- Email: [email protected]
A Case of Melanotic Sarcoma of the Adrenal Glands with a Secondary Tumour in the Bladder
A CASE OF MELANOTIC SARCOMA OF THE ADRENAL GLANDS WITH A SECONDARY TUYIOUR IN THE BLADDER R. A. McCOMB
AND
DONALD BELL SMITH
From the Department of Urology, Toronto General Hospital and the Department of Pathology, University of Toronto
The peculiar features of the case outlined below, the rarity of the neoplasm encountered at operation and autopsy, and the difficulty of final analysis in the latter, seemed sufficient justifi.. cation for placing the details on record. CASE REPORT
The patient, W. C. M., male, aged sixty-five years, was referred to us in June, 1930 by Dr. E. G. Turnbull of Barrie and Dr. J. P. Mitchell, C. N. R. surgeon, Toronto, with a history of increasing frequency and haematuria, and sudden stopping of micturition. The haematuria appeared prior to the frequency. He had always been perfectly healthy and had carried on as a shop-foreman for the Canadian National Railways. No marked sexual change had been noted. On examination he was found to be a very fair skinned, well developed and healthy looking man about the age stated. He had a right inguinal hernia and a slightly palpable chronic left epididymis and hydrocele. There was no history of Neisser infection. The abdomen was negative. There were no palpable tumours. A rectal examination was negative. His blood pressure was 150/90. On cystoscopic examination, there was a gray movable mass, the size of a large plum. It was covered in part with a slough, and did not bleed when probed with a stiff catheter. It at first resembled a calculus, but was diagnosed as a tumour. No pedicle could be seen. His bladder was opened under spinal anaesthesia and a rather soft feeling tumour with a necrotic surface was found, attached by a slender pedicle 0.75 cm. in length, to the anterior surface of the bladder, about 2 cm. above the vesical sphincter. It was removed with a portion of bladder wall and closure made in the usual way. The specimen was sent to the 49
THE JOURNAL OF UROLOGY 1 VOL, XXXv NO.
1
50
R. A. McCOMB AND DONALD BELL SMITH
division of Surgical Pathology of the Toronto General Hospital, where it was diagnosed as a melanotic sarcoma. A description of the specimen (fig. 1) No. S-30-2685 follows: "The specimen consists of a piece of bladder wall measuring 2 x 1 x 1 cm., and a small short pedicle measuring 0.25 cm. in length, to which there is attached a large rounded mass, which measures 3.5 cm. in
FIG. 1
diameter. The tumour mass is rather lobulated, soft in consistency and has a mottled pinkish-red surface. On section, the tumour had a glistening, pinkish-white mottled surface with a few small haemorrhagic areas and spots of yellowish discoloration. "Microscopically, sections show loosely growing rounded spindleshaped cells of the melanoblastic type. These cells vary markedly in
CASE OF MELANOTIC SARCOMA OF ADRENAL GLANDS
51
size with numerous mitoses and some multinucleated cells. The nuclei of the cells vary from oval to round and are deep staining for the most part. The cytoplasm varies markedly, but tends to be abundant and pale pink in staining reaction. Some of the cells show a deposition of brown pigment, which is non-iron containing. This is a fairly rapid new growth.'' A footnote to this description states that the tumour is very rare, only four references being found in the literature (1, 2, 3, 4). An immediate search was undertaken to find a primary tumour, but none could be found. The eye fields were negative. There were no neurological symptoms and no melanomata in the skin. The left epididymis and testicle were removed. On section the former proved to be due to chronic inflammation and the latter was normal. The patient had an uneventful convalescence, returned home and resumed his work. He felt quite well for a period of eleven months, at which time a communication from Dr. Turnbull, in answer to my letter of enquiry, states "The patient is failing rapidly. He first complained of a general weakness and some heaviness across the abdomen, commencing rather suddenly. Two weeks later a mass could be felt in the right side of the abdomen, in the kidney region." Within the next month he became progressively weaker. Several nodules developed in the skin and a great deal of oedema in the dependent parts. He died thirteen months after operation. The paucity of clinical symptoms other than those above mentioned would lead us to believe that the patient had none of the stigmata usually attributed to diseases of the adrenal glands. An autopsy, which was kindly arranged by Dr. Turnbull, was performed fourteen hours after death. AU'fOPSY REPORT
(a.) Gross Autopsy no. A 355-31, Department of Pathology, University of Toronto. The positive findings follow: The body was that of an old, poorly developed white male, weighing approximately 145 pounds and measuring 155 cm. in length. Immediately below the thyroid cartilage was seen a dark nodular swelling measuring 2 cm. in diameter and of stony hard consistency. It was fixed to the underlying tissue, but not to the skin. Similar smaller masses were present in the region of the right clavicle, at its outer end and at a point about 2 inches below
52
R. A. McCOMB AND DONALD BELL SMITH
the right iliac crest. The cut surface presented an irregularly pigmented appearance, small black flecks being scattered over a whitish background. The left testicle was absent. On examination of the skull,
Fm. 2
dura and brain, no demonstrable lesion was seen aside from arteriosclerosis and atheroma of the arteries at the base of the brain. There was a marked hydrothorax on the left side and both lungs showed definite oedema; old pleural adhesions and obsolescent tuberculosis. The
CASE OF MELANOTIC SARCOMA OF ADRENAL GLANDS
53
heart presented a striking flabbiness of the myocardium, calcification of the aortic valve and anteriosclerosis and atheroma of the coronary arteries. The aorta was relatively free from change. On examining the abdomen, a large soft, cystic mass, the size of an orange was present in the position of the left adrenal gland, immediately above the left
:FIG. 3
kidney and in intimate relation to it (fig. 2). The right adrenal gland (fig. 3) showed a very similar appearance, the adrenal in both cases being surrounded by a fibrous capsule, which included the kidney and which stripped with relative ease. The adrenal on the left side was separated from the kidney with ease and presented a pale grayishwhite, rather nodular external surface. The tissue composing the
,54
R. A. McCOMB AND DONALD BELL SMITH
tumour masses was very friable and on tearing released clotted blood. The cut surface showed a grayish-white tissue, which was largely replaced in the central part by a dark red, spongy mass, leaving a thin outer layer measuring on an average, 1 cm. in thickness and sending in: extensions of a grayish-white tissue to the interior. The tumour did not invade the kidney in any part. The liver was greatly enlarged,
FIG. 4
its cut surface presenting a typical "nutmeg" appearance. The pancreas and spleen also presented a marked evidence of a chronic passive congestion. The kidneys were small. The capsule stripped with some difficulty and the capsular surface presented patchy areas of roughness. On the cut surface of the kidney, the cortex and medulla were not well differentiated and the kidney parenchyma was decreased in amount
CASE OF MELANOTIC SARCOMA OF ADRENAL GLANDS
55
with an increase in the peripelvic fat. The urinary bladder was thinwalled, its mucosal surface showing well-marked trabeculation with no evidence of the old operation.
(b) Microscopic Sections of the adrenal presented a striking appearance (figs. 4 and 5). No normal adrenal tissue could be seen. The growth was composed
FIG. 5
of large cells, varying markedly in size and shape with numerous mitoses and many multinucleated giant cells. The nuclei of the cells varied greatly in size and from oval to round in shape. Some were deepstaining while others were markedly vesicular. The cytoplasm was practically without exception abundant and acidophilic. It presented a very finely granular, almost homogeneous, appearance. The cells
56
R. A. McCOMB AND DONALD BELL SMITH
were arranged in, for the most part, no definite order, although in some areas there was a suggestion of cord-like growth; in other places, they appeared to form very atypical cavernous channels, which might, with almost equal justification, be compared to pseudoglands. The cells were embedded in a fairly abundant fibrous stroma, which contained a diffuse lymphocytic infiltration. Areas of necrosis and haemorrhage
FIG. 6
were frequent. Some of the sections showed a deposition of goldenbrown pigment, both in the cells and stroma. When stained with Perle's technique, these were seen to contain iron. No trace of other pigment could be found. Sections stained with Sudan III showed considerable granular and globular fat in the fibrous tissue stroma cells and about them, as well as a lesser quantity in a few of the tumour cells.
CASE OF MELANOTIC SARCOMA OF ADRENAL GL.ANDS
57
The cells did not contain Nissl bodies when stained with methylene blue. Mallory's phosphotungstic acid staining technique failed to reveal fibrillar processes attached to the cells. Many frozen sections were treated with Foote's silver impregnation method as outlined by Foote in an effort to demonstrate a possible derivation from the ganglion cells of the adrenal medulla (5). Our results were disappointing, since the central sections of dog cornea also failed to show the fine net-work of non-medullated nerve fibres. Sections of the nodule from the skin (fig. 6) showed a similar type of cell, but the structure of the tumour was much more compact and the cells, to some extent, appeared in cords. There was a considerable deposition of a golden-brown pigment in and about many of the tumour cells. These did not give Perle's iron reaction, although some ironcontaining pigment was present in the section. In sections stained for fat, the brown pigment was unchanged and no fat seen. RESUME
The patient in June, 1930 had a melanotic sarcoma of the bladder removed by surgical operation. No primary tumour could be found clinically and the case remained incomplete until the patient died of circulatory failure thirteen months later. Autopsy revealed a most unusual and interesting bilateral tumour of the adrenal glands, which had not given rise to any signs of adrenal dyscrasia before death. PATHOLOGICAL DISCUSSION
The case presents three tumours, i.e. (a) a bilateral tumour of the adrenals, (b) multiple tumours of the subcutaneous tissue, and (c) a growth in the bladder. The first tumour contains iron pigment, the latter two contain iron-free pigment and a small amount of iron pigment. That the bilateral tumour of the adrenals is the primary growth seems open to little doubt. The subcutaneous nodules are necessarily metastatic in origin and the bladder growth is equally so. Aside from the inference that the adrenal growth is the only logical primary and that the other tumours are secondary to it, is the striking similarity in appearance of the two adrenals. They seem to have assumed malignant character at the same time and progressed at an equal rate. The presence of malaninlike pigment in the subcutaneous nodules and bladder o:ffers an
58
R. A. McCOMB AND DONALD BELL SMITH
interesting problem. It is known that primary melanotic sarcomata in other regions, such as skin or eye, may be nonpigmented but have pigmented secondaries. It is also known that the cells of a secondary growth endeavor to reproduce the function of the original cell of the primary growth. According to Bloch, destruction of the adrenal medulla releases a precursor of adrenalin with the chemical formula 3-4 dioxyphenylalanine, usually abbreviated to dopa. Dopa is changed by dopa-oxidase to melanin and to this fact Bloch attributes the characteristic skin pigmentation of Addison's disease (6). It is conceivable that the cells of the secondaries are less mature than those of the primary and are producing a small quantity of dopa, insufficient to cause a remote pigmentation, but which is changed at its site of formation to melanin. This theory predicates a medullary origin for the neoplasm, i.e. from the chromaffine cells, as against its derivation from the cortex. The latter possibility was seriously considered, but was not considered tenable. The structure and morphology of the growth do not in any way suggest cortex. The pigment present in the reticulated zone of the cortex is of a lipoid charncter and we were unable to demonstrate any pigment of this variety in the primary or secondary growths. It is, however, impossible to state positively what cell in the medulla gave rise to the new growth. The latter does not conform to the usual types of medullary malignant growths. It contains no nervous tissue demonstrable by the methods at our command and there is no rosette formation. One cannot with certainty deny the presence of chromaffin pigment since no blocks of tissue were originally fixed in chromate, but since that pigment is not seen by ordinary staining methods, one can be sure that none of the pigment seen in the sections is of chromaffin character. The phaeochromocytoma is usually small and discovered accidentally at an autopsy, but on the other hand its constituent cells are similar morphologically to those seen in the present case. The possibility of this tumour being an unusual phaeochromocytoma must be considered, but cannot be definitely postulated under the circumstances (7).
CASE OF MELANOTIC SARCOMA OF ADRENAL GLANDS
59
SUMMARY
1. The patient, a male, aged sixty-five, in June, 1930, was operated upon and a melanotic sarcoma removed from the bladder. 2. Thirteen months later the patient died of circulatory failure. At autopsy a primary bilateral malignancy of the adrenal glands was discovered, with multiple secondary melanotic growths in subcutaneous tissue. 3. The phaeochromocyte is considered as a possible type cell of the growth. REFERENCES (1) KAUFMAN: Textbook of Pathology, p. 1440.
(2) WALKER: Textbook of Genito-Urinary Surgery, p. 488. (3) Transactions of the Pathological Society of London, vol. XLII, 1891. (4) MACLACHLAN, W. W. G.: Jour. Med. Res., xxxiii, No. 1 (New Series, xxviii, No. 1), September, 1915, 93-106. (5) FooTE, N. C.: On the silver impregnation of melanotic tumours. Amer. Jour. Path., 1931, vii, 619. (6) WELLS, GIDEON H.: Pathological Chemistry. W. B. Saunders and Company, Philadelphia, 5th edition, 1925, 528, 530. (7) GoLDZIEHER, MAX A.: The Adrenals. The MacMillan Company, New York, 1929.
AND
DONALD BELL SMITH
From the Department of Urology, Toronto General Hospital and the Department of Pathology, University of Toronto
The peculiar features of the case outlined below, the rarity of the neoplasm encountered at operation and autopsy, and the difficulty of final analysis in the latter, seemed sufficient justifi.. cation for placing the details on record. CASE REPORT
The patient, W. C. M., male, aged sixty-five years, was referred to us in June, 1930 by Dr. E. G. Turnbull of Barrie and Dr. J. P. Mitchell, C. N. R. surgeon, Toronto, with a history of increasing frequency and haematuria, and sudden stopping of micturition. The haematuria appeared prior to the frequency. He had always been perfectly healthy and had carried on as a shop-foreman for the Canadian National Railways. No marked sexual change had been noted. On examination he was found to be a very fair skinned, well developed and healthy looking man about the age stated. He had a right inguinal hernia and a slightly palpable chronic left epididymis and hydrocele. There was no history of Neisser infection. The abdomen was negative. There were no palpable tumours. A rectal examination was negative. His blood pressure was 150/90. On cystoscopic examination, there was a gray movable mass, the size of a large plum. It was covered in part with a slough, and did not bleed when probed with a stiff catheter. It at first resembled a calculus, but was diagnosed as a tumour. No pedicle could be seen. His bladder was opened under spinal anaesthesia and a rather soft feeling tumour with a necrotic surface was found, attached by a slender pedicle 0.75 cm. in length, to the anterior surface of the bladder, about 2 cm. above the vesical sphincter. It was removed with a portion of bladder wall and closure made in the usual way. The specimen was sent to the 49
THE JOURNAL OF UROLOGY 1 VOL, XXXv NO.
1
50
R. A. McCOMB AND DONALD BELL SMITH
division of Surgical Pathology of the Toronto General Hospital, where it was diagnosed as a melanotic sarcoma. A description of the specimen (fig. 1) No. S-30-2685 follows: "The specimen consists of a piece of bladder wall measuring 2 x 1 x 1 cm., and a small short pedicle measuring 0.25 cm. in length, to which there is attached a large rounded mass, which measures 3.5 cm. in
FIG. 1
diameter. The tumour mass is rather lobulated, soft in consistency and has a mottled pinkish-red surface. On section, the tumour had a glistening, pinkish-white mottled surface with a few small haemorrhagic areas and spots of yellowish discoloration. "Microscopically, sections show loosely growing rounded spindleshaped cells of the melanoblastic type. These cells vary markedly in
CASE OF MELANOTIC SARCOMA OF ADRENAL GLANDS
51
size with numerous mitoses and some multinucleated cells. The nuclei of the cells vary from oval to round and are deep staining for the most part. The cytoplasm varies markedly, but tends to be abundant and pale pink in staining reaction. Some of the cells show a deposition of brown pigment, which is non-iron containing. This is a fairly rapid new growth.'' A footnote to this description states that the tumour is very rare, only four references being found in the literature (1, 2, 3, 4). An immediate search was undertaken to find a primary tumour, but none could be found. The eye fields were negative. There were no neurological symptoms and no melanomata in the skin. The left epididymis and testicle were removed. On section the former proved to be due to chronic inflammation and the latter was normal. The patient had an uneventful convalescence, returned home and resumed his work. He felt quite well for a period of eleven months, at which time a communication from Dr. Turnbull, in answer to my letter of enquiry, states "The patient is failing rapidly. He first complained of a general weakness and some heaviness across the abdomen, commencing rather suddenly. Two weeks later a mass could be felt in the right side of the abdomen, in the kidney region." Within the next month he became progressively weaker. Several nodules developed in the skin and a great deal of oedema in the dependent parts. He died thirteen months after operation. The paucity of clinical symptoms other than those above mentioned would lead us to believe that the patient had none of the stigmata usually attributed to diseases of the adrenal glands. An autopsy, which was kindly arranged by Dr. Turnbull, was performed fourteen hours after death. AU'fOPSY REPORT
(a.) Gross Autopsy no. A 355-31, Department of Pathology, University of Toronto. The positive findings follow: The body was that of an old, poorly developed white male, weighing approximately 145 pounds and measuring 155 cm. in length. Immediately below the thyroid cartilage was seen a dark nodular swelling measuring 2 cm. in diameter and of stony hard consistency. It was fixed to the underlying tissue, but not to the skin. Similar smaller masses were present in the region of the right clavicle, at its outer end and at a point about 2 inches below
52
R. A. McCOMB AND DONALD BELL SMITH
the right iliac crest. The cut surface presented an irregularly pigmented appearance, small black flecks being scattered over a whitish background. The left testicle was absent. On examination of the skull,
Fm. 2
dura and brain, no demonstrable lesion was seen aside from arteriosclerosis and atheroma of the arteries at the base of the brain. There was a marked hydrothorax on the left side and both lungs showed definite oedema; old pleural adhesions and obsolescent tuberculosis. The
CASE OF MELANOTIC SARCOMA OF ADRENAL GLANDS
53
heart presented a striking flabbiness of the myocardium, calcification of the aortic valve and anteriosclerosis and atheroma of the coronary arteries. The aorta was relatively free from change. On examining the abdomen, a large soft, cystic mass, the size of an orange was present in the position of the left adrenal gland, immediately above the left
:FIG. 3
kidney and in intimate relation to it (fig. 2). The right adrenal gland (fig. 3) showed a very similar appearance, the adrenal in both cases being surrounded by a fibrous capsule, which included the kidney and which stripped with relative ease. The adrenal on the left side was separated from the kidney with ease and presented a pale grayishwhite, rather nodular external surface. The tissue composing the
,54
R. A. McCOMB AND DONALD BELL SMITH
tumour masses was very friable and on tearing released clotted blood. The cut surface showed a grayish-white tissue, which was largely replaced in the central part by a dark red, spongy mass, leaving a thin outer layer measuring on an average, 1 cm. in thickness and sending in: extensions of a grayish-white tissue to the interior. The tumour did not invade the kidney in any part. The liver was greatly enlarged,
FIG. 4
its cut surface presenting a typical "nutmeg" appearance. The pancreas and spleen also presented a marked evidence of a chronic passive congestion. The kidneys were small. The capsule stripped with some difficulty and the capsular surface presented patchy areas of roughness. On the cut surface of the kidney, the cortex and medulla were not well differentiated and the kidney parenchyma was decreased in amount
CASE OF MELANOTIC SARCOMA OF ADRENAL GLANDS
55
with an increase in the peripelvic fat. The urinary bladder was thinwalled, its mucosal surface showing well-marked trabeculation with no evidence of the old operation.
(b) Microscopic Sections of the adrenal presented a striking appearance (figs. 4 and 5). No normal adrenal tissue could be seen. The growth was composed
FIG. 5
of large cells, varying markedly in size and shape with numerous mitoses and many multinucleated giant cells. The nuclei of the cells varied greatly in size and from oval to round in shape. Some were deepstaining while others were markedly vesicular. The cytoplasm was practically without exception abundant and acidophilic. It presented a very finely granular, almost homogeneous, appearance. The cells
56
R. A. McCOMB AND DONALD BELL SMITH
were arranged in, for the most part, no definite order, although in some areas there was a suggestion of cord-like growth; in other places, they appeared to form very atypical cavernous channels, which might, with almost equal justification, be compared to pseudoglands. The cells were embedded in a fairly abundant fibrous stroma, which contained a diffuse lymphocytic infiltration. Areas of necrosis and haemorrhage
FIG. 6
were frequent. Some of the sections showed a deposition of goldenbrown pigment, both in the cells and stroma. When stained with Perle's technique, these were seen to contain iron. No trace of other pigment could be found. Sections stained with Sudan III showed considerable granular and globular fat in the fibrous tissue stroma cells and about them, as well as a lesser quantity in a few of the tumour cells.
CASE OF MELANOTIC SARCOMA OF ADRENAL GL.ANDS
57
The cells did not contain Nissl bodies when stained with methylene blue. Mallory's phosphotungstic acid staining technique failed to reveal fibrillar processes attached to the cells. Many frozen sections were treated with Foote's silver impregnation method as outlined by Foote in an effort to demonstrate a possible derivation from the ganglion cells of the adrenal medulla (5). Our results were disappointing, since the central sections of dog cornea also failed to show the fine net-work of non-medullated nerve fibres. Sections of the nodule from the skin (fig. 6) showed a similar type of cell, but the structure of the tumour was much more compact and the cells, to some extent, appeared in cords. There was a considerable deposition of a golden-brown pigment in and about many of the tumour cells. These did not give Perle's iron reaction, although some ironcontaining pigment was present in the section. In sections stained for fat, the brown pigment was unchanged and no fat seen. RESUME
The patient in June, 1930 had a melanotic sarcoma of the bladder removed by surgical operation. No primary tumour could be found clinically and the case remained incomplete until the patient died of circulatory failure thirteen months later. Autopsy revealed a most unusual and interesting bilateral tumour of the adrenal glands, which had not given rise to any signs of adrenal dyscrasia before death. PATHOLOGICAL DISCUSSION
The case presents three tumours, i.e. (a) a bilateral tumour of the adrenals, (b) multiple tumours of the subcutaneous tissue, and (c) a growth in the bladder. The first tumour contains iron pigment, the latter two contain iron-free pigment and a small amount of iron pigment. That the bilateral tumour of the adrenals is the primary growth seems open to little doubt. The subcutaneous nodules are necessarily metastatic in origin and the bladder growth is equally so. Aside from the inference that the adrenal growth is the only logical primary and that the other tumours are secondary to it, is the striking similarity in appearance of the two adrenals. They seem to have assumed malignant character at the same time and progressed at an equal rate. The presence of malaninlike pigment in the subcutaneous nodules and bladder o:ffers an
58
R. A. McCOMB AND DONALD BELL SMITH
interesting problem. It is known that primary melanotic sarcomata in other regions, such as skin or eye, may be nonpigmented but have pigmented secondaries. It is also known that the cells of a secondary growth endeavor to reproduce the function of the original cell of the primary growth. According to Bloch, destruction of the adrenal medulla releases a precursor of adrenalin with the chemical formula 3-4 dioxyphenylalanine, usually abbreviated to dopa. Dopa is changed by dopa-oxidase to melanin and to this fact Bloch attributes the characteristic skin pigmentation of Addison's disease (6). It is conceivable that the cells of the secondaries are less mature than those of the primary and are producing a small quantity of dopa, insufficient to cause a remote pigmentation, but which is changed at its site of formation to melanin. This theory predicates a medullary origin for the neoplasm, i.e. from the chromaffine cells, as against its derivation from the cortex. The latter possibility was seriously considered, but was not considered tenable. The structure and morphology of the growth do not in any way suggest cortex. The pigment present in the reticulated zone of the cortex is of a lipoid charncter and we were unable to demonstrate any pigment of this variety in the primary or secondary growths. It is, however, impossible to state positively what cell in the medulla gave rise to the new growth. The latter does not conform to the usual types of medullary malignant growths. It contains no nervous tissue demonstrable by the methods at our command and there is no rosette formation. One cannot with certainty deny the presence of chromaffin pigment since no blocks of tissue were originally fixed in chromate, but since that pigment is not seen by ordinary staining methods, one can be sure that none of the pigment seen in the sections is of chromaffin character. The phaeochromocytoma is usually small and discovered accidentally at an autopsy, but on the other hand its constituent cells are similar morphologically to those seen in the present case. The possibility of this tumour being an unusual phaeochromocytoma must be considered, but cannot be definitely postulated under the circumstances (7).
CASE OF MELANOTIC SARCOMA OF ADRENAL GLANDS
59
SUMMARY
1. The patient, a male, aged sixty-five, in June, 1930, was operated upon and a melanotic sarcoma removed from the bladder. 2. Thirteen months later the patient died of circulatory failure. At autopsy a primary bilateral malignancy of the adrenal glands was discovered, with multiple secondary melanotic growths in subcutaneous tissue. 3. The phaeochromocyte is considered as a possible type cell of the growth. REFERENCES (1) KAUFMAN: Textbook of Pathology, p. 1440.
(2) WALKER: Textbook of Genito-Urinary Surgery, p. 488. (3) Transactions of the Pathological Society of London, vol. XLII, 1891. (4) MACLACHLAN, W. W. G.: Jour. Med. Res., xxxiii, No. 1 (New Series, xxviii, No. 1), September, 1915, 93-106. (5) FooTE, N. C.: On the silver impregnation of melanotic tumours. Amer. Jour. Path., 1931, vii, 619. (6) WELLS, GIDEON H.: Pathological Chemistry. W. B. Saunders and Company, Philadelphia, 5th edition, 1925, 528, 530. (7) GoLDZIEHER, MAX A.: The Adrenals. The MacMillan Company, New York, 1929.