Oestrogen Receptor Positive Metastatic Eccrine Porocarcinoma: A Case Report and Review of Anti-Oestrogen Therapy in Rare Cancers

Rare cancers are defined as neoplasms with an annual incidence rate of 6 per 100,000 people or less; and together constitute around 24% of all cancer diagnoses in Europe [1]. With increasing understanding of the molecular and pathological features of cancers, there is a recognition that many more common cancers may need to be considered collections of similar but distinct malignancies. Rare cancer patients experience diagnostic delays and a reduced availability of therapies due to the lack of clinical trials to provide an evidence base for oncological management [1]. Eccrine porocarcinoma (EPC), a rare tumour of cutaneous sweat glands, makes up less than 0.01% of skin-related malignancies [2]. Surgical techniques such as wide-local excision and Moh’s micrographic surgery are employed in the initial management of EPC [2]. However, eccrine carcinoma carries a potential for recurrent and/or metastatic disease and therefore results in significant morbidity and mortality [3]. 10% of EPC cases are found to be metastatic at diagnosis, with 20% of cases reported to develop regional lymph node metastasis [2].

A variety of regimens have been reported; however, there is no standardised approach to the treatment of metastatic disease, and in the instance of regional lymph node metastasis, 5-year mortality rates may be as high as 67% [2]. Here, we describe a patient diagnosed with metastatic EPC who was found to be oestrogen receptor (ER) positive on histological staining, and who responded to treatment with the anti-oestrogen agent, letrozole. This adds to existing data (primarily case reports) supporting the use of anti-oestrogens in ER expressing cancer, agnostic of site of origin.

We describe a 73-year-old female Caucasian patient who presented to a tertiary cancer centre following an incidental finding of extensive bone metastasis on investigation for presumed renal colic. A further PET-CT scan confirmed skeletal metastasis involving both femora, the ribs and spinal column (shown in Fig. 1a), but with no other sites of metastasis or obvious primary malignancy.

Ten years prior to this presentation, the patient had been diagnosed with stage Tx N2b M0 recurrent eccrine carcinoma of the right scalp, for which she had undergone radical surgical resection and lymph node dissection, with involvement of 2 of 42 lymph nodes. This was followed by adjuvant radiotherapy: 64 Gy in 34# to the right neck. Her only other past medical history was of hypertension and uterine prolapse. Her regular medications were felodipine and bendroflumethiazide. She was a life-long non-drinker and non-smoker.

At the time of presentation, she had a performance status of one with good mobility. Her only reported symptoms were of pain in the lower sacrum and right hip, and weight loss, despite good appetite.

The patient underwent bone biopsy, which confirmed metastatic EPC. Immunohistochemistry showed expression of GATA-3, EMA, CK07, AR, ER, and PR positive status. There was no expression of CEAm, CK05/06, TTF-1, CD56, PAX8, p40, and p63. HER2 score was recorded as up to 1 and therefore regarded as negative.

In light of previous case reports suggesting activity with anti-oestrogen therapy in ER-positive rare cancers, we commenced the patient on daily letrozole (2.5 mg). She also received denosumab 4-weekly in view of bone metastases.

The patient reported her pain improved early on in treatment, requiring less paracetamol at 11 days, and discontinuing this at 28 days post-letrozole initiation, foregoing the need for palliative radiotherapy. Additionally, the patient reported weight stabilisation following letrozole treatment. Prior to diagnosis the patient’s weight was recorded at 49.5 kg, with substantial weight gain occurring 3 months following letrozole commencement; this continues to be stable, with a most recent weight measurement of 53.8 kg. There were no side effects to letrozole reported by the patient.

Serial imaging with PET-CT showed a significant reduction in FDG avidity in all sites of disease (shown in Fig. 1b). At the time of last review, over 20-months from letrozole commencement, she remains well with no signs of progression. Her most recent PET-CT scan reports no new sites of disease and stable appearances of widespread predominantly non-FDG avid sclerotic bone disease.

The CARE checklist has been completed for this case report by the authors and can be found in the attached supplementary material (for all online suppl. material, see https://doi.org/10.1159/000535328).

Primary eccrine carcinoma and mammary ductal carcinomas share similar histological and histogenetic phenotypes, and this has historically led to misdiagnosis of eccrine carcinomas as metastatic breast cancer [4]. This is due to the expression of oestrogen and progesterone receptors (PR) in a proportion of both neoplasms, with a comparative study showing a similar expression of ER and PR in eccrine carcinomas and cutaneous breast cancer metastasis; the authors further noted that epidermal growth factor receptor (EGFR) expression may help with their differentiation [5]. Immunohistochemical analysis of 54 cases of apocrine-eccrine carcinomas found ER expression in 27%, PR expression in 16%, EGFR expression in 85% and HER2 expression in 12% of cases [6]. While HER2 overexpression in breast cancer is well described, a study of 85 cutaneous neoplasms found overexpression in only 3.5% of the study cases [7]. While expression of ER serves as a potential target for anti-cancer therapy in rare cancers, EGFR and HER2 may help with differentiation between apocrine-eccrine and metastatic breast carcinomas.

Anti-oestrogen therapy is well established in breast cancer with large clinical studies showing benefit initially with tamoxifen, and latterly, the aromatase inhibitors (letrozole and anastrozole) in both adjuvant and metastatic settings. The aromatase inhibitors have further shown greater activity compared to tamoxifen in head-to-head studies supporting their first-line use [8]. As described above, several rare cancers are known to express ER, suggesting the receptor could be targeted. However, data relating to the use of oestrogen blockade are primarily in the form of case reports, of which there are a relatively limited number (summarised in Table 1).

The use of anti-oestrogen therapy has been described in sweat-gland tumours. In 1989, Sridhar et al. [9] outlined their treatment of a patient with a scalp eccrine adenocarcinoma with tamoxifen. Subsequently, lymph node metastases were found to regress, and similarly to our described case, this patient found pain relief from bony metastasis for almost 3 years. Daniel et al. [10] also outlined the use of empirical tamoxifen treatment for a patient with ER positive sweat-gland carcinoma, who had over 3 years of disease-free survival. Schroder et al. [11] described the use of tamoxifen for metastatic eccrine adenocarcinoma in a 64-year-old woman, also originating on the scalp. In a similar schedule of events, this patient had undergone surgical intervention and was found to be ER and PR positive on immunohistochemistry leading to initiation of tamoxifen and subsequently 3 years of complete remission.

A further rare sweat-gland tumour, ductal eccrine carcinoma (DEC) also bears histological resemblance to breast cancer, and treatment with letrozole has been described, with beneficial outcomes. After confirmation of diagnosis of DEC and ER-positive immunohistochemistry, a 69-year-old female patient underwent wide excision and adjuvant radiotherapy for an axillary DEC [12]. She was commenced on letrozole and achieved 14 months of disease-free survival. Furthermore, a 70-year-old patient diagnosed with malignant eccrine spiroadenoma achieved 41 months of recurrence-free disease, following surgical excision and lymph node dissection, with tamoxifen therapy after positive ER immunostaining [13].

Varieties of other rare cancers also express the ER; most notably salivary gland tumours, in which reported cases have shown benefit with oestrogen blockade. A 70-year-old female with metastatic ductal carcinoma of the parotid gland achieved 2 years of stable disease with the use of tamoxifen, and 6 further months with second-line anastrozole [14]. Furthermore, Elkin et al. [15] described the use of tamoxifen for 2 cases of salivary gland adenoid cystic carcinoma, both of whom achieved stable disease.

While chemotherapy- and immunotherapy-based regimens have been discussed in the literature [16], the evidence for use of anti-oestrogen therapy has not been as widely interrogated. Our case report and review of the literature highlight the potential benefit of anti-oestrogen therapy; however, it is apparent that there may be underreporting of negative outcomes with anti-oestrogen therapy, resulting in an inherent publication bias. As put forth by Schroder et al. [11] in 2004, a formal prospective basket trial examining the long-term outcomes of ER-blockade in ER-positive rare tumours is warranted, as may be regular baseline workup of hormone receptor tumour expression, which is commonplace in breast tumour management.

In a developing age of targeted and personalised medicine, our case report, and historical evidence in the literature, demonstrates the potential benefit of anti-oestrogen therapy in rare ER expressing cancers. Prospective studies are, however, needed to quantify the proportion of patients benefitting, as well as the likely duration of benefit.

Key learning points/take home messages:

• 1.

  Currently, there is no standardised approach to treatment of metastatic EPC.

• 2.

  Anti-oestrogen therapy should be considered in patients with ER-positive rare cancers.

• 3.

  Formal, prospective trials are needed to evaluate the potential benefit of oestrogen blockade in rare tumours.

The authors obtained informed written consent from the subject to publish this case report, details of their medical history, and their radiological imaging. There is no identifying information included in the manuscript. Ethical approval is not required for this study in accordance with national guidelines.

Dr. Chow, Dr. Kalakonda, and Dr. Mahajan have no conflicts of interest to declare. Dr. Sacco reports grants and personal fees from Immunocore, trial funding from Replimune, non-financial support from MSD, grants and non-financial support from BMS, grants from AstraZeneca, and personal fees from Delcath outside the submitted work. Dr. Olsson-Brown reports honoraria from BMS, MSD, Roche, Novartis, AstraZeneca, Merck/Pfizer and Boehringer Ingelheim. Travel grants from Ipsen and BMS. Grants from Roche, UCB Pharma, Novartis, BMS and Eli Lily outside the submitted work.

There was no specific funding for this work. However, Dr. Kalakonda was an NIHR Clinical Research Fellow at the time of writing. The job role was funded to support research in oncology and haemato-oncology by the CRN North West Coast.

Dr. J. Sacco, Dr. A.C. Olsson-Brown, and Dr. S. Chow contributed to the case report conception and design. Dr. A. Mahajan and Dr. A.J.M. Kalakonda contributed to the formatting and writing of the figures and figure legends. All named authors contributed to the drafting and preparation of the manuscript. All named authors reviewed and approved the final version of the manuscript.

All data generated or analysed are included in this case report. Further enquiries can be directed to the corresponding author.