A case of advanced breast cancer with Gitelman syndrome

Abstract

Gitelman syndrome (GS) is a rare, mostly autosomal recessive disease this is a salt-losing tubulopathy caused by mutation of genes encoding sodium chloride (NCCT) and magnesium transporters in the thiazide-sensitive segments of the distal nephron. We encountered a 45-year-old female who has suffered from whole-body weakness because of hypokalemia for 8 years and diagnosed with Gitelman syndrome clinically. She visited the hospital with a complaint of an unrelieved hard mass of the left breast. The tumor was diagnosed as human epidermal growth factor receptor 2 (HER2)-positive breast cancer. We herein report this first case of a breast cancer patient with Gitelman syndrome who developed other neoplasms including colon polyp, adrenal adenoma, an ovarian cyst, and multiple uterine fibroids and provide a review of the pertinent literature.

Introduction

Gitelman syndrome (GS) is rare (prevalence of 1/40,000) autosomal recessive, salt-losing tubulopathy characterized by renal potassium wasting, hypokalemia, metabolic alkalosis, hypocalciuria, hypomagnesemia, and hyperreninemic hyperalodsteronism [1, 2]. It is caused by the mutation of genes encoding sodium chloride (NCCT) and magnesium transporters in the thiazide-sensitive segments of the distal nephron. Most cases are linked to inactivating mutations of SLC12A3, resulting in functional loss of the thiazide-sensitive sodium-chloride symporter [2].

There have been some reports of associations of malignant neoplasms with GS. We experienced a rare case of a breast cancer patient with GS carrying mutations in the SLC12A3 gene who had relative histories of two breast cancers and two prostate cancers.

We herein report this case and provide a review of the pertinent literature.

Case report

A 45-year-old female noticed an unrelieved hard mass of the left breast approximately 1 month previously and subsequently visited a hospital. Clinically, the craggy breast mass, measuring 8 × 6 cm in size, showed poor mobility and the skin change was not clear. No breast tumor was palpable in the other side.

The patient had no history of pregnancy. Irregular menstruation due to uterine fibroids was prominent, with vaginal bleeding maintained over 20 days a month, and hypermenorrhea were controlled by taking low-dose oral contraceptive pill. Her family history was as follows: her mother had suffered from bronchiectasis and scoliosis for a long time, two of her maternal aunts had suffered from breast cancer and Basedow’s disease, her maternal uncle had prostate cancer, the maternal grandfather had died from prostate cancer. Her father had died from pharyngeal cancer in his 50s, and her paternal grandfather had died from colorectal cancer in his 50s. There was no family history of sudden death or weakness of uncertain cause.

Her comorbidity was GS, which she had had for 8 years and been clinically diagnosed with 2 years ago; Hashimoto’s disease with normal thyroid functions; colon polyps; non-functional adrenal tumor; ovarian cysts; and multiple uterine fibroids. She had no evidence of hypertension.

She was on following medication: spironolactone and potassium chloride for GS, ferric pyrophosphate for iron-deficiency anemia, norgestrel ethinyl estradiol for uterine fibroids, and levocetirizine hydrochloride and montelukast for chronic urticaria. She had a contrast medium allergy and a history of anaphylaxis, as well as an allergy to NIFLEC water as a bowel-cleansing agent and shellfish.

The laboratory examination showed hypoferremia (22 µg/dL) and high unsaturated iron binding capacity (UIBC) value (384 µg/dL). In a complete blood count, hemoglobin was low (9.3 g/dL), and platelet was high (64.5 10⁴/µL). The levels of serum Mg and K were not very low on admission (1.7 mg/dL and 3.7 mmol/L, respectively), and the levels of tumor markers (CEA 0.7 ng/mL, CA15-3 5.1 U/mL and serum HER2 6.4 ng/mL) were not elevated. For the reference, in the laboratory evaluation conducted 2 years ago, the plasma renin activity (PRA) had been 8.2 ng/mL/h, and plasma aldosterone concentration (PAC) had 113 pg/mL with an aldosterone–renin ratio (ARR) of 13.7; therefore, primary aldosteronism was not considered a likely cause of the hypokalemia. Furthermore, the serum cortisol level was 13.7 μg/dL, so the adrenal tumor was considered to be a non-functional adenoma. Anti-thyroglobulin antibody and anti-thyroid peroxidase (TPO) antibody were high, 25.27 IU/mL and 187.70 IU/mL, respectively. Furthermore, thyroid-stimulating hormone receptor antibody and thyroid-stimulating antibody were not elevated.

A mammogram showed an obvious high-density lesion in the left breast. Ultrasonography revealed an ill-defined and ill-circumscribed mass, scaled out of the probe. The lesion demonstrated some heterogeneous internal echo with a slight degree of Doppler signaling and slightly hard elasticity on elastography although that accurate evaluation of elasticity was difficult because of the size. The posterior side of the mass was difficult to discern with ultrasonography (Fig. 1A, B). The lesion indicated malignant, and core needle biopsy was performed under ultrasonography, with a diagnosis ultimately made of breast carcinoma, immunohistochemically negative for estrogen receptor and progesterone receptor and positive for HER2.

Fig. 1.

Preoperative examination. A Mammogram of the patient findings showing high-density mass of the left breast. B US findings showing (left) the tumor to be ill-circumscribed, irregular in-shape and hypoechoic in B-mode, (middle) with vascular Doppler signaling. (right) Elastography of the tumor showing the slightly hard elasticity of the mass. C FDG-PET–CT findings showing uptake in the left breast tumor with a maximal standardized uptake value (SUV max) of 9.5 and uptake in the right ilium with SUV max of 6.2

The patient underwent a plain computed tomography (CT) of the chest and abdomen, which revealed a lobulated mass in the left upper breast with many swollen axillary lymph nodes and a small nodule in the upper lobe of the right lung suspected of being metastasis. Furthermore, a left adrenal tumor 24 × 20 mm in size that was thought to be an adenoma was noted. Plain magnetic resonance imaging (MRI) examination without Gadolinium (Gd)-DTPA enhancement of the breast, because of the patient’s contrast medium allergy, demonstrated a mass 57 mm in size and axillar lymph node swellings. Fluorodeoxyglucose-positron emission tomography (FDG-PET) demonstrated FDG-accumulation in the left breast mass, multiple axillar lymph nodes and the right iliac (Fig. 1C). No accumulation was found in the lung or left adrenal grand. Therefore, we diagnosed the patient with left breast cancer with bone metastasis.

We next sought to identify the genomic mutations for GS and breast cancer. BRCA variants were not detected. Targeted gene sequencing panel for Bartter syndrome and GS was carried out. Sequence analysis revealed that two points of known heterozygote mutation regarded by the SLC12A3 gene was detected. The patient has a heterozygous transition (T→A) at nucleotide 2573 located in exon 22, resulting in a Leu to His substitution at amino acid 858. Another mutation that the patient has is a heterogenous transition (C→T) at nucleotide 2927 located in exon 25, resulting in a Ser to Phe at amino acid 976, and which her mother also had. These mutations were reported previously by Monkawa et al. [3] and Jang et al. [4] (Fig. 2).

Fig. 2.

Sequence analysis result showing two points of known heterozygote mutation regarded by the SLC12A3 gene was detected; heterozygous transition (T→A) at nucleotide 2573 located in exon 22, resulting in a Leu to His substitution at amino acid 858 and heterogenous transition (C→T) at nucleotide 2927 located in exon 25, resulting in a Ser to Phe at amino acid 976, and which her mother also had

Although bone metastasis was found, mastectomy of the right breast was needed for local control. A genetic test of SLC12A3 confirmed GS, and the left mastectomy and axillary lymph nodes dissection was performed. A histopathological examination revealed that the mass with necrotic portion had expanded to 12.5 × 9.5 × 7.0 cm in size. Atypical epithelium with pleomorphic nuclei and clear nucleolus proliferated in restiform, solitary and vesicular nest pattern, infiltrating fat tissue. Mitoses were frequently seen, as was lymphovascular invasion, although perineural invasion was not found. Lymph node metastases were found 26 out of 27 examined. Immunohistochemically, the tumor cells were negative for estrogen receptor and progesterone receptor and positive for HER2, score 3 by immunohistochemistry. The Ki-67 index was 25.4% (Fig. 3).

Fig. 3.

A Macroscopic appearance of the specimen of the left breast. B, C Microscopic appearance of the tumor (HE stain), B low-power field, C high power field, showing atypical epithelium with pleomorphic nuclei with frequent mitosis and clear nucleolus proliferated in restiform, solitary and vesicular nest pattern, infiltrating fat tissue with partial necrosis. D–I Immunohistochemical findings, showing the tumor cells were D negative for ER, E negative for PgR, F Positive for HER2, score 3 by IHC, G Ki-67 index 25.4%, H lymph invasion, and I vascular invasion

After undergoing surgery of the breast, she underwent robotic-assisted myomectomy and bilateral adnexectomies for control anemia before starting chemotherapy for breast cancer. Following these surgeries, chemotherapy with anti-HER2-targeted drugs, trastuzumab, and anti-RANCLE antibody were administered under careful observation. The lung lesions did not change at all during the treatments. Her condition has been improving remarkably.

Discussion

Bartter syndrome (BS) and GS are autosomal recessive disorders characterized by metabolic alkalosis, hypokalemia and hypomagnesemia associated with high plasma renin activity and high aldosterone concentration. The main difference between the two syndromes is in the level of urinary calcium excretion, which is low in GS but high in BS [4]. Regarding GS, neither prenatal hydramnios nor poor weight gain in infancy rarely occur, and its clinical symptoms are less severe than those of BS. Therefore, the diagnoses of GS are mostly made as a result of weakness due to hypokalemia or tetany due to hypomagnesemia in later childhood. Although hypokalemia detected by chance in blood test leads to a diagnosis of GS, data on electrolytes vary among cases. Therefore, a genetic diagnosis is very important to distinguish these diseases.

Two reports regarding Gitelman (or Gitelman-like) syndrome with neoplasm were found. A case of GS with pancreatic neoplasm reported by Sampelean, et al. in 2011 [5]. In addition, a case of Gitelman-like syndrome triggered caused by cisplatin therapy was reported by Panichpisal et al. in 2006 [6]. This case involved acquired electrocyte abnormalities associated with renal tubular dysfunction caused by cisplatin. There may be no concern regarding germline mutations of this type of syndrome and neoplasm. Genetic tests were not performed in either case as the diagnosis of Gitelman syndrome was made based on laboratory parameters. Thus, the relationship of neoplasm and Gitelman syndrome with germline mutations remains unclear, although her family history included close relatives with cancer.

According to the guidelines of our country, resection of primary tumor in metastatic or recurrent breast cancer are not recommended for the sake of improvement of the prognosis, but are weakly recommended for local control. We decided to remove the breast and axillary lymph nodes not only for local control but also for mass reduction. We expected to maintain disease control with as little stress to the patient as possible with a lower dose of systemic anti-cancer therapy. For these reasons, it was necessary to perform the operation before chemotherapy.

Irradiation is considered to be a good choice for local control or the relief of pain due to bone metastasis. However, tiny bone marrow suppression because of irradiation to the chest wall or bone could potentially make it difficult to continue anti-cancer therapy in this case. We, therefore, initially avoided radiotherapy in this case. Fortunately, the local condition of the left breast and bone pain have been well tolerated until now.

After surgery, combination chemotherapy including anti-HER2 targeted drugs and anti-RANCLE antibody was needed in this case. However, GS easily induces electrolyte abnormalities due to various stresses; for example, hypokalemia often causes QT interval prolongation, which can be lethal in some cases, such as Torsades de points. Careful observations were, thus, needed for this patient’s treatment. Among representative anti-HER2 drugs, trastuzumab can induce cardiomyopathy and pertuzumab induce hypokalemia and hypomagnesemia, while anti-RANKL drug denosumab also often induce hypocalcemia.

In Japan, the guidelines concerning first-line treatments for recurrent or inoperable HER2-type breast cancers recommend combination therapy of trastuzumab, pertuzumab and docetaxel. Even slight stress can induce fetal electrocyte abnormalities in patients with this syndrome, so we determined to add these medicines gradually while checking the serum electrocyte levels in the present case. In GS, disturbance in NCCT co-transporter in the distal renal tubule causes various electrolyte disorders. Renal toxicity is not so common with trastuzumab therapy, although it reported to occur 1.0% of the patients. The mechanism is unclear but there is no evidence of influence on the renal tubule in basic data. On the other hand, pertuzumab induces hypokalemia and hypomagnesemia, we, therefore, withheld the use of this agent. Furthermore, she suffered from cancer pain due to multiple bone metastasis; thus, an anti-RANKL drug was administered after we had confirmed that there had been no development of electrocyte disorder in association with trastuzumab. However, the anti-RANKL drug induced slight hypocalcemia and hypomagnesemia, and the replenishment of each was needed. The patient has since been administered trastuzumab and anti-RANKL drugs, and her breast cancer is under control, although her serum Mg level remains slightly unstable. We will consider adding either another molecular-target drug, pertuzumab or docetaxel should her disease progress.

Conclusion

We experienced an extremely rare case of familial breast carcinoma with GS. In this case, the patient has multiple neoplasms and some endocrine diseases in addition to metabolic disorders due to this genetic disease. This rare case, therefore, required continued careful observation.

Abbreviations

GS

Gitelman syndrome

HER2

Human epidermal growth factor receptor 2

PRA

Plasma renin activity

PAC

Plasma aldosterone concentration

ARR

Aldosterone–renin ratio

CT

Computed tomography

UIBC

Unsaturated iron binding capacity

MRI

Magnetic resonance imaging

Gd

Gadolinium

FDG-PET

Fluorodeoxyglucose-positron emission tomography

TPO

Thyroid peroxidase

Author contributions

YT carried out the initial assessment and the management of the patient, literature search and drafted the manuscript. TM supported to do genetic diagnosis of GS and draft the manuscript. YS evaluated histopathological features and contributed histological part. All authors read and approved the final manuscript.

Data availability statement

Data sharing is not applicable to this article as no datasets were generated during the current study.

Declarations

Conflict of interest

The authors fully declare any financial or other potential conflict of interest.