skin metastases
J
Lung Cancer With Skin Metastasis
1. Takeshi Terashima and
2. Minoru Kanazawa
+ Author Affiliations
1.
From the Department of Medicine, School of Medicine, Keio
University, Shinjuku-ku, Tokyo, Japan
Abstract
We describe findings in 34 cases of lung cancer with skin metastases. In
24 men and 10 women, ages ranged from 32 to 85 years (mean, 61 years). In
five, a skin lesion was the first manifestation of the underlying cancer;
in another four, it was found coincidentally with detection of the lung
mass. Pathologic findings included adenocarcinoma in 18 patients,
large-cell carcinoma in 9, squamous cell carcinoma in 5, and small-cell
carcinoma in 2. Among 87 patients with large-cell carcinoma, 9 (10.3
percent) developed cutaneous metastases. A review of 510 autopsies of
primary lung cancer at Keio University from 1958 to 1992 showed 25 cases
with skin metastases (4.9 percent), adenocarcinoma in 13 cases, large-cell
carcinoma in 6, squamous cell carcinoma in 4, and small-cell carcinoma in
2. Skin metastases were proven in 15.4 percent of autopsy cases of
large-cell carcinoma of the lung. Mean survival time from diagnosis of
lung cancer was 10.3 months and that from diagnosis of skin metastasis was
4.9 months. The prognosis for patients having lung cancer with skin
metastasis is thus very poor. In the review of 34 patients and 25
autopsies of lung cancer with skin metastasis, we conclude that the
incidence of cutaneous metastasis is high for large-cell carcinoma and low
for squamous and small-cell carcinoma.
http://dermatology.cdlib.org/1505/reviews/lung_metastases/garcia.html
Volume 15 Number 5
May 2009
Skin metastases from lung cancer
Todd W Mollet1, Carlos A Garcia MD2, Glenn Koester MD3
Dermatology Online Journal 15 (5): 1
1. College of Medicine, University of Oklahoma. todd-...@ouhsc.edu
2. Department of Dermatology, University of Oklahoma.
carlos...@ouhsc.edu
3. Dermatology private practice, Edmond, Oklahoma. edmon...@cs.com
Abstract
Cutaneous metastases from the lung are rare but must be ruled out in
patients with suspicious skin lesions and history of smoking or lung
cancer. All histological types of lung cancer may metastasize to the skin
and clinical lesions are variable. The percentage of patients with lung
cancer that develop cutaneous metastases ranges from 1 to 12 percent. In
20-60 percent of cases the skin lesions present before or synchronously
with the diagnosis of the primary tumor. Skin lesions are often described
as nodular, mobile or fixed, hard or flexible, single or multiple, and
painless. Histologically, cutaneous metastases from the lung are
frequently moderately or poorly differentiated. IHC markers that may be
useful in these cases are anti-thyroid transcription factor (TTF) and
CK7/20. Treatment of solitary cutaneous metastases usually includes
surgery alone or combined with chemotherapy, and/or radiation. If multiple
cutaneous lesions or internal metastases exist, chemotherapy is the
primary option. Cutaneous metastases and their primaries in the lung are
usually incurable and suggest an unfortunate prognosis. Poor prognostic
indicators include non-resectable or small-cell primary tumors, multiple
cutaneous metastases, or other distant metastases. Mean survival is
usually about 5-6 months.
Introduction
Lung cancer is the second most common type of malignancy and the leading
cause of death from cancer [1]. Its incidence is decreasing in men but
increasing in women, and the most common age group is 55 to 65 years old.
Prognosis of lung cancer is quite poor with an overall 5-year survival
rate of about 15 percent. The most common histologic type is
adenocarcinoma, followed by squamous cell carcinoma, small cell carcinoma,
large cell carcinoma, and bronchial carcinoid. Frequent metastatic sites
for lung cancer include hilar nodes, adrenal glands, liver, brain, and
bone [2]. Cutaneous metastases from the lung are rare but must be ruled
out in patients with suspicious skin lesions and history of smoking or
lung cancer. All histological types of lung cancer may metastasize to the
skin and clinical lesions are variable.
Several articles have discussed features of cutaneous metastases from lung
cancer including incidence, location, gross presentation, histology,
immunohistochemistry, ultrastructural characteristics, diagnosis, surgery,
chemotherapy, radiation, and prognosis. To the best of our knowledge,
however, there are no publications covering all these aspects in one
review. Our purpose is to summarize current knowledge on this topic in a
brief but comprehensive paper for future reference.
Methods
We performed a Medline search using PubMed, and performed a manual search
of pertinent references and textbooks (Table 1). Keywords and combination
of terms included "lung cancer, cutaneous, skin, metastases, tumor,
carcinoma, histology, immunohistochemistry, cytokeratin, and TTF." We
selected 45 articles that discussed cutaneous metastases from internal
cancers including lung cancer. We included 22 retrospective studies, 16
case reports, 6 reviews, and 1 prospective study. There were no randomized
controlled trials or case-control studies available.
Results
Incidence of Cutaneous Metastasis from Lung Cancer
Malignancies from the lung, breast, melanoma, oral cavity, colon, kidney,
ovary, and stomach account for 80 percent to 90 percent of all cutaneous
metastases in adults [3, 4, 5], but there are conflicting data regarding
the etiology of skin metastases according to gender.
Previous literature shows that in men with skin metastases, the lung is
the most common primary site (24%), followed by colorectal cancer (19%),
melanoma (13%), and the oral cavity (12%). In women, the lung has been
reported as the fourth most common primary site (4%) after the breast
(69%), large intestine (9%), melanoma (5%), and ovary (4%). [4] In a more
recent study, however, skin metastases in men most often arose from
melanoma (32.3%), lung (11.8%), colorectal (11%), oral cavity (8.7%), and
an unknown site (8.7%). In women, the culprits were the breast (70.7%),
melanoma (12%), ovary (3.3%), unknown site (3%), oral cavity (2.3%) and
lung (2%) [6].
The percentage of patients with lung cancer that develop cutaneous
metastases ranges from 1 to 12 percent [3, 7-12]. In a large series, skin
was only the 13th most common site for metastases from the lung [7], but
the diagnosis should be entertained in any patient with a prior history of
lung malignancy or tobacco abuse [9]. Lung cancer is the fastest among
internal neoplasms to metastasize to the skin after initial diagnosis
(mean time 5.75 months) [13]. In 20-60 percent of cases the skin lesions
present before or synchronously with the diagnosis of the primary tumor
[4, 12, 14].
Cutaneous Manifestations of Lung Malignancy
Clinical Presentation
Internal malignancies generally disseminate to a site close to the primary
tumor but they are capable of metastasizing anywhere on the cutaneous
surface (Table 2) [15]. Lung, melanoma, and breast malignancies are the
cancers most likely to metastasize to remote cutaneous sites [6]. Lung
cancers usually involve the anterior chest, abdomen, and head/neck [10,
14, 15, 16]. In a study from Taiwan, skin metastases from the lung were
the third most common malignancy of the scalp behind primary basal cell
carcinoma and squamous cell carcinoma [17]. Another study from Japan
showed that the most common site was the back [8]. Less common locations
include the shoulder, flank, lower extremity, and upper extremity [10, 14,
15]. Rare sites include the gingiva, scrotum, perianal skin, lip, nose,
burn scars, fingers, and toes [14, 18-23]. In some cases, cutaneous
metastases may also arise at incision sites [3, 6].
Figure 1 Figure 2
Figure 1. Erythematous nodules on forehead from lung metastases
Figure 2. Zosteriform plaque from lung cancer
Figure 3
Figure 3. Fungating lung metastases to the shoulder
Cutaneous metastases from lung cancer do not have a characteristic
presentation [10]. However, they are often described as nodular, mobile or
fixed, hard or flexible, single or multiple, and painless [10, 24]. In a
study of 126 patients, their colors varied from flesh-colored, red, pink,
purple, or bluish black. In this same study, the sizes varied from 2 mm to
6 cm in diameter [10]. Less commonly, these lesions present as papular,
plaque-like, ulcerated, vascular, zosteriform, erysipelas-like, and on the
scalp as scarring alopecia [10, 25-30]. The zosteriform metastases are
rare, often present on the chest or abdomen, may be painful, and are
believed to be a result of penetration of the dorsal root ganglion [27,
30]. The erysipelas-like metastases may mimic true infections locally.
These lesions result from traumatic seeding after chest wall procedures
[26, 28], or from simple lymphatic invasion [14]. We have seen cases
presenting as erythematous nodules on the forehead, a large fungating
tumor on the shoulder, and zosteriform plaques on the thorax (Figs. 1-3).
Histological Presentation
Cutaneous metastases from the lung are frequently moderately or poorly
differentiated [9, 24]. In fact, undifferentiated cutaneous metastases
most often originate from the lung in men, breast in women, or melanoma
[3, 15]. They typically invade the lymphovascular system and are usually
limited to the dermis and subcutaneous layer [31]. The most common type is
adenocarcinoma (ACC), followed by squamous-cell carcinoma or small-cell
carcinoma, and then large-cell carcinoma (LCC) [8, 10, 14, 24, 31]. Some
studies demonstrate adenocarcinoma to have the highest incidence and LCC
to have the lowest incidence [10, 29]. However, two Japanese studies found
large-cell carcinoma to have the highest incidence with about 10 percent
of LCCs of the lung metastasizing to the skin [8, 11]. Other types of lung
cancer rarely metastasizing to the skin include mesothelioma, bronchial
carcinoids, bronchiolar carcinoma, mucoepidermoid carcinoma, pulmonary
sarcoma, intravascular bronchioalveolar tumor, well-differentiated fetal
adenocarcinoma, pleural epithelioid haemangioendothelioma, and adenoid
cystic carcinoma [4, 11, 18, 32-38].
Metastatic ACCs from the lung are usually moderately differentiated [5,
31]. They sometimes show well-differentiated glandular structures or
intracytoplasmic mucin [4]. In these cases, gastrointestinal, ovarian,
kidney, and breast primaries should be ruled-out [3]. Metastatic
squamous-cell carcinomas from the lung are often moderately or poorly
differentiated [4]. In these cases, upper GI primaries should be ruled out
[3]. Small-cell carcinomas are generally anaplastic and have
hyperchromatic nuclei with little cytoplasm [4]. Clinical information,
immunohistochemistry, and electron microscopy detecting dense-core
granules can help distinguish small-cell carcinoma from other
histologically similar cancers [32, 39]. Grossly, these tumors may prefer
to metastasize to the back [6, 40]. LCCs simply present as
undifferentiated tumors with large cells [4]. Mesotheliomas most often
metastasize to the skin by direct invasion or by traumatic seeding but may
rarely metastasize to distant sites [35, 36]. These tumors may resemble
angioendothelioma malignancies [32]. In some cases, mesothelioma may be
diagnosed over adenocarcinoma with electron microscopy [32]. Cutaneous
bronchial carcinoid metastases usually show a trabecular pattern [32, 34].
Another clue to diagnosing these patients may be carcinoid syndrome [40].
Immunohistochemistry
Immunohistochemistry (IHC) may be useful when the primary site of a
cutaneous metastasis is unknown and a shorter differential is desired
[31]. Although not extensively studied in cutaneous metastases from the
lung, markers that may be useful in these cases are anti-thyroid
transcription factor (TTF) and CK7/20. Anti-TTF is both sensitive and
specific for primary adenocarcinomas, bronchioalveolar carcinomas, and
small-cell carcinomas when a thyroid primary is ruled-out [41]. Azoulay et
al. found anti-TTF reactivity in their 1 case of lung cancer metastasizing
to the skin [42]. A CK7+/20- pattern is sensitive but not specific for
primary adenocarcinomas and bronchioalveolar carcinomas (Table 3) [41, 43,
44]. This pattern was found in 1 out of 1 cutaneous metastases from lung
cancer by Saeed et al. and 4 out of 4 by Azoulay et al. [31, 42]. However
in another study, only 5 out of 8 followed this pattern [45]. This is
consistent with a review study where CK7/20 staining patterns in distant
metastases deviated from those in primary lung tumors (Table 4) [46].
Given this data, IHC staining for cutaneous metastases from the lung is
likely less sensitive than hoped and should be reserved for cases where
clinical and histological information is inconclusive [42].
Diagnosis
Diagnosis is most often based on clinical information and histology,
although as mentioned previously, immunohistochemistry and electron
microscopy may be helpful [39, 42]. If the histology of the primary and
metastatic lesions is similar, the diagnosis is confirmed [47]. If there
is no known primary site, one must determine then if the lesion is primary
or secondary [47]. Also, the histological subtype should be used to narrow
the differential diagnosis [3, 32]. A primary site is investigated by
history, physical exam, and multiple screening methods including CBC, CMP,
chest x-ray, mammogram, US, CT, and MRI [47]. With the use of these
imaging tools, Coslett et al found that 87.5 percent of patients (7/8) and
Terashima et al found that 64.7 percent of patients (22/34) had primary
tumors in the upper lobes of the lungs [9, 11]. Coslett et al and Molina
et al propose that lung malignancies in the upper lobes have a greater
tendency to metastasize to the skin [9, 48].
Treatment
Treatment of solitary cutaneous metastases usually includes surgery alone
or combined with chemotherapy, and/or radiation [49, 50]. In one study,
Ambrogi et al treated 2 patients with surgery and chemotherapy. One
patient remained alive at 74 months and the other patient expired at 8
months [49]. In another study by the same authors, 6 patients underwent
surgical treatment. Four of these were also treated with chemotherapy and
2 received chemo-radiation. On average, these patients survived 12.5
months after diagnosis [50]. It was proposed that surgery may increase
survival in this subset of patients [48, 49].
If multiple cutaneous lesions or internal metastases exist, chemotherapy
is the primary option [48]. During chemotherapy, these lesions can be used
to monitor the response of the entire malignancy [10]. Unfortunately,
studies reveal survival rates of only 6.5 to 8 months after chemotherapy
alone [8, 9, 11]. This may partially be due to low perfusion of the skin
[24]. Specific agents used include cisplatin, cyclophosphamide,
adriamycin, mitomycin, interferon-B, etoposide, vindesine, and carboplatin
[8]. Nevertheless, Kamble et al used cisplatin and VP-16 or adriamycin,
cyclophosphamide, and vincristine regimens without adequate responses in
any patients [24].
Radiation has been used alone and or in combination with chemotherapy,
and/or surgery. In a study by Coslett et al., 1 patient survived just 2
months after diagnosis of the cutaneous metastasis with chest radiation
alone and 3 other patients survived a mean of 1.8 months with
chemoradiation [9]. Hidaka et al irradiated the skin lesion in 2 patients
with 1 patient surviving 5 months and the other surviving 1 year and 7
months [8]. Thus, radiation is usually not effective except in rare cases.
However, irradiation of the metastatic lesion may be palliative if the
lesion is painful or bleeding [24].
Prognosis
Cutaneous metastases and their primaries in the lung are usually incurable
and suggest an unfortunate prognosis [6]. Poor prognostic indicators
include non-resectable or small-cell primary tumors, multiple cutaneous
metastases, or other distant metastases [50]. Unfortunately, skin
metastases usually present with other internal metastases [8, 9, 11].
Patients initially presenting with cutaneous metastases live approximately
3-4 months less than patients who develop a skin metastasis later in their
disease process [8, 11, 31]. Mean survival is usually about 5-6 months
after the diagnosis of a cutaneous metastasis, although some patients may
live longer than a year [8, 9, 11].
Conclusion
Cutaneous metastases from the lung, although uncommon, are a very real
problem in our patients. In men and women with suspicious skin lesions,
especially in those who have a smoking or lung cancer history, cutaneous
metastasis from the lung should be in the differential diagnosis. They
most often present as nodules on the chest wall, abdomen, or head/neck,
but they may also present as many other forms and on any cutaneous
surface. The metastases are usually moderately-to poorly-differentiated
adenocarcinomas, squamous-cell carcinomas, small-cell carcinomas, or
large-cell carcinomas. The diagnosis can frequently be made using clinical
information and histology from a skin biopsy, but may require
immunohistochemistry and/or electron microscopy. Unfortunately, cutaneous
metastases from the lung frequently indicate a very poor prognosis.
However, treatment should not be withheld given documented cases of
prolonged survival with treatment.
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