Cutaneous metastases from Cutaneous metastases from different internal different internal

malignancies: a clinical and malignancies: a clinical and prognostic appraisal.prognostic appraisal.

Hu S. et alHu S. et al

JEADV 2008, 22, 735-740JEADV 2008, 22, 735-740

IntroductionIntroduction

• 0.7% to 9% of patients with internal malignancies have 0.7% to 9% of patients with internal malignancies have cutaneous infiltrationcutaneous infiltration

• Metastasis: A tumour needs to detach from the primary Metastasis: A tumour needs to detach from the primary tumour, invade, and intravasate into a blood or lymphatic tumour, invade, and intravasate into a blood or lymphatic vessel; survive in the circulation; extravasate and finally vessel; survive in the circulation; extravasate and finally invade and proliferate at the secondary site.invade and proliferate at the secondary site.

• through hematogeneous, lymphatic, direct contiguous through hematogeneous, lymphatic, direct contiguous tissue invasion, iatrogenic implantation. The first two only tissue invasion, iatrogenic implantation. The first two only are regarded to represent true metastatic spread.are regarded to represent true metastatic spread.

• metastases to the skin typically affect anterior chest, metastases to the skin typically affect anterior chest, abdomen, head and neck. They can occur anywhere abdomen, head and neck. They can occur anywhere though.though.

• Present usually as painless nodules but can mimic benign Present usually as painless nodules but can mimic benign entities as well.entities as well.

• Usually regarded as a poor prognostic factor, Usually regarded as a poor prognostic factor, although differences in prognosis for cutaneous although differences in prognosis for cutaneous metastases arising from different internal metastases arising from different internal malignancies, with breast cancer patients having malignancies, with breast cancer patients having a better prognosis.a better prognosis.

• In classification of tumours, TNM is used with M0 In classification of tumours, TNM is used with M0 or M1 used as a marker of metastasis, which or M1 used as a marker of metastasis, which enables to determine prognosis. However ‘M” enables to determine prognosis. However ‘M” doesn’t’ make a distinction to the location of the doesn’t’ make a distinction to the location of the metastasis.metastasis.

• In addition, previous studies have rarely been In addition, previous studies have rarely been focused on the Asian populations.focused on the Asian populations.

MethodsMethods

• Retrospective review in the clinical records of Retrospective review in the clinical records of Kaohshiung University for the past 20 years. Cases Kaohshiung University for the past 20 years. Cases of biopsy-proven metastases were selected: defined of biopsy-proven metastases were selected: defined as cancer spreading through the lymphatic system as cancer spreading through the lymphatic system or the blood stream (direct extension (eg Paget’s), or the blood stream (direct extension (eg Paget’s), iatrogenic implantation excluded). iatrogenic implantation excluded).

• Hematological malignancies were also excluded as Hematological malignancies were also excluded as these malignancies are characterized by malignant these malignancies are characterized by malignant cells already circulating in the bloodstream and cells already circulating in the bloodstream and lymphatic system, and therefore, their presence in lymphatic system, and therefore, their presence in the skin is not regarded as true metastasis.the skin is not regarded as true metastasis.

• Primary skin malignancies (such as Primary skin malignancies (such as melanomas and cutaneous SCCs) ere melanomas and cutaneous SCCs) ere excluded because metastases in the excluded because metastases in the skin cannot be considered as a form of skin cannot be considered as a form of “secondary” organ spread !“secondary” organ spread !

• Analysis was used using the Kaplan-Analysis was used using the Kaplan-Meier method. P smaller than 0.05 was Meier method. P smaller than 0.05 was considered statistically significant.considered statistically significant.

ResultsResults

Clinical features of cutanous Clinical features of cutanous metastases from different metastases from different internal malignanciesinternal malignancies

• 141 cutaneous malignancies from 141 cutaneous malignancies from internal malignancies were internal malignancies were identified> Mostly from the breast identified> Mostly from the breast (51 cases), lung (23), colon and (51 cases), lung (23), colon and rectum (16), oral mucosa (11) and rectum (16), oral mucosa (11) and stomach (10)stomach (10)

Primary origin of cutaneous Primary origin of cutaneous metastases:metastases:

OriginOrigin nn %%• BreastBreast 5151 36.236.2• LungLung 2323 16.316.3• ColorectalColorectal 1616 11.311.3• Oral MucosaOral Mucosa 1111 7.87.8• GastricGastric 1010 7.17.1• HepatocellularHepatocellular 44 2.82.8• OesophagealOesophageal 33 2.12.1• Bladder/ UTBladder/ UT 22 1.41.4• Uterus/CervixUterus/Cervix 22 1.41.4• LarynxLarynx 11 0.70.7• ThyroidThyroid 11 0.70.7• MISCMISC 88 5.75.7• UnknownUnknown 99 6.4%6.4%

• 61 males, 80 females61 males, 80 females

• age 60.8 (22-88years old):age 60.8 (22-88years old):

-Breast cancer: 50 females 58.4 years old-Breast cancer: 50 females 58.4 years old

-Lung Cancer: 16 males (7 females)63.4 -Lung Cancer: 16 males (7 females)63.4 yoyo

-Colorectal 10m6f 62.1yo-Colorectal 10m6f 62.1yo

-Oral Mucosa 10m1f 52.4yo-Oral Mucosa 10m1f 52.4yo

-Gastric 4m6f 61.9yo-Gastric 4m6f 61.9yo

• Cutaneous metastases represented the first Cutaneous metastases represented the first indication of malignancy in 19 cases indication of malignancy in 19 cases (13.5%)(13.5%)

• Interval between diagnosis and cutaneous Interval between diagnosis and cutaneous metastasis ranged from less than a month metastasis ranged from less than a month to 10 year (mean=27.9months):to 10 year (mean=27.9months):

-Breast Cancer 47.2m (1m-10y)-Breast Cancer 47.2m (1m-10y)-Lung Cancer 15.7m (1m-5y)-Lung Cancer 15.7m (1m-5y)-Colorectal cancer 16.5m (9m-3y)-Colorectal cancer 16.5m (9m-3y)-Oral Mucosa 27.5m (6m-9y)-Oral Mucosa 27.5m (6m-9y)-Gastric cancer 19.8m (7m-4y)-Gastric cancer 19.8m (7m-4y)

• The majority of cutaneous lesions were The majority of cutaneous lesions were correctly identified as metastasis before correctly identified as metastasis before the biopsy in 71% of cases. However some the biopsy in 71% of cases. However some lesions were suspicious for benign entities lesions were suspicious for benign entities such as epidermal cyst, pyogenic such as epidermal cyst, pyogenic granuloma, hemangioma or herpes zoster.granuloma, hemangioma or herpes zoster.

• Most commonly presentation was multiple Most commonly presentation was multiple nodules (46.4%), single nodule (37.7%), nodules (46.4%), single nodule (37.7%), plaques or erythematous patches (9.4%) plaques or erythematous patches (9.4%) and ulcers (6.5%)and ulcers (6.5%)

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

Survival following diagnosis of Survival following diagnosis of cutaneous metastasescutaneous metastases

• After establishing the diagnosis of After establishing the diagnosis of cutaneous metastases, the median cutaneous metastases, the median survival was 7.98 months following the survival was 7.98 months following the diagnosis survival % was a follows:diagnosis survival % was a follows:

-1year-1year 36%36%-3years-3years 23%23%-5years-5years 18%18%-10years-10years 3%3%

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

GroupGroup 1 year survival(%)1 year survival(%)3 year surv.5 year surv.3 year surv.5 year surv.10 year surv.10 year surv.Median(mean)Median(mean)

BSBS 79%79% 51%51% 37%37% 11%11% 42m 42m (57m)(57m)

BSVBSV 43%43% 43%43% 22%22% NANA 12m (25m)12m (25m)

NBSNBS 21%21% 12%12% 12%12% NANA 6m (16m)6m (16m)

• NBS worse survival than BSV NBS worse survival than BSV (p=0.016)(p=0.016)

• NBS worse survival than BS (p NBS worse survival than BS (p smaller than 0.001)smaller than 0.001)

• BSV worse survival than BS BSV worse survival than BS (p=0.012)(p=0.012)

Cox proportional hazards Cox proportional hazards (Increased chance of (Increased chance of mortality…)mortality…)

GroupGroupRelative risk(95& CI) SignificanceRelative risk(95& CI) Significance

BSBS 11

BSVBSV 2.392 (1.127-5.078)2.392 (1.127-5.078) p=0.023p=0.023

NBSNBS 4.308 (2.106-8.813)4.308 (2.106-8.813) p<0.001p<0.001

DiscussionDiscussion• In the asian population studied, cutaneous In the asian population studied, cutaneous

metastases originated most commonly from the metastases originated most commonly from the breast in females and the lung in males. This is breast in females and the lung in males. This is consistent with studies involving Caucasian consistent with studies involving Caucasian populations. Therefore although the most populations. Therefore although the most frequent primary tumours are different, the frequent primary tumours are different, the origins of skin metastases encountered seem origins of skin metastases encountered seem similar.similar.

• In concordance with this certain cancers are more In concordance with this certain cancers are more commonly seen in Taiwan such as hepatocellular commonly seen in Taiwan such as hepatocellular carcinoma (higher incidence than lung or breast carcinoma (higher incidence than lung or breast cancer in Taiwan), carcinoma of the bladder and cancer in Taiwan), carcinoma of the bladder and ureter, nasopharyngeal carcinoma and cervical ureter, nasopharyngeal carcinoma and cervical cancer rarely gave rise to cutaneous metastases. cancer rarely gave rise to cutaneous metastases. Therefore the propensity to metastasize depends Therefore the propensity to metastasize depends on the characteristics of tumour cells, which are on the characteristics of tumour cells, which are similar among different ethnic groups.similar among different ethnic groups.

• Paget wrote the “soil-seed” hypothesis that states Paget wrote the “soil-seed” hypothesis that states that tumours preferentially metastasize to those that tumours preferentially metastasize to those organs with an intrinsically favourable environement. organs with an intrinsically favourable environement.

• In addition certain factors secreted from the epidermis In addition certain factors secreted from the epidermis and dermis may play a crucial role in the skin homing and dermis may play a crucial role in the skin homing mechanism of metastatic cells. Recently, chemokines mechanism of metastatic cells. Recently, chemokines and their receptors have been shown to be involved in and their receptors have been shown to be involved in tumorigenesis and metastasis. The chemokine tumorigenesis and metastasis. The chemokine receptor CCR10 has been demonstrated to be receptor CCR10 has been demonstrated to be involved in cutaneous metastases of melanomas and involved in cutaneous metastases of melanomas and may mediate its survival in the skin. Keratinocytes may mediate its survival in the skin. Keratinocytes produce CCR ligand CCL27/CTACK. This pathway could produce CCR ligand CCL27/CTACK. This pathway could be involved in the preferential metastazisation into be involved in the preferential metastazisation into the skin.the skin.

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

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

• Usually cutaneous metastases have been regarded as Usually cutaneous metastases have been regarded as a sign of advanced and widely disseminated disease. a sign of advanced and widely disseminated disease. However in previous studies, there was considerable However in previous studies, there was considerable variation depending on the primary tumour. In variation depending on the primary tumour. In cutaneous metastases from cancers of the lung or the cutaneous metastases from cancers of the lung or the GI tract, evidence of visceral metastases was present GI tract, evidence of visceral metastases was present in most patients. in most patients.

• However, in cutaneous metastases of breast cancer, However, in cutaneous metastases of breast cancer, the metastatic lesions in this study were confined to the metastatic lesions in this study were confined to the skin in approximately one third of patients. the skin in approximately one third of patients. Therefore, the discovery of cutaneous metastases in Therefore, the discovery of cutaneous metastases in breast cancer does not necessarily indicate breast cancer does not necessarily indicate widespread disease.widespread disease.

• Previous studies have shown different Previous studies have shown different survival times for different malignancies survival times for different malignancies (Schoenlaub et al):(Schoenlaub et al):

-13.8m for breast cancer-13.8m for breast cancer

-2.9m for lung cancer-2.9m for lung cancer

• Also BS group patients have a better Also BS group patients have a better survival time than BSV or NBS group survival time than BSV or NBS group patients.patients.

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

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