Axillary lymph node involvement is a unique pattern of metastasis in BRAF-mutant colorectal cancer

INTRODUCTION

Axillary lymph nodes (axLNs) are a virtually unheard of site of metastasis in patients with metastatic colorectal cancer (mCRC). A search of the National Library of Medicine’s PubMed database identifies six case reports, each describing one patient with axLN metastasis of primary colorectal cancer^1–6 (Table 1).

Table 1.

Characteristics of mCRC cases involving the axilla reported in the literature.

Patient	Age	Sex	Primary site	Axillary LAN1	Presentation of Axillary LAN1
1	75	F	L colon	Left	Swollen left axillary nodes noted on CT
2	49	M	L colon	Left	Large axillary mass approaching 10cm in diameter on physical exam
3	72	F	L colon	Left	Patient-discovered, confirmed on exam
4	46	F	L colon	Left	FNA cytology
5	52	M	R colon	Left	“firm, rubbery, painless” axillary LAN measuring 4cm on physical exam
6	70	M	R colon	Left	Left axillary lymph node metastasis detected on imaging

¹LAN: lymphadenopathy

METHODS

Initially three cases of axLN metastasis were identified clinically in CRC patients, and all were noted to have BRAF-mutant mCRC. Since late 2008, all mCRCs in our institution have been sequenced for KRAS and BRAF mutations. We therefore identified all cases with BRAF mutation between 2008 and 2012 and reviewed clinical and radiology records for evidence of axLN metastases. For a comparison group, we performed a computerized search for patients with mCRC whose tumors were genotyped in 2011 and identified the first 100 sequential cases that were wild-type for BRAF. Cases were reviewed under appropriate Institutional Review Board/Privacy Board waivers for axillary lymphadenopathy on imaging studies in the absence of additional primary malignancies to describe the frequency of axLN greater than 1 cm in these patients.

RESULTS

Three patients identified during their clinical course had biopsy confirmation of CRC metastases to the axilla. Patient 1, a woman in her thirties, presented with mCRC involving the peritoneum and ovaries, treated with complete cytoreduction. She developed a rapid recurrence in the peritoneum, lymph nodes, and pleura, with concurrent increase in size and number of left axLNs. Chest wall biopsy adjacent to the axilla confirmed mCRC and identified BRAF^K601E. Patient 2, a woman in her sixties, developed recurrent disease in the retroperitoneal lymph nodes and lungs with concurrent left axillary lymphadenopathy after resection of a stage I, BRAF^V600E colon cancer. She was resistant to all standard therapies and developed bulky, uncomfortable left axLN up to three centimeters in size. AxLN biopsy confirmed mCRC, and she underwent palliative resection. Patient 3, a woman in her seventies, developed left axLN involvement as the only site of metastasis within six months of resection of a node-positive colon tumor. AxLN biopsy confirmed mCRC and identified BRAF^V600E. The patient progressed through chemotherapy and developed bulky left axLNs with involvement of the left breast and dermis, clinically mimicking an inflammatory breast cancer. Subsequent breast biopsy, however, again showed mCRC.

One hundred additional CRC patients were identified with known BRAF-mutant tumors sequenced at our institution between 2008 and 2012. On review of the 100 sequential BRAF-mutant cases, six additional patients had suspicious axillary lymphadenopathy on imaging; axLNs were greater than 1.4 centimeters on CT, progressed on serial imaging, and were FDG-avid where PET scans were performed (Table 2). In a comparison group of 100 sequential BRAF-wild-type cases, no patients had axLNs that progressed on serial imaging. One patient had an enlarged axLN to 1.3 centimeters on CT that was not FDG-avid and did not progress.

Table 2.

Characteristics of BRAF-mutant mCRC patients with axillary lymphadenopathy suspicious for metastasis.

Patient	Age at dx1	Sex	Mutation	Primary site	Stage at dx	Axillary LAN2	Presentation of Axillary LAN2, 3
1	21	M	V600E	R colon	IV	Bilateral	CT (1.8cm)
2	72	F	V600E	R colon	IV	Left	CT (1.4cm); focal hypermetabolism on PET (SUV 3.1)
3	65	M	V600E	L colon	IV	Left	CT (1.8 cm); focal hypermetabolism on PET (SUV 15.1)
4	48	F	V600E	L colon	III	Left	CT (1.5 cm)
5	62	F	V600E	R colon	III	Bilateral	CT (2.1cm)
6	42	F	V600E	R colon	IV	Left	CT (2.9cm), focal hypermetabolism on PET (SUV 2.1), palpable on PE4 (3cm)

¹dx: diagnosis

²LAN: lymphadenopathy

³For CT, largest axillary lymph node dimension is noted.

⁴PE: physical examination

DISCUSSION

Our data reveal a unique pattern of metastatic spread of BRAF-mutant mCRC, a particularly aggressive subset of mCRC, and extend our understanding of BRAF-mutant mCRC as a distinct subset of CRC. We identified nine cases with likely axLN metastases from CRC, an exceedingly rare site of metastatic involvement in this disease. Several patients in our series developed axillary involvement in the setting of chest wall, skin, or breast involvement, suggesting initial spread and then local extension. Interestingly, overexpression of BRAF-activated long non-coding RNA found in specimens from patients with BRAF-mutant CRC has recently been correlated with increased lymph node metastasis through induction of epithelial-mesenchymal transition (EMT)⁷. Our data suggest that axLN evaluation should be included in the physical examination of BRAF-mutant mCRC patients, and this area should be scrutinized when considering these patients for curative-intent resection.