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Regression of Lymph Node Metastases After Orchidectomy and Stilbestrol in Carcinoma of the Prostate: Report of a Case1
REGRESSION OF LYMPH NODE METASTASES AFTER ORCHIDECTOMY AND STILBESTROL IN CARCINOMA OF THE PROSTATE: REPORT OF A CASE 1 ROGER C. GRAVES
AND
JAMES CROSS
From the Urological Clinic of the Pondville State Hospital (Massachusetts Department of Public Health), Walpole, Mass.
It is not our purpose to discuss the bio-chemical and clinical aspects of the treatment of advanced carcinoma of the prostate by orchidectomy and stilbestrol. This subject has received generous attention by many writers since the startling announcement of Huggins and his associates in 1941. It is sufficient at this time to say that our results with this remarkable palliative program have been highly satisfactory and that we share in the approval that has been so widely expressed. We reserve only the hope that the enthusiasm for the new therapy will not diminish the interest in radical perineal prostatectomy as a curative measure in those cases that properly invite this procedure. The histological changes in the primary tumor and in its metastases, following the use of orchidectomy and stillbestrol, have been described less often thus far and it is for this reason that we present this brief report. Schenker, Burns and Kahle in 1942 published their studies of 6 cases of metastatic carcinoma treated with diethylstilbestrol and diethystilbestrol diproprionate. In every instance, definite regression was noted in the nucleus and cytoplasm of the tumor cells. CASE REPORT
An American salesman, married, aged 51 (Hospital No. 20,745), was admitted to the Pondville Hospital Out-patient Department September 17, 1942, complaining of backache. Six months before, after a fall, he began to suffer pain in the lower region of his back. Strapping was applied by a physician but the pain persisted and it was accentuated by coughing or sneezing. Three or4 weeks before coming to the hospital, a mass developed in the right groin and this was followed by swelling of the right lower extremity from the ankle to the thigh. There was no loss of weight. Except for nocturia, 3 to 4 times, there were no urinary difficulties and there had been no recent change in the history so far as the bladder was concerned. There was a slight cough but no other symptoms were reported. The patient used alcohol regularly in rather large amounts. Previous infection of the genital tract was denied. The first examination in the out-patient clinic found a group of 4 or 5 large, hard, discrete lymph nodes in the right supraclavicular region, the largest measuring about 2.5 cm. in diameter. Enlarged nodes could be felt also in the right inguinal region but these could not be felt so distinctly because of a thick layer of adipose tissue overlying them. Tenderness was noted over the upper lumbar vertebrae and along the tenth and eleventh ribs on the left side. There was marked swelling of the right leg. A firm nodule in the left lobe of the prostate was found on rectal examination and additional nodules were reported in the 1 Read before the American Association of Genito-Urinary Surgeons, Stockbridge, Mass., June 11, 1943. 59
60
ROGER C. GRAVES AND JAMES CROSS
hollmv of the sacrum. The diagnosis of carcinoma of the prostate was made and the question raised of a possible separate process, perhaps a lymphoma. Hospital admission was recommended. The patient entered the hospital on October 5. His laboratory record was as follows: The urine was acid, 1.021; albumin, slight trace; sugar, absent; sediment, an average of 10 red blood cells and 10 white blood cells per high power field. The blood Hinton was negative. The white blood count was 8,900. Red blood count, 4,200,000; hemoglobin, 12.2 gm. or 78 per cent. The differential count was normal. The serum acid phosphatase was 0.5 Bodansky units. X-ray Report: Examination of the pelvis showed no definite evidence of malignant disease. There was abnormality, however, in the fourth lumbar vertebra. The density of the bone was slightly increased and in the anterior view along the right side, there was a mottled appearance. There was also very slight narrowing of the body of the vertebra on that side. No other change was found in the bones of the lumbar spine. The chest film showed a normal outline of the diaphragm. There was prominence of all the lung markings and there was definite enlargement of the hilus shadows. The aorta was dilated but there was no significant increase in the size of the heart. Enlarged hilus and mediastinal glands appeared to be present. Conclusion: The change in the fourth lumbar vertebra could have been due to lymphoma or metastasis from the prostate. The film of the chest was also consistent with lymphoma although metastatic disease could be excluded A gland was removed for biopsy from the right supraclavicular area on October 13, 1942. Pathological report: Study of the specimen showed an oval smooth encapsulated nodule about 2.5 by 1.5 by 1.5 cm. On the cut surface there appeared four closely packed nodes with thin capsules all filled with moderately firm, red-gray homogeneous tissue. .L11icroscopic: The nodes were nearly completely replaced by masses of immature epithelial cells. These were for the most part large clear cells, with round or oval vesicular nuclei containing several prominent nucleoli. Mitoses were frequent. The cytoplasm stained poorly. The cells were tightly packed into large masses or alveolar groups with scattered, well-formed acinar lumina in the central portion. Many clumps lay in dilated lymphoid sinuses and two were present in large blood vessels. Diagnos1·s: Metastatic adenocarcinoma, not typical of carcinoma of the prostate, pharyngeal carcinoma. The patient was first seen in urological consultation on October 21. On rectal examination we found induration in the prostate and the left lobe was particularly firm and fixed. Rectal palpation alone, however, did not warrant a positive diagnosis of malignant disease. A cystoscopic examination was made under spinal anesthesia. The cystoscope was introduced with some difficulty because of marked rigidity in the region of the vesical neck. There was no · neoplasm to be seen at the outlet of the bladder or in the deep urethra. There was some encroachment by the prostate but no significant obstruction except for a moderately large pale median bar. With the transurethral resectoscope, 2 segments of tissue were removed from the prostate posteriorly. Frozen section examination of this tissue found car-
REGRESSION OF LYMPH NODE METASTASES
61
cinoma resembling somewhat the tumor found in the gland of the neck and not typical of primary prostatic carcinoma. Rectally, under anesthesia, the prostate was firm, slightly enlarged and uneven in consistency but there were no changes on which one could base a positive diagnosis. The final decision was made by Dr. Shields Warren who reviewed all of the sections, including those from the supraclavicular lymph node, and identified the tumor as an adenocarcinoma of the prostate (figs. 1, 2 and 3). His microscopic description of the prostate tissue was as follows: "Permanent sections show dilated acini packed with hyperplastic epithelium forming small closely
Fm. 1. Showing primary prostatic carcinoma of anaplastic type. tortion of tissue from heat of high-frequency loop.
There is some dis-
packed alveolar structures. Invasion of the surrounding stroma is seen, as well as perineural spread. The cells are anaplastic, irregular in size and shape and show deeply staining nuclei." On October 27, the patient reported a sudden onset of pain in the left chest and x-ray films revealed a recent fracture of the sixth rib on the left side. This appeared as a complete transverse break, with displacement, about 7 cm. from the vertebral column, probably a pathological fracture, though no signs of metastatic disease were seen in the bone in this region. Bilateral orchidectomy was performed on October 28, 1942. The testis alone was removed on each side leaving the cord and epididymis and parietal layer of the tunica vaginalis. There was no untoward reaction to this operation and the cosmetic result was excellent. The patient left the hospital with no symptoms, on November 7. Pathological report: The specimen consisted of 2 testes each 4 by 3.2 by 2.2 cm. covered by shiny, smooth, gray tunica vaginalis. On section each bulges and shows the normal, soft, bright yellow structure. Microscopic:
62
ROGER C. GRAVES AND JAMES CROSS
FIG. 2. Showing metastasis of undifferentiated carcinoma in cervical lymph node
FIG. 3. Showing fibrous tissue replacing tumor in inguinal lymph node. tumor cells persist.
A few scattered
The tubules showed excellent spermatogenesis with many mitoses in the spermatocytes and numerous spermatozoa. At the first out-patient visit, about 4 weeks after his discharge from the hos-
REGRESSION OF LYMPH NODE ME'l'ASTASES
63
pital, the patient stated that he had gained 10 pounds. He had returned to work. His only discomfort was caused by the swelling of his right leg. Examination found definite regression of the glands in the neck and in the right groin. Stilbestrol was prescribed, 1 mg. every other day. One month later, the general condition was described as highly satisfactory except for the edema of the leg. The glands in the groin had subsided markedly; no nodes could be felt in the supraclavicular area. The dosage of stilbestrol was increased to 1 mg. daily February 20, 1943, about 4 months after orchidectomy and when stilbestrol had been given in small amounts for nearly 12 weeks, a lymph node was removed for biopsy from the right inguinal region. It had been planned at the same time to excise one of the previously enlarged cervical nodes for com parison with the gland removed prior to orchidectomy, but careful palpation failed to find any evidence of enlarged nodes in the neck. Pathological report: The specimen consisted of a rounded moderately firm elastic piece of pale gray tissue about 1 by 0.8 by 0.6 cm. On cut surface, it was shiny, firm and mottled with gray and bright yellow. No clear capsule was evident. Microscopic: Much of the node was replaced by dense but rather edematous connective tissue containing rn,i.merous small capillaries. Scattered in this stroma were about a dozen islands of epithelial cells with large nuclei and scanty but clear cytoplasm. These formed solid masses or occasionally good acini. A few showed pyknosis and disintegration of cells. Occasional large cells were scattered singly in the stroma and may be epithelial in character. Diagnosis: Metastatic carcinoma, apparently regressing. X-ray studies were repeated in the Out-patient Department on April 29th. The previously described changes in the fourth lumbar vertebra were still present, but there appeared to be slightly less density posteriorly than in the earlier films. There had been marked improvement in the chest and the chest film was reported to be normal. At the last out-patient visit, May 26, 1943, the patient stated that he felt perfectly well. He was driving a car regularly as a salesman and working in a Victory garden besides. His weight was 180 pounds-a gain of nearly 20 pounds since leaving the hospital after orchidectomy. The swelling of the right lower extremity had disappeared except for edema of the foot. On rectal examination the prostate showed marked regression. It was described as small and soft and resembling early benign hypertrophy. COMMENT
It seems highly probable that the clinical difficulties of diagnosis in this case, as far as the rectal examination was concerned, were related to the uncommon type of prostatic tumor that was present. It was very cellular and anaplastic and had but little stroma. It was highly malignant and the sections showed blood-vessel invasion which is rare in carcinoma of the prostate. REFERENCE E. L., AND KAHLE, P. J.: The effect of diethylstilbestrol and diethylstilbestrol diproprionate on carcinoma of the prostate gland. II. Cytolog1c changes following treatment. J. Urol., 48: 99-112, 1942.
ScHENKEN,
J. R.,
BURNS,
AND
JAMES CROSS
From the Urological Clinic of the Pondville State Hospital (Massachusetts Department of Public Health), Walpole, Mass.
It is not our purpose to discuss the bio-chemical and clinical aspects of the treatment of advanced carcinoma of the prostate by orchidectomy and stilbestrol. This subject has received generous attention by many writers since the startling announcement of Huggins and his associates in 1941. It is sufficient at this time to say that our results with this remarkable palliative program have been highly satisfactory and that we share in the approval that has been so widely expressed. We reserve only the hope that the enthusiasm for the new therapy will not diminish the interest in radical perineal prostatectomy as a curative measure in those cases that properly invite this procedure. The histological changes in the primary tumor and in its metastases, following the use of orchidectomy and stillbestrol, have been described less often thus far and it is for this reason that we present this brief report. Schenker, Burns and Kahle in 1942 published their studies of 6 cases of metastatic carcinoma treated with diethylstilbestrol and diethystilbestrol diproprionate. In every instance, definite regression was noted in the nucleus and cytoplasm of the tumor cells. CASE REPORT
An American salesman, married, aged 51 (Hospital No. 20,745), was admitted to the Pondville Hospital Out-patient Department September 17, 1942, complaining of backache. Six months before, after a fall, he began to suffer pain in the lower region of his back. Strapping was applied by a physician but the pain persisted and it was accentuated by coughing or sneezing. Three or4 weeks before coming to the hospital, a mass developed in the right groin and this was followed by swelling of the right lower extremity from the ankle to the thigh. There was no loss of weight. Except for nocturia, 3 to 4 times, there were no urinary difficulties and there had been no recent change in the history so far as the bladder was concerned. There was a slight cough but no other symptoms were reported. The patient used alcohol regularly in rather large amounts. Previous infection of the genital tract was denied. The first examination in the out-patient clinic found a group of 4 or 5 large, hard, discrete lymph nodes in the right supraclavicular region, the largest measuring about 2.5 cm. in diameter. Enlarged nodes could be felt also in the right inguinal region but these could not be felt so distinctly because of a thick layer of adipose tissue overlying them. Tenderness was noted over the upper lumbar vertebrae and along the tenth and eleventh ribs on the left side. There was marked swelling of the right leg. A firm nodule in the left lobe of the prostate was found on rectal examination and additional nodules were reported in the 1 Read before the American Association of Genito-Urinary Surgeons, Stockbridge, Mass., June 11, 1943. 59
60
ROGER C. GRAVES AND JAMES CROSS
hollmv of the sacrum. The diagnosis of carcinoma of the prostate was made and the question raised of a possible separate process, perhaps a lymphoma. Hospital admission was recommended. The patient entered the hospital on October 5. His laboratory record was as follows: The urine was acid, 1.021; albumin, slight trace; sugar, absent; sediment, an average of 10 red blood cells and 10 white blood cells per high power field. The blood Hinton was negative. The white blood count was 8,900. Red blood count, 4,200,000; hemoglobin, 12.2 gm. or 78 per cent. The differential count was normal. The serum acid phosphatase was 0.5 Bodansky units. X-ray Report: Examination of the pelvis showed no definite evidence of malignant disease. There was abnormality, however, in the fourth lumbar vertebra. The density of the bone was slightly increased and in the anterior view along the right side, there was a mottled appearance. There was also very slight narrowing of the body of the vertebra on that side. No other change was found in the bones of the lumbar spine. The chest film showed a normal outline of the diaphragm. There was prominence of all the lung markings and there was definite enlargement of the hilus shadows. The aorta was dilated but there was no significant increase in the size of the heart. Enlarged hilus and mediastinal glands appeared to be present. Conclusion: The change in the fourth lumbar vertebra could have been due to lymphoma or metastasis from the prostate. The film of the chest was also consistent with lymphoma although metastatic disease could be excluded A gland was removed for biopsy from the right supraclavicular area on October 13, 1942. Pathological report: Study of the specimen showed an oval smooth encapsulated nodule about 2.5 by 1.5 by 1.5 cm. On the cut surface there appeared four closely packed nodes with thin capsules all filled with moderately firm, red-gray homogeneous tissue. .L11icroscopic: The nodes were nearly completely replaced by masses of immature epithelial cells. These were for the most part large clear cells, with round or oval vesicular nuclei containing several prominent nucleoli. Mitoses were frequent. The cytoplasm stained poorly. The cells were tightly packed into large masses or alveolar groups with scattered, well-formed acinar lumina in the central portion. Many clumps lay in dilated lymphoid sinuses and two were present in large blood vessels. Diagnos1·s: Metastatic adenocarcinoma, not typical of carcinoma of the prostate, pharyngeal carcinoma. The patient was first seen in urological consultation on October 21. On rectal examination we found induration in the prostate and the left lobe was particularly firm and fixed. Rectal palpation alone, however, did not warrant a positive diagnosis of malignant disease. A cystoscopic examination was made under spinal anesthesia. The cystoscope was introduced with some difficulty because of marked rigidity in the region of the vesical neck. There was no · neoplasm to be seen at the outlet of the bladder or in the deep urethra. There was some encroachment by the prostate but no significant obstruction except for a moderately large pale median bar. With the transurethral resectoscope, 2 segments of tissue were removed from the prostate posteriorly. Frozen section examination of this tissue found car-
REGRESSION OF LYMPH NODE METASTASES
61
cinoma resembling somewhat the tumor found in the gland of the neck and not typical of primary prostatic carcinoma. Rectally, under anesthesia, the prostate was firm, slightly enlarged and uneven in consistency but there were no changes on which one could base a positive diagnosis. The final decision was made by Dr. Shields Warren who reviewed all of the sections, including those from the supraclavicular lymph node, and identified the tumor as an adenocarcinoma of the prostate (figs. 1, 2 and 3). His microscopic description of the prostate tissue was as follows: "Permanent sections show dilated acini packed with hyperplastic epithelium forming small closely
Fm. 1. Showing primary prostatic carcinoma of anaplastic type. tortion of tissue from heat of high-frequency loop.
There is some dis-
packed alveolar structures. Invasion of the surrounding stroma is seen, as well as perineural spread. The cells are anaplastic, irregular in size and shape and show deeply staining nuclei." On October 27, the patient reported a sudden onset of pain in the left chest and x-ray films revealed a recent fracture of the sixth rib on the left side. This appeared as a complete transverse break, with displacement, about 7 cm. from the vertebral column, probably a pathological fracture, though no signs of metastatic disease were seen in the bone in this region. Bilateral orchidectomy was performed on October 28, 1942. The testis alone was removed on each side leaving the cord and epididymis and parietal layer of the tunica vaginalis. There was no untoward reaction to this operation and the cosmetic result was excellent. The patient left the hospital with no symptoms, on November 7. Pathological report: The specimen consisted of 2 testes each 4 by 3.2 by 2.2 cm. covered by shiny, smooth, gray tunica vaginalis. On section each bulges and shows the normal, soft, bright yellow structure. Microscopic:
62
ROGER C. GRAVES AND JAMES CROSS
FIG. 2. Showing metastasis of undifferentiated carcinoma in cervical lymph node
FIG. 3. Showing fibrous tissue replacing tumor in inguinal lymph node. tumor cells persist.
A few scattered
The tubules showed excellent spermatogenesis with many mitoses in the spermatocytes and numerous spermatozoa. At the first out-patient visit, about 4 weeks after his discharge from the hos-
REGRESSION OF LYMPH NODE ME'l'ASTASES
63
pital, the patient stated that he had gained 10 pounds. He had returned to work. His only discomfort was caused by the swelling of his right leg. Examination found definite regression of the glands in the neck and in the right groin. Stilbestrol was prescribed, 1 mg. every other day. One month later, the general condition was described as highly satisfactory except for the edema of the leg. The glands in the groin had subsided markedly; no nodes could be felt in the supraclavicular area. The dosage of stilbestrol was increased to 1 mg. daily February 20, 1943, about 4 months after orchidectomy and when stilbestrol had been given in small amounts for nearly 12 weeks, a lymph node was removed for biopsy from the right inguinal region. It had been planned at the same time to excise one of the previously enlarged cervical nodes for com parison with the gland removed prior to orchidectomy, but careful palpation failed to find any evidence of enlarged nodes in the neck. Pathological report: The specimen consisted of a rounded moderately firm elastic piece of pale gray tissue about 1 by 0.8 by 0.6 cm. On cut surface, it was shiny, firm and mottled with gray and bright yellow. No clear capsule was evident. Microscopic: Much of the node was replaced by dense but rather edematous connective tissue containing rn,i.merous small capillaries. Scattered in this stroma were about a dozen islands of epithelial cells with large nuclei and scanty but clear cytoplasm. These formed solid masses or occasionally good acini. A few showed pyknosis and disintegration of cells. Occasional large cells were scattered singly in the stroma and may be epithelial in character. Diagnosis: Metastatic carcinoma, apparently regressing. X-ray studies were repeated in the Out-patient Department on April 29th. The previously described changes in the fourth lumbar vertebra were still present, but there appeared to be slightly less density posteriorly than in the earlier films. There had been marked improvement in the chest and the chest film was reported to be normal. At the last out-patient visit, May 26, 1943, the patient stated that he felt perfectly well. He was driving a car regularly as a salesman and working in a Victory garden besides. His weight was 180 pounds-a gain of nearly 20 pounds since leaving the hospital after orchidectomy. The swelling of the right lower extremity had disappeared except for edema of the foot. On rectal examination the prostate showed marked regression. It was described as small and soft and resembling early benign hypertrophy. COMMENT
It seems highly probable that the clinical difficulties of diagnosis in this case, as far as the rectal examination was concerned, were related to the uncommon type of prostatic tumor that was present. It was very cellular and anaplastic and had but little stroma. It was highly malignant and the sections showed blood-vessel invasion which is rare in carcinoma of the prostate. REFERENCE E. L., AND KAHLE, P. J.: The effect of diethylstilbestrol and diethylstilbestrol diproprionate on carcinoma of the prostate gland. II. Cytolog1c changes following treatment. J. Urol., 48: 99-112, 1942.
ScHENKEN,
J. R.,
BURNS,