Microsatellite stable genome in an epithelioid hemangioendothelioma: An example of a microsatellite stable tumor

Abstract

To the Editor: Epithelioid hemangioendothelioma (EHE) was originally described by Weiss and Enzinger1Weiss S.W. Enzinger F.M. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma.Cancer. 1982; 50: 970-981Crossref PubMed Scopus (1089) Google Scholar as a tumor comprised of endothelial cells with an epithelioid phenotype and variable malignant behavior. Of particular concern is the lack of a consistent correlation between the tumor's pathologic features and the patient's clinical course. We describe a patient with an EHE whose evaluation for genomic microsatellite instability was negative, suggesting that these neoplasms represent a microsatellite stable tumor.A 28-year-old male presented to the dermatology clinic at Vanderbilt University with a 1-year history of a slowly growing nodule on the anterior surface of his right forearm. He had been injured in a motor vehicle accident with cuts and abrasions affecting the involved arm 3 years before presentation. The nodule had recently assumed a faint purple color and was mildly tender to palpation. On the patient's forearm was a freely mobile, subcutaneous nodule measuring 1.6 cm in diameter.Histologically, the neoplasm displayed large aggregates of pleomorphic epithelioid cells with focal areas of spindling (Fig 1). Occasional “hob nail” cells were appreciated. The stroma was intermittently sclerotic with focal areas of mucin deposition. Mitotic activity was sparse. Intracytoplasmic vacuoles, occasionally containing single erythrocytes, were noted (Fig 2). Immunoperoxidase staining for CD31, CD34, and vimentin were positive, but those for pancytokeratin (AE1/AE3), S-100, leukocyte common antigen, neuron specific enolase, CD68, epithelial membrane antigen, and CD30 were negative.Fig 2The tumor cells are epithelioid pleomorphic nuclei, atypical mitotic figures, and intracytoplasmic vacuoles containing occasional erythrocytes. (Hematoxylin-eosin stain; original magnification: ×400.)View Large Image Figure ViewerDownload Hi-res image Download (PPT)The patient underwent a wide excision of the biopsy site. No remaining tumor tissue was noted. Radiographs of the chest and right forearm were unremarkable. To date he has had no recurrence of his tumor.DNA was extracted from paraffin-embedded specimens using the PUREGENE kit (Gentra Systems, Minneapolis, Minn). Genotypes for ten di or tetranucleotide repeat markers representing 5 chromosomes were determined by polymerase chain reaction amplification using fluorescent primers tagged with either HEX, FAM, or TET (Applied Biosystems, Foster City, Calif). Markers analyzed included TP53, D17S520 (17p); APOC2, D19S601 (19q); FGR, D1S253 (1p); D10S215 (10q); and D2S143, D2S116, and D2S334 (2q). Amplicons were subjected to 5% polyacrylamide denaturing gel electrophoresis on an ABI-377 DNA sequencer and analyzed using GeneScan software 3.1 b3 (Applied Biosystems). Identical alleles from both normal and diagnostic tissue specimens were observed for all markers with no evidence of microsatellite instability (MSI) or loss of heterozygosity.EHEs are vascular tumors typically arising in the lung and liver and are associated with a high rate of metastasis and death.2Quante M. Patel N.K. Hill S. Merchant W. Courtauld E. Newman P. et al.Epithelioid hemangioendothelioma presenting in the skin: a clinicopathologic study of eight cases.Am J Dermatopathol. 1998; 20: 541-546Crossref PubMed Scopus (89) Google Scholar Primary involvement in the skin is uncommon. Lesions typically occur on the extremities as a slightly raised, erythematous, and occasionally tender nodule. No predisposing factors have been discerned. Single lesions are the norm, but cases of eruptive EHE have been reported, usually in association with underlying involvement of bone.3Kanik A.B. Hall J.D. Bhawan J. Eruptive epithelioid hemangioendothelioma with spindle cells.Am J Dermatopathol. 1995; 17: 612-617Crossref PubMed Scopus (26) Google Scholar CD31 is expressed in most tumors. CD34, factor VIII, and Ulex europaeus are variably positive. Some EHEs express cytokeratins, but most do not. S-100, lysozyme, CD68, and epithelial membrane antigen are routinely negative.2Quante M. Patel N.K. Hill S. Merchant W. Courtauld E. Newman P. et al.Epithelioid hemangioendothelioma presenting in the skin: a clinicopathologic study of eight cases.Am J Dermatopathol. 1998; 20: 541-546Crossref PubMed Scopus (89) Google ScholarThe prognosis of EHE is relatively poor for those tumors involving the viscera and deep soft tissues, but is often quite good for the solely cutaneous variant.4Roh H.S. Kim Y.S. Suhr K.B. Yoon T.Y. Lee J.H. Park J.K. A case of childhood epithelioid hemangioendothelioma.J Am Acad Dermatol. 2000; 42: 897-899Abstract Full Text Full Text PDF PubMed Google Scholar Weiss et al5Weiss S.W. Ishak K.G. Dail D.H. Sweet D.E. Enzinger F.M. Epithelioid hemangioendothelioma and related lesions.Semin Diagn Pathol. 1986; 3: 259-287PubMed Google Scholar described 46 patients with cutaneous lesions; 6 patients (13%) experienced a local recurrence and 14 (31%) displayed distant metastases. A small percentage of patients whose lesions demonstrated banal pathologic features experienced metastatic spread. There appears to be no clear association between a patient's prognosis and the pathologic features of their tumors.Recently, the concept of microsatellite instability (MSI) has arisen as a means of predicting the biologic potential of certain tumor cells, particularly human non-polyposis colorectal cancer. Microsatellites are repetitive DNA sequences less than 6 bases in length found throughout the human genome. Tumors with variations in the number of repeats at these loci as compared to DNA from normal tissue are said to possess “microsatellite instability.”6Hussein M.R. Wood G.S. Building bridges in cancer: mismatch repair and microsatellite instability.Am J Dermatopathol. 2002; 24: 76-81Crossref PubMed Scopus (13) Google Scholar These repeated sequences are unique for a given individual and are usually present in non-coding regions of DNA.7Hussein M.R. Wood G.S. Microsatellite instability and its relevance to cutaneous tumorigenesis.J Cutan Pathol. 2002; 29: 257-267Crossref PubMed Scopus (26) Google Scholar Tumors are segregated into 3 groups: those with a low frequency of MSI (MSI-L), those with a high frequency of MSI (MSI-H) and those with stable microsatellites (MSS). In tumor tissue where both alleles of an mismatch repair gene have been inactivated, uncorrected somatic replication errors occur in microsatellite repeats sequences both within noncoding and insignificant locations throughout the genome as well as in coding regions of genes involved in cell growth, DNA repair, and signaling.The presence of MSI has been reported in a number of cutaneous neoplasms, including basal cell carcinomas8Sardi I. Piazzini M. Palleschi G. Pinzi C. Taddei I. Arrigucci S. et al.Molecular detection of microsatellite instability in basal cell carcinoma.Oncol Rep. 2000; 7: 1119-1122PubMed Google Scholar and melanomas.9Alvino E. Marra G. Pagani E. Falcinelli S. Pepponi R. Perrera C. et al.High-frequency microsatellite instability is associated with defective DNA mismatch repair in human melanoma.J Invest Dermatol. 2002; 118: 79-86Crossref PubMed Scopus (36) Google Scholar Interestingly, neither sporadically arising actinic keratoses nor squamous cell carcinomas have demonstrated MSI.10Kushida Y. Miki H. Ohmori M. Loss of heterozygosity in actinic keratosis, squamous cell carcinoma and sun-exposed normal-appearing skin in Japanese: difference between Japanese and Caucasians.Cancer Lett. 1999; 140: 169-175Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar The negative MSI analysis in our patient was prescient in two respects. First, although other studies have employed MSI analysis in the evaluation of benign vascular proliferations, this is the seminal report of its use in a malignant or borderline malignant neoplasm of the skin. Second, internal malignancies with MSI have demonstrated an unfavorable prognosis.11Paulson T.G. Wright F.A. Parker B.A. Russack V. Wahl G.M. Microsatellite instability correlates with reduced survival and poor disease prognosis in breast cancer.Cancer Res. 1996; 56: 4021-4026PubMed Google Scholar Evaluation of vascular tumors for MSI might provide clinicians with additional prognostic information. To the Editor: Epithelioid hemangioendothelioma (EHE) was originally described by Weiss and Enzinger1Weiss S.W. Enzinger F.M. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma.Cancer. 1982; 50: 970-981Crossref PubMed Scopus (1089) Google Scholar as a tumor comprised of endothelial cells with an epithelioid phenotype and variable malignant behavior. Of particular concern is the lack of a consistent correlation between the tumor's pathologic features and the patient's clinical course. We describe a patient with an EHE whose evaluation for genomic microsatellite instability was negative, suggesting that these neoplasms represent a microsatellite stable tumor. A 28-year-old male presented to the dermatology clinic at Vanderbilt University with a 1-year history of a slowly growing nodule on the anterior surface of his right forearm. He had been injured in a motor vehicle accident with cuts and abrasions affecting the involved arm 3 years before presentation. The nodule had recently assumed a faint purple color and was mildly tender to palpation. On the patient's forearm was a freely mobile, subcutaneous nodule measuring 1.6 cm in diameter. Histologically, the neoplasm displayed large aggregates of pleomorphic epithelioid cells with focal areas of spindling (Fig 1). Occasional “hob nail” cells were appreciated. The stroma was intermittently sclerotic with focal areas of mucin deposition. Mitotic activity was sparse. Intracytoplasmic vacuoles, occasionally containing single erythrocytes, were noted (Fig 2). Immunoperoxidase staining for CD31, CD34, and vimentin were positive, but those for pancytokeratin (AE1/AE3), S-100, leukocyte common antigen, neuron specific enolase, CD68, epithelial membrane antigen, and CD30 were negative. The patient underwent a wide excision of the biopsy site. No remaining tumor tissue was noted. Radiographs of the chest and right forearm were unremarkable. To date he has had no recurrence of his tumor. DNA was extracted from paraffin-embedded specimens using the PUREGENE kit (Gentra Systems, Minneapolis, Minn). Genotypes for ten di or tetranucleotide repeat markers representing 5 chromosomes were determined by polymerase chain reaction amplification using fluorescent primers tagged with either HEX, FAM, or TET (Applied Biosystems, Foster City, Calif). Markers analyzed included TP53, D17S520 (17p); APOC2, D19S601 (19q); FGR, D1S253 (1p); D10S215 (10q); and D2S143, D2S116, and D2S334 (2q). Amplicons were subjected to 5% polyacrylamide denaturing gel electrophoresis on an ABI-377 DNA sequencer and analyzed using GeneScan software 3.1 b3 (Applied Biosystems). Identical alleles from both normal and diagnostic tissue specimens were observed for all markers with no evidence of microsatellite instability (MSI) or loss of heterozygosity. EHEs are vascular tumors typically arising in the lung and liver and are associated with a high rate of metastasis and death.2Quante M. Patel N.K. Hill S. Merchant W. Courtauld E. Newman P. et al.Epithelioid hemangioendothelioma presenting in the skin: a clinicopathologic study of eight cases.Am J Dermatopathol. 1998; 20: 541-546Crossref PubMed Scopus (89) Google Scholar Primary involvement in the skin is uncommon. Lesions typically occur on the extremities as a slightly raised, erythematous, and occasionally tender nodule. No predisposing factors have been discerned. Single lesions are the norm, but cases of eruptive EHE have been reported, usually in association with underlying involvement of bone.3Kanik A.B. Hall J.D. Bhawan J. Eruptive epithelioid hemangioendothelioma with spindle cells.Am J Dermatopathol. 1995; 17: 612-617Crossref PubMed Scopus (26) Google Scholar CD31 is expressed in most tumors. CD34, factor VIII, and Ulex europaeus are variably positive. Some EHEs express cytokeratins, but most do not. S-100, lysozyme, CD68, and epithelial membrane antigen are routinely negative.2Quante M. Patel N.K. Hill S. Merchant W. Courtauld E. Newman P. et al.Epithelioid hemangioendothelioma presenting in the skin: a clinicopathologic study of eight cases.Am J Dermatopathol. 1998; 20: 541-546Crossref PubMed Scopus (89) Google Scholar The prognosis of EHE is relatively poor for those tumors involving the viscera and deep soft tissues, but is often quite good for the solely cutaneous variant.4Roh H.S. Kim Y.S. Suhr K.B. Yoon T.Y. Lee J.H. Park J.K. A case of childhood epithelioid hemangioendothelioma.J Am Acad Dermatol. 2000; 42: 897-899Abstract Full Text Full Text PDF PubMed Google Scholar Weiss et al5Weiss S.W. Ishak K.G. Dail D.H. Sweet D.E. Enzinger F.M. Epithelioid hemangioendothelioma and related lesions.Semin Diagn Pathol. 1986; 3: 259-287PubMed Google Scholar described 46 patients with cutaneous lesions; 6 patients (13%) experienced a local recurrence and 14 (31%) displayed distant metastases. A small percentage of patients whose lesions demonstrated banal pathologic features experienced metastatic spread. There appears to be no clear association between a patient's prognosis and the pathologic features of their tumors. Recently, the concept of microsatellite instability (MSI) has arisen as a means of predicting the biologic potential of certain tumor cells, particularly human non-polyposis colorectal cancer. Microsatellites are repetitive DNA sequences less than 6 bases in length found throughout the human genome. Tumors with variations in the number of repeats at these loci as compared to DNA from normal tissue are said to possess “microsatellite instability.”6Hussein M.R. Wood G.S. Building bridges in cancer: mismatch repair and microsatellite instability.Am J Dermatopathol. 2002; 24: 76-81Crossref PubMed Scopus (13) Google Scholar These repeated sequences are unique for a given individual and are usually present in non-coding regions of DNA.7Hussein M.R. Wood G.S. Microsatellite instability and its relevance to cutaneous tumorigenesis.J Cutan Pathol. 2002; 29: 257-267Crossref PubMed Scopus (26) Google Scholar Tumors are segregated into 3 groups: those with a low frequency of MSI (MSI-L), those with a high frequency of MSI (MSI-H) and those with stable microsatellites (MSS). In tumor tissue where both alleles of an mismatch repair gene have been inactivated, uncorrected somatic replication errors occur in microsatellite repeats sequences both within noncoding and insignificant locations throughout the genome as well as in coding regions of genes involved in cell growth, DNA repair, and signaling. The presence of MSI has been reported in a number of cutaneous neoplasms, including basal cell carcinomas8Sardi I. Piazzini M. Palleschi G. Pinzi C. Taddei I. Arrigucci S. et al.Molecular detection of microsatellite instability in basal cell carcinoma.Oncol Rep. 2000; 7: 1119-1122PubMed Google Scholar and melanomas.9Alvino E. Marra G. Pagani E. Falcinelli S. Pepponi R. Perrera C. et al.High-frequency microsatellite instability is associated with defective DNA mismatch repair in human melanoma.J Invest Dermatol. 2002; 118: 79-86Crossref PubMed Scopus (36) Google Scholar Interestingly, neither sporadically arising actinic keratoses nor squamous cell carcinomas have demonstrated MSI.10Kushida Y. Miki H. Ohmori M. Loss of heterozygosity in actinic keratosis, squamous cell carcinoma and sun-exposed normal-appearing skin in Japanese: difference between Japanese and Caucasians.Cancer Lett. 1999; 140: 169-175Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar The negative MSI analysis in our patient was prescient in two respects. First, although other studies have employed MSI analysis in the evaluation of benign vascular proliferations, this is the seminal report of its use in a malignant or borderline malignant neoplasm of the skin. Second, internal malignancies with MSI have demonstrated an unfavorable prognosis.11Paulson T.G. Wright F.A. Parker B.A. Russack V. Wahl G.M. Microsatellite instability correlates with reduced survival and poor disease prognosis in breast cancer.Cancer Res. 1996; 56: 4021-4026PubMed Google Scholar Evaluation of vascular tumors for MSI might provide clinicians with additional prognostic information.