- Email: [email protected]
Kaposi's sarcoma
Comment
“pseudo-addiction”, make the point that problematic drugrelated behaviour has a differential diagnosis with profound implications for treatment. Finally, they highlight the need for careful monitoring and appropriate referral of the patient. However, the document1 regrettably provides little practical guidance on selection of patients, structuring of therapy to enhance monitoring and control, or strategies to manage patients whose problematic behaviour is not severe enough to warrant specialist referral. It includes an unsubstantiated statement that short-acting opioids predispose to tolerance and dependence, and sadly neglects the problem of severe chronic pain in patients with known chemical dependency.8 For an American physician, this document is, on balance, all about balance, and deserves praise as such. Clinicians will need other resources to become educated about the important issues it raises.9
1
2
3 4
5
6
Russell K Portenoy Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, New York, NY 10003, USA [email protected] During the past several years, I have received compensation for consulting or for educational projects from several companies that make opioid drugs, including Endo Pharmaceuticals, Janssen Pharmaceutica, Ortho McNeil Pharmaceuticals, and Ligand Pharmaceuticals; similarly, my department has received educational grants or study grants from such companies, including Endo Pharmaceuticals, Janssen Pharmaceutica, Ligand Pharmaceuticals, Purdue Pharma, Cephalon Pharmaceuticals, ZARS Pharmaceuticals, and CIMA Pharmaceuticals.
7
8
9
A consensus statement prepared on behalf of the Pain Society, the Royal College of Anaesthetists, the Royal College of General Practitioners, and the Royal College of Psychiatrists. Recommendations for the appropriate use of opioids for persistent non-cancer pain. London: the Pain Society, March, 2004: http://www.painsociety.org/pdf/opioids_doc_2004.pdf (accessed Aug 9, 2004). A joint statement from 21 health organizations and the Drug Enforcement Administration. Promoting pain relief and preventing abuse of pain medications: a critical balancing act: http://www.medsch.wisc.edu/ painpolicy/Consensus2.pdf (accessed Aug 4, 2004). World Health Organization. Achieving balance in national opioids control policy: guidelines for assessment. Geneva: WHO, 2000. Zacny J, Bigelow G, Compton P, Foley K, Iguchi M, Sannerud C. College on problems of drug dependence taskforce on prescription opioid nonmedical use and abuse: position statement. Drug Alcohol Depend 2003; 69: 215–32. Zenz M, Strumpf M, Tryba M. Long-term opioid therapy in patients with chronic nonmalignant pain. J Pain Symptom Manage 1992; 7: 69–77. American Academy of Pain Medicine, American Pain Society. The use of opiods for the treatment of chronic pain. http://www.painmed. org/productpub/statements/pdfs/opioids.pdf (accessed Aug 4, 2004). Chou R, Clark E, Helfand M. Comparative efficacy and safety of longacting oral opioids for chronic non-cancer pain: a systematic review. J Pain Symptom Manage 2003; 26: 1026–48. Rosenblum A, Joseph H, Fong C, Kipnis S, Cleeland C, Portenoy RK. Prevalence and characteristics of chronic pain among chemically dependent patients in methadone maintenance and residential treatment facilities. JAMA 2003; 289: 2370–78. Portenoy RK, Payne R. Acute and chronic pain. In: Lowinson JH, Ruiz P, Millman RB, eds. Comprehensive textbook of substance abuse, 3rd edn. Baltimore: Williams and Wilkins, 1997; 563–90.
Kaposi’s sarcoma Until recently, if someone had asked the cellular origin of the spindle cells of Kaposi’s sarcoma lesions, the answer would probably have been vague. In fact, the histogenesis of the spindle-cell component, the Kaposi’s sarcoma tumour cell, remains controversial. Most of these spindle cells express endothelial markers, but markers for smooth-muscle cells, macrophages, and dendritic cells are also present.1,2 Several aspects of the origin of the spindle cells in Kaposi’s sarcoma remain poorly understood. Although many studies favour an endothelial cell origin,3,4 some suggest a lymphatic-endothelial origin.5 A recent study by Hesei-Wei Wang and co-workers,6 from Chris Boshoff’s laboratory, suggests that Kaposi’s sarcoma neoplastic cells are closely related to lymphatic endothelial cells. These researchers also assessed the ability of Kaposi’s sarcomaassociated herpesvirus, also called human herpesvirus 8, to alter
the gene-expression pattern of lymphatic endothelial cells and vascular endothelial cells, to make their expression profile more similar to each other. Kaposi’s sarcoma was first described by Moritz Kaposi in 1872,7 and the disease is now the most common neoplasm in people with AIDS.8 Kaposi’s sarcoma-associated herpesvirus is linked to the aetiopathogenesis of all forms of Kaposi’s sarcoma—classic, endemic African, and AIDS types—and is a complication in patients who have had organ transplants. Kaposi’s sarcoma herpesvirus is also associated with lymphoproliferative disorders, including primary effusion lymphoma and multicentric Castleman’s disease. Kaposi’s sarcoma herpesvirus is a -2herpesvirus; these viruses are characterised by their ability to replicate in lymphoblastoid cells.9 Members of this family, such as Epstein-Barr virus10 and herpesvirus saimiri,11 cause lymphoid
Figure: Histopathology of Kaposi’s sarcoma Histological section of patch (A), plaque (B), and nodular stage (C). Haematoxylin and eosin.
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Comment
malignancies. All clinical forms of Kaposi’s sarcoma have indistinguishable histological features. The sarcoma is composed of a variable mixture of irregularly shaped, round capillary, and slit-like endothelial-lined vascular spaces, and spindle-shaped cells accompanied by a variable inflammatory mononuclear-cell infiltrate (figure). In their report Wang and colleagues6 show that Kaposi’s sarcoma neoplastic cells share a more similar gene-expression pattern with endothelial cells than any other cell type analysed. They then show that markers of lymphatic and vascular endothelial cells are present in Kaposi’s sarcoma spindle cells.6 This finding suggests that Kaposi’s sarcoma cells do not truly represent either cell lineage, although the spindle-cell component expresses mainly lymphatic endothelial cell markers. As Wang and colleagues point out, Kaposi’s sarcoma herpesvirus can infect both lymphatic and vascular endothelial cells and induce changes in their transcription pattern, making the geneexpression profile of both cell types closer to each other than to the corresponding uninfected cell type. At the core of these findings is the observation that Kaposi’s sarcoma herpesvirus causes transcriptional reprogramming of the infected cells, and induces over-expression of several cellular cytokines, chemokines, and their receptors. Among these molecules, those related to angiogenesis and lymphangiogenesis, such as angiopoietin-2, VEGF (vascular endothelial growth factor), and VEGF-D, have a particular clinical relevance; their concentrations are substantially higher in plasma of individuals with AIDS and Kaposi’s sarcoma than in healthy donors. In addition, plasma concentrations of angiopoietin-2 and VEGF-D decrease substantially during resolution of Kaposi’s sarcoma with antiretroviral therapy. What do these results mean to the scientific and clinical community? Although the exact mechanisms whereby these lymphatic endothelial cells achieve the Kaposi’s sarcoma phenotype is not clear, Wang and colleagues’ study strongly suggests an involvement of lymphangiogenic molecules in the pathogenesis of the disorder. As the angiogenic phenotype of Kaposi’s sarcoma spindle cells is expected to be dependent on the upregulation of lymphangiogenic molecules, strategies to target these molecules might be useful. Thus one could speculate that neutralising antibodies to angiopoietin-2, VEGF, and VEGF-D
might provide a suitable tool for antilymphangiogenic therapies. Wang’s work should be of interest to a wide readership: a reprogrammed cellular gene expression, which makes different cell types lose their own expression pattern driving the geneexpression profile of one closer to that of the other, is an important mechanism that could be involved in other virally induced cancers. This report will undoubtedly inspire follow-up studies that will further explore the proposed link between Kaposi’s sarcoma herpesvirus and lymphangiogenic molecules.
Ornella Flore Department of Microbiology and Department of Dermatology, NYU School of Medicine, New York, NY 10016, USA ornella.fl[email protected]
I declare I have no conflict of interest. 1
2
3
4
5
6
7 8
9
10 11
Nickoloff BJ, Griffiths CE. The spindle-shaped cells in cutaneous Kaposi’s sarcoma: histologic simulators include factor XIIIa dermal dendrocytes. Am J Pathol 1989; 135: 793–800. Stürzl M, Ascherl G, Blasig C, Opalenik SR, Ensoli B, Browning PJ. Expression of the human herpesvirus 8-encoded viral macrophage inflammatory protein-1 gene in Kaposi’s sarcoma lesions. Aids 1998; 12: 1105–06. Rutgers JL, Wieczorek R, Bonetti F, et al. The expression of endothelial cell surface antigens by AIDS-associated Kaposi’s sarcoma: evidence for a vascular endothelial cell origin. Am J Pathol 1986; 122: 493–99. Roth WK, Werner S, Risau W, Remberger K, Hofschneider PH. Cultured, AIDS-related Kaposi’s sarcoma cells express endothelial cell markers and are weakly malignant in vitro. Int J Cancer 1988; 42: 767–73. Jussila L, Valtola R, Partanen TA, et al. Lymphatic endothelium and Kaposi’s sarcoma spindle cells detected by antibodies against the vascular endothelial growth factor receptor-3. Cancer Res 1998; 58: 1599–604. Wang HW, Trotter MW, Lagos D, et al. Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nat Genet 2004; 36: 687–93. Kaposi M. Idiopatis-ches multiples pigmentsarkom der Haut. Arch Dermatol Syphillis 1872; 4: 265–73. Beral V, Peterman TA, Berkelman RL, Jaffe HW. Kaposi’s sarcoma among persons with AIDS: a sexually transmitted infection? Lancet 1990; 335: 123–28. Roizman B. Herpesviridae: a brief introduction. In: Fields BN, Knipe DM, Howley PM, eds. Fields virology. Philadelphia: Lippincott-Raven, 1996: 2221–31. Baba M, Shigeta S. Antiviral activity of glycyrrhizin against varicella-zoster virus in vitro. Antiviral Res 1987; 7: 99–107. Albrecht JC, Nicholas J, Biller D, et al. Primary structure of the herpesvirus saimiri genome. J Virol 1992; 66: 5047–58.
Faecal occult-blood screening in Burgundy Recently, Jean Faivre and colleagues1 reported a screening trial of over 90 000 French adults aged 45–74 who had been allocated by geographic area, in Burgundy, to receive or not receive an invitation to complete faecal occult-blood screening every 2 years. A total of six rounds of screening were offered, and the population was followed up for 11 years after study entry. Between 50% and 60% of the invited population completed tests at each round, with almost 70% of invitees completing at least one test over the course of the trial. Faivre and colleagues found that allocation to the screening group was associated with a 16% reduction in mortality from colorectal cancer (mortality ratio 0·84, 95% CI 0·71–0·99). The frequency of colorectal cancer did not differ between groups, and www.thelancet.com Vol 364 August 28, 2004
all-cause mortality was not reported. The main methodological limitation was the use of geographic small-area allocation, rather than individual or household randomisation, of intervention and control status. This choice was made on practical grounds, and did not seem to result in unequal or dissimilar groups in terms of age, sex, or baseline frequency of colon cancer. The results of Faivre and colleagues’ trial are consistent with the findings of four previous randomised trials of biennial faecal occult-blood screening of risk reductions for colorectal cancer mortality from 12% to 21%.2–6 Faecal specimens were not rehydrated in the Burgundy trial and dietary restrictions were not used. Test-positive rates were similar to other trials that did not use rehydration: 2·1% were positive on the initial screen and 1·4% 741
“pseudo-addiction”, make the point that problematic drugrelated behaviour has a differential diagnosis with profound implications for treatment. Finally, they highlight the need for careful monitoring and appropriate referral of the patient. However, the document1 regrettably provides little practical guidance on selection of patients, structuring of therapy to enhance monitoring and control, or strategies to manage patients whose problematic behaviour is not severe enough to warrant specialist referral. It includes an unsubstantiated statement that short-acting opioids predispose to tolerance and dependence, and sadly neglects the problem of severe chronic pain in patients with known chemical dependency.8 For an American physician, this document is, on balance, all about balance, and deserves praise as such. Clinicians will need other resources to become educated about the important issues it raises.9
1
2
3 4
5
6
Russell K Portenoy Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, New York, NY 10003, USA [email protected] During the past several years, I have received compensation for consulting or for educational projects from several companies that make opioid drugs, including Endo Pharmaceuticals, Janssen Pharmaceutica, Ortho McNeil Pharmaceuticals, and Ligand Pharmaceuticals; similarly, my department has received educational grants or study grants from such companies, including Endo Pharmaceuticals, Janssen Pharmaceutica, Ligand Pharmaceuticals, Purdue Pharma, Cephalon Pharmaceuticals, ZARS Pharmaceuticals, and CIMA Pharmaceuticals.
7
8
9
A consensus statement prepared on behalf of the Pain Society, the Royal College of Anaesthetists, the Royal College of General Practitioners, and the Royal College of Psychiatrists. Recommendations for the appropriate use of opioids for persistent non-cancer pain. London: the Pain Society, March, 2004: http://www.painsociety.org/pdf/opioids_doc_2004.pdf (accessed Aug 9, 2004). A joint statement from 21 health organizations and the Drug Enforcement Administration. Promoting pain relief and preventing abuse of pain medications: a critical balancing act: http://www.medsch.wisc.edu/ painpolicy/Consensus2.pdf (accessed Aug 4, 2004). World Health Organization. Achieving balance in national opioids control policy: guidelines for assessment. Geneva: WHO, 2000. Zacny J, Bigelow G, Compton P, Foley K, Iguchi M, Sannerud C. College on problems of drug dependence taskforce on prescription opioid nonmedical use and abuse: position statement. Drug Alcohol Depend 2003; 69: 215–32. Zenz M, Strumpf M, Tryba M. Long-term opioid therapy in patients with chronic nonmalignant pain. J Pain Symptom Manage 1992; 7: 69–77. American Academy of Pain Medicine, American Pain Society. The use of opiods for the treatment of chronic pain. http://www.painmed. org/productpub/statements/pdfs/opioids.pdf (accessed Aug 4, 2004). Chou R, Clark E, Helfand M. Comparative efficacy and safety of longacting oral opioids for chronic non-cancer pain: a systematic review. J Pain Symptom Manage 2003; 26: 1026–48. Rosenblum A, Joseph H, Fong C, Kipnis S, Cleeland C, Portenoy RK. Prevalence and characteristics of chronic pain among chemically dependent patients in methadone maintenance and residential treatment facilities. JAMA 2003; 289: 2370–78. Portenoy RK, Payne R. Acute and chronic pain. In: Lowinson JH, Ruiz P, Millman RB, eds. Comprehensive textbook of substance abuse, 3rd edn. Baltimore: Williams and Wilkins, 1997; 563–90.
Kaposi’s sarcoma Until recently, if someone had asked the cellular origin of the spindle cells of Kaposi’s sarcoma lesions, the answer would probably have been vague. In fact, the histogenesis of the spindle-cell component, the Kaposi’s sarcoma tumour cell, remains controversial. Most of these spindle cells express endothelial markers, but markers for smooth-muscle cells, macrophages, and dendritic cells are also present.1,2 Several aspects of the origin of the spindle cells in Kaposi’s sarcoma remain poorly understood. Although many studies favour an endothelial cell origin,3,4 some suggest a lymphatic-endothelial origin.5 A recent study by Hesei-Wei Wang and co-workers,6 from Chris Boshoff’s laboratory, suggests that Kaposi’s sarcoma neoplastic cells are closely related to lymphatic endothelial cells. These researchers also assessed the ability of Kaposi’s sarcomaassociated herpesvirus, also called human herpesvirus 8, to alter
the gene-expression pattern of lymphatic endothelial cells and vascular endothelial cells, to make their expression profile more similar to each other. Kaposi’s sarcoma was first described by Moritz Kaposi in 1872,7 and the disease is now the most common neoplasm in people with AIDS.8 Kaposi’s sarcoma-associated herpesvirus is linked to the aetiopathogenesis of all forms of Kaposi’s sarcoma—classic, endemic African, and AIDS types—and is a complication in patients who have had organ transplants. Kaposi’s sarcoma herpesvirus is also associated with lymphoproliferative disorders, including primary effusion lymphoma and multicentric Castleman’s disease. Kaposi’s sarcoma herpesvirus is a -2herpesvirus; these viruses are characterised by their ability to replicate in lymphoblastoid cells.9 Members of this family, such as Epstein-Barr virus10 and herpesvirus saimiri,11 cause lymphoid
Figure: Histopathology of Kaposi’s sarcoma Histological section of patch (A), plaque (B), and nodular stage (C). Haematoxylin and eosin.
740
www.thelancet.com Vol 364 August 28, 2004
Comment
malignancies. All clinical forms of Kaposi’s sarcoma have indistinguishable histological features. The sarcoma is composed of a variable mixture of irregularly shaped, round capillary, and slit-like endothelial-lined vascular spaces, and spindle-shaped cells accompanied by a variable inflammatory mononuclear-cell infiltrate (figure). In their report Wang and colleagues6 show that Kaposi’s sarcoma neoplastic cells share a more similar gene-expression pattern with endothelial cells than any other cell type analysed. They then show that markers of lymphatic and vascular endothelial cells are present in Kaposi’s sarcoma spindle cells.6 This finding suggests that Kaposi’s sarcoma cells do not truly represent either cell lineage, although the spindle-cell component expresses mainly lymphatic endothelial cell markers. As Wang and colleagues point out, Kaposi’s sarcoma herpesvirus can infect both lymphatic and vascular endothelial cells and induce changes in their transcription pattern, making the geneexpression profile of both cell types closer to each other than to the corresponding uninfected cell type. At the core of these findings is the observation that Kaposi’s sarcoma herpesvirus causes transcriptional reprogramming of the infected cells, and induces over-expression of several cellular cytokines, chemokines, and their receptors. Among these molecules, those related to angiogenesis and lymphangiogenesis, such as angiopoietin-2, VEGF (vascular endothelial growth factor), and VEGF-D, have a particular clinical relevance; their concentrations are substantially higher in plasma of individuals with AIDS and Kaposi’s sarcoma than in healthy donors. In addition, plasma concentrations of angiopoietin-2 and VEGF-D decrease substantially during resolution of Kaposi’s sarcoma with antiretroviral therapy. What do these results mean to the scientific and clinical community? Although the exact mechanisms whereby these lymphatic endothelial cells achieve the Kaposi’s sarcoma phenotype is not clear, Wang and colleagues’ study strongly suggests an involvement of lymphangiogenic molecules in the pathogenesis of the disorder. As the angiogenic phenotype of Kaposi’s sarcoma spindle cells is expected to be dependent on the upregulation of lymphangiogenic molecules, strategies to target these molecules might be useful. Thus one could speculate that neutralising antibodies to angiopoietin-2, VEGF, and VEGF-D
might provide a suitable tool for antilymphangiogenic therapies. Wang’s work should be of interest to a wide readership: a reprogrammed cellular gene expression, which makes different cell types lose their own expression pattern driving the geneexpression profile of one closer to that of the other, is an important mechanism that could be involved in other virally induced cancers. This report will undoubtedly inspire follow-up studies that will further explore the proposed link between Kaposi’s sarcoma herpesvirus and lymphangiogenic molecules.
Ornella Flore Department of Microbiology and Department of Dermatology, NYU School of Medicine, New York, NY 10016, USA ornella.fl[email protected]
I declare I have no conflict of interest. 1
2
3
4
5
6
7 8
9
10 11
Nickoloff BJ, Griffiths CE. The spindle-shaped cells in cutaneous Kaposi’s sarcoma: histologic simulators include factor XIIIa dermal dendrocytes. Am J Pathol 1989; 135: 793–800. Stürzl M, Ascherl G, Blasig C, Opalenik SR, Ensoli B, Browning PJ. Expression of the human herpesvirus 8-encoded viral macrophage inflammatory protein-1 gene in Kaposi’s sarcoma lesions. Aids 1998; 12: 1105–06. Rutgers JL, Wieczorek R, Bonetti F, et al. The expression of endothelial cell surface antigens by AIDS-associated Kaposi’s sarcoma: evidence for a vascular endothelial cell origin. Am J Pathol 1986; 122: 493–99. Roth WK, Werner S, Risau W, Remberger K, Hofschneider PH. Cultured, AIDS-related Kaposi’s sarcoma cells express endothelial cell markers and are weakly malignant in vitro. Int J Cancer 1988; 42: 767–73. Jussila L, Valtola R, Partanen TA, et al. Lymphatic endothelium and Kaposi’s sarcoma spindle cells detected by antibodies against the vascular endothelial growth factor receptor-3. Cancer Res 1998; 58: 1599–604. Wang HW, Trotter MW, Lagos D, et al. Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nat Genet 2004; 36: 687–93. Kaposi M. Idiopatis-ches multiples pigmentsarkom der Haut. Arch Dermatol Syphillis 1872; 4: 265–73. Beral V, Peterman TA, Berkelman RL, Jaffe HW. Kaposi’s sarcoma among persons with AIDS: a sexually transmitted infection? Lancet 1990; 335: 123–28. Roizman B. Herpesviridae: a brief introduction. In: Fields BN, Knipe DM, Howley PM, eds. Fields virology. Philadelphia: Lippincott-Raven, 1996: 2221–31. Baba M, Shigeta S. Antiviral activity of glycyrrhizin against varicella-zoster virus in vitro. Antiviral Res 1987; 7: 99–107. Albrecht JC, Nicholas J, Biller D, et al. Primary structure of the herpesvirus saimiri genome. J Virol 1992; 66: 5047–58.
Faecal occult-blood screening in Burgundy Recently, Jean Faivre and colleagues1 reported a screening trial of over 90 000 French adults aged 45–74 who had been allocated by geographic area, in Burgundy, to receive or not receive an invitation to complete faecal occult-blood screening every 2 years. A total of six rounds of screening were offered, and the population was followed up for 11 years after study entry. Between 50% and 60% of the invited population completed tests at each round, with almost 70% of invitees completing at least one test over the course of the trial. Faivre and colleagues found that allocation to the screening group was associated with a 16% reduction in mortality from colorectal cancer (mortality ratio 0·84, 95% CI 0·71–0·99). The frequency of colorectal cancer did not differ between groups, and www.thelancet.com Vol 364 August 28, 2004
all-cause mortality was not reported. The main methodological limitation was the use of geographic small-area allocation, rather than individual or household randomisation, of intervention and control status. This choice was made on practical grounds, and did not seem to result in unequal or dissimilar groups in terms of age, sex, or baseline frequency of colon cancer. The results of Faivre and colleagues’ trial are consistent with the findings of four previous randomised trials of biennial faecal occult-blood screening of risk reductions for colorectal cancer mortality from 12% to 21%.2–6 Faecal specimens were not rehydrated in the Burgundy trial and dietary restrictions were not used. Test-positive rates were similar to other trials that did not use rehydration: 2·1% were positive on the initial screen and 1·4% 741