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An intersexual or intersex person (or animal of any unisexual species) is one who is born with genitalia and/or secondary sex characteristics determined as neither exclusively male nor female, or which combine features of the male and female sexes. more...

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(The terms hermaphrodite and pseudohermaphrodite, which have been used in the past, are now considered pejorative and inaccurate and are no longer used to refer to an intersexual person.) Sometimes the phrase "ambiguous genitalia" is used.


According to the highest estimates (Fausto-Sterling et. al., 2000) perhaps 1 percent of live births exhibit some degree of sexual ambiguity , and that between 0.1% and 0.2% of live births are ambiguous enough to become the subject of specialist medical attention, including surgery to disguise their sexual ambiguity. Other sources (Leonard Sax, 2002) estimate the incidence of true intersexual conditions as far lower, at approximately 0.018%.

In typical fetal development, the presence of the SRY gene causes the fetal gonads to become testes; the absence of it allows the gonads to continue to develop into ovaries. Thereafter, the development of the internal reproductive organs and the external genitalia is determined by hormones produced by certain fetal gonads (ovaries or testes) and the cells' response to them. The initial appearance of the fetal genitalia (a few weeks after conception) is basically feminine: a pair of "urogenital folds" with a small protuberance in the middle, and the urethra behind the protuberance. If the fetus has testes, and if the testes produce testosterone, and if the cells of the genitals respond to the testosterone, the outer urogenital folds swell and fuse in the midline to produce the scrotum; the protuberance grows larger and straighter to form the penis; the inner urogenital swellings swell, wrap around the penis, and fuse in the midline to form the penile urethra.

Because there is variation in all of these processes, a child can be born with a sexual anatomy that is typically female, or feminine in appearance with a larger than average clitoris; or typically male, masculine in appearance with a smaller than average penis that is open along the underside. The appearance may be quite ambiguous, describable as female genitals with a very large clitoris and partially fused labia, or as male genitals with a very small penis, completely open along the midline ("hypospadic"), and empty scrotum.

There are dozens of named medical conditions that may lead to intersex anatomy. Fertility is variable. The distinctions "male pseudohermaphrodite", "female pseudohermaphrodite" and especially "true hermaphrodite" are vestiges of 19th century thinking that placed "true sex" in the histology (microscopic appearance) of the gonads.

The common habit in the 21st century of elevating the role of the sex chromosomes above all other factors when determining gender may be analogous to the older habit of finding "true" sex in the gonads. Though high school biology teaches that men have XY and women XX chromosomes, in fact there are quite a few other possible combinations such as Turner_syndrome XO, Triple-X syndrome XXX, Klinefelter's Syndrome XXY, XYY, XO/XY, XX male, Swyer syndrome XY female, and there are many individuals who do not follow the typical patterns (such as cases with four or even more sex chromosomes).


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Androgen insensitivity syndrome: An immunohistochemical, ultrastructura, and morphometric study
From Archives of Pathology & Laboratory Medicine, 3/1/99 by Regadera, Javier

* Objective.-To evaluate the morphometric, immunohistochemical, and ultrastructural lesions of the testes in prepubertal and adult patients with androgen insensitivity syndrome.

Methods.-We examined the testicular biopsy using immunohistochemistry for vimentin, smooth muscle actin, and collagen IV antigens. Quantification of seminiferous tubules and testicular interstitium was performed in prepubertal and adult patients with androgen insensitivity syndrome and results were compared with normal testes from both infants and adults.

Results.-The adult testes presented nodular and diffuse lesions that consisted of Sertoli-cell-only seminiferous tubules. Two types of Sertoli cells could be distinguished, namely, immature vimentin-positive Sertoli cells and nearly mature Sertoli cells. In the nodules, the lamina propria was thin and contained a scant number of actin-positive peritubular cells. Leydig cells were hyperplastic. The prepubertal patients showed only diffuse lesions characterized by Sertoli cell hyperplasia, decreased germ cell numbers, and a discontinuous immunoreaction to collagen IV.

Conclusions.-The testicular lesions in androgen insensitivity syndrome are probably caused by primary alterations that begin during gestation. These lesions become progressively more pronounced at puberty, when the nodular lesion pattern (adenomas) is completely developed.

Androgen insensitivity syndrome (AIS), also called testicular feminization syndrome, is a form of X-linked male pseudohermaphroditism that is clinically recognized in patients with a female phenotype.1 The incidence of this syndrome has been reported in 1:20400 new bores.2 In postpubertal patients, the most frequent cause for consultation is primary amenorrhea; however, in prepubertal patients, AIS is often diagnosed during the study of inguinal hernia.2 The karyotype is 46,XY, although cases with chromosomal mosaicism have also been reported.3 Two types of AIS are described: complete and incomplete; the incomplete AIS form differs from the current complete AIS form in a certain ambiguity of the external genitalia and a less complete feminization at puberty.4-6 Removal of the testes is advisable at puberty, when feminization occurs, to avoid the increased risk of neoplasia.7

The molecular biology of AIS has been reviewed previously.6,8,9 The disease is the result of an end-organ resistance to androgens caused by an abnormality in androgen receptors, which may be absent or which may display quantitative or qualitative abnormalities. Occasionally there is a postreceptor abnormality.10 The androgen receptor gene locus spans over 90 kilobases and has been mapped to the q11- l2 region of the human X chromosome.11,12A relatively high number of mutations of this gene were reported in 2 different clusters in exon 5 and exon. 7.13 These mutations cause phenotypic abnormalities of male sexual development14 that range from a female phenotype to that of unvirilized or infertile men.14,15

The histologic pattern of testes removed from adult patients with AIS is similar to that of many cryptorchidic1,16-18 immature,17 or infantile testes.19 Hamartoma and Sertoli cell adenomas are frequent in the testes of AIS patients.19 Although some differences regarding testicular histology between the complete and incomplete forms of AIS were reported in the first studies,17,20 later studies of a wide series of patients concluded that there are no histologic differences in the testicular pattern between the 2 forms.19 Immunohistochemical studies referring to the testes in AIS are sparse. Aumuller and Peter21 studied only one antibody (against vimentin) in only one AIS case and found an increased vimentin immunoreaction in the Sertoli cells. Herein we report the different morphometric, immunohistochemical, and ultrastructural characteristics of the seminiferous tubules and of the Sertoli, peritubular, and Leydig cells observed in the nodular (adenomatous) and diffuse histologic patterns in a series of both prepubertal and adult AIS patients.



The patients ages, clinical findings, and hormonal data are shown in Tables 1 and 2. None of the patients had previously received hormonal treatment. The testes of 3 children and 3 adults with AIS were obtained by surgical removal from their abdominal or inguinal localization. In cases 2, 4, 5, and 6, the epididymides and the initial portion of the spermatic cords were also removed with the testes. In cases 1 and 3, no epididymal tissue was found. In case 6, in which the testes were removed at 6 years of age, the right testis had been biopsied at 3 months of age, when the disease was diagnosed. The testes and epididymides from 10 children (aged 4.8 +/- 2.1 years) and 7 young adult men (aged 23.1 +/- 5.6 years) without testicular or related pathology were obtained at autopsy (6-10 hours after death) and were used as control specimens for the histologic and quantitative studies.


The testes and their epididymides taken from children were longitudinally sectioned in 8-mm segments through the sagittal plane, whereas the adult testes and their epididymides were sliced perpendicular to the sagittal plane, also in 8-mm segments. All sections were fixed in a 10% formaldehyde solution or in Bouin's fixative. Paraffin-embedded blocks were serially cut into 6-lim-thick sections, which were stained with hematoxylin-eosin. Other sections were processed following the avidin-biotin-peroxidase complex method for immunohistochemical studies. The primary antibodies used for this study and the dilutions found to be optimal were (1) anti-pig vimentin monoclonal antibody (1:100; Dakopatts A/S, Glostrup, Denmark), (2) anti-smooth muscle actin monoclonal antibody (1:100; Sigma Chemical Company, Barcelona, Spain), and (3) anti-rabbit collagen IV polyclonal antibody (1:120; Eurodiagnostic, Apeldoorn, Holland). Each antibody was assayed in at least 2 sections of each testis. Another section of each testis was used as negative control for each antibody. Following deparaffinization, sections were hydrated and incubated for 20 minutes in 0.3% hydrogen peroxide in phosphate-buffered saline (PBS) to reduce endogenous peroxidase activity. The sections were then digested with either 0.1% trypsin (Merck, Darmstadt, Germany) in 0.01 mol/L PBS (pH 7.6) for 15 minutes at 37degC or 0.1% pepsin (Sigma, St Louis, Mo) in 0.5 mol/L acetic add for 20 minutes at 37C to enhance antigenic exposure. Pepsin was used for collagen IV detection, and trypsin was used for the remaining antibodies. After incubation with primary antibodies (diluted in PBS containing 1% bovine serum albumin), the sections were washed twice in PBS to remove unbound primary antibody and then incubated with goat anti-rabbit biotinylated immunoglobulin or horse anti-mouse biotinylated immunoglobulin (Biocell, Cardiff, United Kingdom), according to the source of the primary antibody, at a dilution of 1:100 in 20% human serum-PBS buffer, pH 7.6. After 1 hour of incubation with the second antibody, the sections were incubated with avidin-biotin-peroxidase (Dako) for 30 minutes at room temperature and developed with diaminobenzidine (Sigma) (30 mg dissolved in 10 mL Tris hydrogen chloride buffer, pH 7.4, containing 0.015% hydrogen peroxide). Thereafter, the sections were counterstained with Harris' hematoxylin, dehydrated in ethanol and mounted in DePex (Probus, Badalona, Spain).

Small fragments of each testis from all orchiectomy specimens were fixed in 3% glutaraldehyde, postfixed in 2% osmium tetroxide, and embedded in epoxy resin. Semithin sections were stained with toluidine blue. Ultrathin sections were stained with lead citrate and uranyl acetate.

For the quantitative study, the volume of testicular parenchyma after fixation, dehydration, and embedding was estimated by considering the testis as an ellipsoid. Length (2a) and width (2b) were measured in the sections through the sagittal plane and transformed into volume (4 ab^sup 2^)/3. In 10 nonconsecutive, randomly selected paraffin sections of each testis, 15 randomly selected microscopic fields (640000 jim2) showing nodular or diffuse lesions or both were used. The following parameters were calculated on at least 10 cross-sectioned tubules from each field: (1) the mean tubular diameter (MTD), including the lamina propria; (2) the tubular fertility index or percentage of cross-sectioned tubules that contained at least 1 spermatogonium; (3) the Sertoli cell index or average number of Sertoli cells per crosssectioned tubule; (4) the volume density of seminiferous tubules, that is, surface occupied by the seminiferous tubules divided by total surface of the field; (5) the volume density of Leydig cells, that is, surface occupied by Leydig cells divided by total surface of the field; (6) the total volume occupied by seminiferous tubules, calculated by multiplying the volume density of seminiferous tubules by the volume of testicular parenchyma; and (7) the total volume occupied by Leydig cells, calculated by multiplying volume density of Leydig cells by the volume of testicular parenchyma. In each determination, the measurements were performed by the use of an image analyzer. From the average values obtained in each patient for each parameter, the means and standard deviations for the 4 groups of testes (children with AIS, child controls, adults with AIS, and adult controls) were calculated. Differences between children with AIS and their controls, as well as differences between adults with AIS and their controls, were evaluated by analysis of variance and Students t test for comparison of each pair of values.


Clinical Findings

The 6 AIS cases showed a 46,XY karyotype. Case 6 presented incomplete AIS, and the other 5 cases showed complete AIS. Clinical findings and hormonal data are shown in Table 1. Serum follicle-stimulating hormone levels were normal in all cases, whereas luteinizing hormone levels were slightly increased in the adult patients. Serum testosterone levels were slightly decreased in the adult patients and slightly elevated in the prepubertal patients. Serum estradiol levels were slightly increased in all patients. Hormonal assays in case 6 at 3 months of age were normal.

Histologic Study in Adult Patients

Testicular volume in the adult patients with AIS was significantly lower than that of the adult controls (Table 1). The histologic testicular pattern was similar in the 3 patients and presented nodular and diffuse lesions. These lesions were bilateral and appeared to be intermingled (Figure 1, A and B).

Both nodular and diffuse lesions consisted of small seminiferous tubules, which were devoid of apparent lumen, and wide interstitial tissue (Figure 2, A through E). The main difference between the diffuse and nodular patterns was the smaller size of seminiferous tubules in the nodular pattern (Figure 2, A). In the areas showing only the diffuse pattern, the MTD was 87 +/- 9 (mu)m and the mean volume density of seminiferous tubules was 52% +/- 8%. In the areas showing only the nodular pattern, the MTD was 47 + 5 (mu)m, and the mean volume density of seminiferous tubules was 28% +/- 3%. The 2 parameters measured were always significantly lower in both lesion patterns than in control testes (Table 1).

In both nodular and diffuse lesions, the seminiferous tubules contained only Sertoli cells, which formed a pseudostratified epithelium (Figures 1, B and 2, D and E). The Sertoli cell index was significantly higher in the testes of AIS patients than in the control testes (Table 1). No germ cells were found. Carcinoma in situ cells were never seen. Two types of tubules could be distinguished according to the morphology of the Sertoli cell nucleus (Figure 1, B): (a) immature Sertoli cell tubules with a prepubertal appearance, showing a homogeneously dark nucleus without obvious nucleolus (Figures 1, B; 2, B and D; and 3) and (b) nearly mature Sertoli cells showing a pale nucleus with a visible nucleolus (Figure 2, E). The normal mature Sertoli cell in the control testes also presented a pale nucleus with a visible nucleolus, but the nuclear outline was irregular and indented. The cytoplasm of both Sertoli cell types immunostained to vimentin, mainly around the nucleus and in the basal portion (Figure 2, D). The nodular lesions only showed he immature, prepubertal-like Sertoli cell type (Figure 2, D). Both Sertoli cell types were found in the diffuse lesions, although the nearly mature type was predominant (Figures 1, B and Figure 2, E).

In the nodular lesions, the lamina propria was usually very thin and contained scanty actin-immunostained peritubular cells. Many tubular sections showed no actin immunoreaction in the whole lamina propria outline (Figure 2, A). In the diffuse lesions, the lamina propria thickness varied widely, even in the same tubule, from areas showing a thin lamina propria lacking in actin immunoreaction to areas showing a thickened lamina propria, which contained abundant peritubular myoid cells (Figure 2, B). In the diffuse lesions, the basal membrane was either normal in thickness or enlarged, and immunoreaction to type IV collagen displayed 2 layers, which delimited the lamina propria thickness. A hyaline material was deposited between the layers (Figure 2, E).

The interstitial tissue contained numerous Leydig cells showing scarce cytoplasm which immunoreacted to vimentin (Figure 2, D). Volume density of Leydig cells was significantly increased (Table 1). By electron microscopy the Leydig cells presented a variable morphology. Some Leydig cells were ultrastructurally normal, except for the absence of Reinke's crystals. Other Leydig cells had a microvacuolated cytoplasm containing numerous large lipid droplets (Figure 3). Other Leydig cells presented an undifferentiated appearance, displaying an indented nucleus and scanty cytoplasm that contained a moderate amount of smooth endoplasmic reticulum and mitochondria, and abundant filaments (Figure 3). Groups of vimentin-immunostained fibroblasts displaying a storiform pattern, similar to that of the cortical ovarian stroma, were seen often (Figure 2, C). Lymphangiectasis was observed in the interstitial tissue in case 1. The testicular tunica albuginea presented a diffuse smooth muscle cell hyperplasia (Figure 1, A), which was more pronounced on the posterior testicular edge. The rete testis was poorly developed, and the lumen of the rete testis channels was very narrow.

Histologic Study in Prepubertal Patients

Testicular volume in the children with AIS was significantly lower than in their controls (Table 2). The removed testes of the 3 children with AIS showed diffuse lesions (Figure 4, A). No histologic differences between the complete (cases 4 and 5) and incomplete AIS (case 6) cases were observed. The seminiferous tubules were hypoplastic. Their volume density of seminiferous tubules and MTD were lower than the respective values in agematched controls. The tubular fertility index was significantly decreased (Table 2), and some of the scarce spermatogonia were observed (Figure 4, B). In addition, case 5 presented multinucleate spermatogonia. Focal differentiation of spermatocytes and spermatids were observed in the orchiectomy specimen from case 6. Sertoli cells showed a normal prepubertal pattern except for some degree of cytoplasmic vacuolation (Figure 4, B and C) and hyperplasia of intermediate filaments (Figure 4, D). These cells immunoreacted to vimentin (Figure 5, A), and their numbers were increased for the patient's age (Table 2).

The lamina propria was thin and showed a discontinuous immunoreaction to type IV collagen (Figure 5, B). In cases 4 and 6, some tubules were surrounded by a storiform stroma containing vimentin-rich fusiform cells (fibroblasts) (Figure 5, A). Actin-positive smooth muscle cells were observed often. In all cases, the testicular interstitium contained undifferentiated Leydig cells (Figure 4, C). The volume density of these cells did not differ from that of the control testes (Table 2).

The testicular biospy of case 6, performed at 3 months of age, revealed the following normal tubular parameters for his age22: volume density of seminiferous tubules, 57.9%; volume density of Leydig cells, 8.3%; MTD, 78 Fm; Sertoli cell index, 19; and tubular fertility index, 47%. However, the orchiectomy specimens of this patient (at 6 years of age) revealed important decreases in both MTD and tubular fertility index (Table 2).


Hormonal findings in the adult patients studied here agree with those of previous reports on AIS. The characteristic endocrine findings in AIS are serum testosterone concentrations within or above the normal male range and elevated levels of luteinizing hormone.6,23 These alterations are due to an abnormality in the androgen receptor gene that causes end-organ resistance.6,8 It has been reported that the testosterone concentration in the testicular vein was twice the concentration in the peripheral blood, indicating that testosterone biosynthesis is maintained.24 The increase in estradiol levels might result from estrogen production in the testis,25 while the normal serum folliclestimulating hormone levels suggest that AIS patients maintain the regulation of follicle-stimulating hormone secretion by a combined action of estradiol and gonadal hormones such as inhibin.26 Hormonal alterations seem to be established early on, in as much as some alterations were observed in the children studied here.

Rutgers and Scully19 reported 2 histopathologic testicular patterns in AIS, namely, hamartomas (hamartomatous nodules) and Sertoli cell adenomas. Hamartomas consisted of solid tubules filled with immature Sertoli cells, prominent Leydig cells, and rare fascicles of smooth muscle. Multiple hamartomas occurred in 63% of AIS cases (bilateral in 40% of cases). Sertoli cell adenomas consisted of small tubules that were filled by immature Sertoli cells and scant Leydig cells and occurred in 23% of cases. In the present cases, several hamartomatous nodules were superimposed to a diffuse testicular lesion. We think that the development of hamartomas in AIS is a malformative process of the congenitally hypoplastic seminiferous tubules rather than a true benign, neoplastic proliferation of Sertoli cells. In cryptorchidism, the testes can exhibit welldelimited nodules of hypoplastic tubules like those observed in the AIS hamartomas. The lesions in the undescended testes of AIS individuals might be explained as severe malformative alterations of Sertoli cells and Leydig cells. These lesions begin during prenatal development of the testis and become more severe during infancy. The severity of the testicular lesion would be related to the patient's age and the localization of the testis (abdominal cavity, inguinal canal, or labioscrotal folds of the cryptorchid testis).19 Although cases of children showing apparently normal testes that become atrophied after puberty have been reported,27 quantitative data of the present study revealed a decrease in both MTD and testicular volume in the children with AIS.

In our study, no germ cells were found in the adults with AIS. The testes of the children showed spermatogonia, although their numbers were lower than the normal values for the patients' ages. This result agrees with the findings of previous authors, who reported that the number of spermatogonia decreases at puberty.19,27 Such a decrease probably begins in early infancy, since the testicular biopsy of case 6 at 3 months of age showed a normal number of spermatogonia, whereas only scarce germ cells were found in this patient at 6 years of age. In addition, we observed some primary spermatocytes in another child (case 4). Although testicular tumors have been reported in adults with AIS,1,19,28 neither germ cell tumors nor carcinoma in situ cells were observed in the children studied here; however, abnormal spermatogonia, including hypertrophied spermatogonia and multinucleate spermatogonia, were found in these children.

The prepubertal and postpubertal cases reported here showed an increased number of Sertoli cells per crosssectioned tubule. This finding is characteristic of several testicular disorders that show Sertoli-cell-only tubules, including cryptorchidism.29 Sertoli cells with multiple eosinophilic granules (granular transformation) have been reported in both cryptorchidism30 and some cases of AISC19; however, we failed to find granular Sertoli cells in our patients. The occurrence of 2 tubular patterns, which differed in Sertoli cell maturation even in the same testis, might be explained with the hypothesis of differences in androgen sensitivity of the Sertoli cells. The immature Sertoli cells showed a compact distribution of vimentin filaments in the cytoplasm, whereas the Sertoli cells with pubertal differentiation, located in the seminiferous tubules with higher MTD, presented a condensation of vimentin filaments in the basal cytoplasm greater than in the supranuclear portion. This immunohistochemical finding may indicate that these Sertoli cells, which determine the tubular growth at puberty, are functioning better.

In the nodular lesions, we found that the peritubular myoid cells were usually scant. It is well known that, in the human testis, peritubular cells differentiate in the 14th week of gestation and form 4 of 5 layers around the seminiferous tubule. The innermost layers consisted of myoid cells, whereas the 2 outer layers are made of fibroblastlike cells. It is thought that the factors involved in peritubular cell differentiation are produced by the Sertoli cells, Leydig cells, or both.31 It is possible that in the nodular lesions, the regulation of this differentiation is impaired, and peritubular cells are lacking in some tubular segments and grouped in other segments.

In the diffuse lesions, the thickness of the lamina propria is normal in prepubertal testes, but it often becomes thickened and hyalinized in the diffuse lesions of adult testes. In our study, the lamina propria appeared delimited by 2 (inner and outer) type IV collagen layers. These lesions are similar to those reported in some infertile men,ls aging testes,31 and in cryptorchid testes removed after puberty.32

Leydig cells have appeared to be hyperplastic in the majority of published AIS descriptions,1,19,33,34 although a quantitative study of Leydig cells has been reported in only 1 patient, and in this case the number of Leydig cells was in the low-normal range.34 The present quantitative study revealed a significant increase in the total Leydig cell volume per testis in adults. This hyperplasia might be related to the important alterations in the regulation of the hypothalamic-hypophyseal-testicular axis in these patients.6 Many Leydig cells in adult patients are immature or multivacuolate, and the few well-differentiated Leydig cells are lacking in Reinke's crystals. These findings agree with previous reports.2,33 The immature Leydig cells are more similar to Leydig cell precursors35 than to dedifferentiated Leydig cells. In the testicular interstitium, fibrotic areas36 and areas showing an ovarian-like stroma have been reported.19,27,33 Our immunohistochemical study revealed that these areas comprised vimentin-rich fibroblasts and fascicles of actin-rich smooth muscle cells. In conclusion, the testes of adult AIS patients present diffuse and nodular testicular lesions, which are characterized by the occurrence of Sertoli-cell-only tubules with immature, or not completely mature, hyperplastic Sertoli cells with many vimentin filaments, an altered lamina propria showing deficiencies in actin immunoexpression (scant in some areas and excessive in others), and hyperplastic Leydig cells that are not well differentiated. These lesions are probably caused by important primary alterations that begin early, during gestation, and become progressively more pronounced through infancy and childhood. The lesions become morphologically more evident at puberty, when the nodular lesion pattern (adenomas) is completely developed.

This work was supported by grants from the Direccion General de Investigacion Cientifica y Tecnica, Spain (PB 93-270) and Fondo de Investigaciones de la Seguridad Social, Spain (94-399). The authors thank Carmen Sanchez-Palomo for technical assistance.


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24. Meeks GR, Whitworth NS, Renfroe MS. Testicular vein and peripheral vein testosterone, follicle stimulating hormone, luteinizing hormone, and prolactin concentrations in a patient with androgen insensitivity syndrome. J Miss State Med Assoc 1993;34:263-266.

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Javier Regadera, MD; Francisco Martinez-Garcia, MD; Ricardo Paniagua, PhD; Manuel Nistal, MD

Accepted for publication October 18, 1998.

From the Department of Morphology, School of Medicine, Autonomous University, Madrid, Spain (Drs Regadera, Martinez-Garcia, and Nistal); the Department of Cell Biology and Genetics, University of Alcala, Alcala de Henares, Madrid, Spain (Dr Paniagua); and the Department of Pathology, La Paz Hospital, Madrid, Spain (Dr Nistal).

Reprints: Manuel Nistal, MD, Department of Morphology, School of Medicine, Autonomous University, c/ Arzobispo Morcillo 2; E-28029 Madrid, Spain.

Copyright College of American Pathologists Mar 1999
Provided by ProQuest Information and Learning Company. All rights Reserved

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