Dermatologic Manifestations of Metastatic Carcinomas

Updated: Feb 19, 2016
  • Author: Thomas N Helm, MD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Overview

Cutaneous metastases from carcinoma (see the image below) are relatively uncommon in clinical practice, but they are very important to recognize. Cutaneous metastasis may herald the diagnosis of internal malignancy, and early recognition can lead to accurate and prompt diagnosis and timely treatment. However, a high index of suspicion is required because the clinical findings may be subtle.

Alopecia neoplastica due to metastatic breast canc Alopecia neoplastica due to metastatic breast cancer.

See Cutaneous Clues to Diagnosing Metastatic Cancer, a Critical Images slideshow, to help identify various skin lesions that are cause for concern.

The recognition of cutaneous metastases often dramatically alters therapeutic plans, especially when metastases signify persistence of cancer originally thought to be cured. Some tumors metastasize with a predilection for specific areas. Recognition of these patterns can be useful in directing the search for an underlying tumor.

Primary tumors

The breast, skin, stomach, lungs, uterus, large intestine, and kidneys are the most frequent organs to produce cutaneous metastases. Cancers that have the highest propensity to metastasize to the skin include melanoma (45% of cutaneous metastasis cases) and cancers of the breast (30%), nasal sinuses (20%), larynx (16%), and oral cavity (12%). Because breast cancer is so common, cutaneous metastasis of breast cancer is the most frequently encountered type of cutaneous metastasis in most clinical practices. [1] (See the images below.)

Low-power view of breast cancer metastasis with su Low-power view of breast cancer metastasis with surrounding fibrosis.
Breast cancer metastasis with hyperchromatic cells Breast cancer metastasis with hyperchromatic cells extending between thickened collagen bundles. Dilated lymphatics are noted.

Some common tumors, however, may not result in metastasis in a manner that parallels their incidence in the overall population. For example, prostate cancer is very common, but cutaneous metastasis from prostate carcinoma is relatively uncommon.

Unknown primary site

The term carcinoma of unknown primary site (CUPS) is used when dealing with a metastasis that occurs before primary tumor diagnosis. In dealing with cutaneous CUPS, the age, sex, and affected skin region of the patient, as well as the histology of the lesion, are useful in determining the location of the likely primary tumor. Immunohistochemistry can be invaluable in identifying the tissue of origin.

Differentials

Conditions to consider in the diagnosis of dermatologic metastases include the following:

  • Branchial cleft cyst
  • Cellulitis
  • Dermatofibroma
  • Herpes zoster
  • Pyogenic granuloma (lobular capillary hemangioma)

Patient education

For patient education information, see the Cancer Center, as well as Skin Cancer and Skin Biopsy.

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Distinguishing Metastases From Primary Tumors

Certain attributes distinguish metastases from primary tumors. Some features include neoplastic cells in lymphatic and blood vessels, a large portion of neoplasm in the deep reticular dermis, and subcutaneous fat and neoplastic cells lined up between collagen bundles.

Metastatic tumors are usually round, discrete tumor lobules in the dermis, with a Grenz zone, and are usually unassociated with the epidermis. Physical patterns vary among different carcinomas. Fibrosis and inflammation may be present. Vascular involvement is rare. Sometimes, unusual patterns can be identified.

Paget disease typically has a distinct clinical and histologic presentation, with involvement of the nipple or the areola. Symptoms may include an eczematous patch, with intense scaling, pain, and bleeding in later stages. Paget disease may be a sign of underlying breast, genitourinary, or colon cancer, or it may be a primary neoplasm of indeterminate glands in the skin. In extraordinary situations, lesions may be pigmented and epidermotropic and simulate melanoma.

Some primary melanomas may arise in the dermis and simulate a metastasis. [2] On the other hand, some metastases may be epidermotropic and simulate a primary epidermal tumor. [3]

Primary cutaneous adnexal carcinomas may be difficult to distinguish from metastases in certain situations. Primary cutaneous apocrine carcinomas can be particularly difficult to differentiate from adenocarcinomas of mammary origin because of the identical morphological and immunohistochemical features they may exhibit. Sometimes adnexal carcinomas arise in the setting of a precursor benign adnexal neoplasm, making diagnosis straightforward. Mahalingam et al have shown that positive staining with D2-40, p63, and CK15 also favors a primary adnexal carcinoma. [4]

In practice, careful clinical evaluation is essential when a cutaneous adenocarcinoma is identified in the absence of a precursor neoplasm. A confident diagnosis of primary cutaneous apocrine carcinoma requires exclusion of underlying adenocarcinoma by a thorough clinical examination and imaging studies. Further work is underway to find even better immunohistochemical techniques to make this distinction ,which has important prognostic and therapeutic implications.

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Etiology

Metastases arise as disconnected extensions of a primary tumor. This occurs when cancerous cells break away from a primary tumor and spread elsewhere. By definition, this makes the primary tumor malignant. Determining whether a primary neoplasm will metastasize is difficult because of many factors, but, generally, the larger and faster a neoplasm grows, the more likely it will metastasize.

Metastatic pathways

The mechanism for metastasis varies, and several different pathways are thought to be important. Regional spread by way of tissue most often occurs through body cavities, especially the peritoneal cavity. Transplantation can be caused, albeit rarely, by mechanical transport of tumor fragments by instruments during surgery or other invasive procedures.

Lymphatic and vascular routes are the most common pathways, although differentiating the routes is difficult because they are interconnected. Lymphatic spread is the most common pathway for the initial spread of carcinoma. Hematogenous spread is commonly associated with metastasis from sarcomas, although carcinomas may also use this pathway.

Cells may have a predictable metastatic spread, but unusual sites of metastasis may be encountered. The use of sentinel lymph node studies is an attempt to define likely paths of metastasis to identify whether metastasis has occurred. Unfortunately, for some tumors (such as melanoma), there is as of yet no clear evidence that lymphatic spread is the predominant mode of metastasis. Although sentinel node studies may provide useful information on prognosis, this does not enhance overall survival.

Establishment of metastases

Many steps have to be met for metastasis to occur. The primary tumor has to be large enough to release a sufficient amount of neoplastic cells into the circulatory or lymphatic system. These cells need certain properties, such as cell suspension and mitotic rate, to survive while in circulation. Most single neoplastic cells released are destroyed by the immune system, whereas clusters of 6 or 7 cells have a better chance of metastasis.

To establish metastases once the neoplastic cells are in the circulatory system, the neoplastic cells need to attach and penetrate vessel walls. The circulatory path influences the location of the most common attachment sites, but the neoplastic cells also have affinities for certain target tissues.

Once attachment occurs, a thrombus forms around the neoplastic cells through endothelial cell injury. This thrombus serves as protection for the neoplastic cells. The new metastasis establishes itself and obtains nutrition initially through diffusion; it then forms its own vessels.

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Prognosis

The mortality rate is high in patients with cutaneous metastases. The appearance of these neoplasms signals widespread metastatic disease, resulting in a poor prognosis. Patients often survive for a short period, depending on the type of carcinoma, but this is changing. Exciting advances in chemotherapy have greatly increased survival in recent years; many patients now survive for a number of years with directed therapy.

In a retrospective study, Song et al found that 2.8% of patients with advanced non-small cell lung cancer (NSCLC) initially presented with cutaneous metastases and that these metastases were indicative of a poor prognosis. In the study, 60 out of 2130 patients with advanced NSCLC had an initial diagnosis of cutaneous metastases. (Fifteen patients had only cutaneous metastases, and 45 patients had a combination of cutaneous and noncutaneous metastases.) The overall length of survival for patients with cutaneous metastases was 3.9 months, compared with 10 months for patients who did not present with cutaneous metastases. [5]

The serum TA90 immune complex assay, developed at M.D. Anderson Cancer Center and licensed through Quest Diagnostics, can predict the likelihood of melanoma recurrence with 70% sensitivity and 85% specificity. [6] Similar studies are being developed for other types of cancer to help identify patients at high risk for metastasis.

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Epidemiology

The incidence of cutaneous malignancy varies. In some autopsy studies of patients with metastatic carcinoma, as many as 9% of individuals were noted to have cutaneous metastases. Other studies suggest a range of 3-4%. A 2003 meta-analysis [7] estimated a rate of cutaneous metastasis of 5.3%. A recent large study shows that the incidence of cutaneous metastases due to melanoma is increasing. [8]

Sex-related demographics

The most common sources of cutaneous metastases in woman are the breasts (69%), the colon (9%), melanomas (5%), the ovaries (4%), and the lungs (4%). In men, the most common sources are the lungs (24%), the colon (19%), melanoma (13%), and the oral cavity (12%).

Age-related demographics

Cutaneous metastases are very rare in children. Rhabdomyosarcoma, leukemia, and neuroblastoma are the most frequent causes in children.

In men younger than 40 years, the most common sources of cutaneous metastases (in decreasing order of frequency) are melanoma, colon cancer, and lung cancer. In men older than 40 years, the most common sources of cutaneous metastases (in decreasing order of frequency) are lung cancer, colon cancer, squamous cell carcinoma in the oral cavity, and melanoma.

In women younger than 40 years, the most common sources of cutaneous metastases are breast cancer, colon carcinoma, and ovarian carcinoma. In women older than 40 years, they are breast carcinoma, colon carcinoma, lung cancer, ovarian carcinoma, and melanoma.

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History

In most cases, cutaneous metastases develop after the initial diagnosis of the primary malignancy (eg, metastases of breast carcinoma involving the chest wall several years after a mastectomy). In a very small percentage of patients, metastases may be discovered at the same time or prior to the diagnosis of a primary tumor (eg, lung and renal cell carcinoma presenting as scalp metastases in a man who otherwise appears well and gives no history of prior malignancy).

Patients may present with rapidly developing nodules or tumors. Although asymptomatic in most instances, pain and tenderness may be noted. Any rapidly developing or eruptive lesions should warrant careful consideration of the possibility of metastasis.

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Physical Examination

Most cutaneous metastases occur in a body region near the primary tumor. The most common presentation of cutaneous metastases is nodules. The nodules are often nonpainful, round or oval, firm, mobile, and rubbery in texture. The nodules are usually flesh colored, although they may also be other colors (eg, from flesh colored to brown or blue-black).

Often, the nodules from the metastases of renal cell carcinoma and occasionally thyroid carcinoma are red and purple. They vary in size from barely perceptible lesions to large tumors. Multiple nodules appear rapidly before growth slows down.

Breast cancer

Carcinoma may engender a brisk inflammatory response mimicking cellulitis. This pattern is referred to as inflammatory breast carcinoma. When many telangiectatic blood vessels are encountered, the pattern is referred to as carcinoma telangiectodes. Occasionally, the skin may have an orange peel–like appearance (peau d'orange) and/or changes in the local blood flow may occur. In other cases, the skin may feel firm and have a breastplatelike appearance, which is referred to as carcinoma en cuirasse.

Breast cancer is one of the most common malignancies to spread to the skin. The most likely site for cutaneous metastases in women is the chest; less common sites include the scalp, the neck, the upper extremities, the abdomen, and the back.

Occasionally, patients with metastatic breast cancer have a firm, scarlike area in the skin. When this occurs on the scalp, hair may be lost, and the clinical appearance may mimic alopecia areata, except that the skin exhibits marked induration on palpation. This condition, known as alopecia neoplastica, is shown in the images below.

Alopecia neoplastica due to metastatic breast canc Alopecia neoplastica due to metastatic breast cancer.
Close-up view of patient with alopecia neoplastica Close-up view of patient with alopecia neoplastica due to metastatic breast cancer shows telangiectases and nodularity. The plaque was markedly indurated on palpation; in contrast, patients with alopecia areata would exhibit normal skin texture.

Lung cancer

The most frequently encountered metastases in men come from lung cancer. The most common site for cutaneous metastases in men is the chest, followed by the abdomen and the back. Other areas (in decreasing order of frequency) include the scalp, neck, face, extremities, and pelvis. For women, the most common areas (in decreasing order of frequency) are the chest, abdomen, back, and upper extremities.

Gastrointestinal cancer

Gastrointestinal cancers (usually colon and stomach cancer) often metastasize to the abdomen and the pelvis. Gastrointestinal carcinomas may spread along the urachus and produce nodules at the umbilicus; those at the umbilicus have been referred to as Sister Mary Joseph nodules. (Sister Mary Joseph was a nurse at the Mayo Clinic who helped to prepare patients prior to operation for gastrointestinal surgery. She noted that the nodules at the umbilicus were an ominous sign of extensive involvement of colorectal carcinoma.)

Malignant melanoma

About 60,000 Americans develop malignant melanoma each year, but only 9000 deaths are attributed to the disease annually in the United States. When malignant melanoma metastasizes, the skin is commonly involved. In men, melanomas are likely to metastasize to the chest, extremities, and back. A large portion of female patients have metastases to the lower extremities. Recent reviews indicate that the proportion of metastases due to melanoma is increasing. This finding is not unexpected as the incidence of melanoma continues to rise. [8]

Metastases of melanoma may simulate blue nevi and may be epidermotropic or simulate primary cutaneous melanoma. A zosteriform appearance reportedly is rare. [9]

Other cancers

Cutaneous metastases from squamous cell carcinoma in the oral cavity usually remain in the local area, most often affecting the neck and face.

Renal cell carcinoma may metastasize to the scalp, operative scars, or many other surfaces. Because of the prominent vascular supply of renal cell carcinoma, lesions may mimic a hemangioma or a pyogenic granuloma.

Metastases from the ovary and the uterus are seen in the skin of the lower abdomen, the groin, or the upper thigh.

Summary

Common cutaneous metastasis sites and their probable primary sites are as follows:

  • Metastasis to scalp - Breast, lung, kidney
  • Metastasis to neck - Oral squamous cell carcinoma
  • Metastasis to face - Oral squamous cell carcinoma, renal cell, lung
  • Metastasis to extremities - Malignant melanoma, breast, lung, renal, intestinal
  • Metastasis to chest - Breast, lung, malignant melanoma
  • Metastasis to abdomen - Colon, lung, stomach, breast, ovary
  • Metastasis to umbilicus - Stomach, pancreas, colon, ovary, kidney, breast
  • Metastasis to pelvis - Colon
  • Metastasis to back - Lung
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Imaging Studies

Magnetic resonance imaging (MRI), computed tomography (CT) scanning, and ultrasonography can be used in select cases to gauge the extent of metastases or to identify metastases if biopsy samples are inconclusive. Imaging studies are also of value when proximity to vital organs makes performing a biopsy dangerous.

Determining the presence of metastases is important in staging. Fluorine 18-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging is useful in staging melanoma, especially in patients with American Joint Committee on Cancer (AJCC) stage III or IV cancer. [10]

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Immunohistochemical Studies

Failure to perform a biopsy on a metastasis may lead to a delay in treatment. Lesions that exactly mimic cysts, dermatofibromas, pyogenic granulomas, or hemangiomas have all been reported. A high index of suspicion is needed so that tumors are not overlooked.

The diagnosis of metastatic carcinoma hinges on histopathologic evaluation of involved skin. Tumors may show characteristics of the underlying tumor, or they may have a more anaplastic appearance. In the situation of an anaplastic tumor, immunohistochemical marker studies and ultrastructural examination may help to delineate the tissue of origin.

It is important to perform a panel of immunohistochemical marker studies and to carefully correlate the resultant findings with light microscopic findings and clinical information. As with any test, false-positive and false-negative findings may occur. Clinicians should look at the overall clinical situation when making therapeutic decisions.

Punch or excisional biopsy usually provides sufficient tissue for diagnosis. Fine-needle aspiration cytology can also be useful in certain circumstances. [11]

Immunophenotypes

Carcinoma immunophenotypes, with the location and antibody positivity/negativity, are as follows, with (+) indicating "always positive,” (-) indicating "negative but with rare exceptions," CK representing types of cytokeratin, TTF standing for thyroid transcription factor, Ber-EP4 representing an antihuman epithelial antigen, WT-1 referring to Wilms tumor protein, CEA standing for carcinoembryonic antigen, ER representing estrogen receptor, CA referring to cancer antigen, CD standing for cluster of differentiation, CAM 5.2 being a clone developed against certain keratins, DPC4 being a tumor-suppressor gene, and S100 being a family of calcium-binding proteins:

  • Breast: CK7 (+), CAM 5.2 (+), vimentin (-), TTF-1 (-), Ber-EP4 (+), WT-1 (-), DPC4 (-)
  • Lung adenocarcinoma: CK7 (+), CAM 5.2 (+), CEA (+), Ber-EP4 (+), WT-1 (-), DPC4 (-)
  • Colorectal: CK20 (+), CAM 5.2 (+), CK17 (-), CK19 (+), CEA (+), TTF-1 (-), Ber-EP4 (+), S100 (-), WT-1 (-), DPC4 (-)
  • Gastric: CAM 5.2 (+), vimentin (-), TTF-1 (-), ER (-), Ber-EP4 (+), WT-1 (-), DPC4 (-)
  • Prostate: CK7 (-), CK20 (-), CAM 5.2 (+), CD5/6 (-), CK17 (-), CEA (-), vimentin (-), TTF-1 (-), ER (-), Ber-EP4 (+), S100 (-), WT-1 (-), DPC4 (-)
  • Pancreas: CK7 (+), CAM 5.2 (+), vimentin (-), TTF-1 (-), ER (-), Ber-EP4 (+), S100 (-), WT-1 (-), DPC4 (+)
  • Renal: CK7 (-), CK20 (-), CAM 5.2 (+), CEA (-), TTF-1 (-), CA125 (-), ER (-), CD10 (+), WT-1 (-), DPC4 (-)
  • Neuroendocrine: CK20 (-), CK5/6 (-), CA125 (-), ER (-), Ber-EP4 (-), WT-1 (-), DPC4 (-)
  • Squamous cell carcinoma: CK7 (-), CK20 (-), CK5/6 (+), CK17 (+), TTF-1 (-), CA19.9 (-), CA125 (-), ER (-), Ber-EP4 (-), CD10 (-), S100 (-), WT-1 (-), DPC4 (-)
  • Merkel cell carcinoma: CK7 (-), CK20 (+), CK5/6 (-), CEA (-), CEA (-), CA125 (-), Ber-EP4 (+), CD10 (-), S100 (-), WT-1 (-), DPC4 (-)

Screening studies

Immunohistochemical screening studies can be used in cases in which no clues point to a particular type of underlying cancer. Immunohistochemical markers and the cellular tissue of origin are as follows:

  • CKAE1/AE3 and CAM 5.2 : Epidermis and appendageal tumors
  • Desmin: Smooth muscle tumors
  • Vimentin: Mesenchymal cells, melanoma, lymphoma, sarcoma
  • CEA: Glandular or gastrointestinal tumors
  • S-100: Melanocytic tumors, tumors of eccrine or apocrine glands
  • CD34: Vascular tumors, dermatofibrosarcoma protuberans, angiosarcoma
  • Chromogranin: Neuroendocrine cells
  • Prostate-specific antigen: Prostate carcinoma

Screening immunophenotypes for undifferentiated neoplasms are as follows:

  • Carcinoma: AE1/AE3 antibodies (positive), vimentin (negative), LCA (leukocyte common antigen; negative), S-100 (negative)
  • Sarcoma: AE1/AE3 antibodies (negative), vimentin (positive), LCA (negative), S-100 (negative)
  • Lymphoma: AE1/AE3 antibodies (negative), vimentin (negative), LCA (positive), S-100 (negative)
  • Melanoma: AE1/AE3 antibodies (negative), vimentin (positive), LCA (negative), S-100 (positive)

Evaluation algorithm

Advances in immunohistochemistry have led to recommendations regarding a logical algorithmic approach to the immunohistochemical evaluation of a poorly differentiated neoplasm from an unknown primary source. Pancytokeratin (AE1/AE3 antibodies), CAM 5.2, CK7, and CK20 represent tests that can be performed first. Depending on the results, additional choices in a "decision tree" can lead to specific diagnoses. [12]

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Histologic Findings

A biopsy of the skin helps in confirming a diagnosis of tumor. The pattern and microscopic appearance often suggest the likely tissue of origin. The initial diagnosis can be made by examining frozen sections, but the final diagnosis should be reserved until permanent sections are included. Generally, the histologic features of the metastases are similar to the primary tumor, although metastases may be more anaplastic and exhibit less differentiation.

High-powered microscopic examination reveals tubul High-powered microscopic examination reveals tubules composed of clear cells, hemorrhage, and a prominent vascular pattern characteristic of metastatic renal cell carcinoma.
Biopsy of a nodule on the scalp revealed a precoci Biopsy of a nodule on the scalp revealed a precocious metastasis from renal cell carcinoma. Cutaneous metastases are sometimes the first presentation of internal disease. Histologic examination reveals a spherical tumor in the dermis with no connection to the overlying epidermis. Hematoxylin and eosin‒stained sections; original magnification 20x.
Biopsy of metastatic melanoma reveals a well-circu Biopsy of metastatic melanoma reveals a well-circumscribed tumor in the dermis with no connection with the overlying epidermis. Hematoxylin and eosin‒stained sections; original magnification 20x.

In some cases, such as in patients with renal cell carcinoma, the cancer can be identified through characteristic histologic findings, but metastases usually are classified only broadly as adenocarcinoma, squamous cell carcinoma, or undifferentiated carcinoma. (See the images below.)

Low-power view of breast cancer metastasis with su Low-power view of breast cancer metastasis with surrounding fibrosis.
Breast cancer metastasis with hyperchromatic cells Breast cancer metastasis with hyperchromatic cells extending between thickened collagen bundles. Dilated lymphatics are noted.
Breast cancer with an Indian file pattern of metas Breast cancer with an Indian file pattern of metastasis.
A well-circumscribed metastasis of renal cell carc A well-circumscribed metastasis of renal cell carcinoma is surrounded by compressed collagen, which is indicative of rapid growth.
Pleomorphic clear cells with prominent vasculature Pleomorphic clear cells with prominent vasculature are characteristic of metastatic renal cell carcinoma.
Metastatic squamous cell cancer typically does not Metastatic squamous cell cancer typically does not involve the epidermis, allowing for differentiation of metastases from primary cutaneous squamous cell cancer.
High-powered examination reveals a nest of atypica High-powered examination reveals a nest of atypical melanocytes with enlarged and pleomorphic nuclei. Melan-A and S-100 stains were positive and helped confirm the diagnosis. Hematoxylin and eosin‒stained sections; original magnification 200x.

 

High-power examination reveals neoplastic epitheli High-power examination reveals neoplastic epithelioid cells within dilated lymphatics. Hematoxylin and eosin‒stained sections; original magnification, 400x.
Inflammatory breast carcinoma. Inflammatory breast carcinoma.
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Palliative Treatment

Effective treatment depends on treatment of the underlying tumor. Palliative care is given if lesions are asymptomatic and the primary cancer is untreatable. This care includes keeping lesions clean and dry and debriding the lesions if they are bleeding or crusted. Hydrocolloid dressings may be used to help prevent secondary infection.Topical retinoids offer promise in select cases, and studies indicate that the immune modulator imiquimod 5% cream (Aldara) may lead to regression of metastases in some patients with melanoma. Photodynamic therapy also may be useful for palliation of skin metastases.

Short-wavelength radiation therapy may be helpful for providing symptomatic relief from painful lesions, using superficial electron beam therapy. Carbon dioxide laser therapy, [13, 14] electrochemotherapy, [15] liquid nitrogen cryotherapy with temperature probe control, and other treatment approaches may also be of value.

Pulsed dye laser treatment, which can reduce blood flow to highly vascularized lesions, may be of value. Intralesional chemotherapy and cytokines can also be helpful.

Medical camouflage with cosmetics (eg, Dermablend) may be of value to disguise visible metastases for cosmetic purposes.

Surgical care

In many cases, cutaneous metastases can cause disfigurement or social embarrassment, or they can diminish the quality of the patient's life. Surgical approaches are generally the most effective as a temporizing measure for cutaneous metastases. Excision and removal of metastases may be warranted to enhance the patient's quality of life, but excision of select metastases does little to increase survival. Simple excision is usually the treatment of choice.

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