Cutaneous metastases may be the first indication of a visceral cancer, ¹¹ the incidence in one series being 0.8%. ¹² These precocious metastases are particularly likely to present at the umbilicus, or less frequently on the scalp. The kidney, ¹³ lung, ¹⁴ thyroid, ¹⁵ and ovary¹¹ are organs whose tumors may present in this way. ¹⁶

With most tumors the metastases develop some months or years after the primary malignancy has been diagnosed¹¹– so-called ‘metachronous metastases’. In about 7% of cases, this interval exceeds 5 years. Tumors of the breast and kidney and malignant melanomas may give rise to delayed metastases. ¹⁷

The term ‘synchronous metastasis’ is used when the cutaneous metastasis and the primary tumor are diagnosed simultaneously. ¹⁸ This sometimes occurs with tumors of the breast and oral cavity.

Cutaneous metastases are more likely to be found in older individuals. ¹⁹ In neonates they are usually derived from a neuroblastoma or, less commonly, from a rhabdomyosarcoma. ²⁰ Metastases from germ cell and trophoblastic tumors, although rare in the skin, develop there particularly in young adults.

Cutaneous metastases usually present as multiple, discrete, painless, freely movable nodules of sudden onset.^{6.16. and 21.} They usually show rapid enlargement. ²² Sometimes several small nodules are localized to one area. ²³ Solitary metastases occur in about 10% of cases. The nodules are usually 1–3 cm in diameter. Much larger lesions and also occult lesions have been recorded.^{24. and 25.} They vary in color from red to bluish-purple to light brown or flesh colored. Occasionally plaques are formed. One variant of this form develops in the scalp as patches of alopecia (alopecia neoplastica), sometimes resembling alopecia areata.^{26.27.28.29. and 30.} Cicatricial plaques also form: metastases from the breast,^{26. and 27.} lung, and kidney may give this pattern on rare occasions.

There are isolated reports of other patterns of cutaneous metastases. ⁵ For example, they may resemble erythema annulare, ⁵ a chancre, ³¹ a hematoma, ³² an epidermal cyst, ³³ a condyloma, ⁵ or an ulcer. ⁵ They may present in a zosteriform or target-like pattern.^{34.35.36.37.38.39.40.41.42.43.44.45.46.47. and 48.} In one case, herpes zoster was associated with the metastases. ⁴⁹ Elephantiasis of the lower limbs due to lymphatic obstruction and facial or eyelid lymphedema are rare clinical presentations.^{50.51. and 52.} Metastases have also been reported in an area of radiation dermatitis. ⁵³

There are three clinical patterns of metastasis which are almost exclusively related to carcinomas of the breast: carcinoma erysipelatoides (‘inflammatory carcinoma’), carcinoma telangiectaticum, and carcinoma en cuirasse.^{19.54.55.56.57.58. and 59.} The inflammatory pattern presents as a large, tender, warm plaque which may resemble erysipelas.^{17.54. and 60.} It is found in less than 2% of all breast carcinomas. Some would regard this as being due to direct extension from the underlying carcinoma, and not a true metastasis. ¹⁶ Rarely, this pattern is seen with metastases from melanoma⁶¹ and mesothelioma, ⁶² and from carcinomas of the esophagus, ⁶³ stomach, ⁶⁴ pancreas, ⁶⁵ colon,^{58. and 66.} rectum,^{67. and 68.} prostate, ⁵⁵ bladder, ⁶⁹ and lung.^{35. and 70.} It follows the obstruction of lymphatics at all levels of the dermis, with resulting edema. ⁶⁰ There are often some perivascular and perilymphatic inflammatory cells. Carcinoma telangiectaticum presents as a telangiectatic sclerotic plaque, often studded with pink papules and pseudovesicles.^{54. and 71.} There is massive subepidermal edema resulting from obstruction by tumor of small blood vessels and lymphatics in the upper dermis. Other vessels are congested. Rarely, metastases from the lung will give this picture. Carcinoma en cuirasse is a diffuse induration of the breast resulting from some dermal fibrosis and a diffuse infiltrate of tumor cells between collagen bundles, sometimes in an ‘Indian-file’ pattern. ⁵⁴

Metastases tend to occur on the cutaneous surfaces near the site of the primary tumor, although there are many exceptions. ⁶ Metastases from tumors of the lung often involve the chest wall and proximal parts of the upper extremities, whereas those from the oral cavity and esophagus may metastasize to the head and neck, and those from the gastrointestinal and genitourinary systems to the abdominal wall.^{23. and 72.} Approximately 5% of metastases involve the scalp.^{6.11. and 73.} This is a common site for metastases from the thyroid. ⁷⁴ In a series of 398 Taiwanese patients with malignant cutaneous tumors of the scalp, metastatic tumors accounted for 51 of these cases; 18 of these 51 cases were from the lung. ⁷⁵

Metastasis to the umbilicus is also quite common.^{76. and 77.} The lesion that results has been called the Sister Mary Joseph nodule, in recognition of a nursing superintendent at the Mayo Clinic, Rochester, Minnesota, who is credited with recognizing the clinical significance of these nodules. ⁷⁷The underlying primary tumor is usually an adenocarcinoma of the stomach, large bowel, ovary, pancreas, gallbladder, endometrium, or breast (Fig. 39.1).^{76.77.78.79.80. and 81.} Rare primary tumors have included transitional cell carcinoma of the bladder, ⁸² a peritoneal mesothelioma, ⁸³ a carcinoid, and a leiomyosarcoma of the intestine. In one case the umbilical tumor resembled an ovarian serous papillary tumor, but no ovarian tumor was ever found. ⁸⁴ Other rare sites are listed in the review of all cases reported between 1960 and 1995. ⁸⁵ Leukemia cutis rarely presents in this way. ⁸⁶ Sister Mary Joseph nodules are usually solitary and firm, sometimes with surface fissuring. In 12 of a series of 85 cases reported in 1984, the umbilical nodule was the initial presentation of the tumor. ⁷⁷ There are various routes by which tumor cells can reach the umbilicus. They include contiguous extension and spread by lymphatic and venous channels, often associated with embryological vestiges in this region. ⁷⁷

The penis may be the site of metastases from the bladder and prostate.^{87. and 88.} The deposits are usually multiple and sometimes associated with priapism. ⁸⁷ Metastatic tumors involving the vulva are rare, although 66 cases were reported from one institution (the M.D. Anderson Cancer Center) in 2003. ⁸⁹ In 29 cases the site of origin was non-gynecological, while in 31 cases the primary was in a gynecological site, 15 of these being in the cervix. The primary site was unknown in six cases. ⁸⁹

The lower extremities, excluding the thighs, are uncommonly involved with metastases. ¹¹ Other rare sites include the nail bed,^{90. and 91.} thumb, finger, ⁹² big toe, ⁹³ scrotum, eyelid, eyebrow, nasal tip, and ear.^{2.5.94.95.96. and 97.}

Cutaneous metastases may develop at the site of a surgical or diagnostic procedure.^{2.98.99. and 100.} Metastases are sometimes seen in abdominal, perineal, mastectomy, and nephrectomy scars, around colostomy sites, and along the tract produced by a thoracentesis needle. However, seeding along the needle tract is unexpectedly rare following percutaneous biopsy of prostatic carcinomas. ¹⁰¹ Metastases to soft tissue are beyond the scope of this book. ¹⁰²

Metastasis to a nevocellular nevus is a rare event.^{103. and 104.}

The detailed studies of Brownstein and Helwig (1972) have provided valuable information regarding the most frequent sites of origin of the tumors that give rise to cutaneous metastases. ⁷² They studied 724 patients in whom there was histopathological confirmation of both the primary tumor and the secondary deposit in the skin. Their studies complement the earlier report by Gates in 1937. ⁹⁴

The most frequent primary tumors in men were carcinoma of the lung (24%), carcinoma of the large intestine (19%), melanoma (13%), and squamous cell carcinoma of the oral cavity (12%). ⁷² In women, they were carcinoma of the breast (69%), carcinoma of the large intestine (9%), melanoma (5%), and carcinoma of the ovary (4%). ⁷² A study from India in 1988 showed that the lung and esophagus were the most common sites of the primary tumor in men and the breast and ovary in women. ¹⁰⁵ Breast cancer and melanoma were the most common origins for skin metastases in the study of 4020 patients with metastatic carcinoma, ⁶ a finding repeated in a recent report from Spain. ²² A study in 2004 from a large Veterans Administration hospital in the United States showed that the lung, melanoma, and gastrointestinal tract were the three most common primary sites of cutaneous metastases. ¹⁰⁶

Sometimes, despite exhaustive investigations, no primary lesion can be identified. ¹⁰⁷ This may result from an extremely small primary tumor or its regression.

The development of cutaneous metastases is usually a grave prognostic feature, as dissemination to other organs has usually already occurred. The average survival time after the appearance of cutaneous metastases is 3–6 months, ²³ although this has improved slightly in recent times. ⁶ However, there are many reports of patients with carcinoma of the breast, neuroblastoma, and other tumors¹⁵ who survived many years after the appearance of the cutaneous metastases.

More than 60% of metastases are adenocarcinomas, usually arising in the large intestine, lung, or breast.^{6.17. and 23.} If the glandular structures are well differentiated, the colon or rectum should be suspected as the primary site. Tumors from the breast usually have a very undifferentiated pattern, with sheets of cells or sometimes columns between the collagen bundles. Signet-ring cells can be found in some metastases of mammary origin, but they are more usual in secondary deposits of gastric origin. ¹⁰⁸

About 15% of metastases are of squamous cell type. They usually arise from the oral cavity, lung, or esophagus. The remainder of cutaneous metastases are melanomas, anaplastic tumors, or other rare specific patterns. ¹⁰⁹

Metastases usually resemble the primary tumor, although the features are sometimes more anaplastic. ²³ The metastases from a clear cell renal cell carcinoma can appear disarmingly benign: ¹¹⁰ a mistaken diagnosis of a benign appendage tumor may be made in these circumstances (Fig. 39.2). Clear cell hidradenoma shows a vesicular to finely vacuolated cytoplasm, in contrast to the sometimes granular cytoplasm seen in renal cell carcinoma. ¹⁰⁹

Metastases are centered on the dermis, although there is sometimes extension into the subcutis. The epidermis is usually intact, and there is an underlying narrow zone of compressed collagen separating the tumor from the epidermis (grenz zone). Occasionally a metastatic squamous cell carcinoma will touch the undersurface of the epidermis, making distinction from a primary carcinoma difficult. ¹¹¹ Epidermotropic metastases are exceedingly rare, except for cutaneous melanomas. ¹¹² Dermal sclerosis is uncommon, but can be seen with some breast carcinomas.

Lymphatic permeation is a prominent feature of the so-called ‘inflammatory carcinomas’ (see p. 928). It is sometimes present at the edge of a cutaneous metastasis. Uncommonly, lymphatic channels throughout the dermis are involved (Fig. 39.3 and Fig. 39.4).

Immunohistochemistry is of increasing value in the interpretation of cutaneous metastases.^{109. and 113.} Monoclonal antibodies against thyroglobulin, calcitonin, prostatic antigens, leukocyte common antigen (CD45), epithelial membrane antigen, S100 protein, neuron-specific enolase, various cytokeratins, vimentin, and desmin can be used to elucidate or confirm the nature of the primary tumor that gave rise to the cutaneous metastasis. A truncated immunohistochemical battery using CK7, CK20, and S100 protein has been recommended as a starting point in the assessment of a suspected cutaneous metastasis; ¹⁰⁶ often they need to be combined with other markers. ¹¹⁴ A different panel, including p63, B72.3, calretinin, and CK5/6 has been used to differentiate metastatic carcinoma from primary skin adnexal tumors. ¹¹⁵ The majority of primary adnexal tumors express p63 whereas cutaneous metastases from internal adenocarcinomas are usually negative.^{116.117. and 118.} In a more recent study p63 was positive in 5 of 45 (11%) cutaneous metastases. ¹¹⁹ This investigative field is expanding rapidly, with many new markers appearing.

The anterior chest wall is commonly involved by recurrences of carcinoma of the breast, although distant cutaneous metastases are uncommon.^{120. and 121.} In his review of cutaneous metastases, Rosen mentions two autopsy series of carcinoma of the breast where cutaneous metastases were found in 18.6% and 37.7% of cases, respectively. ² Brownstein and Helwig, in their study of 724 patients with cutaneous metastases, recorded 168 cases in women with carcinoma of the breast (69% of the total number of women in the series) and 9 in men. ⁷² In 20 of these there were single distant metastases; in 3 there were multiple metastases. ⁷² In the remainder, only the chest wall was involved. Extensive cutaneous metastases are sometimes observed with carcinoma of the breast, in both males and females.^{122.123.124. and 125.}

The scalp is a favored site of distant metastases, ¹²⁰ but the thigh may also be involved. ¹²⁶ Patches of alopecia resembling alopecia areata (alopecia neoplastica) may result.^{26.27.28.127.128.129.130. and 131.} Other clinical patterns found on the chest wall include the so-called ‘inflammatory carcinoma’,^{55.56.57.58. and 132.} carcinoma telangiectaticum, ¹³³ and carcinoma en cuirasse.^{54.134. and 135.} Pigmented metastases mimicking malignant melanoma have also been reported.^{136. and 137.} Prolonged survival has been recorded after the appearance of the cutaneous lesions.^{128. and 138.}

Carcinoma of the inframammary crease is an uncommon but distinctive pattern of presentation which results from early invasion of the skin by a peripherally situated tumor.^{139. and 140.} It is exophytic and fissured and may simulate a primary epidermal tumor both clinically and microscopically. ¹⁴¹

Cutaneous metastases are found in 4% or less¹⁵¹ of patients with carcinoma of the lung. In a small number of cases these are precocious metastases. ¹⁴ The chest wall and abdomen are the usual sites, although ‘oat-cell’ (small cell) carcinomas appear to have a predilection for metastasizing to the back. ¹⁸ The finger and skull are extremely rare sites.^{152. and 153.} Rarely, an inflammatory or zosteriform pattern is produced. Death usually occurs within 3 months of the development of the skin lesions. Eyelid edema, secondary to superior vena cava syndrome, can be the presenting sign of a primary bronchogenic carcinoma. ¹⁵⁴ The histopathological pattern is squamous cell carcinoma in 40%, adenocarcinoma in 20%, and undifferentiated carcinoma in 40%.^{18.155. and 156.} One bronchiolar and one mucoepidermoid bronchial carcinoma were among the tumors of lung reported by Brownstein and Helwig in their review on cutaneous metastases. ⁷² Fetal adenocarcinoma of the lung with preceding cutaneous metastasis, and basaloid carcinoma of the lung presenting concurrently with cutaneous metastasis have been reported.^{157. and 158.} Pleural mesotheliomas rarely metastasize to the skin.^{62.159.160.161. and 162.} Metastasis to the lip was the initial presentation of mesothelioma in two cases. ¹⁶³ The cells stained with cytokeratin (CK) 5/6, epithelial membrane antigen (EMA), HBME1, calretinin, and CK7. ¹⁶³

Tissue-specific transcription factor (TTF1), expressed in epithelial cells of thyroid and lung, is often expressed in cutaneous metastases of lung tumors. ¹⁴⁸ It is not present in Merkel cell carcinomas. The immunohistochemical profile of lung metastases is shown in Table 39.2.

Tumors of the oral cavity usually spread to the face or neck. ⁷² In some instances this results from direct extension of the tumor rather than true metastasis. ¹⁶ The tumors are usually squamous cell carcinomas.

Less than 2% of esophageal carcinomas metastasize to the skin. ¹⁸ The primary lesion is usually a squamous cell carcinoma in the lower esophagus; ¹⁸ metastatic adenocarcinoma is sometimes seen.^{164. and 165.} The metastases are multiple nodules with a predilection for the upper part of the trunk and the neck. Acral metastases, and metastases to the breast, masquerading as an inflammatory breast carcinoma have been recorded.^{63. and 166.} Squamous cell carcinomas of the esophagus are usually CK5/6 positive. ¹⁴⁸

Brownstein and Helwig reported 29 cases of gastric carcinoma with metastasis to the skin. ⁷² The trunk, particularly the umbilical area, is a favored site.^{77.167. and 168.} The tip of the finger,^{92. and 169.} the face, ¹⁷⁰ the axilla, ¹⁷¹ and a congenital nevus on the occiput¹⁰⁴ are uncommon sites of involvement. The tumors are usually poorly differentiated adenocarcinomas. Signet-ring cells and extracellular mucin pools may be present. ¹⁷⁰ Eczematous and erythematous lesions on the face, resulting from cutaneous metastases, have also been reported.^{172. and 173.} A monoclonal antibody HIK1083 specific for gastric O-glycan can be used in differentiating a cutaneous metastasis of gastric carcinoma from primary sweat gland carcinoma in which it is negative. ¹⁷⁴ This stain is superior to CK20, which while often present in metastatic carcinomas of skin, is also found in metastatic colorectal cancer and occasional metastases from the lung and breast. ¹⁷⁴

The colon is a common source of cutaneous metastases. Brownstein and Helwig recorded 90 males and 22 females in this category. ⁷² This makes it the second most common primary site in both males and females. Brady et al reported a 3.5% incidence of cutaneous metastases in patients coming to autopsy with adenocarcinoma of the colon and rectum. ¹⁸ The metastases are usually multiple and metachronous, and most often are in the skin of the abdominal wall or perineal region.^{18.68. and 72.} The umbilicus, or the colostomy site, may be involved.^{77.175.176. and 177.} The appearance of multiple metastases is a bad prognostic sign. The deposits are usually composed of well-differentiated adenocarcinoma, although mucinous, less well-differentiated variants are found. The metastases are typically ‘dirty’, with some neutrophils and degenerate cells in the lumina of the glands (Fig. 39.6).

Peritoneal mesotheliomas, metastatic to the umbilicus, have been reported.^{83. and 178.}

The immunohistochemical profile of gastrointestinal metastases is listed in Table 39.3.

Cutaneous metastases occur in nearly 3% of patients with malignant hepatomas of the liver.^{179.180. and 181.} Rarely, it is the presenting manifestation,^{182. and 183.} although death still follows in several weeks. ¹⁸⁰ A 12-year-old child with cutaneous metastases on the thorax and epigastrium has been reported. ¹⁸⁴ In another case, a metastasis to the gingiva mimicked a pyogenic granuloma. ¹⁸⁵ The histopathological pattern may be either a cholangiocarcinoma or a hepatocellular carcinoma.^{180.186.187.188. and 189.} A sarcomatoid carcinoma is extremely rare. ¹⁹⁰ An immunohistochemical marker of hepatocellular differentiation is now available for use on paraffin sections (Hep Par 1). ¹⁹¹

Brownstein and Helwig recorded 15 cases of metastatic pancreatic carcinoma involving the skin. ⁷² The umbilicus is a favored site for these metastases.^{76.192.193. and 194.} Rarely, an inflammatory or epidermotropic pattern is present.^{65.195. and 196.} Metastasis to the skin from a vasoactive intestinal polypeptide tumor (VIPoma) of the pancreas has been reported. ¹⁹⁷

There are several reports in which the primary tumor was in the gallbladder.^{198.199.200. and 201.} Rarely, the metastasis in such cases is to the umbilicus.^{77. and 78.}

Metastases have been reported in the skin in from 2.8% to 6.3% of renal carcinomas. ¹⁸ They accounted for 6% of the cutaneous metastases in males, and 0.5% in females, in the series of Brownstein and Helwig. ⁷² As such, they rank after breast, lung, gastrointestinal tract, and melanoma in order of frequency. ⁷² The metastases are solitary in from 15% to 20% of cases.^{91.110. and 202.} The head, particularly the scalp, is a common site of involvement.^{110.202. and 203.} They may also be found in nephrectomy scars and the external genitalia. ²⁰² The metastases are sometimes precocious. Metachronous metastases usually appear within 3 years of the nephrectomy, ⁷² although an interval of 23 years has been recorded. ¹¹⁰ The deposits can be quite vascular, and even resemble a pyogenic granuloma²⁰⁴ or Kaposi’s sarcoma. ²⁰⁵

Most cases are clear cell renal cell carcinomas in which the cells contain considerable glycogen and some fat (Fig. 39.7).^{110. and 206.} Mitoses are sparse. There is usually extravasation of blood, with subsequent deposition of hemosiderin in the stroma. Metastasis to the skin of a transitional cell carcinoma of the renal pelvis,^{207. and 208.} and of a Wilms’ tumor is occasionally reported. ¹¹⁰

A renal cell carcinoma marker (RCC-Ma), a monoclonal antibody to a proximal tubule antigen, is positive in nearly two-thirds of cutaneous metastases of renal cell carcinomas. ²⁰⁹ It is highly specific for this tumor and is not expressed by other clear cell tumors of the skin. ²⁰⁹ The cells often express epithelial membrane antigen. ²¹⁰ Less than 10% of conventional renal cell carcinomas express CK7 or CK20. ²¹¹ The immunohistochemical profile of renal metastases is shown in Table 39.4.

Cutaneous metastases from carcinomas of the urinary bladder are rare,82.^{212. and 213.} ranging from 0.18%²¹⁴ to 1.8%. ¹⁸ Brownstein and Helwig reported only 10 cases in their review of 724 patients with cutaneous metastases. ⁷² The urethra is more rarely the primary site.^{212. and 215.} Most patients die within months of the diagnosis of a skin metastasis. ²¹⁶

Metastases from the bladder are usually multiple and at a single site. ¹⁸ When solitary, they may be confused with primary skin cancers. ²¹⁷ The upper extremities, trunk, abdomen, scrotum, and penis are the usual sites.^{186. and 212.} Rarely, they are zosteriform or herpetiform in distribution.^{218. and 219.} The tumors are transitional cell carcinomas or anaplastic carcinomas which may show areas of squamous differentiation. ²¹⁵

Immunohistochemistry is positive for the cytokeratin markers CK7, CK19, and CK20. Nearly half of transitional cell carcinomas are also CK14 positive. ²²⁰

In one study of 321 metastatic lesions in 176 autopsy cases of carcinoma of the prostate, 4 lesions metastatic to the skin were found. ²²¹ Brownstein and Helwig recorded only 5 cases in their large series. ⁷² The metastases are usually firm violaceous nodules, although unusual clinical patterns⁸⁷ such as Sister Mary Joseph nodules (see p. 928),^{77.222. and 223.} penile deposits,^{87.88.224.225. and 226.} metastasis to a gynecomastic breast, ²²⁷ a zosteriform pattern, ³⁴ and a nodule simulating a sebaceous cyst³³ or an angiosarcoma^{228. and 229.} have been recorded. Most metastases are in the inguinal region²³⁰ but other sites have been reported. ²³¹ The primary tumor is usually an adenocarcinoma,^{232. and 233.} but one transitional cell carcinoma has been documented. ²³⁴ Immunoperoxidase staining for prostate-specific antigen is a useful technique for confirming the prostatic origin of these metastatic adenocarcinomas.^{235.236. and 237.}

There are several reports of cutaneous metastases from testicular tumors. ²³⁸ The histopathological pattern has included seminoma, ²³⁸ teratocarcinoma, ²³⁹ and choriocarcinoma.^{23.240.241. and 242.} There is one report of cutaneous metastases in the suprapubic region from an adenocarcinoma of the rete testis. ²⁴³ Primary cutaneous germ cell tumors of the skin and subcutis are exceedingly rare. Only two cases have been reported in adults, although a few more have been reported in young children. ²⁴⁴

Squamous cell carcinomas of the penis rarely give rise to cutaneous metastases. ¹⁷

Cutaneous metastases are found in approximately 2% of patients with fatal ovarian carcinoma. ¹⁸ Brownstein and Helwig recorded 10 cases, which represents 4% of the cutaneous metastatic lesions in females. ⁷² There are usually multiple nodules at a solitary site on the chest or abdomen. The umbilicus and thighs may be involved.^{245. and 246.} The pattern is usually that of a well-differentiated adenocarcinoma, sometimes having a papillary configuration with psammoma bodies. ⁷² A carcinoma of mucinous pattern and a Brenner tumor²⁴⁷ have also been reported. Paraneoplastic associations such as dermatomyositis may be a presenting sign of ovarian carcinoma. These associations were reviewed in 2008. ²⁴⁸ Ovarian tumors are usually CK7 positive and CK20 negative, but some mucinous ovarian tumors may be CK20 positive.^{114. and 249.}

Cutaneous metastases are unusual in carcinoma of the cervix^{97.250.251. and 252.} and uterine body,^{253.254.255.256. and 257.} even in the terminal phases.^{258. and 259.} They usually involve the lower abdomen, groin, upper thighs,^{260. and 261.} or umbilicus,^{77.245.254.262. and 263.} but a case metastatic to the scalp producing alopecia neoplastica, and another metastatic to the face producing a cellulitis-like picture, have been reported.^{30. and 264.} Epidermotropic metastases to the lower abdominal wall, mimicking Bowen’s disease, have been reported from a squamous cell carcinoma of the cervix/vagina. ²⁶⁵ Endometrial tumors are adenocarcinomas²⁵³ or, very rarely, a mixed mullerian tumor, ²⁶⁶ whereas those from the cervix may be squamous cell carcinomas,^{250. and 260.} adenosquamous carcinomas^{21. and 23.} or, rarely, neuroendocrine in type.^{267. and 268.} In a review of the literature of genital carcinomas with metastases to the umbilicus, Galle recorded 18 of ovarian origin, 12 from the uterine body, one squamous cell carcinoma from the cervix, and 2 adenocarcinomas from the fallopian tube. ²⁴⁵ There is one report of cutaneous metastases from an adenocarcinoma of the vulva. ²⁶⁹ Squamous cell carcinoma of the vagina rarely causes a cutaneous metastatic deposit.^{270. and 271.} Metastasis to the vulva also occurs (see above). ⁸⁹

Skin metastases are an unfavorable prognostic sign in gestational trophoblastic disease. They occur only in association with widespread disease.^{272. and 273.} Gluteal metastases, ²⁷⁴ and a solitary nodule in the scalp²⁷⁵ have been reported. There have been several cases of placental choriocarcinoma metastasizing to the skin of a neonate. ²⁷⁶ The histopathology is usually similar to the primary lesion, with large syncytial trophoblastic cells and much hemorrhage. ²⁷⁵ Chorionic gonadotrophin can be demonstrated using immunoperoxidase techniques.

Cutaneous metastasis of thyroid carcinoma is a rare event; ²⁷⁷ Brownstein and Helwig recorded only 4 cases. ⁷² In one autopsy study, cutaneous metastases were noted in 2 of 12 medullary carcinomas and 4 of 12 giant-cell carcinomas. ²⁷⁸ Rarely, follicular, Hürthle cell, papillary and spindle-cell patterns are encountered.^{15.277.279.280.281.282.283.284.285.286. and 287.} In a review of 43 patients with skin metastases from thyroid carcinoma, a papillary carcinoma was the most common (41%), followed by follicular (28%), anaplastic (15%), and medullary (15%) carcinomas. ⁷⁴ The scalp was the most common site of metastasis. ⁷⁴

A skin nodule may be the presenting sign of the disease. ¹⁵ An unusual presentation in one case was the development of multiple pulsatile nodules on the face, suggesting Kaposi’s sarcoma. ²⁸⁸ Carcinoma erysipeloides is another rare clinical presentation. ²⁸⁹ Long survival has been reported after the development of cutaneous metastases, ¹⁵ although the average survival in one series was 19 months. ⁷⁴ Immunoperoxidase methods can be used to demonstrate calcitonin in medullary carcinomas,^{290. and 291.} and thyroglobulin in papillary, follicular and some anaplastic tumors.^{280.281.287. and 292.}

Cutaneous carcinoid tumors may be derived from the bronchus,^{293.294. and 295.} stomach, ²⁹⁶ small bowel, appendix, and large bowel.^{297.298. and 299.} The bronchus is the most common primary site. Several cases purporting to be primary cutaneous carcinoids have now been reported;^{297.300.301. and 302.} they appear to behave in a benign fashion. ³⁰³ A cutaneous metastasis from an occult primary lesion must be excluded before accepting a case as a primary carcinoid of the skin. ³⁰⁴ Metastases from non-cutaneous tumors are usually multiple, and on the trunk. ²⁹³ Solitary,^{294. and 298.} umbilical metastases³⁰⁵ and precocious metastases³⁰⁶ have been recorded. The carcinoid syndrome may be present.^{307. and 308.} Its cutaneous features include flushing, rosacea, and scleroderma. ³⁰⁹ Pellagra is a not uncommon cutaneous manifestation of the carcinoid syndrome, although it is not specifically related to the presence of cutaneous metastases.^{309. and 310.}

Neuroblastomas are the most common tumors of childhood.^{20.312.313.314.315.316. and 317.} Whereas cutaneous and subcutaneous metastases are found in only 2.6% of cases of neuroblastoma of all ages, they are found in 32% of neonatal tumors. ³¹⁷ Cutaneous nodules may be the presenting sign of neonatal neuroblastoma.^{313. and 318.} They characteristically blanch on pressure.^{312. and 314.} The pattern of cutaneous metastases may sometimes resemble that of the ‘blueberry muffin baby’, which is more usually associated with the congenital rubella syndrome. ³¹⁵

The skin and subcutaneous tissue are common sites of metastases in melanoma.^{6.319. and 320.} Often they are the first site to become involved. ³²¹ There is great variability in the incidence reported in the literature, which reflects in part the different criteria used for inclusion of cases. Local and in-transit (see below) cutaneous metastases are specifically excluded in some series.^{321. and 322.} Metastases to the skin have been present at autopsy in from 10% to 75% of patients with fatal melanoma.^{323.324. and 325.} It has been the site of the first metastasis in from 6% to 22% of cases.^{321. and 322.} Late metastases are rare, ³²⁶ but as Carlson has pointed out, melanomas with slow tumor doubling times may give rise to late metastases. ³²⁷ It has been stated that in nearly 5% of patients a metastasis is the initial presentation of the disease, and no primary lesion can be found.^{328. and 329.} In the author’s experience it is less than 0.5%. Usually these individuals present with a lymph node metastasis, but sometimes it is in the skin. ³²⁸ Brownstein and Helwig reported 75 cases of metastatic melanoma in the skin, making melanoma the third most common source of cutaneous metastases. ⁷² In a recent report (2005), five cases of completely regressed primary cutaneous melanomas with nodal and/or visceral metastases were reviewed. ³³⁰

Recently, DNA microarray technology has been used to study gene changes in melanoma cells in cutaneous metastases. There is significant up-regulation of several mitogen-activated protein kinase genes in melanoma metastases. ³³¹

A distinct pattern of cutaneous metastasis which is almost unique to melanoma is the development of multiple small nodular deposits, often on a limb, between the site of the primary lesion and the regional lymph nodes. ³³² These in-transit metastases probably originate from cells trapped in lymphatics. ³³³ The nodules are bluish, black, or pink in color, ³³² and are small and painless. Larger lesions may ulcerate.

Rare clinical presentations have included inflammatory metastases,^{61. and 334.} a pattern resembling Kaposi-like angiodermatitis due to lymphatic spread, ³³⁵ a hematoma-like lesion, ³³⁶ a pedunculated tumor, ³³⁷ a zosteriform distribution,^{38.338. and 339.} a miliary pattern, ³⁴⁰ metastasis to the breast, ³⁴¹ and diffuse melanosis.^{342.343.344. and 345.} Vitiligo is an uncommon finding in metastatic melanoma. ³⁴⁶ Hypercalcemia from bone marrow involvement has also been reported. ³⁴⁷ Although widespread cutaneous metastases are usually a bad prognostic sign, some patients with in-transit metastases localized to a limb can survive for many years. In one study, a positron emission tomography (PET) scan had low sensitivity in detecting metastases. ³⁴⁸

Long-term complete remission of cutaneous melanoma metastases has been reported in a patient using a folk remedy consisting of the ingestion and application of the plant Thymus vulgaris (thyme). ³⁴⁹ Topical imiquimod has also been used with success in one case. ³⁵⁰ The use of anti-tumor necrosis factor therapies may lead to reactivation of latent melanoma metastases. ³⁵¹

Rare primary lesions that have been known to metastasize to the skin include an adenoid cystic carcinoma, an acinic cell carcinoma, a myoepithelial carcinoma, and adenocarcinoma of the salivary gland,^{365.366.367.368.369. and 370.} an adenoid cystic carcinoma of the lacrimal gland, ³⁷¹ an ameloblastoma, ³⁷² a thymoma, ³⁷³ an adrenal carcinoma,^{374. and 375.} a pheochromocytoma, ³⁷⁶ and carcinomas of the hypopharynx, ³⁷⁷ nasopharynx,^{31.378. and 379.} and larynx.^{380.381.382.383. and 384.} Medulloblastomas,^{385. and 386.} hemangiopericytoma, ³⁸⁷ and other tumors, particularly glioblastomas, rarely metastasize to the skin;^{388. and 389.} when they do so it is usually to the scalp.^{390. and 391.} The author has seen a retinoblastoma metastatic to the skin.

Squamous cell carcinomas of the skin may occasionally metastasize to other cutaneous sites.^{39.40.43. and 392.} Rarely, it is zosteriform in type. ³⁹³ Metastasis from skin cancer in organ transplant recipients has a poor prognosis, particularly if the initial metastasis is distant rather than regional or in-transit. ³⁹⁴

Brownstein and Helwig reported 19 metastatic sarcomas in their 724 cases of cutaneous metastases. ⁷² A footnote in the article states that this figure ‘includes leiomyosarcoma, rhabdomyosarcoma, fibrosarcoma, chondrosarcoma, Ewing’s sarcoma, osteogenic sarcoma, and undifferentiated sarcomas’. ⁷² Leiomyosarcomas of the uterus,^{266. and 395.} small intestine, ³⁹⁶ mesentery, ³⁹⁷ and colon metastatic to the skin have been recorded, as have rhabdomyosarcomas^{20.398.399. and 400.} and fibrosarcoma and malignant fibrous histiocytoma of soft tissues and bone,21.^{401. and 402.} a giant cell tumor of bone, ⁴⁰³ Hodgkin’s disease, ⁴⁰⁴ Ewing’s sarcoma,^{20. and 405.} a chondroblastoma, ⁴⁰⁶ several cases of chondrosarcoma,^{407.408.409. and 410.} a mesenchymal chondrosarcoma of soft tissue origin, ⁴¹¹ a metaplastic breast carcinoma with chondrosarcomatous features, ¹⁴³ an osteogenic sarcoma (osteosarcoma),^{412.413.414.415.416. and 417.} a paraganglioma, ⁴¹⁸ and an angiosarcoma of the aorta⁴¹⁹ and heart. ⁴²⁰ Mesotheliomas may rarely metastasize to the skin.^{421. and 422.} Several cases of chordoma metastatic to the skin have been reported;^{423.424.425. and 426.} direct extension to the skin is more common.^{427. and 428.}

Finally, atrial myxomas may embolize to the skin, producing a varied clinical appearance.^{429. and 430.} The tumor emboli, which have a characteristic myxomatous appearance, do not usually extend beyond the vessel wall (Fig. 39.9). ⁴³¹