RECURRENT INVASIVE DUCTAL BREAST CARCINOMA PRESENTING AS PRIMARY ADRENAL INSUFFICIENCY WITH ADRENAL CRISIS

Abstract

Objective:

We report the first case of recurrent ductal breast carcinoma presenting as primary adrenal insufficiency.

Methods:

We describe a patient who developed a recurrence of invasive ductal breast carcinoma which went undetected until the patient presented with fulminant adrenal crisis. We describe here an overview of the clinical presentation, work-up, diagnosis, and treatment of adrenal crisis.

Results:

Adrenal crisis due to bilateral adrenal metastases secondary to invasive ductal breast carcinoma is an exceedingly rare occurrence. To our knowledge, this is the first case of recurrent breast carcinoma in which the presenting feature is primary adrenal insufficiency.

Conclusion:

Patients with a history of breast carcinoma and bilateral adrenal enlargement should be evaluated for the presence of primary adrenal insufficiency.

INTRODUCTION

Although adrenal metastasis is a common phenomenon in advanced malignancy, adrenal crisis due to bilateral adrenal metastases secondary to invasive ductal breast carcinoma is an exceedingly rare occurrence, with most prior reports being associated with lung and gastrointestinal malignancies (1).

CASE REPORT

We present the case of a 70-year-old woman with a history of right-sided invasive ductal carcinoma (IDC) estrogen receptor (ER)/progesterone receptor (PR) negative, human epidermal growth factor receptor 2 (Her2/neu) positive, diagnosed in December, 2012, treated with segmental mastectomy and single-agent Herceptin. The patient had a local recurrence of right IDC in February, 2014, and was treated with a total mastectomy, axillary lymph node dissection, and Abraxane/Herceptin.

She presented to the hospital with a 10-day history of weakness, nausea, vomiting, and diarrhea. She was found to be hypotensive (mean arterial pressures of 50 mm Hg), tachycardic (heart rate of 100 to 110 beats per minute), hyponatremic (125 mmol/L) and hyperkalemic (6.3 mmol/L), and was admitted for fluid resuscitation, vasopressor support, and broad-spectrum antibiotics. Computed tomography of the chest, abdomen, and pelvis revealed mass-like thickening of bilateral adrenal glands as well as axillary, mediastinal, and abdominal lymphadenopathy (Fig. 1). The patient failed to improve with guideline-directed therapy for septic shock and was becoming increasingly obtunded.

Fig. 1.

Computed tomography demonstrating mass-like thickening of bilateral adrenal glands.

After noting hyperpigmentation present on the patient's face, knuckles, palmar creases, buccal mucosa, and areolae, a diagnosis of adrenal insufficiency was suspected (Fig. 2 through 4). A random afternoon cortisol level was 2.6 mcg/dL (normal, 2.7 to 10.5 mcg/dL) along with an elevated adrenocorticotropic hormone (ACTH) of 480 pg/mL (10 to 48 pg/mL). A random aldosterone level <1 ng/dL (normal, <30 ng/dL), DHEA-sulfate <1 mcg/dL (normal, <84 mcg/dL), and a cosyntropin stimulation test (following 250 mcg intravenous [IV] cosyntropin, a plasma cortisol level at 30 minutes of 2.8 mcg/dL, and at 60 minutes of 2.2 mcg/dL) confirmed primary adrenal insufficiency.

Fig. 2.

Knuckle pigmentation.

Fig. 4.

Darkening and pigmentation of facial skin.

Fig. 3.

Pigmentation of the palmar creases.

The patient was administered hydrocortisone 100 mg IV every 8 hours, and within a few hours showed dramatic improvement. Biopsy of an axillary lymph node confirmed the diagnosis of metastatic invasive ductal carcinoma. Immunohistochemical staining demonstrated ER/PR negative, Her2/neu positive expression (Fig. 5 and 6). The patient was transitioned to oral dosing and discharged on hydrocortisone 20 mg per os (PO) at 8:00 am, 10 mg PO at 3:00 pm, and fludrocortisone 0.1 mg PO 4 times a day, and made a full symptomatic recovery.

Fig. 5.

Immunostaining of adrenal metastatic disease, HER2 (immunohistochemistry, ×200). Tumor cells with HER2 2+.

Fig. 6.

Histologic section of adrenal metastatic disease (hematoxylin and eosin, ×100). Tumor cells arranged in solid nests infiltrating lymph node tissue.

DISCUSSION

Breast cancer is the most commonly occurring malignancy and the second leading cause of death in women worldwide (2). In patients with metastasis, the most common sites were noted to be bone, liver, lung, and brain, but rarely to the adrenals (3). This is important as the site of first metastasis has been used in prognostication and has shown to directly correlate with overall survival rate (4).

In a study conducted over a 30-year period, 464 patients were found with metastatic disease in the adrenal glands. The primary tumors were most commonly hematopoietic neoplasms (lymphomas/leukemias), lung carcinomas, and gastric carcinomas, with 67% of patients having adrenal metastasis detected incidentally during the diagnosis of the primary tumor. Of these, only 2.9% of cases involved metastasis from breast cancer, and none of them were adrenal metastasis from IDC (5).

Distinct metastatic pathways for breast cancer subtypes driven by specific biomarkers have been proposed, with tumorigenesis resulting when tumor-specific factors are complemented by the host microenvironment (6). Kennecke et al (7) investigated sites of metastatic spread in 3,726 patients and demonstrated marked differences in site predilection on the basis of breast cancer subtype.

In a study of metastatic patterns of breast cancer, Borst et al (8) reported that in a group of 2,246 patients with invasive ductal carcinoma, there were no observations of adrenal gland metastasis. This occurrence has only been demonstrated in prior case reports (3,6,9–12). Adrenal involvement usually occurs in the setting of widespread metastasis with solitary adrenal metastasis exceedingly rare (2). As a result, distinct metastatic pathways for invasive ductal carcinoma are yet to be fully understood.

Adrenal crises are the most severe manifestation of adrenal insufficiency and can occur at a rate of 5 to 10 crises per 100 patient-years (13,14). Signs and symptoms of adrenal insufficiency are seldom recognized and often overlooked in patients with an established diagnosis of cancer. This presentation can overlap with that of the primary malignancy, creating a diagnostic conundrum for clinicians. While the adrenal glands are a common site of involvement in disseminated malignancy, the incidence of adrenal insufficiency is low and develops only in patients with large bilateral metastases (15), with destruction of more than 90% of the functional cortex (16).

Signs and symptoms of adrenal crisis include nausea, vomiting, weakness, confusion, with biochemical abnormalities consisting of hyponatremia, hyperkalemia, hypercalcemia (13,14). These patients typically also present with hypotension and hypovolemia (16). Although no universally accepted definition of adrenal crisis exists, directed efforts have been ongoing to come to a consensus (13). As of 2019, Rushworth et al (14) defined adrenal crisis in an adult is as “an acute deterioration in health status associated with absolute hypotension (systolic blood pressure <100 mm Hg) or relative hypotension (systolic blood pressure ≥20 mm Hg lower than usual), with features that resolve within 1 to 2 hours after parenteral glucocorticoid administration (i.e., a marked resolution of hypotension within 1 hour and improvement in clinical symptoms over a period of 2 hours).”

A high index of suspicion is paramount in patients with a prior history of cancer presenting with hypotension, fatigue, nausea, vomiting, weakness, particularly in the setting of hyponatremia and normal to high potassium levels. The prevalence of adrenal insufficiency in bilateral adrenal metastasis is approximately 8%, which was calculated using strict inclusion criteria of documented bilateral disease and ACTH stimulation test for diagnosis (17). Secondary outcomes also demonstrated that 15% (3/20) of the cases were caused by breast cancer (17). Adrenal insufficiency should be considered as it may be the solitary sign of disease, as demonstrated in our patient.

Generally, inflammatory stressors are the precipitating events for adrenal crisis (14). This is fueled mostly by infections, whether bacterial or viral (14). Other etiologies include trauma, major surgery, nonadherence to glucocorticoid replacement therapy, and undiagnosed thyrotoxicosis (14). There have additionally been reports of vaccinations triggering cytokine release leading to adrenal crisis (14). Fortunately, with prompt recognition, patients are responsive to replacement therapy with supplemental corticosteroids.

Treatment of adrenal crisis consists of expeditious administration of IV hydrocortisone 100 mg, followed by IV hydrocortisone 200 mg/24 hours as a continuous infusion or divided into IV 50 mg every 6 hours (13,14,18). Usually, after 24 hours, treatment success is noted, and further doses are then tailored to the clinical response with tapering to a maintenance dose over the next 72 hours (14). Guidelines for the management of isolated adrenal metastasis in breast cancer have yet to be delineated; however, adrenalectomy has shown to produce mortality benefit in patients with lung (19), gastric (20), and colonic cancer (21).

CONCLUSION

Tumors that commonly metastasize to the adrenals include carcinomas of the lung, kidney, colon, esophagus, pancreas, liver, stomach, and breast. Metastases are often bilateral, frequently an incidental finding in disseminated metastatic disease, and rarely symptomatic. Primary adrenal insufficiency due to metastatic breast carcinoma is an occurrence previously recorded only in solitary case reports. To our knowledge, this is the first case of recurrent invasive ductal breast carcinoma presenting as primary adrenal insufficiency with Addisonian crisis.

Abbreviations

IDC

invasive ductal carcinoma

IV

intravenous