranin A in that few prolactin (PRL) and adenocorticotrophic hormone (ACTH) adenomas stained positively, whereas all other adenoma subtypes were reactive. The ACTH adenomas had a unique profile with positive staining for galanin, neurophysin, vasopressin, and ubiquitin. These results indicate that (1) pituitary adenomas do not express a single “generic” immunophenotype; (2) synaptophysin is the most reliable and best broad spectrum marker for pituitary adenomas; (3) the neuroendocrine granule marker chromogranin A is useful in the identification of null cell adenoma, a tumor that usually does not stain for anterior pituitary tumors; and (4) among pituitary tumors, ACTH adenomas have a unique immunoprofile.     

Pituitary Hormone mRNA in Null Cell Adenomas and Oncocytomas by In Situ Hybridization Comparison with Immunohistochemical and Clinical Data

Null cell adenomas and oncocytomas are clinically inactive adenomas of the pituitary gland. They do not show any significant hormone content detectable by immunohistochemistry. This study aimed at demonstrating mRNAs for all main pituitary hormones in 32 null cell adenomas and 31 oncocytomas by non-isotopic in situ hybridization using digoxigenin-labeled oligonucleotide probes. The results were compared with immunohistochemical and clinical data. Immunohistochemistry (ABC method) was done with monoclonal antibodies against PRL, GH, FSH, LH, TSH, ACTH, alpha-subunit, and Ki-67 (mib-1). The signals for hormone production were detected in both adenoma types in a range from 42% for GH in oncocytomas to 78% for beta-FSH in null cell adenomas. However, these signals are apparently not effective on hormone production, as was shown by almost negative immunostaining. Owing to the simultaneous detection of at least two mRNAs in 78% of null cell adenomas and in 94% of oncocytomas, we assume that both tumor types originate from pluripotential precursor cells that are capable of producing various hormones. According to our data, it is unlikely that the signals influence the clinical behavior.     

Pituitary corticotroph adenoma containing many apoptotic cells: a histologic,immunohistochemical, ultrastructural and molecular study

Apoptosis regulates cell turnover in normal tissues and occurs during the neoplastic process. Owing to difficulties in recognizing apoptotic cells by histology alone, several complementary approaches have been introduced, which disclosed the presence of cells with typical nuclear and cytoplasmic changes characteristic of apoptosis. Electron microscopy remains the most conclusive method to reveal the structural changes. Identification of caspase cleaved keratin 18 intermediate filament rearrangements can contribute to the identification of early apoptotic changes. The authors present here an unusual case of a pituitary corticotroph adenoma removed surgically from a young woman with Cushing disease. The tumor contained many apoptotic cells identified by histology. In addition, the apoptotic events were investigated using various morphologic techniques, including electron microscopy, the in situ end-labeling technique, and immunohistochemistry to confirm the caspase-cleaved keratin 18 rearrangements.     

Subcellular Distribution of Urokinase and Urokinase Receptor in Human Neutrophils Determined by Immunoelectron Microscopy

A high-affinity receptor for urokinase-type plasminogen activator (uPAR) has been identified on the plasmamembrane of a number of different cell types, and has been shown to be important for plasminogen activation, cell adhesion, and possibly signal transduction. uPAR and uPA cosediment with secretory vesicles and specific granules by subcellular fractionation and translocate to the plasma membrane upon activation of neutrophils. Here the subcellular distribution of uPAR and uPA is studied by electron microscopy of neutrophils using immunogold double labeling for uPAR and uPA and a set of markers for well-defined subtypes of granules: matrix metalloproteinase type-9 (MMP-9) for gelatinase granules, lactoferrin (LF) for specific granules, and myeloperoxidase (MPO) and neutrophil elastase (NE) for primary granules. With this technique uPAR colocalizes with uPA in 71% of labeled granules. In granules containing uPAR the degree of coexpression with MMP-9, MPO and NE was 19, 66, and 74%, respectively. In granules labeled for uPA the corresponding overlap with MMP-9, MPO and NE was 24, 64, and 51%, respectively. Low levels of co-localization were found for uPAR and LF (7%) and for uPA and lactoferrin (5%). The results indicate that uPAR and uPA arepresent in gelatinase granules and primary granules, but rarely in specific granules. The demonstration of uPAR and uPA in primary granules is of particular interest, and may indicate that uPAR and uPA participate in the activation of latent hepatocyte growth factor of neutrophils.     

Ultrastructural features of adenoma malignum of the uterine cervix: demonstration of gastric phenotypes

Histochemical staining has shown that so-called adenoma malignum (the mucinous type of minimal deviation adenocarcinoma [mucinous MDA]) of the uterine cervix expresses gastric phenotypes. The present ultrastructural study was undertaken to explore the fine structure and phenotypic expression of this tumor, and to make comparisons with normal cervical glands and gastric pyloric mucosa. Post-embedding, double-immunogold staining for gastric gland mucous cell mucin (HIK1083-reactive mucin) and lysozyme revealed localization exclusively to the matrix and to the core of the mucin granules, respectively, both in mucinous MDA and gastric pyloric mucosa. Mucin granules of normal cervical gland cells lacked core structures and showed no immunoreactivity with HIK1083 or lysozyme. Thus, mucinous MDA was confirmed to be a tumor expressing gastric phenotypes ultrastructurally. Both markers should be useful for the identification of tumor cells.     

Pituitary adenoma producing thyrotropin and prolactin

Summary A pituitary adenoma with suprasellar extension that had caused hyperthyroidism due to secretion of excess thyrotropin (TSH), as well as mild hyperprolactinemia, was studied with differential staining, immunocytochemistry and electron microscopy. Most cells of the tumor stained lightly with aldehyde thionin, which demonstrates the granules of normal thyrotrops, and immunocytochemically with antiserum to the hormone-specific chain of TSH. A minority of the cells was immunoreactive for prolactin. Electron microscopy revealed light cells interspersed with highly pleomorphic dark cells. Both were sometimes multinucleated, and contained variable numbers of small secretion granules, multiple Golgi complexes, and abundant endoplasmic reticulum.Supported by NIH grant AM-2463Recipient of NIH Research Career Award AM-13,576The technical assistance of Paul Hebl is gratefully acknowledged.     

Clinicopathologic Analysis of Pituitary Adenoma: A Single Institute Experience

Pituitary adenoma (PA) is a common benign neuroendocrine tumor; however, the incidence and proportion of hormone-producing PAs in Korean patients remain unknown. Authors analyzed 506 surgically resected and pathologically proven pituitary lesions of the Seoul National University Hospital from 2006 to 2011. The lesions were categorized as: PAs (n = 422, 83.4%), Rathke''s cleft cysts (RCCs) (n = 54, 10.6%), inflammatory lesions (n = 8, 1.6%), meningiomas (n = 4), craniopharyngiomas (n = 4), granular cell tumors (n = 1), metastatic renal cell carcinomas (n = 2), germinomas (n = 1), ependymomas (n = 1), and unsatisfactory specimens (n = 9, 1.8%). PAs were slightly more prevalent in women (M: F = 1:1.17) with a mean age of 48.8 yr (9-80 yr). Immunohistochemical analysis revealed that prolactin-producing PAs (16.6%) and growth hormone-producing adenomas (9.2%) were the most common functional PAs. Plurihormonal PAs and nonfunctioning (null cell) adenomas were found in 14.9% and 42.4% of patients with PAs, respectively. The recurrence rate of PAs was 11.1%, but nearly 0% for the remaining benign lesions such as RCCs. 25.4% of patients with PAs were treated by gamma-knife after surgery due to residual tumors or regrowth of residual tumor. In conclusion, the pituitary lesions and the proportions of hormone-producing PAs in Korean patients are similar to those of previous reports except nonfunctioning (null cell) PAs, which are unusually frequent.

Graphical Abstract

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Immunocytochemical Investigations on the Vascularization of Pituitary Adenomas

Blood vessels within pituitary adenomas were visualized using the immunocytochemical reaction for Factor VIII (von Willebrand Factor), a specific marker of the vascular endothelium. The number of immunopositive vascular profiles were counted and expressed as a mean number per one microscopic field. The results were related to the type of adenoma, established on the basis of immunocytochemical investigation using the antibodies against pituitary hormones or α-subunit (α-SU). It was found that the richest vascularization occurred in adenomas expressing follicle-stimulating hormone (FSH). The possible role of FSH in pituitary angiogenesis is discussed.     

Atypical Endocrine Granules in Atypical Endocrine Tumor (AET) of the Lung: An Immunoelectron Microscopic Study

Highly dense granules are a hallmark for recognizing atypical endocrine tumor (AET) of the lung. We report a case of AET with many atypical neurosecretory type granules: moderately dense granules (mean size 373.7nm) and "target" granules with a central dense core (425.1 nm), both apparently larger than the highly dense granules (223.3nm). lmmunoelectron microscopical studies demonstrated that all three types of granule were positive for gastrin releasing peptide (GRP), human chorionic gonadotropin α-subunit (hCGα), calcitonin or serotonin. Although the size profiles of positive granules were similar for calcitonin and hCGα, they were different from those of GRP or serotonin granules. The presence of atypical granules and the different size profiles of hormonal products in AET indicate that caution is required in ultra-structural evaluation of granules in lung carcinomas.     

Plasmacytoid Monocytes in Epithelioid Cell Granulomas: Ultrastructural and Immunoelectron Microscopic Study

Plasmacytoid monocytes, the so-called plasmacytoid T cells, were originally described in rare cases of lymphadenitis. Recent immunohistochemical studies have demonstrated their monocytic origin. Plasmacytoid monocytes have in common with epithelioid cells and multinucleated giant cells the expression of several antigens; they also occur in close topographic association with epithelioid and multinucleated giant cells in epithelioid cell granulomas. On the basis of these data it has been suggested that plasmacytoid monocytes may transform into epithelioid cells. The present ultrastructural and immunoelectron microscopic study of epithelioid cell granulomas provides furthei arguments in favor of this hypothesis. Moreover, the existence of a transitional cell type with characteristics of plasmacytoid monocytes and epithelioid cells is documented. Subplasmalemmal linear densities present on focal areas of the plasma membrane of the main cell components of granulomas are also discussed.