In addition to a 65-fold higher risk of developing squamous cell carcinoma (SCC), SCC that develop in adult transplant recipients are at higher risk for metastasis, 5-7%, compared to the general population, ~2% (1). ~13% of SCC that occur in pediatric patients (those <18 y/o) metastasize. SCC that occur on the lip of pediatric patients are at particularly high risk (2).

SCC metastasis is generally associated with a poor prognosis with a 3-year disease-free survival rate in adult patients of 56%(3). Relapse of SCC is common, with the cumulative relapse rate ~29% within 1-year of treatment.

Read about:

• Clinical Characteristics of Metastatic Squamous Cell Carcinoma
• In-Transit Metastasis
• Regional Lymph Node Metastasis
• Distant Metastasis

Clinical Characteristics of Metastatic Squamous Cell Carcinoma:

Onset:
Few large studies of metastatic cutaneous squamous cell carcinoma (SCC) are available. One of the largest was performed by Martinez et al 2003 who followed 68 pts with 73 distinct metastatic skin cancers(3). In this study, the mean onset of metastatic SCC occurred 10.7-years following transplantation. The mean time with which metastatic SCC was detected after diagnosis of the primary SCC lesion was 1.4-years.

Location:
The location where metastatic SCC was detected varied. 36% of patients had in-transit metastasis, metastasic foci located between the primary tumor and the closest lymph node region. These usually represent SCC spread along lymphatic vessels and/or nerves. 78% had lymph node metastasis occurring in draining nodal basins, and 35% had distant systemic/visceral metastasis. The most common sites for distant disease were lung and bone.

Size:
The median size of the primary tumor was 120 mm2 and the median depth was 3.2 mm.

Prior NMSC:
All metastatic SCC patients had prior history of several non melanoma skin cancers (BCC or SCC). 39 patients had a median of 11 prior NMSC over a mean of 10.4-years.

Immunosuppresive regimens:
The predominant immunosuppressive regimen in patients that developed metastatic squamous cell carcinoma was CAP (cyclosporine, azathioprine, prednisolone) 53% versus AP (azathioprine, prednisolone) 22% and CP 15% (cyclosporine, prednisolone). This data supports other studies which suggest that cyclosporine and azathioprine may have small, but significant effects in directly inducing squamous cell carcinoma in transplant patients.(4, 5)

In-Transit Metastasis:

In-transit metastases are cutaneous metastatic foci located between tumor and the closet lymph node region. Analogous to in-transit metastasis found in melanoma, these represent metastatic spread along lymphatic vessels and/or nerves and their presence is a poor prognostic indicator. Overall, in-transit metastasis occur most frequently from SCC risk stratified as "high risk" lesions (see risk stratification of SCC) although all SCC that occur in immunosuppressed patients have the potential for distant spread.

Characteristics of primary tumors that develop into metastatic SCC include diameters >120mm2, invasion to a depth >3.2mm, and invasion of underlying SQ fat, muscle or bone(1, 6). A good review of in-transit metastasis can be found in Carucci et al., Dermatologic Surgery, 30; 651 (2004).

Clinically, in-transit metastasis are nondescript, subtle, waxy, gray-white to flesh colored SQ papules 2-6mm in diameter that are not contiguous with the primary lesion(1).

Treatment:
Local control of in-transit metastasis should be achieved with Mohs surgical technique or some other surgical method where surgical margins are rigorously evaluated for residual tumor, perineural extension or intravascular invasion. (e.g. excision with intraoperative frozen section control or excision with postoperative margin assessment). Post operative radiation should be strongly considered. The radiation field often involves the primary tumor site, the in-transit metastatic site, and the draining lymph node basin.

Other treatments or diagnostic procedures that can be considered include:

• Systemic retinoids
• Sentinal lymph node biopsy
• Reduction/alteration in immunosuppressive regimen

Follow-up:
90% of metastatic SCC occur within 3-years of diagnosis of the primary tumor. The majority of these metastatic lesions come from primary tumors stratified in the "high-risk" category (see risk stratification of SCC). Current guidelines from the International Transplant Skin Cancer Consortium (ITSCC) suggest that patients with high risk SCC should be examined every 2-3 months. Clinical exams should include a full body skin examination, palpation of previous excision sites and examination of the skin between primary tumor sites and draining lymph nodes for in-transit metastasis. Regional lymph nodes should be palpated for lymphadenopathy and any suspicious lymph node enlargement should be evaluated by biopsy, imaging, or both.

Prognosis:
The 1-year disease-specific survival for in-transit or regional nodal metastasis is 89%.

Some studies have found that development of in-transit metastasis from primary cutaneous SCC in transplant patients is associated with a 22% 2-year mortality rate (1, 3).

Regional Lymph Node Metastasis:
Regional nodal metastasis is the most common site for metastatic disease to be detected. in transplant patients(3). If suspicious lymph nodes are found on clinical exam, the most common way to confirm nodal spread is by fine needle aspiration (FNA) or less commonly by excisional lymph node biopsy.

Imaging techniques using CT or CT/PET are useful for staging and detecting distant disease. MRI provides superior resolution of soft tissue tumors, particularly in the head and neck region and should be considered for metastases that occur in these regions.

The neck lymph nodes are most commonly involved (41%) followed by the axiallary lymph nodes (28%), parotid lymph nodes (22%) and inguinal lymph nodes (3%).

Characteristics of primary tumors that develop into metastatic SCC include diameters >120mm2, invasion to a depth >3.2mm, and invasion of underlying SQ fat, muscle or bone(1, 6)

Treatment:
Regional lymph node metastasis is most commonly treated by lymph node dissection followed by post-operative radiation. A complete staging work up should completed prior to any surgery.

Adjunctive treatments include:

• Oral retinoids
• Reduction/alteration in immunosuppressive regimen

Prognosis:
The 1-year disease-specific survival for in-transit or regional nodal metastasis is 89%.

Distant Metastasis:

Distant metastasis, including distant nodal involvement or metastasis to systemic organs, is the most feared complication of cutaneous squamous cell carcinoma. 35% of transplant patients who develop metastasis will have distant metastasis. The most common sites are the lung (21%), bone (18%), central nervous system (6%) and liver (4%). Distant metastasis is generally associated with a poor prognosis with a 3-year disease-free survival rate in adult transplant patients of 56%(3).

Characteristics of primary tumors that develop into metastatic SCC include diameters >120mm2, invasion to a depth >3.2mm, and invasion of underlying SQ fat, muscle or bone(1, 6)

Treatment varies depending on the site of metastasis and may include:

• Surgery(7)
• Radiation(8)
• Chemotherapy(9)
• Chemoradiotherapy(9)
• Reduction of immunosuppression(10)
• Combination of the above

Of these modalities, surgical extirpation of SCC is the most commonly utilized primary therapeutic modality (63% of treatments (3)). Surgery with adjunctive radiation is the next most common treatment (8% of treatments (3)).

Chemotherapy is rarely utilized, however, the current role and recent advances in chemotherapy for advanced cutaneous SCC as well as for advanced and metastatic head and neck squamous cell carcinoma (HNSCC) was recently reviewed by Martinez et al., Dermatologic Surgery, 30; 679 (2004) . These authors concluded that chemotherapy alone is likely to be ineffective as a curative treatment but concurrent use of chemotherapy and radiation (chemotherapy) may play a role in organ preservation as an alternative to surgery in the presence of unresectable disease or for patients too ill to undergo general anesthesia or major surgery. Additionally, chemotherapy may play a distinct role in palliation of patients with advanced disease. Although palliative chemotherapy has no proven increase in overall survival, some studies suggest that the greatest benefit is improved quality of life through short term control of disfiguring or painful tumors. The most active chemotherapeutic agents used in single agent chemotherapy include cisplatin, carboplatinin, paclitaxel, doetaxel, 5-flurouracil and methotrexate.

Patients with advanced metastatic disease should be considered for reduction of immunosuppression. Although there are no randomized controlled trials studying reduction of immunosuppression as a therapeutic intervention, some evidence suggests that his strategy may be beneficial as an adjunctive treatment (reviewed in Otley Dermatologic Surgery, 31; 163 (2005). Changes in immunosuppression regimens should always occur in close consultation with the patient's transplant physicians and with a clear understanding that the risk for organ rejection is elevated.

Recent data suggests that Rapamycin, an immunosuppressant with potent anti-proliferative effects, may decrease the risk of developing skin cancer (11). Although long term clinical trials have yet to be completed, transplant patients who develop > 5 skin cancers per year or those who have developed metastatic SCC might merit consideration for Rapamycin in place of other immunosuppressants agents known to elevate skin cancer risks.

Prognosis:
The 3-year disease-free survival rate in adult transplant patients with distant metastatic disease is 56%(3). The type of treatment significantly impacts disease survival. Those individuals treated with surgery alone had a 1-year disease-free survival rate of 87% versus 67% in patients who where treated with non-surgical means. Patients who had no treatment had a 30% 1-year disease-free survival rate.

Of those patients who receive treatment for metastatic SCC, 29% relapse within 1-year. The mean time from first metastasis to first relapse is 0.7 ± 0.5 year. Once relapse occurs, the disease-specific survival after 1-year is 44%.

Patients with in-transit or regional metastasis as their first site of metastases have better survival rates that those patients whose initial diagnosis included a distant nodal or systemic site. This highlights the benefits of serial clinical exams that closely follow draining nodal basins to detect metastases at an early stage.

References:
1. J. A. Carucci et al., Dermatologic Surgery 30, 651 (2004).
2. I. Penn, J Pediatr Surg 29, 221 (Feb, 1994).
3. J.-C. Martinez et al., Arch Dermatol 139, 301 (March 1, 2003, 2003).
4. P. Jensen et al., J Am Acad Dermatol 40, 177 (Feb, 1999).
5. P. O'Donovan et al., Science 309, 1871 (Sep 16, 2005).
6. J. D. Wagner et al., Arch Dermatol 140, 75 (Jan, 2004).
7. T. Stasko et al., Dermatol Surg 30, 642 (Apr, 2004).
8. M. T. Ballo, K. K. Ang, Oncology (Williston Park) 18, 99 (Jan, 2004).
9. J. C. Martinez, C. C. Otley, S. H. Okuno, R. L. Foote, J. L. Kasperbauer, Dermatol Surg 30, 679 (Apr, 2004).
10. C. C. Otley, S. L. Maragh, Dermatol Surg 31, 163 (Feb, 2005).
11. S. Euvrard, C. Ulrich, N. Lefrancois, Dermatol Surg 30, 628 (Apr, 2004).
12. C. Traywick, F. M. Reilly, Dermatologic Therapy 18, 12 (2005).
13. I. M. Neuhaus, W. D. Tope, Dermatol Ther 18, 28 (Jan-Feb, 2005).
14. G. Stallone et al., N Engl J Med 352, 1317 (Mar 31, 2005).