Destination Unknown: A Unique Case of Metastatic Colorectal Carcinoma to the Breast, Axilla & Skin

involving the liver and lung, as these are the commonest sites of distant colorectal cancer spread. Metastesis to the skin, breast and axilla, however, are far rarer and there is very little data regarding the optimal treatment strategy and long-term outcomes, even in cases of isolated lesions. The case presented here describes the clinical history of a lady diagnosed with primary colorectal carcinoma with a solitary hepatic metastasis. One year after undergoing intended curative treatment, she developed cutaneous, right breast and axillary metastases, each of which were treated with aggressive local resection. Despite this, she has maintained a good functional status with isolated recurrences at four years from her initial diagnosis. The discussion is based on the approach to best treatment in such rare cases: whether aggressive surgical resection should be sought in favour of limiting options to systemic palliative therapy alone. ABSTRACT The commonest sites of distal colorectal cancer spread are the liver and the lungs. Metastesis to the skin, breast and axilla are very rare. Very little data exists regarding the optimal treatment methods and its long-term outcomes. We present a unique case of colorectal cancer patient who initially presented with solitary hepatic metastesis, subsequently underwent low anterior resection with synchronous resection of the hepatic mets after neoadjuvant chemotherapy. At one year followup, she developed a cutaneous, mets to right lateral chest wall and treated with wide local excision and adjuvant therapy. At four years of follow up she again develops metastasis to the right breast and axillary lymph node. Wide local excision of the breast lump and axillary lymph node dissection were performed. Despite recurrent metastesis the patient has maintained a good functional status. A literature review was done to highlight the best treatment options in these rare cases.


Introduction
Hellman and Weichsel Baum first proposed the theory of oligometastasis in 1995. This concept recognizes that in some cancer patients, a limited number of metastases may suggest improved patient outcomes with local removal [1]. Thus, the traditional view of metastatic disease has changed, with treatment now aimed at cure, instead of prolonged survival or palliative care in some cases of metastatic disease. Perhaps the most common malignancy to undergo such a significant alteration in treatment is that of colorectal cancer. Metastases to the liver and lung can now be considered amenable to local resection or ablative therapies.
Colorectal carcinoma is globally the third most common malignancy diagnosed each year. In the united states, 15-20% of patients have metastatic disease at the time of diagnosis. Modern systemic therapies have helped to improve the survival for such patients with nearly 20% surviving up to five years beyond diagnosis [2].
Published data has demonstrated that surgery can provide a cure in cases of isolated metastases and, when combined with systemic therapies, can also improve long-term survival in cases where metastases involve more than organs [3]. However, much of this data is centered around metastases involving the liver and lung, as these are the commonest sites of distant colorectal cancer spread.
Metastesis to the skin, breast and axilla, however, are far rarer and there is very little data regarding the optimal treatment strategy and long-term outcomes, even in cases of isolated lesions. The case presented here describes the clinical history of a lady diagnosed with primary colorectal carcinoma with a solitary hepatic metastasis. One year after undergoing intended curative treatment, she developed cutaneous, right breast and axillary metastases, each of which were treated with aggressive local resection. Despite this, she has maintained a good functional status with isolated recurrences at four years from her initial diagnosis. The discussion is based on the approach to best treatment in such rare cases: whether aggressive surgical resection should be sought in favour of limiting options to systemic palliative therapy alone.

The Case
A 55-year-old female, presented to the outpatient breast clinic for evaluation of right sided breast and axillary lumps which she noticed nine months prior and were increasing in size. She reported no breast pain, skin or nipple/areolar complex changes or nipple discharge over this period. She experienced menarche at 14 years old and was nulliparous, still experiencing regular menstrual cycles. She had never used oral contraception or hormone replacement and had no significant family history of breast or other malignancies. The patient had a complex past medical history, which included hypothyroidism treated with levothyroxine and Hodgkin's lymphoma treated with chest wall radiation 25 years ago.

Discussion
Colorectal carcinoma is the third most common malignancy diagnosed around the world with a lifetime risk in developed countries as high as 4% [2]. In the Caribbean, this disease ranks among the top five leading cancers diagnosed annually in both males and females. Warner et al reported incidence rates of almost 11% and 3% for colon and rectal cancers respectively in Trinidad and Tobago between 1995 and 2009. They also reported that over 10% of most cancers in Trinidad and Tobago (including colorectal) were diagnosed at advanced stages, which highlights that tumour biology in this region may be particularly aggressive or that cancers are not diagnosed early enough [4]. Cancer metastasis is a complex multi-step process by which cancer cells acquire certain properties that allow them to move from the primary tumour and invade a distant organ. They do this while maintaining the ability to survive and travel within the body (directly entering the bloodstream or indirectly via lymphatic's) . Some circulating tumour cells are postulated to remain dormant while maintaining the ability to grow and this is thought to be one of the contributing factors responsible for the development of metastases after a primary tumour is removed [5]. The patient in the case presented here developed rare distant metastases three years after undergoing treatment with curative intent for colorectal carcinoma with a solitary hepatic metastasis. Unlike skin metastases occurring in 24% of metastatic breast carcinomas, data suggests that cutaneous metastases occur in just 4% (2.3-6%) of colorectal carcinomas. They are mostly found on the skin of the abdominal wall, especially at the sites of surgical scars related to treatment of the primary tumour, as occurred in this case [6]. The most common primary tumours associated with breast metastases include cancers of the contralateral breast, leukaemia, melanoma, lung, ovary and stomach [10]. Distant metastasis of colorectal carcinoma to the breast, however, is extremely rare, with a handful of cases reported in the literature. Even rarer, is the involvement of axillary lymph nodes as described by Perin et al [11]. An analysis of 32 cases of this entity by Zhang et al found that the majority (94%) occur in females at an average age of 51 years and at a time ranging from 1 to 10 years after initial diagnosis of the primary tumour [12]. In the case presented here, for cancer cells to reach the breast and axilla having had previous involvement of the liver and skin, suggests that this patient's disseminated disease is particularly aggressive, with travel specifically along the haematogenous and lymphatic's. Imaizumi  Weichselbaum's concept of oligometastases, which proposes that the biology of a tumour predicts if its metastatic potential is limited to specific regions. Tumour size and pathological grade are perhaps the two most frequently used characteristics that may help guide knowledge on a cancer's oligometastatic potential. On the contrary, this is vastly different from the term micro metastases, which describes very small but extensive cancer metastases. Colorectal carcinoma is one of the most commonly described malignancies that can exist in an oligometastatic state. Successful treatment with good survival outcomes is well documented, particularly in the treatment of hepatic or pulmonary metastases [1].
An oligometastatic state theoretically puts forward the possibility that malignant disease can be amenable to cure, with therapies targeted towards treating both the primary tumour and the limited extent of metastatic lesions. But, for treatment to be effective, all metastatic sites must be identified and targeted. This concept may be applicable to the case presented here, but still, the existence of a true oligometastatic state remains controversial and this view point is not shared by all clinicians. In metastatic colorectal carcinoma, 40-70% of cases spread to the lymph nodes first but the liver is often the first distant site of spread, due to drainage of the intestine via the portal venous system [12]. Spread to the lungs can occur via direct drainage of rectal carcinoma through the inferior vena cava and thereafter other sites like the bones and brain may become involved [2]. However, involvement of sites like the skin, breast and axilla is extremely rare and may be associated with particularly aggressive subtypes of colorectal carcinoma (BRAFmutant cases for example) [15]. Therefore, the majority of the data guiding the optimal approach to treatment in these cases is limited to information provided by published case reports.
The successful treatment of colorectal cancer with liver or pulmonary metastases is extensively described in the surgical literature. With liver-only metastases, approximately 20-25% of patients can achieve disease-free survival of over ten years [1]. The role of a multidisciplinary team approach is crucial here to determine the ideal treatment strategy for these patients, especially when surgery can be combined with ablative therapies including systemic chemotherapy, radiofrequency or microwave ablation or intraarterial chemotherapy among others. The National Comprehensive Cancer Network (NCCN) recommends that patients with resectable synchronous liver and/ or lung metastases can undergo resection and/ or local ablative therapies, although resection is preferred [9].
In colorectal cancer with isolated pulmonary metastases amenable to treatment with curative intent, surgical resection can lead to fiveyear survival of 45-65% [1]. However, the treatment of metastases to the breast and axilla is complicated and the selection of the optimal strategy depends on the primary tumour, involvement of other sites and the overall condition of the patient. Barthelmes et al suggested against surgical excision in these cases due to the underlying disseminated state of disease, predicted short life expectancy and the risk of tumour seeding onto the skin [10,16].
Others, like Fernandez de Bobadilla, suggest that excision can help to achieve local control of disease and prolong survival when combined with systemic chemotherapy [17].
Because of the rarity of this phenomenon, however, there is no high level evidence supporting an ideal approach and this decision is often made on a case-based approach [12]. In the case described here, the decision to proceed with surgical excision of isolated rare distant metastases was influenced by the fact that the patient had approached four-year survival with isolated metastases only and maintained a good quality of life despite this. She will continue to be surveyed for future metastases as well as her overall outcome.

Conclusion
Systemic therapies are standard aspects of treatment of various metastatic malignancies and traditionally were the only options for treating metastatic colorectal carcinoma. However, modern advances in science and technology have allowed improved survival and in some cases, cure, for select patients with metastatic colorectal cancer. This has been clearly demonstrated in cases of metastases to the liver and lungs, but metastases to the skin, breast or axilla are so uncommon that there is currently no general consensus regarding the best treatment options for these patients.
Treatment decisions here are often made based on multidisciplinary discussions and information derived from published case reports or series. A decision to perform excision or provide systemic treatment of isolated metastases to these areas is also derived from the concept of an oligometastatic versus micrometastatic disease state. In the oligometastatic state, the presence of small diffuse metastases (micro metastases) is inherently denied and theoretically, local excision or ablative therapies should be sufficient to control the extent of disease and possibly provide a cure. However, success in treating cases like this relies on the fact that primary tumour biology influences its metastatic potential.
This explains why some patients can achieve cure of their disease even if initially considered unresectable at diagnosis. But it also explains why overall cure rates have not significantly improved although several advances in treatment have occurred over the years. Colorectal cancer metastases to the skin, breast and axilla are extremely rare and based on the published literature generally signify a poor prognosis. However, limited metastatic potential, as perhaps described in this case, may show that local therapeutic options, including surgical excision, may improve quality of life and survival.