Sentinel bruising as a presentation of metastatic melanoma

Abstract

A 46-year-old man presented with a 4-week history of bruising with subcutaneous nodules and weight loss. He also had a 2-week history of progressive back and hip pain. He had been diagnosed with stage Ib cutaneous melanoma 30 months previously, which had been fully excised. A sentinel lymph node biopsy was negative. On examination, there were five skin lesions at different stages. Each had spontaneously appeared as a bruise with a central subcutaneous nodule, and the bruising then faded to leave a persistent subcutaneous nodule. Excision of one of the nodules demonstrated a 4.5 mm diameter partly necrotic melanoma deposit in the dermis. CT scan of the head, chest, abdomen and pelvis showed widespread metastases. This rare presentation of cutaneous malignant melanoma metastases has been termed ‘sentinel bruising’. There are fewer than 10 cases reported in the literature.

Background

Melanoma is a highly aggressive disease caused by the malignant transformation of epidermal melanocytes.¹ It accounts for 22 000 deaths annually in Europe,² and its incidence continues to increase—particularly in young adults.³

Cutaneous melanoma can metastasise to any organ.⁴ The first presentation of metastasis is to the skin in 2%–8% of cases (cutaneous malignant melanoma metastases [CMMM]).⁵ Diagnosis of CMMM can be difficult as the presentation is widely variable. ‘Sentinel bruising’ is a particularly rare presentation, with fewer than 10 cases reported in the literature.

Case presentation

A 46-year-old Caucasian man presented with a 4-week history of bruising and subcutaneous nodules, 2 weeks of progressive back and bilateral hip pain, and one stone of weight loss over a period of 1 month. There was no preceding trauma. His medical history was significant for stage Ib (T2a, N0, M0) cutaneous melanoma 30 months previously, which had been excised with clear margins. This had presented on the superior helix of the left ear and had a Breslow thickness of 1.3 mm. There was probable perineural invasion and invasion into the reticular dermis (Clark level 4), but no lymphovascular or microsatellite metastases were identified, and the mitotic index was 5 per mm². A sentinel lymph node biopsy was negative. The patient had attended all follow-up appointments, the most recent of which was 6 weeks prior to presentation. The only medication the patient used was paracetamol.

On examination, there were five lesions: one on the right shoulder; one on the medial right clavicle and three on the abdomen. The natural history of these lesions was that they spontaneously appeared as a bruise with a central subcutaneous nodule (figure 1), and the bruise then regressed, leaving only a non-tender subcutaneous nodule which persisted (figure 2). There was no lymphadenopathy.

Figure 1.

(A) Two bruises with central non-tender subcutaneous nodules. The subcutaneous nodule of the lesion overlying the right clavicle was excised for histological examination. (B) Close-up image of the bruising.

Figure 2.

Bruising of lesions gradually cleared to leave only a subcutaneous nodule (white arrow).

Investigations

Laboratory investigations revealed a mild anaemia (haemoglobin 101 g/L) and mildly elevated inflammatory markers (white cell count 13.3×10⁹ cells/L, C reactive protein 25 mg/L). Renal function, liver function and calcium levels were normal. There was no coagulopathy and platelet count was normal.

A subcutaneous nodule was excised from near the medial right clavicle. This showed a 4.5 mm diameter partly necrotic melanoma deposit in the dermis (figure 3A). Immunohistochemically, the cells were positive with HMB45 (figure 3B), and to a lesser extent, Melan A and S100. An NRAS mutation in exon 3, codon 61 was detected. No BRAF mutation was detected.

Figure 3.

(A) H&E stain showing well-demarcated dermal melanoma deposit (x20). (B) HMB45 immunohistochemical staining of the deposit showing diffuse strong uptake.

A CT scan of the head, chest, abdomen and pelvis showed widespread metastases, including a nodule in the parietal lobe, several lung nodules, multiple abdominal subcutaneous skin nodules and an anterior wedge compression fracture of T12. An MRI of the whole spine was performed due to the onset of leg weakness during the admission, which further delineated the pathological T12 fracture and revealed an epidural mass associated with L3 and L4 vertebral body deposits—but without cauda equina compression (figure 4). MRI of the head confirmed a solitary 5 mm lesion in the right parietal lobe.

Figure 4.

T2-weighted sagittal MRIs of the spine showing pathological T12 fracture as well as L3 and L4 vertebral body deposits.

Differential diagnosis

Bruises (ecchymoses) commonly occur secondary to trauma. Easy or spontaneous bruising can occur due to abnormalities in collagen production, platelet count, platelet function and the coagulation cascade. Collagen abnormalities include vitamin C deficiency and Ehlers-Danlos syndrome. Disruptions to the coagulation cascade or platelet function may be iatrogenic, due to medications such as antiplatelets or anticoagulants. Immune thrombocytopaenic purpura and bone marrow failure secondary to haematological malignancy also need to be considered for a low platelet count in both adults and children. In our case, a full blood count and clotting screen were normal.

Although multiple primary melanomas should be considered when diagnosing cutaneous metastases of melanoma, it would be extremely unusual for primary melanoma to present as a bruise/ecchymosis.⁶

Treatment

In stage IV melanoma, a poor prognostic score is associated with poor performance status (PS); high lactate dehydrogenase (LDH); low albumin and involvement of multiple organs, such as brain and liver. For patients with a PS of <2 (ie, able to go about their normal daily activities but who tire on exertion), systemic palliative oncological treatment can be considered. These include targeted molecular therapies and immunotherapies.

For patients with a BRAF mutation and high-grade disease, targeted molecular therapy (a BRAF inhibitor with a MEK inhibitor) can be used, which have a quicker onset of action.^{7 8} For patients who do not carry a BRAF mutation, such as this patient, immunotherapies should be used. These include programmed death ligand 1 (PD-L1) blockade (either nivolumab (PD-1 blockade) or pembrolizumab (PD-L1 blockade) (both licensed by National Institute for Health and Care Excellence with similar efficacies and side effect profiles)) and/or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antagonists (ipilimumab).⁹ Durable efficacy from doublet immunotherapy has been shown in CHECKMATE-067 study.¹⁰

In the indexed patient, as he presented with a high-grade, fast-deteriorating disease, emergency radiotherapy was given for his bone disease and pain. As he had a good PS and extensive disseminated disease, the MDT recommended that he should be offered doublet immunotherapy with an anti-PD-1 antibody and CTLA-4 antagonists (nivolumab and ipilimumab).

Outcome and follow-up

Doublet immunotherapy has a 75% response rate and for patients who respond, 60% will still be on treatment at 3 years. There is also a small but real subset of patients (10%–15%) who have durable long-term remission after immunotherapy, which can equate to long-term control of disease despite stage IV disease. Ongoing trials are still collecting these long-term data.^{11 12} However, this is a regimen for the fittest of patients as it carries a >90% chance of side effects, of which 50% will require hospital admission. The potential side effects include life-threatening diarrhoea, Addison’s disease, hypothyroidism and hepatitis. Skin reactions are also common, occurring in 50% of patients.

After the first dose of ipilimumab and nivolumab, the patient was admitted to hospital with diarrhoea. While this settled quickly, the patient then developed hepatitis and dermatitis requiring prednisolone 60 mg daily and mycophenolate mofetil 1 g two times a day. He also developed further cerebral metastases. Due to hepatitis and symptomatic cerebral metastases, the steroids could not be weaned down to a level to allow further immunotherapy. The patient sadly passed away 4 months after admission.

Discussion

Sentinel bruising as a presentation of CMMM is very rare. The first reports in the English literature were made in 2003,^{13 14} and subsequently, there have been only a further seven reports.^15–21 In a minority of these cases, it is the presenting feature.^{14 16 17} The lesions of sentinel bruising appear to be more common on the trunk,^{13 16 21} and in some cases, the subcutaneous nodules are tender.^{14 21} The reason for the infiltrating tumour cells causing bruising is not known, but suggested theories include aberrant angiogenesis and rupture of native vessels.^{21 22} It has been postulated that sentinel bruising may herald aggressive disease.¹⁶

The American Joint Committee on Cancer (AJCC) melanoma staging system is as an invaluable tool for predicting outcomes for patients diagnosed with melanoma, being based on data derived from the analysis of tens of thousands of patients.¹ The most recent (eighth) edition assesses four factors: Breslow thickness, the presence of lymph node metastases; the presence of satellite and/or in-transit metastases and/or local recurrence; and the presence of distant metastases. The indexed patient’s initial diagnosis of stage Ib melanoma had a favourable prognosis, with a 97% 5-year survival rate and a 94% 10-year survival rate.²³ However, melanoma is a complex disease and, as evinced in this case, some seemingly low‐risk stage I and II tumours will still go on to metastasise.

There were some prognostically unfavourable features in our case which are not accounted for in the AJCC staging. First, patients with head and neck primary melanomas have a higher frequency of developing direct distant metastases compared with those on other sites.²⁴ This may reflect that NRAS mutations are more common in areas of chronic sun exposure, with some evidence suggesting that NRAS and BRAF mutant tumours may behave more aggressively than wild-type tumours—but the extent to which this is independent of anatomical location is unclear.⁴ Second, one study reported that tumours between 0.75 and 1.5 mm in thickness have the highest rate of direct distant metastases,²⁵ although results from a different study were discordant.²⁴ Finally, males have inferior survival to females even after adjustment for various prognostic factors.²⁶

Identifying patients with high-risk disease not predicted by AJCC stage alone represents an important actionable goal.²⁷ Two recently proposed tools have been a gene expression profile test and the AJCC’s web-based Individualized Melanoma Patient Outcome Prediction Tool.²⁷ The former identifies high-risk, early-stage melanomas through the evaluation of 31 genetic targets, and the latter uses tumour thickness, ulceration, lesion site (axial vs limb) and patient age. Using the AJCC’s web-based tool for our patient’s first presentation with stage Ib melanoma gives a less favourable prognosis than AJCC (eighth edition) staging, with a predicted 5-year survival of 91.4% and a 10-year survival of 83.7%. There is evidence that combining these methods can better identify patients with stage I and II cutaneous melanoma who are at high risk for developing metastases.²⁷ These higher risk patients could benefit from more intense surveillance or even adjuvant therapy.

The rationale for adjuvant therapy is that even small tumours can release millions of cancer cells into the circulation, and that these cells are not eradicated by the surgical removal of the primary tumour or the regional lymph nodes. These cells can remain dormant for many months or years,²⁸ and a landmark study on melanoma progression showed that the time course from detection of the primary melanoma to the development of distant metastases was between 24 and 30 months—which is consistent with the time period observed in our case.²⁵ Studies have shown improved survival with new immunotherapies and targeted therapies for stage III and IV resected melanoma,²⁹ and adjuvant treatment—with single-agent immunotherapy or BRAF inhibitor tablets—is now available for all high-risk AJCC (seventh edition) resected stage III and IV melanoma.

In conclusion, we describe a very rare presentation of cutaneous melanoma and highlight the ongoing issue of identifying patients with high-risk disease.

Learning points.

• Cutaneous melanoma can metastasise to any organ.

• In 2%–8% of cases, the first presentation of metastatic melanoma will be cutaneous malignant melanoma metastases.

• Cutaneous malignant melanoma metastases can present with a variety of skin lesions. Sentinel bruising is a very rare presentation, with fewer than 10 reported cases.

• In addition to American Joint Committee on Cancer (AJCC) (eighth edition) staging, an AJCC web-based tool is available which predicts survival for localised cutaneous melanoma or melanoma with regional metastasis.