Chr. Hedinger

Papillary thyroid carcinomas

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 evident 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.

Histopathology of undescended testes

This paper presents a survey of the morphological findings in cryptorchid testes, especially of children. There is no doubt that undescended testes not operated on early in life are seriously damaged. Cryptorchid testes of adults are much smaller than normal. The tubules are atrophic, the germinal epithelium is generally largely absent and the Leydig-cells are vacuolated, and loaded with lipids. Foci of hypoplastic tubules and so-called ring-like tubular structures are frequent.In children the testicular lesions of cryptorchidism are less pronounced than in adults. They are characterized by disturbances in tubular structure and particularly by a diminution of germ cells or, especially in cases of bilateral cryptorchidism, by a complete lack of such elements. These tubular lesions are manifested already in the second year of life. In addition, the interstitial tissue of undescended testes is generally more abundant and Leydig-cells seem to be more atrophic than in normal testes. Some of these lesions found in cryptorchid testes seem to be the result of a malformation rather than of testicular malposition alone.Finally, in patients with cryptorchidism the higher risk of developing a testicular germ cell tumor must be considered. In adults with cryptorchidism so-called atypical germ cells can be demonstrated even if there are no clinical signs of a malignant testicular tumor. Considering the relatively high frequency of malignant germ cell tumors in adults with cryptorchidism, testicular biopsies should be performed if a primary orchidectomy is refused. As testicular tumors may not only develop in the cryptorchid testis but in the descended partner as well, even bilateral testicular biopsies may be indicated.

Duodenal and ampullary carcinoid tumors

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 Recklinghausens disease and in both of them the carcinoid was located in the ampulla. One of these patients also had a pheochromocytoma.

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.

Ultrastructure of developing germ cells in the fetal human testis

SummaryElectron microscopic studies of the testis were performed on 12 human embryos and fetuses between 9 and 30 weeks post conceptionem. According to their ultrastructural features, the fetal germ cells could be divided into the following three stages of differentiation: 1) gonocytes, 2) intermediate cells, and 3) fetal spermatogonia. Sertoli cells were present among the germ cells in all the testes studied.The gonocytes showed the highest nucleo-cytoplasmic ratio. Their round nucleus contained a centrally located, prominent nucleolus. The cytoplasm displayed a well developed Golgi apparatus, lipid droplets and parallel arrays of short cisternae of the rough surfaced endoplasmic reticulum (rER). Microfilaments were numerous, particularly just beneath the cell membrane.The intermediate cells were found to extend several cytoplasmic processes and to contain a moderate number of long, branched and/or widened rER cisternae which were frequently connected to the perinuclear cisterna. Intermediate cells were often connected to one another by intercellular cytoplasmic bridges.The fetal spermatogonia also displayed cytoplasmic bridges. These cells showed the lowest nucleo-cytoplasmic ratio and a more condensed nuclear chromatin. The mitochondria were situated close to the nucleus. Many of them were connected by a cementing substance. Lipid droplets and rER cisternae were rare in these cells.Infoldings of the inner nuclear membrane were often present in the gonocytes and in the intermediate cells, but were rarely observed in the fetal spermatogonia. Glycogen particles, polyribosomes, and chromatoid bodies (“nuage”) were present in all the three germ cell types.With the maturation of the fetus, the number of gonocytes was found to decrease, whereas the number of fetal spermatogonia increased. The Sertoli cells also changed their ultrastructure, showing an increase in the number of rER cisternae, as well as of microfilaments, lipid droplets, and secondary lysosomes.

Geographic pathology of thyroid diseases.

The thyroid is one of the organs which demonstrates clearly the influence of extrinsic and especially geographically determined influences in the development of diseases. Endemic goiter and cretinism are the most typical examples. The question as to whether thyroid cancer arises more frequently in goiters that in normal thyroids, cannot be answered definitely as yet. But without doubt, the relative frequency of different types of thyroid neoplasms in goiter areas is not the same as in region without endemic goiter. The most common type of thyroid carcinoma observed in a nonendemic region is papillary carcinoma. Follicular and anaplastic carcinomas, however, are more often associated with goiter. Under the influence of iodine prophylaxis, the relative frequency of the different types of thyroid carcinoma approaches that of these carcinomas in nongoiter regions. The malignant hemangioendothelioma is observed nearly exclusively in some Alpine goiter areas. Since the introduction of preventive measures in Switzerland, its occurrence has diminished progressively. In contrast to endemic goiter, focal thyroiditis and even Hashimotos disease seem to be on the increase since institution of iodine prophylaxis of endemic goiter. As the development of malignant lymphoma may be related to thyroiditis, a possible increase of such tumors should be considered.

The differential diagnosis of testicular germ cell tumors in theory and practice

To better appreciate the conflicts and controversy surrounding the classification of testicular tumors, and to reappraise their morphologic substrate under the advent of tumor markers, 389 of our own cases are reviewed, classified according to the systems advocated by the World Health Organization (WHO) and the Testicular Tumour Panel and Registry (TTPR) of Great Britain, and evaluated statistically. While many cases fit easily into either classification, the following difficulties were manifest: 1) Discrepancies in definitions and diagnostic criteria are the reason that considerably more germ cell tumors could be classified as mixed choriocarcinomas (WHO) than as trophoblastic teratomas (TTPR). It was found that tumor markers supply histochemical data that often conflict with rather than supplement morphologic ones in diagnosis and differential diagnosis. Similarly, the incidence of yolk sac structures, as yet not recorded separately by the TTPR, varies as either morphologic or histochemical criteria are applied. 2) The division of the morphologic spectrum of teratomatous differentiation by criteria of distinction that are unequal in the two systems yield comparable but non-congruent tumor entities. Consequently, borderline cases may undergo shifts to noncorresponding groups as they are translated from one system to the other. 3) Criteria separating teratoma with malignant transformation and polyembryoma (WHO) from closely allied lesions proved impractical. 4) Diagnostic labels that incorporate not only a morphologic pattern but a definite level in the histogenetic hierarchy generate a climate of incompatibility between systems whose histogenetic perspectives differ. Embryonal carcinomas claim to totipotence, in particular, leads to a conceptual split with the teratomas and brings the WHO system by itself into theoretic difficulties. Moreover, as the morphologic criteria for embryonal carcinoma are not in keeping with its histogenetic premise, the rigid separation is difficult to enforce in practice. Once the air is cleared, a resolution is easily reached. In the combined use of both classifications their real difference, splitting vs lumping, becomes a true asset.

Immunohistological findings in Hashimoto's thyroiditis, focal lymphocytic thyroiditis and Thyroiditis de Quervain

65 cases of focal lymphocytic thyroiditis and Hashimotos disease and five cases of thyroiditis de Quervain were studied with immunohistological methods. In both focal lymphocytic thyroiditis and Hashimotos disease, lymph follicles with active germinal centers were found which contained germinal center cells that stained positively for intracytoplasmic immunoglobulins (heavy and/or light chains). Positively staining germinal center cells made up only a minor portion of overall immunoglobulin-positive cells; most of the positive infiltrating cells were plasmacytes arranged in small groups or clusters among thyroid follicles. Thus the number of immunoglobulin-containing cells differed greatly between focal lymphocytic thyroiditis, where sites of infiltration were represented by lymph follicles, and Hashimotos disease. In the former, only a few cells outside lymph follicles stained positively for intracytoplasmic immunoglobulins, whereas in the latter numerous cells within areas of coherent infiltration did. Furthermore, in most cases of Hashimotos disease macrophages and giant cells with positive staining for lysozyme were present in variable numbers, while in focal thyroiditis they were less frequent or absent. Between these two immunohistologically separable groups, i.e. focal lymphocytic thyroiditis and Hashimotos disease, there were many cases with features of both. Considering the occurrence of such intermediate forms and some immunohistological similarities between Hashimotos disease and focal lymphocytic thyroiditis (nearly identical ratio of the different immunoglobulin classes and similar distribution of immunoglobulin-positive germinal center cells), it is likely that these lesions represent different activities of a same immunological process. Thyroiditis de Quervain was characterized immunologically by numerous macrophage clusters and giant cells that both stained positively for lysozyme. Compared with the giant cells seen in Hashimotos disease (mainly of Langhans type), those of de Quervains thyroiditis (mainly of foreign body type) were larger and more numerous. Lymph follicles (with or without active germinal centers) were not observed. Among infiltrating cells, numerous plasmacytes that stained positively for intracytoplasmic immunoglobulins were identified. Their number and the distribution pattern of the different classes of immunoglobulins contained within them was similar to those seen in Hashimotos disease.

The significance of giant cells in human testicular seminomas. A clinico-pathological study

In order to study the nature and significance of various giant cells encountered in seminomatous tumors of the testis, we reviewed the morphology of 243 consecutive pure seminomas and 107 combined (mixed) tumors, as well as the long term clinical follow-up in 26 patients. Giant cells were grouped into histocytic or neoplastic ones and the latter subtyped according to morphologic and immunocytochemical characteristics. Neoplastic giant cells were found in 34.6% of all pure seminomas and in 11.2% of all combined tumors, i.e. twice as often as histocytic giant cells in either tumor group. The various types of neoplastic giant cells were found alone or in combinations with other types. Giant cells capable of elaborating B-HCG were seen in 19.3 % of all pure seminomas and in 9.3% of seminomatous components of combined tumors. These incidences argue strongly against a trophoblastic element infiltrating a seminoma from a concomitant occult choriocarcinomatous focus. Large mononuclear giant cells, seen in spermatocytic seminomas, were observed in 15.6% of all pure seminomas, particularly in combination with B-HCG producing giant cells. Another type, characterized by marginated nuclei and eosinophilic cytoplasm were invariably part of a mononuclear cell population of similar features and encountered focally in 9.1% of all pure seminomas. Clinical follow-up, particularly in cases with B-HCG positive giant cells, revealed that treatment as for conventional seminomas at an early stage at least is followed by an excellent course.

Comparison of histologic types of primary testicular germ cell tumors with their metastases

61 autopsy cases with malignant germ cell testis tumors were examined. Both the primary tumors and their metastases were classified histologically according to the nomenclature of the WHO Panel on Testicular Tumours and to the modified nomenclature of the British Testicular Tumour Panel. The classification of the primary and metastatic tumor tissues is relatively easy to handle with both nomenclatures. The comparison of histological structures of the primary tumors with their metastases evoked a variety of deviations, depending on the tumor categories investigated and the nomenclature applied. The seminomas are a very homogenous tumor category usually metastasizing as seminoma. However, anaplastic seminomas can be indistinguishable from solid embryonal carcinomas. The distinct seminomas combined with nonseminomatous germ cell tumors do not seem to metastasize. From the point of view of histologic patterns of metastases and primary tumors, the embryonal carcinoma combined with teratoma i.e. teratocarcinoma (malignant teratoma intermediate) and the pure embryonal carcinoma (malignant teratoma undifferentiated) are not distinct entities. The term of malignant teratoma for these tumor types used by the British authors interprets these events more adequately, reflecting the occurrence of transitional types between teratoma and embryonal carcinoma supported by the appearance of different histologic types of metastases. Pure forms of choriocarcinoma are extremely rare. Yet in our cases of choriocarcinoma combined with other types, the metastases are always of the pure choriocarcinomatous type, and clinical courses were rapidly fatal in less than one year. The distinction of pure forms from combined forms of choriocarcinoma is not of great clinical relevance. 10% of our patients with metastatic germ cell tumor disease revealed testicular lesions referred to as so-called “burned-out” testis tumors. A tumor category of “burned-out” testis tumors is proposed. Bei 61 Autopsiefällen mit metastasierenden malignen Keimzelltumoren der Hoden wurden sowohl die Primärtumoren als auch die Metastasen histologisch nachkontrolliert und nach den Nomenklaturen des “WHO Panel on Testicular Tumours” und des “British Testicular Tumour Panel” klassifiziert. Beide Nomenklaturen sind in Bezug auf die Einteilung der Primärgeschwülste und der Metastasen relativ einfach anwendbar. Der Vergleich der histologischen Strukturen der Primärtumoren mit denjenigen der zugehörigen Metastasen ergibt aber gewisse strukturelle Abweichungen, die je nach Tumorkategorie verschieden ausgeprägt sind. Seminome bilden eine anscheinend recht einheitliche Gruppe; sie metastasieren in der Regel auch als Seminome. Anaplastische Seminome können aber unter Umständen nicht von ausgesprochen solid wachsenden embryonalen Karzinomen unterschieden werden. Der Seminomanteil innerhalb kombinierter Tumoren scheint in der Regel nicht zu metastasieren. Die Betrachtung des histologischen Aufbaus der Metastasen und der Primärtumoren der embryonalen Karzinome kombiniert mit Teratom (maligne Teratome, Intermediärtyp nach der englischen Nomenklatur) und der reinen embryonalen Karzinome (maligne Teratome, undifferenzierter Typ) ergibt, daß diese beiden Tumorformen keinen eigenständigen Kategorien entsprechen. Der Überbegriff des malignen Teratoms der Briten trägt dieser Tatsache Rechnung, umfaßt er doch auch diese Übergangsformen zwischen Teratomen und embryonalen Karzinomen. Reine Choriokarzinome sind ausgesprochen seltene Hodengeschwülste. Unsere Patienten mit primären Choriokarzinomen im Rahmen von Teratomen, also Choriokarzinome kombiniert mit anderen histologischen Tumortypen, wiesen jedoch ebenfalls nur Metastasen von rein choriokarzinomatöser Struktur auf. Sie starben zudem alle innerhalb eines Jahres an ihren Metastasen. Die Unterscheidung reiner und kombinierter Formen von Choriokarzinomen, wie das die WHO vorschlägt, ist deshalb klinisch ohne Bedeutung. 10% unserer Patienten mit metastasierenden Keimzellgeschwülsten wiesen Hodenläsionen auf, die als sogenannte ausgebrannte Hodentumoren bezeichnet werden. Eine entsprechende Tumorkategorie fehlt in beiden Nomenklaturen.