Yonago Acta medica 2010;53:71–75

ACTH-Producing Breast Cancer: A Patient Report
Naotaka Uchida, Kiyosuke Ishiguro, Takako Suda, Yasushi Horie* and Motonobu
NishimuraDivision of Organ Regeneration Surgery, Department of Surgery, School of Medicine, Tottori University Faculty of Medicine and *Division of Pathology, Tottori University Hospital, Yonago 683-8504,
Japan

Ectopic ACTH secretion in the setting of breast cancer is extremely rare but when present affects both the tumor’s behavior and the incidence of complications. The patient, a58-year-old woman, first presented with a mass in her left breast as well as multiple osseous metastases and a right femur fracture. Laboratory data revealed a hypokalemic alkalosis. Her plasma ACTH level was elevated. She was diagnosed with breast cancer withectopic ACTH secretion, and underwent a left mastectomy and axillary lymph node dissection. Histological examination demonstrated a poorly differentiated neuroendocrine carcinoma with ectopic ACTH secretion. Although the signs and symptoms of ectopic ACTH
secretion from a breast cancer are frequently subtle, the recognition of ectopic ACTH secretion from breast cancer is important for patient management.
Key words: adrenocorticotropic hormone; breast cancer; neuroendocrine cancer

The ectopic secretion of ACTH in the setting ofcancer is well demonstrated in small-cell lung carcinoma, neuroendocrine tumors of the lung, thymus, gastrointestinal tract, islet cell carcinoma of
the pancreas, pheochromocytoma and medullary
thyroid carcinoma (Isidori and Lenzi, 2007). Many
breast cancers are steroid hormone dependent andmay influence the pathological course of the disease by stimulating the initial phase of steroid hormone biosynthesis converting cholesterol to pregnenolone in the adrenal cortex (Wigg et al., 1999).
Especially, in post-menopausal patients, most of
the circulating estrogen is produced by the aromatization of adrenal androgens in peripheral tissues.
Therefore, it is speculated that ACTH would impact the behavior of breast cancer. However, ectopic ACTH secretion from breast cancer is rare, andis associated with less than 1% of tumors (Isidoriand Lenzi, 2007). The incidence rate of neuroendocrine cells in breast cancer has been reported tobe 21.0% (17/81 patients); however, none of the 17

expressed ACTH (Yao et al., 2003). Furthermore,
it is subtle and produces few signs of clinicallyrecognizable Cushing’s syndrome. Consequently,
assessment for ectopic ACTH expression is notroutinely performed in the management of breast
cancer. Here, we report a case of immunohistochemically confirmed ectopic ACTH secretion ina breast cancer patient, which was identified when
she developed hypokalemic metabolic alkalosis.

Patient Report
The patient, a 58-year-old woman, was first presented with a 7-month history of a mass in herleft breast. On physical examination, she had anulcerated 7 cm mass on her left breast. She had no
Cushingoid features including central abdominal
obesity, pigmentation, striae or facial hirsuitism. Amammogram showed a high density, microlobulated, oval mass and pleomorphic segmental calcifi71

N. Uchida et al.

Fig. 1. Bilateral MLO views by mammography. L-MLO view shows a high density, microlobulated, oval mass and pleomorphic segmental calcification, which is highly suggestive of malignancy. L, left; MLO, mediolateral oblique; R, right.

µg/dL). Her plasma ACTH level was elevated to83.5 pg/mL (normal range: 7.2–63.3 pg/mL). Her
serum aldosterone and renin levels were within thenormal range. Her daily urinary secretion of potassium was 26.0 mEq/day, which was within normal range. Her pituitary gland appeared normalon MRI.
The patient was diagnosed as with presumptive stage IV breast cancer with suspected ectopic
ACTH secretion. She underwent a left mastectomy
and axillary lymph node dissection for local control. Histological examination of tissue obtained
from the primary mass revealed a poorly differentiated neuroendocrine carcinoma (Fig. 2). One of
12 axillary lymph nodes was positive for metastatic
carcinoma. The resected tissue was positive forsynaptophysin on immunohistochemistry (Fig. 3),
neuron-specific enolase, chromogranin A andACTH (Fig. 4). The tumor also expressed both
estrogen and progesterone receptors. Human epidermal growth factor receptor type 2 expression
was negative on immunostaining and fluorescencein situ hybridization. Ki-67 staining revealed that42­% of the cells were positive.

cation (Fig. 1). The tumor was oval and ill-definedwith low echogenicity on ultrasound. Aspiration
biopsy cytology revealed suspected malignancy,
which we presumed to be invasive ductal carcinoma. Computed tomographic scan demonstrated
a mass at the left primary site. Lesions consistent
with osseous metastases were present in the cranialbone, sterna bone, ribs, vertebras, bilateral iliumand bilateral femurs. These were also evident on abone scintigram. The right femur demonstrated apathological fracture. The patient also had a meningeal metastasis. The following tumor markerswere elevated: carcinoembryonic antigen (CEA),
135.0 ng/mL; carbohydrate antigen15-3 (CA15-3),
138.5 U/mL; and national cancer center-ST439(NCC-ST439), 470.0 U/mL. Breast cancer antigen225 (BCA225) [93.6 U/mL] and tissue polypeptide antigen (TPA) [38 U/L] were within the normalrange.
Initial serum chemistry studies revealed ahypokalemic metabolic alkalosis with a serum
potassium level of 2.3 mEq/L, bicarbonate of 32.7mmol/L and pH 7.45. The patient’s morning serum
cortisol was 11.54 µg/dL (normal range: 6.7–22.672

ACTH-producing breast cancer

Postoperatively, the patient
was initially treated with letrozol for 2 months; however, hertumor marker values graduallyincreased, and administrationof tamoxifen was initiated.
Her plasma ACTH level wasdecreased to 36.4 pg/mL at 3
postoperative months. She also
received radiation therapy toher vertebral metastasis. Her
hypokalemia was treated withpotassium supplement. She
survives 3 months after surgery,remaining stable, and has been
followed as an outpatient.

Fig. 2. Micrograph ofthe primary breast tumor.
Eosinophilic tumor cells areshown (hematoxylin-eosinstain). Bar = 100 µm.

Fig. 3. Tumor cells with synaptophysin positivity are diffuselypresent. Arrow shows a representative one (synaptophysinstaining). Bar = 100 µm.

Fig. 4. Tumor cells with ACTH positivity are diffusely present. Arrowshows a representative one (ACTHstaining). Bar = 100 µm.

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N. Uchida et al.

Table 1. Cases of breast cancer with ACTH secretion
Reference

Patient Signs and symptoms
Age*		ACTH
(pg/mL)

Cortisol Pottasium(µg/dL) (mEq/L)

Prognosis

Cohle et al.

1979

70			
Cushing’s syndrome like
puffy face, pedal edema,
hypertension and hyperglycemia were present

540

48–72†

1.8

Died from sepsis(2 years after surgery)

Woodard et al.

1981

44			
Cushingoid appearance

188–190

54–87

1.8

Died from multiple metastases (10 years after surgery)

Parker and Jackson 1984

69			Cushing’s syndrome wasobvious, with moon face,plethora, hirsutism,a dorsocervical fat padand centri petal obesity

290

78

1.6

Died from pulmonary
sufficiency and congestive
heart failure(16 years after first surgery)

Wigg et al.

1999

56			
Cushing’s syndrome wasobvious, with facial fullness,
central abdominal obesity
and moderate facial hirsutism

395

46

2.7

Died from pneumonitis andadult respiratory distresssyndrome(11 months after surgery)

Pelte et al.

2004

50			
Cushing’s syndrome waspresent

240

Unknown

1.8

Died from progressive heart
failure and arrhythmia

Present patient

2010

58			
No Cushing’s syndrome

83.5

11.54

2.3

Survive(3 months after surgery)*Age (year). Gender of patients, female.
†mg/dL.

other ectopic ACTH-producing cancers such aslung and bronchial carcinoid tumors, in which
the majority of patients present classical signs
and symptoms of Cushing’s syndrome (Isidori etal., 2006). It is probably because the amount ofACTH secreted by the tumors was insufficient tocause clinical manifestations of hormonal hyperactivity. To our knowledge, only 5 cases of breast
cancer with Cushing’s syndrome were previously
published (Cohle et al., 1979; Woodard et al., 1981;
Parker and Jackson, 1984; Wigg et al., 1999; Pelte
et al., 2004) (Table 1). Reported patients had mean
plasma ACTH levels as 188 to 540 ng/L, while ourpatient had a mean plasma ACTH level of 83.5 ng/
L (Table 1). These suggest that the clinical presentation of ectopic ACTH-producing breast cancer
varies and reflects the underlying severity of theACTH secretion.
Although our patient lacked the classic stigmata of Cushing’s syndrome, ACTH-producing
breast cancer was identified by hypokalemic meta-Discussion
In the breast, there are two main types of neuroendocrine tumors: neuroendocrine differentiated carcinoma and breast carcinoma with neuroendocrine
differentiation. The latter is identified in 10 to 15%of breast cancers. In the former, the majority ofcells (more than 50%) display a neuroendocrine
phenotype, often with a visible endocrine morphology and expression of synaptophysin, neuron-specific enolase and /or chromogranin A by immunohistochemistry. In our patient, the majority of cells
were positive for synaptophysin, neuron-specificenolase and chromogranin A. Furthermore, immunostaining of ACTH was positive. Therefore, we
made the diagnosis of a neuroendocrine differentiated carcinoma with ectopic ACTH secretion.
In ectopic ACTH-producing breast cancer,
few patients show symptoms of Cushing’s syndrome (Poddar et al., 2005). It is contrastive to74

ACTH-producing breast cancer

bolic alkalosis enough to be required to correctone. Hypokalemia has been reported to be present
in 70% of the patients with ectopic ACTH secretion(Isidori et al., 2006). Reported patients with ACTHproducing breast cancer along with Cushing’s syndrome had severe hypokalemia (Table 1). Thesesuggest that ectopic ACTH secretion should beincluded in the differential of breast cancer patientswith significant, unexplained hypokalemia.
Even though the ACTH level in our patient
was low, ACTH could continuously stimulate theadrenal cortex in a sub-clinical manner to produce
excess androgens, thereby modifying the course of
the disease. A recent finding is that up to 50% of
patients with ectopic ACTH secretion may present
osteoporosis or fractures (Ilias et al., 2005). Ourpatient had a fracture of her right femur associatedwith a metastatic lesion. It is possible that ectopic
ACTH secretion not only influences disease progression but also increases the rate of associatedcomplications. Therefore, awareness of covert
ectopic ACTH secretion is important in the management of breast cancers with neuroendocrinefeatures.
The treatment of ectopic ACTH secretion
requires a multimodal approach including surgery
and medications to control tumor growth and associated symptoms. If a single source is located,surgery is associated with complete remission in
more than 80% of patients (Isidori et al., 2006).
Patients with overt, severe ectopic ACTH secretion
are treated with ketoconazole or metyrapone (Isidoriand Lenzi, 2007; Pelte et al., 2004; Wigg et al.,1999).
The prognosis of cancers with ectopic ACTH
secretion depends on the primary tumor histology
and the presence of metastases (Isidori and Lenzi,2007). The survival of patients with an occultsource of ACTH, but adequately controlled hypercortisolemia, is reported to be favorable (Isidori etal., 2006). In our patient, the tumor histology ofa poorly differentiated neuroendocrine carcinoma

with a high Ki-67 index and several metastases
predicts a poor prognosis irrespective of the patient’s ACTH level.
In conclusion, ectopic ACTH secretion froma breast cancer is rare and the signs and symptoms
are frequently subtle; however, recognition of ectopic ACTH secretion is important for patient management.
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Received October 1, 2010; accepted October 20, 2010
Corresponding author: Naotaka Uchida, MD, PhD75