About the knowledge of the lymphomatous change in the thyroid gland (goiter lymphomatosa).
from dr H. Hashimoto, Assistant to the I. surgeon. University Hospital in Kiushiu, Japan (Director: Prof. Dr. H. Miyake).
By the term “lymphomatous change in the thyroid” which I have recently coined, I mean an overgrowth of the lymphatic elements with lymphoid follicle formation, as well as some change in the parenchyma and interstitium seen in the excised goiter tissue.
Such findings aroused my interest and prompted me to work on the above topic.
For 6 years I observed four such cases of goiter in our clinic, which I would like to call “goiter lymphomatosa”, and since this affection has not yet been described in detail in the literature, to the best of my knowledge, may I be permitted to present this affliction in more detail.
The lymphoid tissue is found in the body in two different forms, one in diffuse, i.e. without a specific shape, as in many mucous membranes, especially the alimentary canal, the lungs, the trachea, the urethra, the genital organs, in the conjunctiva, the bone marrow and the salivary gland; in another form it tends to form the basis of the lymphoid organs.
The simplest form of the lymphoid organs
The simplest form of the lymphoid organs are the so-called solitary follicles (noduli lymphatici solitarii). These peripheral lymph nodules can be compared to the so-called cortical nodules that are present in the cortex of the lymph gland.
The lymph nodules are 0.5-2.5 mm in size and form rounded, nodular aggregates of lymphoid elements. The reticulum of the follicle has a somewhat denser structure at the edge and is said to be here according to v. Ebner contain elastic fibers.
The lymphoid cells are often arranged to form concentric rings when sectioned. In the middle of the follicle there is often a rounded area in which the cells are not so closely packed together as the peripheral parts. This is called the germinal center or secondary nodule.
There are peculiar cell shapes in the germinal centers. One species of these contains a larger, pale nucleus in relatively richly developed protoplasm. Among them are numerous cells involved in mitotic division.
According to Flemming, this accumulation of cells represents a place where leukocytes form. In the peripheral zone of the follicle, the cell body is sparse and the nucleus is intensively stained.
The follicle is nourished by a rich but delicate network of vessels. His indicates that the center of the follicle is often left bare of it.
There is no full agreement about the lymph vessels in the lymph follicle. According to Rauber they pass through the lymph nodes and are perhaps in open connection with the adenoid substance.
The nerve fibers do not enter the follicles directly, except in those cases where they are accompanied by blood vessels. The solitary follicle is surrounded by a plentiful vascular network which, according to His, sometimes expands into sinusoidal formations.
In pathological cases, such as inflammations, tumors, leukemic and aleukemic lymphomas, etc., proliferation of lymphatic tissue occurs in various organs.
In leukemic and aleukemic lymphomas, powerful hyperplastic growths of the lymphatic tissue of the lymph glands or lymphocyte foci appear as so-called lymphomas in various organs, e.g. in the kidneys, the skin, the peritoneum, the dura, the heart, the intestines, the oral cavity, the lacrimal glands, the salivary glands, etc. Perhaps changes similar to those I have just mentioned could take place in my cases.
As far as the occurrence of lymphocyte foci, partly provided with germinal centers, in the thyroid gland is concerned, the same has already been found by A. Kocher and Howald in Morbus Basedowii, and by Hedinger in goiter sarcomatosa.
The case histories of our cases
1. Recorded on 11/21/1907. Ms JU, 61 years old. The father died of apoplexy, otherwise not hereditary. The patient was healthy from childhood, never suffered from any illness worth mentioning.
Venereal disease negated. Only 7 months ago, the patient noticed a tumor on the median part of the neck, which reportedly has not enlarged since. Insomnia, palpitations or disturbances of the general condition are missing so far.
Status present. Medium stature, moderately built and well fed. Internal organs intact. No signs of Basedow’s disease. The tumor located on the median part of the neck has a horseshoe shape, as a whole about the size of a hen’s egg, rising on swallowing, not tender, somewhat firm, fixed on the trachea, freely movable against the skin and the surrounding area. Glandular and skeletal systems show nothing abnormal.
Diagnosis: goiter parenchymatous. Operation on November 22, 1907 under chloroform anesthesia. collar cut according to Kocher; subcapsular resection from both lobes. The preparation of the goitre was done without any particular difficulty; bleeding minor. Extirpated goiter tissue somewhat firm.
Course: Slight fever up to 38°. Patient feels very weak. Drainpipe and sutures removed after a week. Healed per primam and on 18.12. dismiss. There is very slight postoperative hoarseness. According to a letter dated March 7, 1911, the patient is completely healthy and the operated area has not yet swelled again.
2. Recorded on 05/30/1909. YN, 40-year-old farmer, comes from a healthy family. Had smallpox when she was 2 years old. Suffered from leukorrhea for 20 years. 40 days ago, the patient noticed a painless tumor near the cricoid cartilage, which so far has not noticeably enlarged. For a month the patient became aware that her voice was choked. There are also occasional headaches. appetite somewhat disturbed.
Status present: Medium stature, gracefully built, moderately nourished, somewhat anemic. All internal organs intact. On the median part of the neck there is a horseshoe-shaped tumor consisting of two lobes and a connector: right lobe 7 cm high, 3.5 cm wide; left lobe 5.5 cm high, 4.5 cm wide; 6.5 cm wide at the base.
The tumor is not sensitive to pressure, is noticeably firm, finely bumpy, lifts when swallowing, and is difficult to move on the underlying surface; otherwise no adhesion. Nothing abnormal on the rest of the body, especially the glandular and skeletal system.
Diagnosis: suspected goiter maligna. Operation on July 2, 1907 under chloroform anesthesia. Kocher collar cut. The entire thyroid tissue enlarged like a tumour, to be palpated evenly everywhere. When dissecting the crop skin, it bleeds quite heavily.
Both lobes were excised, namely a 6 cm: 3.5 cm from the right one. 2.5 cm and from the left a 5 cm : 3.4 cm : 2 cm piece. The surface of the excised goiter tissue is finely bumpy and divided into lobules. The cut surface not pithy.
History: Unresponsive, smooth history. The wound healed per primam and the patient was discharged on 7/19. discharged cured. Findings at that time: complexion still anemic. appetite good. There is still a bit of tumor left at the operated site.
Readmitted for follow-up examination on January 27, 1911. For about three quarters of a year after being discharged, the patient felt very weak all over and was unable to work. From the beginning of 1910, physical strength gradually increased and the patient was able to work.
The status at that time was: complexion anemic, nutrition moderately good. All internal organs intact. The residual tumor that could be felt upon discharge has disappeared without a trace.
Feces contain copious amounts of anchylostome eggs. Aborted anchylostomes by internal use of thymol and naphatalin. Wassermann’s reaction and tuberculin injection were negative.
3. Recorded on 06/19/1905. Ms. ST, 55 years old, had a premature birth once, otherwise in good health. Syphilis negated. 30 days ago the patient accidentally discovered a tumor on the anterior neck which has not yet shown any significant increase in volume.
There are complaints of a feeling of tension in the shoulders and occasional slight headaches.
Status present: Short in stature, moderately nourished, somewhat anemic. Internal organs intact. On the anterior median part of the neck a tumor corresponding exactly to the thyroid gland: right lobe the size of a hen’s egg, the left lobe the size of a pigeon’s; horseshoe-shaped as a whole.
The tumor is not tender, is generally very firm, is lodged on the trachea, and is free to move against the skin and surrounding tissue. The glandular and skeletal systems, as well as the rest of the body, do not present anything abnormal.
Diagnosis: goiter fibrosa. Operation on June 20, 1905 under chloroform anesthesia. Kocher collar cut. The right thyroid lobe the size of a hen’s egg, very hard, swollen like a tumour; the one on the left is the size of a pigeon’s egg and is similar in structure to the preceding one. resection of both lobes. The excised tumor tissue is exactly the same as in case 2.
Course: Voice occupied, slight pain when swallowing. Feeling of tension in the throat. general well-being disturbed. Stitches removed, healed per primam. Hoarseness gradually subsided. patient feels good. Healed and discharged on July 7, 1905. In the operated area of the neck one can still palpate a firm tumor remnant, which was intentionally left behind during the operation.
There is still slight anemia and hoarseness. Examined in a polyclinic on March 20, 1911, i.e. 5 2/4 years after the operation. After discharge, general weakness and poor appetite persisted for a while. In winter the patient was noticeably cold and weakened.
In 1906 edema of the body appeared throughout the year, naturally with certain remissions and exacerbations. From the beginning of 1907 the condition had gradually improved. Edema of body greatly improved by internal use of thyroid preparation.
Status present: Moderately nourished, not anemic. Voice only slightly husky, urine free of albumen. Despite careful palpation, nothing abnormal can be found in the thyroid region.
4. Taken on 9/19/1907. SK, widow, 45 years old, never experienced significant illness; venereal disease negated. Three days ago the patient noticed a tumor on the anterior median neck, which has so far remained symptom-free without any particular increase in volume.
Present status: Large stature, strong build, slightly anemic. Internal organs intact. On the anterior neck under the cricoid cartilage there is a hen’s egg-sized, horseshoe-shaped tumor that rises when swallowing, is not sensitive to pressure, is firmly attached to the ground, and is mobile in relation to the surrounding tissue.
Cervical glands nowhere swollen. Bone system and other body parts show nothing abnormal.
Diagnosis: Strum fibrosa. Surgery on October 20th. under chloroform anesthesia. collar cut. Uniformly swollen thyroid tissue of a very coarse consistency can be seen. When dissecting the crop skin, there is profuse bleeding. Both lobes and isthmus are resected. The excised tissue section appears similar to case 2.
Course: Slight fits of coughing with sputa, otherwise reactionless, smooth course. Healing first. On 13.10. discharged with status: complexion pale; appetite good; Remaining part of the crop still palpable. On March 13, 1911, 3 1/3 years after the operation, examined in the outpatient clinic.
There was a long-lasting general weakness after discharge. In addition, slight edema appeared on the face from time to time. Allegedly, in the summer of 1910, an asymptomatic swelling in the thyroid area reappeared, but this subsided spontaneously.
Status present: Nutrition moderately good. Mild anemia. Internal organs intact. Voice only slightly occupied. In the anterior region of the neck one feels both thyroid lobes swollen somewhat with a goiter. The lobes are not sensitive to pressure, but are coarse.
If we summarize the previous clinical observations, there were a total of four patients, all of whom were female and over 40 years old. They came from healthy families and did not live in goiter areas. None of her relatives had goiter.
The way of life of the patients was nothing remarkable. The patients had never been seriously ill before, and above all they had not suffered from any serious infectious diseases, which are often followed by diseases of the thyroid gland, especially strumitis. Lues and tuberculosis could be clinically ruled out.
The enlargement of the thyroid was discovered incidentally in all cases. There were no significant complaints. With a good general condition and a normal body temperature, we found a not particularly rapid enlargement of the thyroid gland.
Both lobes were always affected. The size of the tumor was variable. Severe pressure symptoms such as dyspnea or aphonia were never present.
Only in one case had a slight hoarseness set in before the operation, in which defective closure of both vocal cords could be determined, which was due to defective function of the interarytenoid muscle.
There was no trace of inflammation in the swollen thyroid gland. The mobility of the tumor was fairly free. But the consistency was usually so coarse that one could think of a malignant tumor or Riedel’s strumitis. The lymph glands could not be palpated anywhere in the region, including on other parts of the body. We could not find anything abnormal on the internal organs.
The surgical findings did not show any particularly strong adhesions with the surrounding tissues, as is the case with Riedel’s goiter, which was expressly emphasized by the author concerned. A postoperative hoarseness has more or less remained in all cases, although it was always of a very mild degree.
In the further course after the operation, there was said to be edema all over the body, which used to disappear with internal administration of thyroid preparations.
It should be particularly emphasized that, while the postoperative course of the other benign goiter cases observed in our clinic was very smooth, the cases mentioned above always required a long period of convalescence before the full state of health was restored.
In one case (Case 4) a recurrence of goiter was said to have occurred for a period of time, but soon receded to a minimum.
It was made out in 90 proc. alcohol (case 1, 3 and 4) or in 10 proc. a small piece of tissue stored in formol solution (case 2) was excised, embedded in celloidin, and fine sections made. Staining was done with hematoxylin-eosin double staining and van Gieson.
In individual cases, Weigert’s coloring was also used. Staining methods used in other ways will be given when the relevant histological description is given.
All of our 4 cases have a significant pathological-anatomical finding among themselves. In particular, the second and third cases are characterized by particularly instructive changes.
Case 4 is the most severely affected in terms of round cell infiltration of the tissue and parenchymal degeneration. The lymphatic follicles are remarkably well developed in cases 2 and 3.
Since cases 2 and 3 generally show a well-developed clinical picture, I would like to deal mainly with these two cases in the following. Case 4 presents a somewhat different picture from the other three. But it cannot be interpreted otherwise than as an advanced change.
Under the microscope we see various remarkable findings, but above all the striking abundance of lymphatic follicles, diffuse changes in the glandular follicles and the associated formation of new connective tissue.
The lymph follicles are particularly abundant on the edge zone of the extirpated glandular tissue. They are either scattered or densely located within the lobules and in the interstitium. The shape and size of the lymph follicles is highly variable, mostly polygonal, spindle-shaped, rounded or irregular.
Inside they usually have a germinal center that is sharply demarcated from the environment, in which we find a characteristic cell shape, which usually has a pale colored, blistered nucleus. The shape of the nuclei of these cells is very diverse in our preparations: oval, rounded, triangular or square, rhombic, crescent-shaped or irregular.
In the germinal center there are always large and small lymphocytes, the latter fewer in number than the former. Their nuclei are heavily stained with 1 to 4 particularly well differentiated granules. Here and there we see capillaries lined with endothelial cells, as well as reticulum cells.
Very occasionally we also find plasma cells whose nuclei are located eccentrically and are provided with a chromatin network arranged in a typical manner.
In addition, we see in the germinal center extremely small, rounded granules that can be strongly tinged by hematoxylin, which most probably correspond to what Flemming called “tingible bodies”. In addition, it should be noted that the mitotic nuclear division figures can be seen very abundantly in the germinal center.
The peripheral zone of the lymph follicle consists of reticular connective tissue and contains tightly packed lymphocytes in its meshwork. Here we also find the endothelial cells of the capillaries, another type of cells that appear identical to that of the germinal center, as well as numerous small lymphocytes.
The lymphocytes near the germinal center are arranged in parallel rows and enclose reticulum cells on the inside. Elastic fibers are difficult to find in the lymph follicle.
The size of the bubbles varies greatly depending on the case. In case 1, the bubbles are generally large, but in case 4, they are small. The size of the individual bubbles varies between 30 and 360 µ in cross-section.
As for the shape of the small to medium-sized vesicles, they mostly show roundish or oval cross-section, on the other hand, where the vesicles appear large, we see an irregular shape. The ratio of the number of bubbles of different sizes to one another is generally difficult to determine.
It primarily relates to the condition of the interstitium and round cell infiltration. Where the connective tissue of the interstitium was well developed or the round cell infiltration was conspicuous, the smaller vesicles were to be seen in the majority.
In case 4 in particular, the smaller bubbles predominate. There are also cells here that consist almost exclusively of very small vesicles with a diameter of about 30 μm, and even epithelial cells that often lie randomly next to one another in heaps.
So there is no longer any indication of a bubble structure. These latter vesicles also occur in cases 1, 2 and 3 and are accompanied by proliferating interstitial connective tissue.
In the hyperplasia of the connective tissue there are usually a few epithelial cells lying together in a group or only a few scattered epithelial cells. These cells, by their size, shape, and nuclear behavior, easily indicate that they are descended from atrophied vesicles.
As to the form of the vesicles, we find flattened when bulging, cubic when less full, and cylindrical in that containing only a small quantity of colloidal matter, or anything abnormal in its place.
While the vesicles filled with colloid were only disseminated through almost the entire tissue in case 1, in the other cases we found diffuse, characteristic vesicles that are characterized by their cubic to long-cylindrical shape.
The wall epithelium of the follicle is usually arranged in a single layer. The protoplasm of these cells is beautifully stained in some places by eosin, or dirty in others. The nucleus was in the basal part of the cylindrical cells, but exclusively in the middle of the cubic cells. The nuclei were mostly oval or round in shape, with fine, abundant granules and one to four nucleoli.
In the cell body and between the individual cells we find here and there small, immigrated, mononuclear leukocytes, which sometimes have an elongated oval shape.
Within the epithelial cells (case 2) we see black granules that can be tinted by Flemming’s solution and reddish by Sudan III or scarlet red. It may be the structures already described in detail by Erdheim in normal and pathologically altered thyroid glands that this researcher interprets as fat granules.
These granules are found both in the epithelial cells of the ordinary follicles and in cells simply arranged in clusters. In fact, in the first cell types, these granules are found crowded close to the central part of the cells. The contour of the follicles is usually not sharp. In some places, however, it appears quite clear.
The colloid in the vesicles behaves in many different ways in our cases. In certain follicles they are filled with colloid, so that the wall epithelium has been pressed and flattened.
The formation of vacuoles, which probably represents an artificial product that may have arisen from the coagulation of the colloid, can often be detected in large numbers as small cavities on the inner edge or rarely in the center of the follicle.
As far as the colorability of the colloid is concerned, it behaves differently depending on the place. In well preserved vesicles the colloid is usually well stained, but in others where the follicular epithelium is highly altered poor colloid stainability is encountered.
In the latter cases heaps of dirty eosinophilic granules are found inside the vesicles instead of the homogeneous eosinophilic colloid.
Generally speaking, it may be said that the colloidal substance is greatly diminished, even in altered follicles almost to the point of disappearance. The colloid-like substance was found to be bulging in the lymphatic vessels in case 1, but we could not find it in the lymphatic vessels, veins or arteries of others.
In the vesicles we also find various other elements, of which the colloid-poor are particularly abundant: These elements consisted of epithelial cells, leukocytes or their derivatives, as well as a clumpy mass.
Some of the epithelial cells here are almost like normal wall epithelium, with a sharp cell configuration and well-stained cell components.
We also find epithelial cells with indistinct ptotoplasm or aggregated conglomerate of epithelial cells which are in the process of sclerosing or have already completely transformed into clods.
The migrating cells with mostly rounded or very rarely lobed nuclei are present in the vesicles in varying numbers. The epithelial cells lie in the vesicles without a sharp border close to the wall or inside at a certain distance from the wall.
In small numbers we see cells well stained with eosin in the vesicles, the core pigment of which is arranged in a radar-like pattern: they are therefore plasma cells.
The behavior of the connective tissue is very important in our cases. Pronounced proliferation was evident everywhere, which presents a very beautiful picture through van Gieson’s coloring. The same was diffuse and was particularly pronounced in case 4, so that the lobular arrangement of the vesicles was no longer recognizable.
Also of interest was the relationship between connective tissue proliferation and vesicle changes. The vesicles in the proliferating connective tissue appeared very sparsely and were distinguished by their small size.
They contained little substance, and what little was presented as a small amount of amorphous, dirty pale red colored substance. In isolated places one can see a circumscribed, powerfully developed mass of connective tissue, which enclosed a number of very small vesicles in its interior.
Furthermore, it appeared very striking that the connective tissue was diffusely infiltrated by mononuclear leukocytes. This round cell infiltration, composed mainly of small lymphocytes, showed the same characteristic finding in all our cases. Between these round cells we saw a moderate number of plasma cells, the protoplasm and nuclei of which were quite typically stained.
Round cell infiltration mainly affected the area around some large vessels. In case 4, the giant cell-like structures, which were provided with peripheral, numerous nuclei and red-stained protoplasm, were found scattered through the proliferating connective tissue.
As to the vessels, they did not appear to be appreciably altered in any of our cases. We saw relatively plentiful vessels in the nodal points of the trusses of connective tissue passing through the vesicles and dividing them into lobules. A profuse formation of new vessels was, however, not significant in any case.
Incidentally, I had not neglected to look for numerous paraffin sections for bacteria (carbolic fuchsin, methylene blue, Gram’s stain, etc.). Despite keen searches, no microorganisms were found anywhere.
Summary of histological change
It follows from the histological findings just quoted that the main changes in all of our cases are:
- 1. In numerous lymphatic follicle formations
- 2. in a striking change in the vesicular epithelium and its contents
- 3. In extensive new formations of connective tissue
- 4. In diffuser Rundzelleninfiltration.
If we look through the pathological-anatomical findings of our 4 cases, we can immediately find changes that correspond, even if they also show gradual differences.
In case 1, the change in the vesicles is very slight, being found to be well filled with colloid, provided with almost normal follicles, and with well-preserved epithelial cells. Here, however, the vesicles are not as large as we are accustomed to see in pronounced colloid goiter.
In cases 2 and 3, the vesicles have changed in a typical way: They show epithelial cells that tend to become sclerosing, atrophied vesicle remains and abnormal contents. In case 4, the vesicles are generally small, atrophic, with little colloid and abnormal contents.
The round cell infiltration is only slight in case 1, moderate in cases 2 and 3, but strikingly strong in case 4. These round cells consist of both mononuclear lymphocytes and plasma cells. The lymph follicles are moderately abundant in case 1 and very abundant in cases 2 and 3.
The proliferation of connective tissue can hardly be detected in case 1, but in cases 2 and 3 it developed quite strongly and in case 4 very strongly. The change in the parenchyma is only mild in case 1, moderate in cases 2 and 3, and highly advanced in case 4.
So we can assume with all probability that the lymphatic elements were stimulated by a certain moment to develop, which manifested itself in the formation of lymph follicles and in infiltration of lymphocytes. However, we cannot rule out whether the migration of blood cells from the vessels is also involved.
While in case 1 doubtful inflammatory changes can be detected both in the parenchyma and in the interstitium, in the other 3 cases one sees a finding that speaks more for chronic inflammation.
As can be seen in chronic inflammation, especially in mucosal catarrhs, lymphocyte infiltration and the formation of proper small lymph follicles, one can assume that this change also takes place in the thyroid gland in a similar sense.
However, we must think of various other possibilities before discussing the genesis of this change, since we know that a similar clinical picture can also occur in other organs, which has been interpreted differently by some authors.
Mikulicz’s disease is probably a good example of this. I should like to come back later to the closer connection between this affection and ours.
In any case, it is difficult to decide whether the changes mentioned in our preparations are the result of chronic inflammation or in the sense of Mikulicz’s disease.
If we compare the clinical and histological findings of our cases with those of other similar diseases of the thyroid, we come to a very interesting conclusion. Clinically, all of my cases are characterized by their coarse consistency, suggesting goiter fibrosa or maligna.
Goiter fibrosa occurs seldom and appears sometimes as a circumscribed, sometimes nodular or nodular tumor, especially in old goiters, but very rarely as a diffuse thickening of a lobe or of the whole gland.
The circumscript form of such a goiter is characterized by numerous, hard nodes the size of peas to chicken eggs.
Rarely do these nodes reach a considerable size. However, all together can make a powerful goiter. The diffuse form is often accompanied by a considerable reduction in the size of the said organ.
Our goiter did not show the nodular appearance characteristic of circumscript goiter fibrosa. Only the fibrous growth in our cases showed any resemblance to diffuse fibrous goiter.
There is also a major difference between , since the typical parenchymatous changes with diffuse round cell infiltration and lymphatic follicle formation are completely absent in goiter.
We also harbor a certain suspicion of malignant goiter, although we could not demonstrate any strong adhesions with the surrounding area and no glandular metastasis. The microscopic findings and the postoperative course gave us reliable information that it was neither goiter fibrosa nor goiter maligna.
It is true that our cases presented a multilayered structure of the high follicular epithelium, grouping of the scattered epithelial cells in the proliferating connective tissue, and lack of colloid mass, all of which speak for a malignant tumor. But I don’t want to make the diagnosis of malignant neoplasm, because nowhere was atypical neoplasm of the epithelial cells detectable.
Clinically, we could not determine any glandular swelling or bone deformation suspected of metastasis anywhere on the body. Although I believe that the above explanations have sufficiently ruled out the suspicion of an epithelial new formation, the question of the possibility of a new formation of connective tissue nature with lymph follicles and accumulations of lymphocytes still remains to be answered. Here, the lymphosarcoma comes primarily into consideration.
Since the lymphosarcoma originates in the lymphatic tissue, it still has the lymphatic structure as a basic feature in its structure. The metastases are mainly formed in the neighboring lymphatic apparatus.
The elements of the tumor consist mainly of lymphocytes, vascular reticulum, which is attached to endothelia, and eosinophilic cells. On the other hand, we completely miss the characteristic structure of lymphatic vessels on the one hand and follicles on the other.
In addition, the same are only very imperfectly formed. In our cases we find everywhere innumerable lymphocytic infiltrations over an extensive area. In other places they form distinct lymphoid follicles.
The typical lymphoid follicles with clear germinal centers never occur as a main component of the tumor in lymphosarcoma. Thus, we can confidently interpret our findings as a benign change.
Other sarcoma forms are not considered here. Furthermore, our cases, after the exclusion of true neoplasms, are particularly distinguished by the fact that the tumor residues gradually disappeared of their own accord after the operation.
The comparison of inflammatory processes of the thyroid gland
I now turn to the comparison with the inflammatory processes of the thyroid gland.
Acute inflammation of the thyroid can be divided into interstitial and parenchymatous. The first has hitherto only been described in purulent cases or in purulent fusion. The latter can be observed in nonsuppurative thyroiditis.
According to Quervain , this is caused by the increase, rejection and degeneration of the epithelial cells, by changes and atrophy of the colloid, by the penetration of multilocular leukocytes, small round cells and larger cellular elements into the vesicles, by the formation of foreign body giant cells around non-resorbed colloid clumps and finally by the appearance characterized by a connective tissue organization.
Acute thyroiditis usually begins suddenly with the general symptoms of a febrile illness, even with chills. In our cases the subjective as well as the objective symptoms of the acute inflammation were completely absent. There was also no sign of acute inflammation in the histological picture, since polynuclear lymphocytes were nowhere to be found.
The thyroid gland in toxic and infectious diseases has been studied in detail by Roger and Garnier , Torri , Kashiwamura , especially lately by Bayon and Quervain .
The material used came from various diseases, such as acute exanthema, scarlet fever, variola, measles, follicular intestinal catarrh, diphtheria, typhoid, pneumonia, puerperal infections, osteomyelitis, erysipelas, purulent peritonitis, tuberculosis, etc.
According to Roger and Garnier , who limited themselves to examining acute infectious diseases and tuberculosis, the supporting tissue was mostly normal, i.e. without leukocyte accumulation; only it was apparently thickened by the intercalation of colloid matter between the cavities. Apart from the increased blood content, the vessels were little changed.
But here and there arteritic and phlebic changes with the formation of thromboses were found. The vesicles consisted of either colloid or desquamated, ruptured cells and were endowed with enlarged nuclei and granulated protoplasm.
The epithelial cells of the vesicles were often arranged in several layers. The amount of the colloid depends on the severity of the disease, but can sometimes disappear almost completely.
The authors found in tuberculosis a decrease in the weight of the thyroid gland and an increase in the connective tissue in it. Decomposing vesicles were often found in these septa.
While the veins are little affected, the arteries show some degree of periarteritis, and sometimes of endarteritis. The parenchyma shows a proliferation of vesicle cells in places, as well as the cell clusters between the vesicles.
Torri examined the thyroid glands of persons who had died of acute and chronic infectious diseases and found hypersecretion of the colloid and epithelial proliferation. He also demonstrated active new formation of the epithelium in tuberculosis, and frequently an increase in the colloid masses.
According to Kashiwamura , connective tissue proliferation comes to the fore in most cases of pulmonary consumption. However, he also pointed out the same finding for other infectious and toxic diseases. In the majority of cases the author found colloid in the lymphatic vessels in varying amounts.
Blood vessels and capillaries are often heavily filled with it. According to him, the findings, which are characterized by the presence of particularly numerous small follicles, cannot be used as characteristic findings for infectious diseases.
According to Quervain , to whom we owe the systematic and thorough investigations on this subject, the corpses found in infectious diseases consisted of disturbances in colloid formation, proliferation or desquamation of the epithelial cells, and hyperemia. But the character of a bacterial infectious process with the release of multinucleated leukocytes was never shown.
In assessing the question of whether thyroiditis is bacterial or toxic in a given case, the histological findings are more important than the culture results. According to this author, it would not be appropriate to classify the changes found in the corpse as a result of infections and intoxications under the term inflammation with the name “toxic thyroiditis”.
He suggested the term “toxic reaction” for this, as it has nothing to do with real inflammation.
Sarbach had examined the behavior of the thyroid in infections and intoxications and came to the following conclusions: Acute infectious diseases, especially scarlet fever, can cause marked histological changes in the thyroid.
The nature of the changes is essentially the same as in other acute infectious diseases. They are characterized by general hyperemia, liquefaction and wasting of the colloid, and desquamation of the epithelial cells.
The author points to a damaging effect on the thyroid tissue in the case of chronic alcohol abuse of a higher degree. Alcohol abuse produces a histological change similar to that of infectious diseases.
As far as chronic pulmonary tuberculosis is concerned, he found in the majority of cases a conspicuous new formation of connective tissue, which, moreover, can cause gradual atrophy of the follicles. On the other hand, he could find no change in chronic nephritis, uraemia, cancer cachexia and sarcoma.
Comparing our findings with those of other investigators dealing with infections and toxic diseases, we must emphasize above all that the enlargement of the thyroid gland was not particularly characteristic in their cases.
In contrast to other researchers, I would like to point out the formation of numerous lymphoid follicles in my histological examinations, a finding which, to my knowledge, has not yet been pointed out. The change in the follicular epithelium, which I was able to ascertain in our cases, is not new and has often been mentioned.
I could not find any infectious or toxic disease in the anamnesis of any of my patients.
On the whole, our histological findings are neither infectious nor toxic, nor tumorous, but probably a peculiar kind of chronic inflammation which, to the best of my knowledge, has not yet been made known. So I will now turn to the discussion of chronic inflammation of the thyroid gland.
Rokitansky stated that when the thyroid becomes inflamed, fibrous exudates deposited later give rise to resistant fibrous tissue as the glandular vesicles are progressively atrophied.
Virchow emphasized that the development of fibrous goiter is also due to an inflammatory process.
According to Wölfler , chronic inflammation of the glandular parenchyma presents itself as follows:
In the cortical substance of the inflamed thyroid, normal glandular vesicles are almost always absent. Only here and there do you still see scattered colloid lumps as the former contents of the vesicles.
In the connective tissue there is an overgrowth of the vascular endothelium and thus also oval, spindle-shaped and tailed cells, which by their appearance alone can be identified as elements of the connective tissue.
In the central part, between the well-preserved vesicles, we see here and there light spaces, as if filled with coagulated lymph, in which multinucleated formation cells (giant cells) can be found. There is also a strange, washed-in mass in the vesicles in some places, which differs from the colloid in its granulation.
The more we move away from the periphery, the more we see a diminution of the epithelial elements. In the fibrous tissue, which in some places is the only essential tissue component, there are blood extravasates of varying extent.
We also note the presence of giant cells and inflammatory processes around numerous large vessels, from which the formation of new connective tissue begins.
Since the vessel wall shows an inflammatory change, it is not difficult to follow the further transformation of these vessels into stratified connective tissue nodes and fibrous strands.
The end result of these inflammatory processes is probably always the transformation into fibrous nodes, strands and calcification foci.
Chronic inflammation of the thyroid gland is a very rare disease. Therefore, its clinical and histological description is neglected in the literature.
At the 15th Surgery Congress (1896) Riedel reported on a peculiar kind of chronic inflammation of the thyroid gland and drew attention to the fact that a conspicuous formation of tumors was evident, similar to chronic inflammation of the pancreas.
Since then, similar cases have been reported by other authors, and aroused lively interest in our circles.
The peculiarity of the disease consists in a hard, as Riedel puts it, “iron-hard” immovable tumor which, according to the entire clinical picture, speaks more for a malignant neoplasm than for an inflammation.
During the operation, the adhesions to the vessels and nerves were found to be so intimate that the surgeon in question took them for an inoperable tumor and, apart from a small excision of the tumor, refrained from any further intervention.
Such cases have hitherto been observed by Riedel , Tailhefel , Cordua , Carle , Courmont et Chalier , Silatschek , Spannaus , & c. Such a goiter begins painlessly, shows relatively rapid growth, has an extremely hard consistency and fixation in depth, is never associated with adhesion to the skin and disease of the regional lymph glands, and does not make the patient cachectic.
Furthermore, the affection made itself felt, sometimes more, sometimes less, accompanied by aphonia, dyspnoea, difficulty in swallowing, palpitations (without tachycardia, exophthalmos, or tremors).
The histological examination reveals infiltrated and fibrous thickened connective tissue. Sometimes, however, one finds young, almost embryonic connective tissue in some places. Little of the thyroid substance is present.
In a few cases a structure resembling that of ordinary colloid goiter appears in the depth of the thyroid gland. The follicular structure is gradually destroyed by the young connective tissue, and tough, fibrous tissue takes the place of the latter.
In the case of Riedel, we miss the tough connective tissue. Only accumulations of round cells were found. Perhaps the process has not existed long enough at this point to lead to the formation of connective tissue.
The vessels exhibit on the whole a normal structure, in that they sometimes show such profuse endothelial proliferation that their lumen would be almost obstructed by it.
The age of the patients is not uniform. The disease mostly affects young or middle-aged people who were formerly healthy. In terms of gender, twice as many men as women were affected .
During the operation, which was usually carried out because of the suspicion of malignant new growth, one found strong, inseparable adhesions of the tumor with the surroundings, so that in most cases one had to be content with the excision of a part of the tumor at most.
In the further course there was always an improvement in the symptoms and a general reduction in the size of the tumor until it completely disappeared. The case recently reported by Riedel was of a benign nature of such a peculiar type of goiter.
He operated on a case of such a goiter, which had been the size of a man’s fist and had caused shortness of breath, which escalated to attacks of suffocation, especially at night.
During the operation the author discovered that the tumor was very hard and it was impossible to separate it from the surrounding area. Here only a walnut-sized piece was extirpated from the tumor mass for later examination, which microscopically proved strumitis chronica. After about 5 months, attacks of suffocation reappeared.
Another wedge was cut out of the isthmus of the thyroid gland. The patient slowly recovered from this. ¾ years later the tumor had shrunk and the patient was able to work again about 1 ½ years after the operation.
The difference between our and Riedel’s goiter cases
Now I would like to deal with the difference between our and Riedel’s goiter cases.
All of our and Riedel’s patients were otherwise healthy and had not previously had any significant illness, especially no serious infectious diseases. Riedel’s goiter favored the 3rd decade and was much more common in men than in women.
All of our cases involved women over 40 years of age. In most of our cases, the consistency of the tumor was remarkably firm. But you can’t call them “hard as iron”.
In the cases of Riedel’s goiter that were operated on, extirpation was unsuccessful because of firm adhesions with large vessels and nerves, and only a small piece of it was excised. On the other hand, in our cases we were able to carry out the resection as in a benign goiter, despite the fairly difficult dissection of the capsule.
In the histological picture, we see round cell infiltration, connective tissue proliferation and the reduction of vesicular epithelium both in our cases and in Riedel’s goiters.
We have no knowledge of the formation of lymph follicles in Riedel’s goiters. The further course was almost the same in both cases. The palpable tumor residues gradually receded.
Tuberculosis of the thyroid occurs in two different anatomical forms. The first, more frequent form occurs as part of the general tuberculosis in the form of miliary tuberculosis and affects sometimes the whole gland, sometimes individual parts of it. The nodules vary in size, are gray, off-white, or yellow in color.
The second form has larger tubercle nodes or kascherde. This type of nodule is rare but practically important because it is chronic and can lead to enlargement of the thyroid gland.
P. Bruns describes a case deceptively similar to malignant goiter, which was clinically primary tuberculosis of the thyroid gland.
It is true that our cases show a certain resemblance to tuberculosis, but the clinical picture was so different that it does not seem necessary to say anything more about it.
The syphilitic disease of the thyroid occurs relatively frequently in the case of fresh infection, but rarely in the late form. Engel-Reimers had made detailed investigations into the involvement of the organ in the early period of syphilis.
As a rule, the affection is a soft, completely painless swelling, which does not bother the patient at all, and therefore remains unknown to most. Sometimes there is a pronounced swelling.
Thyroid syphilis interests us in two directions. On the one hand, the glandular parenchyma can be completely destroyed by the syphilitic process, and symptoms of loss can be caused. Secondly, a malignant neoplasm can be feigned by the formation of a syphilitic goiter.
In this case we saw sudden rapid growth of the goiter, which can cause difficulty in breathing and paralysis of the recurrent nerves, as well as pain, adhesion to the surrounding area, and swelling of the neighboring lymphatic glands.
The actual goiter syphilitica is usually based on gummous degeneration of the thyroid gland and consists of connective tissue permeated by round cells without remnants of thyroid parenchyma and without specific formation. In addition, as already mentioned, a temporary slight goiter can be observed in fresh syphilis, but more rarely a large goitrous tumor.
Our cases speak in every respect against fresh syphilis. We were also not able to establish a greasy appearance of the cell tissue during the operation, which is characteristic of syphilitic goiter.
Histologically we found no gum nodules in our cases, nor any vascular alteration which tends to be somewhat characteristic of the interstitial, fibrous form of syphilitic goiter.
Thyroid actinomycosis and echinococcus, which are very rare, were missed in our cases.
Needless to say, we compared our histological findings with those of parenchymal and vasculosa goiter. In the latter two, however, the characteristic changes, such as those shown in our cases, are absent.
All in all, at least among the literature available to me, we cannot find a single case similar to mine.
If we look for such a change in other organs, in which we can demonstrate lymphofollicle formation with lymphocytic infiltration and with some parenchymatous decline, Mikulicz’s disease comes primarily into consideration.
In 1892, v. Mikulicz fundamentally published a clinical picture which is characterized by symmetrical disease of the lacrimal and salivary glands. Since then, a number of related works have appeared.
However, until now there has been no consensus on the views regarding the etiology and the pathological-anatomical position of this peculiar symptom complex. Since there is a great variety among the cases designated by the name of Mikulicz’ disease, Max von Brunn suggested distinguishing a number of disease groups.
The decisive difference is given by the behavior of the blood. While the blood remains free from change, a form of symmetrical swelling of the parotid gland alone, without lymph gland and spleen swelling, occurs. In other cases, symmetrical swelling of the lacrimal or oral salivary glands, sometimes with skin infiltration, swelling of the lymph glands and spleen without blood changes could be observed. In a minority of cases, severe anemia with lymphocytic pseudoleukemia and bone marrow aplasia or leukemia was noted.
Mikulicz’s disease without blood changes, without swelling of the lymph glands and spleen, which over a long period of time leads to a changing combination of painless lacrimal and salivary gland tumors, is always clinically benign.
The disease process appears to be confined to the affected glands only. There is no metastasis or recurrence after surgery. The swelling is due to internal treatment or sometimes to febrile illnesses.
The histological picture of the diseased gland shows the formation of lymphoid follicles or diffuse round cell infiltration in various ways, with or without clear parenchymal atrophy.
In some cases the main mass of the tumor consists of a fairly evenly arranged tissue of small round cells. These cells lie close together here, in meshes of reticular connective tissue there.
In addition to the lymphocyte-like round cells, we sometimes also see eosinophilic cells and plasma cells. Lymphocytes and plasma cells sometimes contain nuclear division figures. Giant cells have also been observed: they are therefore described as large, roundish structures with 2, 3 or more nuclei. They are regarded by some authors as phagocytic foreign body giant cells.
However, these structures are interpreted differently by other authors, namely as those in decay or dying gland cells. The interstitial tissue generally shows hypertrophy. Of particular importance is the relationship of the pathological tissue to the glandular substance.
The parenchyma is sometimes apparently unchanged, sometimes it appears to be very poor in cells, sometimes even no remains of glandular substance were found. Tuberculosis of the affected glands has sometimes been reconciled with the rest of the clinical finding that they bore some histological resemblance to tuberculous lesions. Here, however, it was determined by a detailed examination that it was not a question of tuberculosis.
The symmetrical swelling of the lacrimal and parotid glands, or the same with skin infiltration, are sometimes combined with swelling of the lymphatic glands or spleen.
These did not differ significantly clinically from the first-mentioned cases. The swelling of the glands always occurs gradually and usually has a coarse consistency.
The lymph gland swellings are located in different parts of the body, but they usually only reach a small extent. The prognosis of these cases is consistently favourable, with the swelling resolving either through internal treatment or spontaneously following febrile illness.
With regard to the histology, we have to repeat almost exactly the same changes which we mentioned in the incoming cases of spleen and lymph gland engorgement.
The pathological tissue was sometimes interpreted as a proliferation of lymphadenoid tissue, sometimes also as granulation tissue. Giant cells have been found by many authors.
The degeneration of the glandular parenchyma seems, according to one author, to play a passive role, while another assumes that it is a primary process; for the glandular acini, which are little or not at all infiltrated by round cells, may present a regressive appearance.
The histological examination of Mikulicz’s disease with accompanying severe anemia in the form of lymphatic pseudoleukemia or leukemia shows a similar change in the affected gland as that of cases without blood changes.
The concluding sentences regarding Mikulicz’s disease are as follows: The symptom complex of the symmetrical swelling of the oral salivary gland and lacrimal gland offers a clinically and histologically uniform picture, both with and without pseudoleukemic resp. leukemic symptoms. There is no unity of views about the cause of the disease.
If we now compare the clinical and histological findings of our goiter cases with those of Mikulicz’s disease, we find a great similarity between the two.
In both, the glands swell with the formation of firm tumors, but no noticeable symptoms of inflammation. Both are not malignant neoplasms, but the benign outcome is the invariable rule.
Both affections show conspicuous round cell infiltration, lymphoid follicle formation and parenchymal atrophy. Giant cell-like formations have only been observed once in our goiters. They are very common in Mikulicz’s disease.
The new formations of connective tissue are pronounced in both affections. Although it is rarely observed in Mikulicz’s disease, there are certain changes in this regard.
Unfortunately, in our cases, a detailed blood test is missing. Only once, in case 2, at the time of the second admission, did we do a more detailed blood test as follows:
|Hemoglobin content (Sahli)||:||73 pCt.|
|erythrocytes||:||3 368 181|
|W : R||:||526|
|Small Lymphocytes||:||159 = 24,31 pCt.|
|Large lymphocytes||:||65 = 9,94 pCt.|
|Large mononuclear leukocytes||:||5 = 76,0 pCt.|
|Polynuclear neutrophilic leukocytes||:||381 = 58,26 pCt.|
|Eosinophilic Leukocytes||:||13 = 1,99 pCt.|
|transitional forms||:||28 = 4,28 pCt.|
|mast cells||:||3 = 0,46 pCt.|
Polychromatophilia, granular degeneration and anisocytosis were detectable.
So I found an increase in the lymphocytes in this patient, but no other changes worth mentioning that could indicate a blood disease.
We know little about the blood results of other patients because the examination had not been carried out at the time of admission. Subsequent examination of the patients in 1911 showed that they had no blood diseases.
In all cases there was no evidence of swelling of the lymph glands anywhere on the body accessible to the sense of touch. None of the patients had a splenic tumor or skin infiltration.
Furthermore, we have so far not been able to find any signs in our patients that speak in any way of Basedow’s disease.
A. Kocher and Howald pointed out that it is characteristic of Morbus Basedowii that, in addition to the typical glandular hyperplasia, the occurrence of lymphocyte foci with or without germinal centers in the stroma and in the intralobular connective tissue can be found with striking frequency.
A perivascular round cell infiltration consisting of leukocytes is seen in a manner similar to certain chronic inflammations.
In terms of histological structure, Basedow’s disease is considered by some to be an analog of Mikulicz’s disease. In this respect our cases are much closer to Mikulicz’s disease.
In sarcomatous goiter, Hedinger was able to demonstrate a large number of clusters of lymphocytes, which often include typical germinal centers. These structures tend to develop from the border of the tumor towards the thyroid tissue. According to him, similar changes also occur in benign goiters.
We can’t say anything definite about the cause of our gooses at the moment. However, it is probable that a chronic, inflammatory process may have taken place in it.
The diffuse round cell infiltration and the decline of the parenchyma, connective tissue hyperplasia, etc. support our assumption.
We have no clue about the infectious or toxic influences.
Despite the ambiguity of the etiological factors, I have named the clinical picture “lymphomatous changes in the thyroid gland” after the histological result.
This view assumes that there must normally be lymphoid tissue in the thyroid gland, from which lymphoid follicle formation and diffuse round-cell infiltration can occur under certain circumstances.
If this assumption were correct, there is no doubt that similar changes can also occur in other thyroid diseases, such as in Basedow’s disease.
If I summarize everything again briefly, I come to the following conclusions:
- 1. There is a type of goiter which I have called goitre lymphomatosa and which is characterized histologically by a proliferation of the lymphatic elements, especially the lymph follicles, and by certain parenchymatous and interstitial changes.
- 2. In an advanced form, goiter lymphomatosa presents a strikingly firm consistency of the gland, which can simulate a malignant tumor.
- 3. In the further course after the operation, it usually took a long time before health was restored.
- 4. The prognosis is favorable quoad vitam.
- 5. Surgical therapy makes the tumor disappear, but one must beware of excessive resection. There is no harm in leaving part of the growth behind. Over time, it falls victim to the decline of its own accord.
Finally, I would like to thank my dear boss, Prof. Dr. H. Miyake for kindly providing the material and for encouraging me to do this work.
I am also Prof. Dr. H. Nakayama , head of the local pathological institute, for his extremely valuable advice on histological examination, and Prof. Dr. Warmest thanks to T. Sakurai for the gracious willingness with which he prepared the relevant photomicrographs for me.