Quadruple synchronous primary cancers in a single patient

Abstract

Patients diagnosed with quadruple synchronous primary cancers are extremely rare and we present here, to the best of our knowledge, the first case report of this combination of primary cancers. A 70-year-old woman was diagnosed with cervical adenocarcinoma, melanoma on the right leg, invasive ductal cell carcinoma metastasis in the left axilla with no primary breast tumour detected and multiple basal cell carcinomas on the limbs, all within 2 months. The management was conducted in collaboration with six medical specialties. The cancers were surgically managed, with further adjuvant chemotherapy and ongoing hormone therapy for her breast cancer. Four years after the diagnosis, no signs of recurrence or further metastases from any of the cancers are present.

Background

Today, patients are more frequently diagnosed with multiple primary cancers due to better diagnostic tools, increasing longevity and more extensive follow-ups after being diagnosed with cancer, but quadruple synchronous cancers are still extremely rare.^{1 2}

The criteria for multiple primary cancers established by Warren and Gates in 1932 are that each tumour must present a definite picture of malignancy, each must be distinct and the possibility that one was a metastatic lesion from another must be excluded.² Definitions of ‘synchronous cancers’ have varied, with the relevant interval for diagnosis ranging from 2 to 6 months, to as long as one to 2 years.³ Our emphasis is on the importance of evaluating the location, stage and prognosis of all primary cancers. Furthermore, the possibility of a genetic mutation linking the cancers or an association with other cancers must be explored. A multidisciplinary effort of several medical specialties is required to treat and monitor similar cases. Therefore, we highlight the significance of treating the patient holistically rather than employing the tunnel-vision approach that is often the result of highly specialised medical training.

Case presentation

A 70-year-old woman presented to her general practitioner (GP) because of postmenopausal bleeding. The patient reported no previous history of cancer, nor a family history of cancer. Her medical history included hypertension, collagenous colitis and a mild myocardial infarction. Her medications notably did not include any hormone replacement therapy or immunosuppressives. Moreover, her occupational history did not include known hazards for cancer, for example, night shifts, and her body mass index was within the normal range. The GP also observed suspicious tumours on the patient’s left elbow, left thigh and right knee. Hence, the patient was referred to a gynaecologist and a dermatologist.

The patient was reviewed by a dermatologist and was diagnosed with basal cell carcinomas on her left elbow, left thigh and right knee. The dermatologist also discovered a naevus suspicious for melanoma on the right lower leg and referred the patient for evaluation at the department of plastic surgery. Subsequently, the patient received further diagnosis of melanoma after it was primarily excised with a margin of 5 mm (figure 1).

Figure 1.

Photograph of the melanoma excised from the right leg primarily with 5 mm margin.

Following an investigation at the department of gynaecology, the patient was diagnosed with adenocarcinoma of the cervix. As part of the cancer staging investigation, a full-body positron emission tomography (PET)-CT scan was performed, which showed a focus located in the left axilla (figure 2). This was biopsied using fine-needle aspiration. Immunohistochemical evaluation revealed the oestrogen receptor (ER) 90% positive, and human epidermal growth factor receptor 2 protein overexpression. The tumour cells responded strongly to staining for CK19 and mammaglobin, consistent with metastasis from the breast. Hence, the conclusion of invasive ductal carcinoma metastasis was made. However, further imaging investigations of the breast tissue with mammography, ultrasound and MRI modalities did not detect a primary tumour in the breasts. All four cancer diagnoses and treatments were initiated within 2 months of referral from the GP.

Figure 2.

PET-CT image with a hypermetabolic focus in the left axilla.

Differential diagnosis

Postmenopausal vaginal bleeding is a classical red flag symptom of gynaecological cancer and is estimated to occur at presentation to secondary care in 90% of endometrial cancer cases,^{4 5} whereas 4%–5% of patients with postmenopausal bleeding are found to have endometrial cancer,^{6 7} although further investigations may reveal benign pathology such as endometrial polyps. Examination to exclude pathologies of the vaginal and cervix is essential, and in this case, the diagnosis of cervical cancer was reached through gynaecological examination together with transvaginal ultrasound and biopsy of the cervical lesion.

Differential diagnoses of basal cellular carcinoma include adnexal tumours with follicular, sweat gland or sebaceous differentiation, where only histology can reveal the diagnosis as these can be hard to distinguish clinically.⁸ With pigmented skin lesions, a number of differentials are possible, but malignant melanoma is the most concerning given mortality. Differential diagnoses include pigmented basal cell carcinoma, or alternatively, benign pathologies are possible such as blue naevus. The only way to distinguish with certainty is to excise the entire lesion and have it assessed by a pathologist, as was done in this case.

The cause of the focus found on the PET-CT in the left axilla was more obscure and could have represented a pathology of the lymph nodes such as infection, primary malignancy in the lymph nodes or metastasis from cancers at other locations. A primary breast cancer sited in the axillary extension of the breast could present with a tumour in that location; however, in this case, biopsy and histology revealed the tumour to be a metastasis from breast cancer.

Treatment

The dermatologist treated the basal cell carcinomas with curettage. On histological examination, all three basal cell carcinomas were found to be of the superficial spreading variant, of stage T1N0M0.

For the melanoma on the right lower leg, the treatment was wide local excision with a 2 cm margin and sentinel node biopsy. Histology identified a superficial spreading malignant melanoma of 1.1 mm tumour thickness, no ulceration, mitoses or regression, and no metastasis was found in the sentinel node, hence, stage T2N0M0.

The adenocarcinoma of the cervix was solely surgically managed. Treatment was a laparoscopic radical hysterectomy, bilateral salpingo-oophorectomy and pelvic lymph node dissection. The histological examination found cervical cancer with no metastasis to pelvic lymph nodes, FIGO stage 1b2. The tumour tested positive for human papillomavirus (HPV) 18.

Invasive ductal cell carcinoma metastatic lesion was surgically managed with dissection of the lymph nodes from level I and II of the left axilla. Histology revealed metastasis in 12 of 15 lymph nodes excised. An invasive ductal cell carcinoma of stage TxN3M0 was diagnosed. Further oncological treatment following the operation included adjuvant chemotherapy, trastuzumab (Herceptin), letrozole (anti-oestrogen therapy) and radiotherapy to the left axilla.

Outcome and follow-up

Following an uneventful postoperative course, and now almost 4 years after the initial presentation, the patient is alive and free from cancer recurrence. The patient receives follow-up care at the department of oncology and still receives antioestrogen treatment for the ER-positive invasive ductal cell carcinoma and does not present with any adverse effects from the medical treatment. Furthermore, the patient undergoes yearly full-body skin examinations at a private-practicing dermatology clinic and has been treated several times for new basal cell carcinomas on the extremities.

Discussion

A review of current literature indicated that this is the first report of a patient with quadruple synchronous primary cancers of the breast, cervix and the skin, that is, melanoma and basal cell carcinoma. A case report of synchronous primary cancers of the breast and cervix is described by Verstovsek et al.⁹ In the case we report, the timing of diagnosis being within 2 months is consistent with previous definitions of synchronous cancers. The four primary cancers are not thought to be linked by hereditary gene mutations. The cervical cancer is likely to be due to the patient being infected with HPV 18, as it is a known oncovirus with 70% of all cervical cancers are due to infection with HPV 16 or 18.¹⁰ In this case, the patient was treated surgically, but treatment options for cervical cancer stage Ib2 may include primary radiotherapy, depending on local clinical guidance, considering patient preference and comorbidity.¹¹

Regarding the metastasis in the axilla from the invasive ductal cell carcinoma, breast cancer is the most common cancer diagnosis among women, and in Denmark, 4694 women are diagnosed with breast cancer every year, with the risk of breast cancer by the age of 75 years ~1 in 10.¹² The occurrence of occult cancer (where metastasis to the axilla is detected with no primary breast tumour identified) is thought to comprise 0.1%–0.8% of breast cancers. Occult cancers may result from the immune system eliminating the primary tumour.¹³

BRCA2 gene mutation carriers have been found to be at a heightened risk of developing malignant melanoma¹⁴; however, as the patient has no family history of breast cancer or ovarian cancer, the chance of the patient being a BRCA1 or BRCA2 mutation carrier is very low. Both melanoma and basal cell carcinoma are likely to be because of cumulative exposure to ultraviolet radiation, as these cancers were in frequently sun-exposed areas, and furthermore, the patient has Fitzpatrick skin type 2 which puts her more at risk of developing skin cancer.¹⁵

Patient’s perspective.

During the time of diagnosis and treatment I felt very well looked after and I felt the doctors involved with my care were well informed of my other diagnoses. I hope that this article will inspire doctors to remember that it is the patient as a whole who is always in for a consultation. If you as a healthcare professional can’t help with the immediate problem take the time to help by pointing the patient in the right direction.

Learning points.

• Synchronous quadruple primary cancers are extremely rare.

• Multiple primary cancers are on the rise due to improved diagnostic technology increasing life expectancy, and vigorous follow-up and surveillance after cancer.

• Communication and coordination of care is key to the management of patients with synchronous cancers.

• As doctors, we have to remember to always look at the patient as a whole even though with more specialisation we are keen to look at patients with a narrower lens.