ACTH-SECRETING CARCINOMA OF THE BREAST
STEPHEN D. COHLE, MD, JAIME A. TSCHEN, MD, FRANK E. SMITH, MD, MONTAGUE LANE, MD, AND MALCOLM H. McGAVRAN, MD
We report a case of ACTH-secreting carcinoma of the breast. Membrane- bound secretory granules were seen within the cancer cells electron micro- scopically. Cytoplasmic granules reacting immunochemically to anti-ACTH antisera were seen on light microscopy. Breast cancers have been shown to secrete calcitonin, parathyroid hormone, human chorionic gonadotropin, and norepinephrine in addition to ACTH. This suggests either the presence of neuroendocrine cells in the breast as a source of such neoplasms, as in the lung, or genomic derepression during neoplastic transformation. Cancer 43:2370-2376, 1979.
S INCE THE FIRST DESCRIPTION of the ectopic ACTH syndrome,8,10 many neoplasms, notably oat cell carcinoma of lung, thymomas, and islet cell tumors of the pancreas, have been shown to secrete ACTH. Only one ACTH secreting carcinoma of the breast has been mentioned8; we report a well-documented case.
CASE REPORT
A 70-year-old obese white woman with moderate hypertension of many years duration first presented with a seven month history of pain in the right breast. Six weeks prior to admission the breast became firm and warm with peau d’orange indura- tion anteriorly. A xeromammogram showed calcifi- cations and she underwent a right simple mastec- tomy in December 1975. Pathologic examination (Fig. 1) showed infiltrating lobular carcinoma in all quadrants except the upper inner. A bone scan and bone roentgenograms demonstrated multiple osseous metastases. She was treated with radio- therapy, including implantation of radioactive seeds in the mastectomy scar and was placed on ethinyl estradiol. In January 1976, she was admitted for acute thrombophlebitis of the left leg and diarrhea that had been present since the onset of estrogen therapy. Since thrombophlebitis has been associated with estrogen therapy such was discon- tinued and she was begun on fluoxymesterone. Hormone therapy was subsequently discontinued after 8 months because of progressive bone
From the Division of Anatomical Pathology, Depart- ment of Pathology and the Section of Oncology, Depart- ment of Medicine and Division of Clinical Oncology, Department of Pharmacology, Baylor College of Medicine, and The Methodist Hospital, Houston Texas.
Address for reprints: Malcolm H. McGavran, MD, Department of Pathology, MS 205 Methodist Hospital, 6516 Bertner, Houston, TX 77030.
Accepted for publication January 19, 1979.
lesions requiring focal radiotherapy for relief of pain. She was subsequently treated with thiotepa which resulted in 14 months of objective and sub- jective improvement followed by relapse in October 1977.
She was readmitted for clinical recurrence of neoplasm in the medial aspect of the surgical scar and her therapy was changed to tamoxifen. A bone scan, liver spleen scan, brain scan, and spine films were all negative for metastatic disease.
In November 1977, she was again admitted with a three week history of fatigue, bilateral pedal edema and back pain. Her admission physical ex- amination showed a blood pressure of 160/100 mm Hg, a puffy face and pedal edema. Laboratory values included a blood glucose of 417 mg/dl, sodium of 144 mEq/1, potassium of 1.8 mEq/l, chloride of 85 mEq/1, CO2 of 44 mEq/l and a serum calcium of 7.1 mg/dl, and serum phosphorus 2.0 mg/dl. She had a left pleural effusion. Because of the hypokalemia, alkalosis and hyperglycemia, morning and evening cortisol levels were deter- mined and found to be elevated: morning 72 mg/dl, (normal 10-26 mg/dl), evening 48 mg/dl (normal 2-10 mg/dl). Dexamethasome, 2.0 mg every 6 hours was administered for 72 hours and cortisol levels after the test were found to be 63 mg/dl in the morning and 68 mg/dl in the evening. Twenty- four hour urinary 17-OH corticosteroids were 56 mg (normal 3-8 mg) and 17-Ketosteroids were 28 mg (normal 5-15 mg) after the test. Serum ACTH levels were 540 pg/ml (30 times normal). Pituitary suppression was suspected on the basis of radioimmunoassay of TSH, FSH, and LH, which showed subnormal levels and a flat TSH stimula- tion curve, using TRH. The pleural effusion was found to contain malignant cells and despite intra- pleural nitrogen mustard therapy it twice reac- cumulated. Hyperglycemia and glycosuria required insulin therapy. The patient was treated with metyrapone eight days prior to death, with a transient decrease in serum glucose, disappearance of glycosuria, and an elevation in serum potassium.
She was treated with 5-fluorouracil and adriamycin and became leukopenic, thrombocytopenia and febrile. Sepsis was suspected although blood and pleural fluid cultures were negative. She died despite treatment with broad spectrum bactericidal antibiotic.
At autopsy, metastatic infiltrating lobular carci- noma identical to that seen in the right mastectomy specimen was found in the left breast, the left pectoralis major muscle, the anterior mediastinum, the left parietal pleura, the right adrenal, the scar of the right mastectomy and the left axillary and anterior mediastinal lymph nodes. Step sections of the hypothalamus showed a single microscopic metastasis. The adrenals weighed 13 g and 14 g, showing adrenal cortical hyperplasia.
MATERIALS AND METHODS
Samples for electron microscopic examina- tion were fixed in 3% gluteraldehyde and embedded in Spurr plastic resin. Sections were stained en bloc with osmium tetroxide and uranyl acetate and lead citrate. Samples of the carcinoma from the mastectomy in 1975 (after deparaffinization and postfixation in
3% gluteraldehyde), of the carcinoma from necropsy, and of the pituitary were studied.
Tissues studied for the presence of ACTH included autopsy material from the left breast and left submammary metastasis. Control tissues were from patients without evidence of Cushing’s syndrome and included a pituitary removed at autopsy from a woman who died of endometrial stromal sarcoma, a section of breast with infiltrating lobular carcinoma, and a section of breast with infiltrating ductal carcinoma. All tissues were formalin fixed and paraffin embedded. Sections were cut at 4 microns, rinsed in deionized water, covered with rabbit anti-ACTH serum 1:250 (courtesy Burroughs Wellcome Co.) for one hour, and washed in phosphate buffered saline 3 times for 10 minutes each. Swine anti-rabbit serum 1:20 was added for 30 minutes and rinsed again in the same manner. Rabbit peroxidase anti-peroxidase 1:100 was added for 30 minutes and rinsed in PBS 3 times. Sections were stained with 0.3% DAB for 15 minutes and counterstained with hematoxylin. Controls
were blocked by covering sections with ACTH ing lobular carcinoma or the infiltrating ductal (40 units, dissolved in 1 cc of 1:20 swine serum) carcinoma used as controls. prior to the addition of anti-ACTH.
RESULTS
Electron microscopy of metastatic carcinoma found at autopsy showed membrane-bound granules measuring from 148 nm to 333 nm (Fig. 2). Similar granules were seen in sections of breast tumor removed at surgery in 1975, but they were far fewer in number. Sections of pituitary stained with toluidine blue showed widespread Crooke’s hyaline change (Fig. 4). Electron microscopy showed a decrease in the number of secretory granules and an increased amount of cytoplasm filaments in affected pituitocytes.
PAP staining for ACTH showed a very fine dark brown cytoplasmic granularity in scat- tered tumor cells (Fig. 3) resembling closely the pattern seen in the control pituitary. This granularity was not seen in sections to which ACTH was added prior to the addition of anti-ACTH, nor was it present in the infiltrat-
DISCUSSION
The clinical data in this case are compatible with hypercorticism due to excessive produc- tion of ACTH, i.e., weakness, hyperglycemia, hypokalemic alkalosis, elevated plasma cortisol levels without diurnal variations, increased urinary excretion of 17-OH corticosteroids and 17-ketosteroids and markedly increased levels of serum ACTH. An ectopic source of ACTH is strongly supported by the fact that plasma cortisol and urinary 17-OH cortico- steroid levels remained elevated despite the administration of 2 mg of dexamethasone every 6 hours for 3 days, since pituitary- derived ACTH is usually suppressed with that dose of dexamethasone.15 The absence of significant changes in physical appearance classically associated with Cushing’s syndrome is also characteristic of the ectopic ACTH production. The presence of hypothalamic metastases suggests the possibility that it
caused, via increased CRF release, a pituitary ACTH hypersecretion. It is also possible that the tumor itself produced CRF, which would account for the hypercorticism. These pos-
sibilities are unlikely in the face of ACTH- containing secretory granules in the breast carcinoma cells. The diameter of the secretory granules in our case-ranging from 148 to
330 nm-is comparable to that seen in Bardi et al.‘s1 case of thyroid medullary carcinoma, in which cells thought to contain ACTH had granules ranging from 85 to 485 nm in diameter. ACTH-containing granules in nor- mal pituitary are thought to range from 200- 500 nm.12
This is the first well-documented report of an ACTH-secreting carcinoma of the breast. In the case mentioned by Liddle et al. 8 ACTH was extracted from tumor tissue and urinary 17-OH corticosteroids and 17-ketosteroids were elevated but secretory granules were not observed, and neither plasma ACTH levels
| Hormone | Signs & symptoms | Biochemical evidence | Morphologic evidence | Cell type | Authors |
|---|---|---|---|---|---|
| ACTH | Hyperglycemia, hypokalemia, edema | ¡urinary 17-OHCS; îplasma cortisol; No suppression with dexametha- sone (2.0 mg q 6h x 8) îplasma ACTH | Secretory granules in cancer cells containing ACTH | Infiltrating lobular Ca. | Cohle et al. |
| Not given | îurinary 17-OHCS; ACTH in tumor extract | Not given | Not given | Liddle et al.8 | |
| Calcitonin | Not given | îplasma calcitonin; calcitonin in tumor extracts | Not given | Not given | Hillyard et al.3 |
| Hormone | Signs & symptoms | Biochemical evidence | Morphologic evidence | Cell type | Authors |
|---|---|---|---|---|---|
| Norepineph- rine | Not given | îserum calcitonin; calcitonin secreted by breast cancer cells in culture | Not given | Infiltrating ductal carcinoma, medullary carci- noma & colloid carcinoma | Coombes et al.3 |
| calcitonin pro- duced by breast cancer cells grown in nude mice | |||||
| Hypertension, 78-year-old man | Urinary norepi- nephrine 238 mg/day | Neurosecretory granules on EM Argyrophil granules on light microscopy | Carcinoid tumor | Kaneko et al. 6 | |
| Parathyroid hormone | Not given | Serum Ca. 16 mg/dl; Serum PO, 4 mg/dl; PTH in tumor extract | Not given | Not given | Mavligit et al.º |
| Vomiting | Serum Ca. 21.6 mg/dl; Serum PO, 3.3 mg/dl; PTH in tumor extracts | Not given | Not given | Melick et al. 11 | |
| HCG | Not given | ¡serum HCG by RIA | Not given | Infiltrating ductal Ca. | Sheth et al. " |
| Not given | îplasma HCG by RIA | Not given | Not given | Braunstein et al.2 | |
| Not given | HCG secreted by breast cancer cells grown on cell culture | Not given | Infiltrating ductal Ca. Colloid carcinoma | Coombes et al.3 |
nor the results of the dexamethasone suppres- sion test are mentioned. The data are sug- gestive but the lack of ultrastructural and immunochemical studies makes it impossible to conclude that ACTH was secreted by that tumor.
Kay7 reports the presence of bilateral adrenal hyperplasia in two patients with breast cancer, but did not suggest the possibility of ACTH production by the breast carcinoma. Rose et al. 13 observed that one third of patients with locally recurrent or metastatic breast cancer had elevated levels of corticosteroid sulfate in their urine, but this may represent response to stress
and was not associated with clinical or chemical hypercorticism.
Other hormones have been produced by breast neoplasms (Table 1). Primary carcinoid tumors occur in the breast4 suggesting the presence of neuroendocrine cells in normal breast duct epithelium. Kaneko et al.6 hypoth- esize that if such exist they will be in the lactiferous duct near the outlet. Cubilla and Woodruff4 noted secretory granules in the three primary carcinoid tumors of the breast they examined electron microscopically. Though not performed, immunochemical studies might have shown hormones to be present.
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