The journal of Dermatology Vol. 18: 218-224, 1991
Cutaneous Metastasis of Renal Cell Carcinoma: An Electron Microscopic Study Tomoe Haruki, Shozo Takahashi, Masaaki Morohashi, Tomohiro Maruyama and Mitsuru Ida Abstract
A case ofcutaneous metastasis of renal cell carcinoma in a 67-year-old man is described. Right side nephrectomy had been performed three years earlier, and a renal cell carcinoma was diagnosed. Following a bruise, the patient noticed an erythematous nodule on the scalp. Histological examination of this skin lesion showed atypical tumor cells consisting predominantly of clear cells with a honeycomb-like or adenoid structure. Electron microscopic examination revealed that the tumor cells were divided into three groups: clear cells with abundant glycogen, dark cells with abundant mitochondria, and intermediate cells containing both glycogen and mitochondria in varying proportions. Some of the tumor cells with an adenoid pattern had a brush border-like structure in the lumen. These results support the diagnosis of metastatic renal cell carcinoma. An electron microscopic approach may aid in diagnosis of cutaneous metastasis from renal cell carcinoma. Key words:
cutaneous metastasis; renal cell carcinoma; clear cell; electron microscopy; trauma
Introduction The incidence of cutaneous metastasis from internal malignant neoplasms is very low, between 1 to 4.4%; metastasis is more common to the lung, liver or bone than to the skin (1, 2). Cutaneous metastasis is generally regarded as a late manifestation. It has been reported that nearly 7% of all cutaneous metastatic tumors are of renal origin (1-5). There have been an increasing number of reports in the literature of cutaneous metastasis of renal cell carcinoma; however, to our knowledge, only a few have included electron microscopic studies (6, 7). The clinical course and histological findings usually play important roles in deciding the origin of the metastatic renal cell carcinoma. However, there are some doubtful cases, in Receivedjune 11, 1990; accepted for publication March 5,1991. Department of Dermatology, Faculty of Medicine, Toyama Medical and Pharmaceutical University (Director: Professor Masaaki Morohashi), Toyama,japan. Reprint requests to: Dr. Tomoe Haruki, Department of Dermatology, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama-shi, Toyama 930-01,japan.
Fig. 1. An erythematous nodule on the scalp (parietal region). Superficial telangiectases are prominent. which electron microscopic examination of the skin lesion may help establish a diagnosis (6). We report a case of renal cell carcinoma metastasizing to the scalp with special reference to the electron microscopic findings.
Cutaneous Metastasis
219
B A Fig. 2. Light microscopic examination. A: A low magnification view of the tumor cells. The nest is enclosed within a fibrous capsule. xIS. B: The tumor cells consist predominantly of clear cells with atypical nuclei. x300. Hematoxylin-eosin staining.
Report of a Case A 67-year-old japanese man was referred to our dennatology clinic on january 4th, 1985, with a nodule on the scalp. He had undergone right nephrectomy in November, 1981; at this time a diagnosis of renal cell carcinoma (clear cell type) was made. Metastatic lesions to his right lung were detected in December, 1981, one month after the operation. The lung was partially resected, and he Was treated with chemotherapy (5-FU, MMC) preand postoperatively. However, a chest X-ray showed a gradual progression in the lung metastasis. In February, 1984, bone metastasis was found in the vertebrae, and radiation therapy was tried. Chemotherapy (etoposide) and immunotherapy (y-interferon) were repeated to prevent further progress of the disease. A month before his first visit to our clinic, he knocked his head against the floor and
developed a bruise on the parietal region, which gradually enlarged to become a tender erythematous nodule two weeks later. The nodule (12 x 13 x 7 mm) was dome-shaped with superficial telangiectasia but was not pulsating (Fig. 1). The results of laboratory tests included a CRP 2+, a moderate rise in ESR, multiple metastases in the chest X-ray, and abnormal uptakes in the ribs and vertebrae on bone scan. Ail other laboratory tests were within normal limits. The skin tumor was totally resected on january 4th, 1985. After this operation, two subcutaneous tumors appeared on the abdomen and increased in size. He suffered from severe pain due to bone metastasis and developed dyspnea as the invasion of tumor cells in the lung increased. His general condition deteriorated gradually and he died on April 10th, 1985, of cachexia.
Haruki et al
220
Fig. 3. An electron micrograph of a clear cell. Glycogen granules (g) are abundant in the cytoplasm. The tumor cells were connected by a desmosome (JZ). x6,000. Insert: a high magnification of the desmosome. x45,000.
Materials and Methods The biopsy specimen was cut into two parts; one was fixed in 10% formalin in neutral buffer for light microscopy, and the other was fixed into a 4%
glutaraldehyde solution for electron microscopy. After dehydration in graded concentrations of ethanol, the tissue for electron microscopy was embedded in epoxy resin. Ultrathin sections were cut and stained with uranyl acetate and lead citrate
Fig. 4. Clear cells with numerous lipid droplets of various sizes (L) and abundant glycogen granules (g). The deeply indented nucleus (N) is atypical. x4,300.
221
Cutaneous Metastasis
Fig. 5. An electron micrograph showing a dark cell with numerous mitochondria (m) and well-developed Golgi apparatus. The indentation of the nucleus (N) is prominent. x6,OOO.
and examined with a Hitachi H-700 electron microscope. Results
Light microscopic findings The specimen taken from the nodule had a thin and atrophic epidermis, From the upper dennis to the subcutaneous tissue, a tumor cell nest surrounded by a fibrous capsule, which stained red with the Elastica van Gieson method and blue with Azan-Mallory, was observed. Atypical tumor cells consisting predominantly of clear cells, with some dark cells among them, formed a honey comb-like or adenoid structure and invaded a portion of the capsule (Fig. 2). The cytoplasm ofthe clear cell was full of PAS-positive granules before, but not after, digestion with diastase, indicating that these contained glycogen. Although capillary proliferation with dilatation and extravasation of red blood cells was observed in the interstitium of the tumor, no tumor cells were found in the vascular lumen (Fig. 2). Electron microscopic,findings The tumor cells could be divided into three groups. The first one had many aggregated
glycogen granules, moderate lipid droplets, and fewer mitochondria (clear cells) (Figs. 3,4). The second group had relatively well-developed mitochondria and very few glycogen granules (dark cells) (Fig. 5). The third group were intermediate, containing both glycogen and mitochondria in varying proportions (Fig. 6). All the tumor cells had atypical nuclei with indentations and prominent nucleoli (Figs. 4-6). Some of those in the adenoid pattern had microvilli which faced the lumen of the adenoid structure and contacted each tumor cell. Autophagic vacuoles and pinocytotic vesicles were also present below the microvilli (Fig. 7). The tumor cells were connected by desmosomes or desmosome-like structures (Fig. 3). These electron microscopic findings resembled those of the brush border structure of the proximal tubules of the kidney. Based upon these findings, our diagnosis was cutaneous metastasis of renal cell carcinoma. Discussion Renal cell carcinoma is an insidious tumor which occurs predominantly in males, has a high propensity to invade venous systems and
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Haruki et al
Fig. 6. An intermediate cell contains mitochondria (rn) and glycogen granules (g) equally. N: indented nucleus. x6,OOO.
Fig. 7. An electron micrograph showing microvilli (-+) among the tumor cells. Arrowhead: autophagic vacuoles, C: clear cell, D: dark cell. x6,OOO.
metastasizes early to distant organs (1, 3-5). Approximately one-fourth of all patients with renal cell carcinoma have evidence of metastasis when first seen (1, 3). Skin is the seventh most common site of metastatic involvement
(3). More than half of the patients with cutaneous metastasis from renal cell carcinoma have undergone nephrectomy within two years prior to the appearance of the cutaneous lesions (1, 5); a few patients develop skin
Cutaneous Metastasis
involvement after a longer interval (1, 3). Renal cell carcinoma and breast cancer show a relatively higher frequency of delayed metastasis than do other malignant neoplasms (8). In 10% to 20% of patients with skin involvement, cutaneous metastasis precedes recognition of the underlying renal cell carcinoma (3-5). The average interval between the appearance of cutaneous metastasis and death is about one year (1, 3). Cutaneous metastasis from renal cell carcinoma usually presents itself as a raised, soft, well-circumscribed, intracutaneous nodule, averaging about 1.5 cm in diameter. The color is red, pink, blue, or purple. The nodule is vascular and, sometimes, pulsatile. It evolves suddenly, grows rapidly, and rarely ulcerates (1, 3-5). Skin lesions may be seen anywhere on the body. However, it has been reported that the scalp is the most common site of metastasis in most series. The incidence of scalp involvement is between 4.5% and 30% (1, 3-5). In the literature, some anatomical aspects of the scalp are mentioned, for example, abundant skin appendages with numerous small vessels and small amounts of soft tissue (9). The patients may quickly become aware of the lesions because of the exposed area (5). Skin metastasis in the scalp may result from tumor cells traveling via the paravertebral venous plexus, which are not filtered by the lungs (1, 3, 10). It is difficult to account for the high frequency of scalp involvement When a nodular lesion appears on the scalp of a male patient, we must always consider the possibility of cutaneous metastasis from renal cell carcinoma as well as lung cancer (11). It is not known exactly how malignant cells invade host tissues. Tumor cells may move into host tissues actively or passively (11). Some studies have suggested a relationship between trauma and cutaneous metastasis. Cutaneous metastasis of breast cancer has also been reported to occur in bruised skin (12). Cutaneous metastasis of lung carcinoma tends to occur in areas of skin frequently traumatized by injection needles (13) and cutaneous metastasis of uterine carcinoma has been reported to occur in irradiated skin (14). In an experi-
223
mental model with mice, traumatized tissues were shown to attract metastatic cells in histopathology (15). In our case, the metastatic lesion appeared at a site· which had been bruised a month earlier. It is possible to speculate that external trauma damaged the blood vessels and connective tissue, which then trapped metastatic cells in the circulation. However, we can not rule out the alternative possibility that the cutaneous metastasis had already occurred before the patient developed the bruise. If the tumor cells were present before the bruise, the traumatic force might act as a trigger to activate these silent cells. If we could obtain a few biopsies from the same site before and after the bruise, the detailed process of metastasis would be proven. Based on the mentioned reports and experiments (8, 12-15), we propose that mechanical factors exert some effect on the distribution and viability of circulating or lurking tumor cells in metastasis formation. The careful and quantitative observations of many cases are necessary to prove the pathogenesis of cancer metastasis. It has been shown that, in renal cell carcinoma, tumor cells closely resemble the proximal convoluted tubules of the kidney histologically (6, 7, 16). Immunofluorescent and immunohistochemical techniques have also shown that the antigenic characteristics of tumor cells were identical to those of proximal tubules (16). In electron microscopic examination, the two types of tumor cells, clear and dark, differ from each other. Clear cells, so named because of their pale cytoplasm, contain many glycogen granules, a moderate number of lipid droplets, and some autophagic vacuoles in the cytoplasm. Microvilli are also observed in intercellular spaces. Tight junctions and desmosomes or desmosome-like structures are also seen. There are also some infoldings of the basement membrane. Dark cells, however, which appear granular under a light microscope, show an increase in the number and size of rod-shaped mitochondria. Ultrastructural characteristics of microvilli such as autopha~c vacuoles and infolding; of the basal labynnth, are seen in both the dark cells and the clear cells. These electron microscopic
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Haruki et al
findings also suggest that tumor cells differentiate from the proximal convoluted tubules of the kidney (6, 7, 16). Generally, pathological features of metastatic lesions are in close agreement with those ofthe primary neoplasm. Under the electron microscope, the spectrum ofultrastructural metastatic renal cell carcinoma appearance in various locations is comparable with that seen in primary kidney tumors, although several differences are present, such as decreased amounts of mitochondria, a greater degree of nuclear pleomorphism, and a tendency towards solid packing of the cells without intervening clefts or microvilli (6). In our case, a portion of the tumor cells in the cutaneous lesion were intermediate between the clear cells and the dark cells, containing moderate amounts of both glycogen and mitochondria. Since electron microscopic examination of the primary tumor was not performed, we were not able to state definitely whether these intermediate cells appeared during the metastatic process. The presence of an intermediate cell type in renal cell carcinoma has never been, to our knowledge, described previously. Further immunocytochemical work is needed to clarify the nature and function of these intermediate cells. It is sometimes difficult to diagnose cutaneous metastasis, especially when poorly-differentiated sarcomatous tumors are involved and when cutaneous metastasis precedes the detection of the primary neoplasm (4-6). Metastatic skin lesions from renal cell carcinoma are occasionally mistaken for sebaceous or sweat gland tumors, vascular tumors, or melanoma with balloon cell change (1, 5, 6). In such cases, electron microscopic examination of the skin lesions may be critical in identifying the origin of the tumor cells. We hope that the photographs showing characteristic features of the clear cells and dark cells in the cutaneous metastasis will provide a valuable reference for
diagnosis. References 1) Peterson jL, McMarlin SL: Metastatic renal cell carcinoma presenting as a cutaneous hom,] Dermatol Surg Oncol, 9: 815-818, 1983. 2) Spencer PS, Helm TN: Skin metastases in cancer patient, Cutis, 39: 119-121,1987. 3) Menter A, Boyd AS, McCaffree DM: Recurrent renal cell carcinoma presenting as skin nodules: two case reports and review of the literature, Cutis, 44: 305-308, 1989. 4) jevtic AP: Skin metastasis from renal cell carcinoma presenting as an inflammatory lesion, Aust] Derm, 28: 18-20,1987. 5) Connor DH, Taylor HB, Helwig EB: Cutaneous metastasis of renal cell carcinoma, Arch Pathol, 76: 339-346, 1963. 6) Mackay B, Ordonez NG, Khoursand j, Bennington jL: The ultrastructure and immunocytochemistry of renal cell carcinoma, Ultrastruct Pathol, 11: 483-502, 1987. 7) Shimoda N, Azisaka Y, Hashizume S, Kubo K: illtrastructural studies of metastatic cutaneous tumors,] Clin Electron Microscopy, 14: 510-511, 1981. 8) Simoda N, Fukuhara T, Azisaka Y, Chiba T: Metastatic cutaneous tumor, Rinsho Derma (Tokyo), 26: 463-474, 1984. (in japanese) 9) Gates 0: Cutaneous metastases of malignant disease, Amer]Cancer, 30: 718-730, 1937. 10) Weigensberg I]: Metastatic renal carcinoma: Unusual and deceptive presenting features, South MedJ, 65: 611-616,1972. 11) Brownstein MH, Helwig EB: Patterns of cutaneous metastasis, ArchDerm; 105: 862-868, 1972. 12) Poste G, Fidler IJ: The pathogenesis of cancer metastasis, Nature, 283: 139-146, 1980. 13) Tanaka M, Imura H, Yamamoto T, Takeda K, Kuwahara A, Kinoshita H: A clinicopathologic study of metastatic skin cancer, with special reference to site and prognosis,jpn] Clin Dermatol, 30: 893-898, 1976. (in japanese) 14) Marley NF, Marley WM: Skin metastases in an area of radiation dermatitis, Arch Dermatol, 118: 129-131, 1982. 15) Fukuhara T: Experimental studies on metastatic skin cancer,Jpn] Dermatol, 93: 1-18, 1983. (in japanese) 16) Zollinger HU, Mihatsch Mj: Renal cell carcinoma, in Renal Pathology in Biopsy, Springer-Verlag, Berlin, 1978, p 556.
Cutaneous Metastasis of Renal Cell Carcinoma: An Electron Microscopic Study Tomoe Haruki, Shozo Takahashi, Masaaki Morohashi, Tomohiro Maruyama and Mitsuru Ida Abstract
A case ofcutaneous metastasis of renal cell carcinoma in a 67-year-old man is described. Right side nephrectomy had been performed three years earlier, and a renal cell carcinoma was diagnosed. Following a bruise, the patient noticed an erythematous nodule on the scalp. Histological examination of this skin lesion showed atypical tumor cells consisting predominantly of clear cells with a honeycomb-like or adenoid structure. Electron microscopic examination revealed that the tumor cells were divided into three groups: clear cells with abundant glycogen, dark cells with abundant mitochondria, and intermediate cells containing both glycogen and mitochondria in varying proportions. Some of the tumor cells with an adenoid pattern had a brush border-like structure in the lumen. These results support the diagnosis of metastatic renal cell carcinoma. An electron microscopic approach may aid in diagnosis of cutaneous metastasis from renal cell carcinoma. Key words:
cutaneous metastasis; renal cell carcinoma; clear cell; electron microscopy; trauma
Introduction The incidence of cutaneous metastasis from internal malignant neoplasms is very low, between 1 to 4.4%; metastasis is more common to the lung, liver or bone than to the skin (1, 2). Cutaneous metastasis is generally regarded as a late manifestation. It has been reported that nearly 7% of all cutaneous metastatic tumors are of renal origin (1-5). There have been an increasing number of reports in the literature of cutaneous metastasis of renal cell carcinoma; however, to our knowledge, only a few have included electron microscopic studies (6, 7). The clinical course and histological findings usually play important roles in deciding the origin of the metastatic renal cell carcinoma. However, there are some doubtful cases, in Receivedjune 11, 1990; accepted for publication March 5,1991. Department of Dermatology, Faculty of Medicine, Toyama Medical and Pharmaceutical University (Director: Professor Masaaki Morohashi), Toyama,japan. Reprint requests to: Dr. Tomoe Haruki, Department of Dermatology, Faculty of Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama-shi, Toyama 930-01,japan.
Fig. 1. An erythematous nodule on the scalp (parietal region). Superficial telangiectases are prominent. which electron microscopic examination of the skin lesion may help establish a diagnosis (6). We report a case of renal cell carcinoma metastasizing to the scalp with special reference to the electron microscopic findings.
Cutaneous Metastasis
219
B A Fig. 2. Light microscopic examination. A: A low magnification view of the tumor cells. The nest is enclosed within a fibrous capsule. xIS. B: The tumor cells consist predominantly of clear cells with atypical nuclei. x300. Hematoxylin-eosin staining.
Report of a Case A 67-year-old japanese man was referred to our dennatology clinic on january 4th, 1985, with a nodule on the scalp. He had undergone right nephrectomy in November, 1981; at this time a diagnosis of renal cell carcinoma (clear cell type) was made. Metastatic lesions to his right lung were detected in December, 1981, one month after the operation. The lung was partially resected, and he Was treated with chemotherapy (5-FU, MMC) preand postoperatively. However, a chest X-ray showed a gradual progression in the lung metastasis. In February, 1984, bone metastasis was found in the vertebrae, and radiation therapy was tried. Chemotherapy (etoposide) and immunotherapy (y-interferon) were repeated to prevent further progress of the disease. A month before his first visit to our clinic, he knocked his head against the floor and
developed a bruise on the parietal region, which gradually enlarged to become a tender erythematous nodule two weeks later. The nodule (12 x 13 x 7 mm) was dome-shaped with superficial telangiectasia but was not pulsating (Fig. 1). The results of laboratory tests included a CRP 2+, a moderate rise in ESR, multiple metastases in the chest X-ray, and abnormal uptakes in the ribs and vertebrae on bone scan. Ail other laboratory tests were within normal limits. The skin tumor was totally resected on january 4th, 1985. After this operation, two subcutaneous tumors appeared on the abdomen and increased in size. He suffered from severe pain due to bone metastasis and developed dyspnea as the invasion of tumor cells in the lung increased. His general condition deteriorated gradually and he died on April 10th, 1985, of cachexia.
Haruki et al
220
Fig. 3. An electron micrograph of a clear cell. Glycogen granules (g) are abundant in the cytoplasm. The tumor cells were connected by a desmosome (JZ). x6,000. Insert: a high magnification of the desmosome. x45,000.
Materials and Methods The biopsy specimen was cut into two parts; one was fixed in 10% formalin in neutral buffer for light microscopy, and the other was fixed into a 4%
glutaraldehyde solution for electron microscopy. After dehydration in graded concentrations of ethanol, the tissue for electron microscopy was embedded in epoxy resin. Ultrathin sections were cut and stained with uranyl acetate and lead citrate
Fig. 4. Clear cells with numerous lipid droplets of various sizes (L) and abundant glycogen granules (g). The deeply indented nucleus (N) is atypical. x4,300.
221
Cutaneous Metastasis
Fig. 5. An electron micrograph showing a dark cell with numerous mitochondria (m) and well-developed Golgi apparatus. The indentation of the nucleus (N) is prominent. x6,OOO.
and examined with a Hitachi H-700 electron microscope. Results
Light microscopic findings The specimen taken from the nodule had a thin and atrophic epidermis, From the upper dennis to the subcutaneous tissue, a tumor cell nest surrounded by a fibrous capsule, which stained red with the Elastica van Gieson method and blue with Azan-Mallory, was observed. Atypical tumor cells consisting predominantly of clear cells, with some dark cells among them, formed a honey comb-like or adenoid structure and invaded a portion of the capsule (Fig. 2). The cytoplasm ofthe clear cell was full of PAS-positive granules before, but not after, digestion with diastase, indicating that these contained glycogen. Although capillary proliferation with dilatation and extravasation of red blood cells was observed in the interstitium of the tumor, no tumor cells were found in the vascular lumen (Fig. 2). Electron microscopic,findings The tumor cells could be divided into three groups. The first one had many aggregated
glycogen granules, moderate lipid droplets, and fewer mitochondria (clear cells) (Figs. 3,4). The second group had relatively well-developed mitochondria and very few glycogen granules (dark cells) (Fig. 5). The third group were intermediate, containing both glycogen and mitochondria in varying proportions (Fig. 6). All the tumor cells had atypical nuclei with indentations and prominent nucleoli (Figs. 4-6). Some of those in the adenoid pattern had microvilli which faced the lumen of the adenoid structure and contacted each tumor cell. Autophagic vacuoles and pinocytotic vesicles were also present below the microvilli (Fig. 7). The tumor cells were connected by desmosomes or desmosome-like structures (Fig. 3). These electron microscopic findings resembled those of the brush border structure of the proximal tubules of the kidney. Based upon these findings, our diagnosis was cutaneous metastasis of renal cell carcinoma. Discussion Renal cell carcinoma is an insidious tumor which occurs predominantly in males, has a high propensity to invade venous systems and
222
Haruki et al
Fig. 6. An intermediate cell contains mitochondria (rn) and glycogen granules (g) equally. N: indented nucleus. x6,OOO.
Fig. 7. An electron micrograph showing microvilli (-+) among the tumor cells. Arrowhead: autophagic vacuoles, C: clear cell, D: dark cell. x6,OOO.
metastasizes early to distant organs (1, 3-5). Approximately one-fourth of all patients with renal cell carcinoma have evidence of metastasis when first seen (1, 3). Skin is the seventh most common site of metastatic involvement
(3). More than half of the patients with cutaneous metastasis from renal cell carcinoma have undergone nephrectomy within two years prior to the appearance of the cutaneous lesions (1, 5); a few patients develop skin
Cutaneous Metastasis
involvement after a longer interval (1, 3). Renal cell carcinoma and breast cancer show a relatively higher frequency of delayed metastasis than do other malignant neoplasms (8). In 10% to 20% of patients with skin involvement, cutaneous metastasis precedes recognition of the underlying renal cell carcinoma (3-5). The average interval between the appearance of cutaneous metastasis and death is about one year (1, 3). Cutaneous metastasis from renal cell carcinoma usually presents itself as a raised, soft, well-circumscribed, intracutaneous nodule, averaging about 1.5 cm in diameter. The color is red, pink, blue, or purple. The nodule is vascular and, sometimes, pulsatile. It evolves suddenly, grows rapidly, and rarely ulcerates (1, 3-5). Skin lesions may be seen anywhere on the body. However, it has been reported that the scalp is the most common site of metastasis in most series. The incidence of scalp involvement is between 4.5% and 30% (1, 3-5). In the literature, some anatomical aspects of the scalp are mentioned, for example, abundant skin appendages with numerous small vessels and small amounts of soft tissue (9). The patients may quickly become aware of the lesions because of the exposed area (5). Skin metastasis in the scalp may result from tumor cells traveling via the paravertebral venous plexus, which are not filtered by the lungs (1, 3, 10). It is difficult to account for the high frequency of scalp involvement When a nodular lesion appears on the scalp of a male patient, we must always consider the possibility of cutaneous metastasis from renal cell carcinoma as well as lung cancer (11). It is not known exactly how malignant cells invade host tissues. Tumor cells may move into host tissues actively or passively (11). Some studies have suggested a relationship between trauma and cutaneous metastasis. Cutaneous metastasis of breast cancer has also been reported to occur in bruised skin (12). Cutaneous metastasis of lung carcinoma tends to occur in areas of skin frequently traumatized by injection needles (13) and cutaneous metastasis of uterine carcinoma has been reported to occur in irradiated skin (14). In an experi-
223
mental model with mice, traumatized tissues were shown to attract metastatic cells in histopathology (15). In our case, the metastatic lesion appeared at a site· which had been bruised a month earlier. It is possible to speculate that external trauma damaged the blood vessels and connective tissue, which then trapped metastatic cells in the circulation. However, we can not rule out the alternative possibility that the cutaneous metastasis had already occurred before the patient developed the bruise. If the tumor cells were present before the bruise, the traumatic force might act as a trigger to activate these silent cells. If we could obtain a few biopsies from the same site before and after the bruise, the detailed process of metastasis would be proven. Based on the mentioned reports and experiments (8, 12-15), we propose that mechanical factors exert some effect on the distribution and viability of circulating or lurking tumor cells in metastasis formation. The careful and quantitative observations of many cases are necessary to prove the pathogenesis of cancer metastasis. It has been shown that, in renal cell carcinoma, tumor cells closely resemble the proximal convoluted tubules of the kidney histologically (6, 7, 16). Immunofluorescent and immunohistochemical techniques have also shown that the antigenic characteristics of tumor cells were identical to those of proximal tubules (16). In electron microscopic examination, the two types of tumor cells, clear and dark, differ from each other. Clear cells, so named because of their pale cytoplasm, contain many glycogen granules, a moderate number of lipid droplets, and some autophagic vacuoles in the cytoplasm. Microvilli are also observed in intercellular spaces. Tight junctions and desmosomes or desmosome-like structures are also seen. There are also some infoldings of the basement membrane. Dark cells, however, which appear granular under a light microscope, show an increase in the number and size of rod-shaped mitochondria. Ultrastructural characteristics of microvilli such as autopha~c vacuoles and infolding; of the basal labynnth, are seen in both the dark cells and the clear cells. These electron microscopic
224
Haruki et al
findings also suggest that tumor cells differentiate from the proximal convoluted tubules of the kidney (6, 7, 16). Generally, pathological features of metastatic lesions are in close agreement with those ofthe primary neoplasm. Under the electron microscope, the spectrum ofultrastructural metastatic renal cell carcinoma appearance in various locations is comparable with that seen in primary kidney tumors, although several differences are present, such as decreased amounts of mitochondria, a greater degree of nuclear pleomorphism, and a tendency towards solid packing of the cells without intervening clefts or microvilli (6). In our case, a portion of the tumor cells in the cutaneous lesion were intermediate between the clear cells and the dark cells, containing moderate amounts of both glycogen and mitochondria. Since electron microscopic examination of the primary tumor was not performed, we were not able to state definitely whether these intermediate cells appeared during the metastatic process. The presence of an intermediate cell type in renal cell carcinoma has never been, to our knowledge, described previously. Further immunocytochemical work is needed to clarify the nature and function of these intermediate cells. It is sometimes difficult to diagnose cutaneous metastasis, especially when poorly-differentiated sarcomatous tumors are involved and when cutaneous metastasis precedes the detection of the primary neoplasm (4-6). Metastatic skin lesions from renal cell carcinoma are occasionally mistaken for sebaceous or sweat gland tumors, vascular tumors, or melanoma with balloon cell change (1, 5, 6). In such cases, electron microscopic examination of the skin lesions may be critical in identifying the origin of the tumor cells. We hope that the photographs showing characteristic features of the clear cells and dark cells in the cutaneous metastasis will provide a valuable reference for
diagnosis. References 1) Peterson jL, McMarlin SL: Metastatic renal cell carcinoma presenting as a cutaneous hom,] Dermatol Surg Oncol, 9: 815-818, 1983. 2) Spencer PS, Helm TN: Skin metastases in cancer patient, Cutis, 39: 119-121,1987. 3) Menter A, Boyd AS, McCaffree DM: Recurrent renal cell carcinoma presenting as skin nodules: two case reports and review of the literature, Cutis, 44: 305-308, 1989. 4) jevtic AP: Skin metastasis from renal cell carcinoma presenting as an inflammatory lesion, Aust] Derm, 28: 18-20,1987. 5) Connor DH, Taylor HB, Helwig EB: Cutaneous metastasis of renal cell carcinoma, Arch Pathol, 76: 339-346, 1963. 6) Mackay B, Ordonez NG, Khoursand j, Bennington jL: The ultrastructure and immunocytochemistry of renal cell carcinoma, Ultrastruct Pathol, 11: 483-502, 1987. 7) Shimoda N, Azisaka Y, Hashizume S, Kubo K: illtrastructural studies of metastatic cutaneous tumors,] Clin Electron Microscopy, 14: 510-511, 1981. 8) Simoda N, Fukuhara T, Azisaka Y, Chiba T: Metastatic cutaneous tumor, Rinsho Derma (Tokyo), 26: 463-474, 1984. (in japanese) 9) Gates 0: Cutaneous metastases of malignant disease, Amer]Cancer, 30: 718-730, 1937. 10) Weigensberg I]: Metastatic renal carcinoma: Unusual and deceptive presenting features, South MedJ, 65: 611-616,1972. 11) Brownstein MH, Helwig EB: Patterns of cutaneous metastasis, ArchDerm; 105: 862-868, 1972. 12) Poste G, Fidler IJ: The pathogenesis of cancer metastasis, Nature, 283: 139-146, 1980. 13) Tanaka M, Imura H, Yamamoto T, Takeda K, Kuwahara A, Kinoshita H: A clinicopathologic study of metastatic skin cancer, with special reference to site and prognosis,jpn] Clin Dermatol, 30: 893-898, 1976. (in japanese) 14) Marley NF, Marley WM: Skin metastases in an area of radiation dermatitis, Arch Dermatol, 118: 129-131, 1982. 15) Fukuhara T: Experimental studies on metastatic skin cancer,Jpn] Dermatol, 93: 1-18, 1983. (in japanese) 16) Zollinger HU, Mihatsch Mj: Renal cell carcinoma, in Renal Pathology in Biopsy, Springer-Verlag, Berlin, 1978, p 556.
