[Problems in the classification of thyroid tumors. Their significance for prognosis and therapy]. / Probleme der Klassifizierung von Schilddrüsentumoren. Ihre Bedeutung für Prognose und Therapie.

Standardized nomenclatures of tumors are mandatory for epidemiological investigations as well as for the correct interpretation of pathological diagnoses by the clinician. Not least thanks to the activity of the World Health Organization (WHO), uniform tumor nomenclatures in worldwide use have been adopted for most organs. This applies also for the thyroid, even in Switzerland, where many pathologists had formerly been convinced that only the special and rather complicated nomenclature of Langhans, adapted by Wegelin, was consistent with the special tumor situation in Switzerland, a former endemic goiter area. The simplified classification of WHO is demonstrated for the group of malignant tumors of the thyroid and the problems concerning their classification are discussed. Difficulties of classifications arise in well differentiated tumors rather than in undifferentiated, anaplastic forms. For example, it is not possible to assess unequivocally the malignancy of strongly encapsulated forms of highly differentiated follicular tumors. They are then called, rather evasively, "atypical adenomas". The difficulties do not lie in the system of classification but in the tumor's specific manner of growth, and the clinician should be aware of this. Otherwise he may overstrain the diagnostic potentialities of his pathologist.

Hyperplasia and hypertrophy of Leydig cells associated with testicular germ cell tumours containing syncytiotrophoblastic giant cells.

In patients with seminomas and non-seminomatous germ cell tumours of the testis syncytiotrophoblastic giant cells (STGC) are largely responsible for elevated levels of chorionic gonadotropin. In searching for these cells, the question arises whether hyperplasia and/or hypertrophy of Leydig cells in the adjacent testicular tissue is a relevant finding. To elucidate this problem we analysed the tumour-free testicular tissue of 20 seminomas and 20 combined seminomatous and non-seminomatous germ cell tumours with or without immunohistochemically demonstrable STGC morphometrically. Extension of Leydig cell areas and the surface areas of Leydig cells per tubule are increased significantly in seminomas and combined tumours when STGC are present. There is also an apparent increase in the number of Leydig cells per tubule in seminomas and combined germ cell tumours with STGC. The difference, however, is not significant statistically in the group of seminomas. Hypertrophy and/or hyperplasia of Leydig cells must be considered as a relevant finding in germ cell tumours with STGC. It is most easily recorded by evaluating the surface area of Leydig cells per test area or per tubule.

Differences between subcutaneous and intraperitoneal forms of three human testicular teratocarcinomas in nude mice.

Three human testicular teratocarcinomas were serially passaged following subcutaneous transplantation into nude mice. Tumor cell suspensions from selected passages were injected intraperitoneally. The subcutaneous transplants of each tumor conserved the morphological characteristics of one component of the primary tumor, namely an embryonal carcinoma in one case and a yolk sac tumor in two. The latter maintained the capacity to synthesize alpha-fetoprotein (AFP). After intraperitoneal injection of cell suspensions, tumors, either attached to or even invading abdominal organs or in the form of free-floating tumor spheroids, were observed. AFP could be localized within the attached growths but not in the spheroids. A critical tumor volume and/or vascularization seemed to be necessary for AFP production in tumor cells. In spheroids from one tumor, cytogenetic analysis revealed both human and murine cells. Thus, these spheroids, apparently composed of tumor cells in the center and murine cells at the periphery, can not be considered to be embryoid bodies.

Intracranial mixed germ cell tumor with syncytiotrophoblastic giant cells and precocious puberty.

A 9-year-old male patient developed a germ cell tumor in the right basal ganglia which secreted beta-human chorionic gonadotropin (beta-HCG) and caused precocious puberty. Histology and immunohistochemical staining for placental alkaline phosphatase (PLAP), alpha-fetoprotein (alpha-FP), and beta-HCG showed a mixed population of neoplastic germinocytes, embryonal carcinoma, and syncytiotrophoblastic giant cells (STGC). Immunohistochemical double-staining for alpha-FP and beta-HCG revealed that these two markers were produced by different subsets of cells. Expression of the proliferation marker Ki-67 showed a growth fraction of 53% for the neoplastic germinocytes and embryonal carcinoma cells, but only 21% for the STGC.

Abnormal basement membrane structures in autoimmune thyroid disease.

Thyroidectomy specimens of 8 patients with focal thyroiditis, 7 with diffuse thyroiditis, 13 with Graves' disease and 5 with nodular goiter were investigated by electron microscopy for changes in the follicular basement membrane. Five different types of abnormal basement membrane structures (ABMS), analogous to the ones described in the glomerular basement membrane, were found. Type 1 ABMS were present in all diagnostic groups and seemed to be nonspecific. Type 2 ABMS, thought to represent immune complex deposits, were frequently present in patients with focal or diffuse thyroiditis and in patients with Graves' disease, but could not be demonstrated in thyroidectomy specimens of patients with nodular goiter. The occurrence of type 2 ABMS in both focal and diffuse thyroiditis suggests a common etiology of these two morphologic entities. ABMS types 3, 4, and 5 could not be detected in nodular goiter but were seen in various amounts in all other diagnostic groups. The origin of these structures remains to be explained.

A human testicular germ cell tumor with borderline histology between seminoma and embryonal carcinoma secreted beta-human chorionic gonadotropin and alpha-fetoprotein only as a xenograft.

Two macroscopically distinguishable components (designated soft and firm) of a human testicular germ cell tumor with borderline histology between seminoma, embryonal carcinoma and yolk sac tumor, were maintained as xenografts in nude mice for over 20 passages. Levels of beta-human chorionic gonadotropin (beta-HCG) and of alpha-fetoprotein (AFP) were normal in the patient's serum and were undetectable by immunohistochemical studies of the surgical specimen. The xenografted soft part, however, with morphologic characteristics of an embryonal carcinoma, secreted beta-HCG and AFP during early passages. The firm variant, histologically resembling a seminoma, did not produce these markers. Chromosomal and flow cytophotometric analyses showed genetic differences between the clonally stable variants. A common origin, however, is indicated by two similar marker chromosomes present in both variants.

Duodenal and ampullary carcinoid tumors. A report of 12 cases with pathological characteristics, polypeptide content and relation to the MEN I syndrome and von Recklinghausen's disease (neurofibromatosis).

Twelve duodenal carcinoid tumours are presented, 4 of them located in the ampulla. Symptoms included the Zollinger-Ellison syndrome (4 patients), the carcinoid syndrome (1 patient), mechanical obstruction (3 patients), bleeding (1 patient) and abdominal pain (1 patient). Two further tumours were detected by chance. Three patients with the Zollinger-Ellison syndrome had additional endocrine tumours characteristic of the MEN I syndrome. In 2 of them the duodenal carcinoids were of very small size and were multiple. They were observed in close proximity to focal areas of endocrine cell hyperplasia. Immunohistochemical investigations showed gastrin and somatostatin to be the predominant polypeptide hormones produced by these tumours. No somatostatinoma syndrome was encountered. In half of our cases additional production of insulin, VIP or even calcitonin in smaller amounts was found. Two of our patients had cutaneous manifestations of von Recklinghausen's disease and in both of them the carcinoid was located in the ampulla. One of these patients also had a pheochromocytoma.

Histopathology and ultrastructure of primary adrenocortical nodular dysplasia with Cushing's syndrome.

The characteristic adrenal lesions of five patients with bilateral primary adrenocortical nodular dysplasia and Cushing's syndrome developing in adolescence are presented histopathologically, and in two cases ultrastructurally. Two of the patients were siblings with additional extra-adrenal lesions such as pigmented spots on the face, myxoid cutaneous tumours and in one case familial cardiac myxoma. The adrenals were small with an uneven surface due to numerous small brown to black pigmented nodules in the inner cortex. The nodules were composed of eosinophilic giant cells filled with lipofuscin granules. The familial cases in addition revealed a pronounced disorganization of the adrenocortical architecture with capsular disruption and infiltration of periadrenal fatty tissue. The early onset of Cushing's syndrome in the second decade, the bilateral involvement of adrenal glands despite ACTH independence and the familial occurrence in combination with other peculiar rare lesions are strongly suggestive of a malformative process of the zona reticularis of the adrenal glands.

Pathologic study of parathyroid glands in tertiary hyperparathyroidism.

Tertiary hyperparathyroidism is defined as persistent parathyroid hyperfunction developing from the secondary hyperplasia that occurs after restoration of renal function by dialysis or kidney transplantation. Controversy continues as to whether parathyroid adenoma or hyperplasia accounts for the autonomous hyperfunction. A review of 128 parathyroids from 41 patients with tertiary hyperparathyroidism revealed marked hyperplasia in 39 patients (95 per cent), with a predominance of chief cells, an abundance of oxyphil cells, and 10- to 40-fold increases in parathyroid mass. This hyperplasia was considered to be the predominant morphologic feature of tertiary hyperparathyroidism. Adenomas, found only in two patients (5 per cent), seem to be rare. Diffuse, moderately enlarged hyperplastic glands were found predominantly in patients with transplants, whereas nodular, markedly enlarged hyperplastic parathyroids were observed more frequently in patients treated by dialysis. In spite of the different patterns of hyperplasia and the different gland sizes in these two groups of patients, the grades of hypercalcemia were similar. The results of ultrastructural studies indicate that the majority of parenchymal cells in diffuse, and some cellular areas in nodular, hyperplasia may consist of cells with high secretory activity that do not respond normally to hypercalcemia. It is concluded that both increased parenchymal mass and cellular differentiation, leading to hyperactivity, account for tertiary hyperparathyroidism.

Follicular carcinoma.

The workshop participants agreed on the following points regarding follicular carcinoma: Follicular carcinoma should be divided into two groups according to its degree of invasion: encapsulated and widely invasive. Patients in the first group only occasionally develop distant metastases, whereas in the second group the prognosis is much poorer. In encapsulated follicular tumors, high cellularity and nuclear atypia should not be used as criteria of malignancy; this diagnosis should be based on the presence of vascular or capsular invasion. Only tumor thrombi occurring in vessels in or outside the capsule should be regarded as indicative of vascular invasion. Capsular invasion should be diagnosed only if penetration of the whole capsule is seen. We agree that some tumor islands within the capsule may represent true tumor invasion, but we believe that some others may be due to capsular infoldings or tangential sectioning. Whenever tumor tissue within the capsule is seen, additional tissue blocks from the capsular area should be processed in a search for capsular penetration or vascular invasion. The degree of differentiation in follicular carcinoma does not correlate to the course of disease as clearly as the degree of invasion, although the so-called insular or poorly differentiated, subtype seems to have a poorer prognosis. Thyroid carcinomas composed of large eosinophilic cells (Hürthle cell carcinomas) usually show follicular differentiation and are therefore included in the category of follicular carcinoma. The same diagnostic criteria of malignancy that apply for other follicular tumors should be used when evaluating these tumors. Although follicular carcinomas often show foci of clear cells, tumors composed solely of clear cells are rare. Most pure clear-cell tumors in the thyroid represent metastatic tumors, usually from the kidney. In the distinction of follicular carcinoma from papillary carcinoma, all differential diagnostic criteria should be used. However, in some cases, the diagnosis can be based on one criterion only, mainly the presence of widespread ground-glass nuclei or abundant neoplastic papillae in papillary carcinoma. The presence of occasional papillae in encapsulated tumors composed of large eosinophilic cells is not sufficient for the diagnosis of papillary carcinoma if the other microscopic features of this tumor are lacking.

Differentiation of human testicular embryonal carcinoma and teratocarcinoma grown in nude mice and soft-agar cultures.

The differentiation pattern of two human germ cell tumors, grown in nude mice and in vitro is described. Tumor A was an embryonal carcinoma (EC) of borderline histology with characteristics of yolk sac tumor and of seminoma; tumor B was a teratocarcinoma with yolk sac elements and syncytiotrophoblastic giant cells. The morphology of an EC as well as cytogenetic characteristics were maintained during 20 passages in nude mice from tumor A and over 11 passages from tumor B. Tumor A did not grow in vitro. Cell suspensions prepared from xenografted tumor B grew into cystic embryoid bodies in semi-solid tissue culture medium. These embryoid bodies showed cuboidal and flattened cells with microvilli, junctional complexes, peripheral microfilaments, and annulated lamellae, reminiscent of the 'inner cell mass' of a blastula and of endoderm, respectively. When such colonies were transplanted into nude mice, however, only tumors with the morphology found in the transplants appeared.

Undifferentiated thyroid tumors of diffuse small cell type. Histological and immunohistochemical evidence for their lymphomatous nature.

A histological review of 72 undifferentiated thyroid tumors was performed in order to discover small cell anaplastic carcinomas and Non-Hodgkin lymphomas. Cases suspected to be lymphoma were examined for the presence of Ig and keratin and lectins with a PAP-procedure. Among the 72 cases, 68 (94,5%) were anaplastic carcinomas of various types. Four cases (5,5%) were diffuse small cell tumors, which had previously been regarded as anaplastic carcinomas. All four could be identified as Non-Hodgkin lymphomas by histology, immunohistochemistry, repeat biopsy or autopsy. The findings suggest that the majority of small cell anaplastic thyroid tumors are lymphomas and that true anaplastic small cell carcinoma of the thyroid must be extremely rare. Its diagnosis requires electronmicroscopy and/or immunohistochemistry to demonstrate the epithelial nature of tumor cells.

Mixed medullary and follicular carcinoma of the thyroid.

We report a case of medullary carcinoma of the thyroid which on light microscopy showed not only the well known arrangement of cells in sheets and nests but also unequivocal follicular structures. These follicular structures are present both in the primary tumor and in lymph node metastases. Immunohistochemical investigations revealed that the cells lining the follicles produce thyroglobulin, whereas the remaining tumor tissue is positive for calcitonin and carcinoembrionic antigen. This case represents a medullary carcinoma of the thyroid with an atypical pattern consisting of both thyroglobulin and calcitonin producing cells.

Abnormal basement membrane structures of seminiferous tubules in infertile men.

Testicular biopsies from 60 patients with impaired fertility were investigated by electron microscopy for changes in the basement membrane of seminiferous tubules. Six different types of abnormal basement membrane structures (ABMS)--analogous to those of glomerular basement membrane disease--have been found to a variable extent in biopsies of 33 cases. The occurrence of ABMS correlated with the severity of tubular changes, and ABMS were absent in tubuli seminiferi with an intact germinal epithelium. Except for ABMS type 2, thought to represent immune complex deposits, the origin of ABMS is unknown. ABMS type 2 was present in 21 cases. Since similar deposits have been observed in rabbits developing immune complex orchitis after vasectomy, our findings indicate the occurrence of immune complex orchitis in infertile men.

Immune complex orchitis in infertile men. Immunoelectron microscopy of abnormal basement membrane structures.

Testicular biopsies from 30 patients with fertility disorders were investigated by peroxidase-labeled antibodies against IgG and C3 at an ultrastructural level. Three types of abnormal basement membrane structures (ABMS) proved to be positive. Immune-type deposits (ABMS type 2), ABMS with vesicular particles (ABMS type 4), and those with membranous structures (ABMS type 5) stained positively for IgG and C3. In 21 cases ABMS were positive for at least one of the antisera. Two additional cases showed a linear reaction for IgG and C3 in the basement membrane. According to the number and size of positive ABMS, the cases were divided into three groups. Group I contained 10 cases with extensive ABMS types 2, 4, and 5 positive for IgG and C3 and two cases with linear positivity. At light microscopy, the changes varied from light to severe tubular atrophy. In these latter cases ABMS types 4 and 5 predominated, whereas in the light and focal tubular lesions ABMS type 2 did. In group II, eight cases revealed few and small ABMS positive by immunoelectron microscopy and no more than slight tubular changes at light microscopy. In group III, minimal or no ABMS were present, but in three cases mast cells were numerous in the interstitial tissue. The demonstration of immune deposits in the basement membrane of seminiferous tubules is interpreted to be the result of an antibody-mediated damage to the germinal epithelium leading to tubular atrophy. In one case obstruction of the sperm ducts and in another torsion of the testis are incriminated as events triggering the autoimmune process. Linear staining of the basement membrane for IgG and C3 in two cases suggests the development of antibasement membrane orchitis.

Ultrastructural findings in Hashimoto's thyroiditis and focal lymphocytic thyroiditis with reference to giant cell formation.

Ultrastructural findings in two cases of Hashimoto's disease and two cases of focal lymphocytic thyroiditis are reported. Stimulated thyrocytes, oncocytes and degenerating thyrocytes were observed in all cases. Multinucleated thyrocytes and epithelial pseudogiant cells were identified in Hashimoto's disease only. Infiltrating lymphocytes, plasma cells, monocytes and macrophages were present in all cases. The ultrastructure of germinal centres was similar to that seen in lymphatic organs. Giant cells of both intra- and extrafollicular localization were seen in Hashimoto's disease. Most of the giant cells were macrophage-derived. Two different ways of giant cell formation were identified: besides the familiar dissolution of plasma membranes of adjacent macrophages, another mechanism of fusion was observed. At sites of contact, peculiar membrane structures were developed and disintegration of plasma membranes occurred in parts adjacent to these structures. These are not identical to desmosomes and are different from Langerhans' granules. They probably represent special organelles for the initiation of cellular fusion.

Papillary thyroid carcinomas. Morphology and prognosis.

It is generally believed that the histological pattern of papillary thyroid carcinomas has no influence on the course of the disease. However, we were puzzled by the evidence differences in the clinical course of these tumours and decided to re-examine all microscopic specimens available at the Institute of Pathology of the University of Zürich. These had been obtained from 169 surgical cases operated on between 1962 and 1977. We classified the material according to precise morphological criteria and matched it with a number of clinical and catamnestic data in order to determine which parameters correspond best with the development of the disease. Although the fate of patients below 50 years of age is slightly more favourable than that of older subjects, age is by no means the most important factor. In fact, the prognosis correlates significantly better with the initial local extension of the primary tumour (occult, intrathyroid or extrathyroid). Furthermore, this parameter is closely related to the histological pattern of our various papillary carcinoma subtypes which we graded according to differentiation. All factors considered, the morphological pattern appears to offer a rewarding approach to the provision of an accurate prognosis.

Primary adrenocortical nodular dysplasia with Cushing's syndrome and cardiac myxomas. A peculiar familial disease.

In a family with 4 children, 2 had slowly developing Cushing's syndrome and were adrenalectomized between the ages of 18 and 28 years. As in other cases with familial Cushing's syndrome, primary adrenocortical nodular dysplasia, the so-called adrenocortical adenomatosis, was demonstrated. The brother, now 39 years old, is in good health. The sister, however, died at the age of 36 years. Autopsy revealed a cardiac myxoma of the left atrium. A cardiac myxoma had been found incidentally at autopsy of these two patients' oldest brother, a boy who died at the age of 4 years. Both siblings with Cushing's syndrome presented additional Peutz-Jegher-like hyperpigmentation and myxomatous tumours of the skin. Identical observations of familial adrenocortical nodular dysplasia, Cushing's syndrome and cardiac myxomas have not been reported to date. However, the familial occurrence of cardiac myxomas and adrenocortical dysplasia in combination with bilateral large cell calcifying Sertoli cell tumours of the testis has been published recently.