Cutaneous metastases from different internal malignancies: a clinical and prognostic appraisal.

1. Cutaneous metastases from different internal malignancies: a clinical and prognostic appraisal. Hu S. et al JEADV 2008, 22, 735-740

2. Introduction • 0.7% to 9% of patients with internal malignancies have cutaneous infiltration • Metastasis: A tumour needs to detach from the primary tumour, invade, and intravasate into a blood or lymphatic vessel; survive in the circulation; extravasate and finally invade and proliferate at the secondary site. • through hematogeneous, lymphatic, direct contiguous tissue invasion, iatrogenic implantation. The first two only are regarded to represent true metastatic spread. • metastases to the skin typically affect anterior chest, abdomen, head and neck. They can occur anywhere though. • Present usually as painless nodules but can mimic benign entities as well.

3. Usually regarded as a poor prognostic factor, although differences in prognosis for cutaneous metastases arising from different internal malignancies, with breast cancer patients having a better prognosis. • In classification of tumours, TNM is used with M0 or M1 used as a marker of metastasis, which enables to determine prognosis. However ‘M” doesn’t’ make a distinction to the location of the metastasis. • In addition, previous studies have rarely been focused on the Asian populations.

4. Methods • Retrospective review in the clinical records of Kaohshiung University for the past 20 years. Cases of biopsy-proven metastases were selected: defined as cancer spreading through the lymphatic system or the blood stream (direct extension (eg Paget’s), iatrogenic implantation excluded). • Hematological malignancies were also excluded as these malignancies are characterized by malignant cells already circulating in the bloodstream and lymphatic system, and therefore, their presence in the skin is not regarded as true metastasis.

5. Primary skin malignancies (such as melanomas and cutaneous SCCs) ere excluded because metastases in the skin cannot be considered as a form of “secondary” organ spread ! • Analysis was used using the Kaplan-Meier method. P smaller than 0.05 was considered statistically significant.

6. Results

7. Clinical features of cutanous metastases from different internal malignancies • 141 cutaneous malignancies from internal malignancies were identified> Mostly from the breast (51 cases), lung (23), colon and rectum (16), oral mucosa (11) and stomach (10)

8. Primary origin of cutaneous metastases: Origin n % • Breast 51 36.2 • Lung 23 16.3 • Colorectal 16 11.3 • Oral Mucosa 11 7.8 • Gastric 10 7.1 • Hepatocellular 4 2.8 • Oesophageal 3 2.1 • Bladder/ UT 2 1.4 • Uterus/Cervix 2 1.4 • Larynx 1 0.7 • Thyroid 1 0.7 • MISC 8 5.7 • Unknown 9 6.4%

9. 61 males, 80 females • age 60.8 (22-88years old): -Breast cancer: 50 females 58.4 years old -Lung Cancer: 16 males (7 females)63.4 yo -Colorectal 10m6f 62.1yo -Oral Mucosa 10m1f 52.4yo -Gastric 4m6f 61.9yo

10. Cutaneous metastases represented the first indication of malignancy in 19 cases (13.5%) • Interval between diagnosis and cutaneous metastasis ranged from less than a month to 10 year (mean=27.9months): -Breast Cancer 47.2m (1m-10y) -Lung Cancer 15.7m (1m-5y) -Colorectal cancer 16.5m (9m-3y) -Oral Mucosa 27.5m (6m-9y) -Gastric cancer 19.8m (7m-4y)

11. The majority of cutaneous lesions were correctly identified as metastasis before the biopsy in 71% of cases. However some lesions were suspicious for benign entities such as epidermal cyst, pyogenic granuloma, hemangioma or herpes zoster. • Most commonly presentation was multiple nodules (46.4%), single nodule (37.7%), plaques or erythematous patches (9.4%) and ulcers (6.5%)

12. The locations were chest (30.3%), abdomen (20%), scalp (12.6%). Uncommon in the extremities (UL=7.4%, LL=1.7%). Other locations: face (8.6%), neck (9.1%) and back (10.3%). Metastases usually in the vicinity of the primary (Abdomen, Thorax…) and multiple sites of cutaneous metastases were seen in 19% of patients.

13. Survival following diagnosis of cutaneous metastases • After establishing the diagnosis of cutaneous metastases, the median survival was 7.98 months following the diagnosis survival % was a follows: -1year 36% -3years 23% -5years 18% -10years 3%

14. Additional survival analysis was performed for the breast cancer group (the largest): -(BS)=breast cancer with skin metastasis only -(BSV)=breast cancer with skin and visceral metastasis -(NBS)=non breast cancer with skin metastasis

15. Group1 year survival(%)3 year surv.5 year surv.10 year surv. Median(mean) BS 79%51%37%11%42m (57m) BSV 43%43%22%NA12m (25m) NBS21%12%12%NA6m (16m)

16. NBS worse survival than BSV (p=0.016) • NBS worse survival than BS (p smaller than 0.001) • BSV worse survival than BS (p=0.012)

17. Cox proportional hazards (Increased chance of mortality…) Group Relative risk(95& CI) Significance BS 1 BSV 2.392 (1.127-5.078) p=0.023 NBS 4.308 (2.106-8.813) p<0.001

18. Discussion • In the asian population studied, cutaneous metastases originated most commonly from the breast in females and the lung in males. This is consistent with studies involving Caucasian populations. Therefore although the most frequent primary tumours are different, the origins of skin metastases encountered seem similar. • In concordance with this certain cancers are more commonly seen in Taiwan such as hepatocellular carcinoma (higher incidence than lung or breast cancer in Taiwan), carcinoma of the bladder and ureter, nasopharyngeal carcinoma and cervical cancer rarely gave rise to cutaneous metastases. Therefore the propensity to metastasize depends on the characteristics of tumour cells, which are similar among different ethnic groups.

19. Paget wrote the “soil-seed” hypothesis that states that tumours preferentially metastasize to those organs with an intrinsically favourable environement. • In addition certain factors secreted from the epidermis and dermis may play a crucial role in the skin homing mechanism of metastatic cells. Recently, chemokines and their receptors have been shown to be involved in tumorigenesis and metastasis. The chemokine receptor CCR10 has been demonstrated to be involved in cutaneous metastases of melanomas and may mediate its survival in the skin. Keratinocytes produce CCR ligand CCL27/CTACK. This pathway could be involved in the preferential metastazisation into the skin.

20. Cutaneous metastases are known to frequently occur in anatomical areas close to the primary tumour: -Sister Joseph Nodules for Colorectal and Gastric cancers (hematogenous dissemination through vascular anastomoses between the umbilical skin and the gastrointestinal tract) -Chest for breast and lung -12.6% however are distant in the scalp [vascularity?]

21. Following the results about preclinical presentation, the appearance of multiple nodules (46.4%,for single nodules (37.7%) and plaques) should warrant a high index of suspicion of cutaneous metastases when facing a patient with a history of malignancy

22. Usually cutaneous metastases have been regarded as a sign of advanced and widely disseminated disease. However in previous studies, there was considerable variation depending on the primary tumour. In cutaneous metastases from cancers of the lung or the GI tract, evidence of visceral metastases was present in most patients. • However, in cutaneous metastases of breast cancer, the metastatic lesions in this study were confined to the skin in approximately one third of patients. Therefore, the discovery of cutaneous metastases in breast cancer does not necessarily indicate widespread disease.

23. Previous studies have shown different survival times for different malignancies (Schoenlaub et al): -13.8m for breast cancer -2.9m for lung cancer • Also BS group patients have a better survival time than BSV or NBS group patients.

24. Therefore, more accurate information regarding survival may be provided to the breast cancer patients with stage IV (M1 disease.

25. Further studies are warranted to determine whether cutaneous metastases have different prognostic implications compared with visceral metastases in other types of malignancies