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Interventions for squamous cell carcinoma of the conjunctiva in HIV-infected individuals

  1. Stephen Gichuhi1,*,
  2. James H Irlam2

Editorial Group: Cochrane HIV/AIDS Group

Published Online: 28 FEB 2013

Assessed as up-to-date: 19 FEB 2007

DOI: 10.1002/14651858.CD005643.pub3


How to Cite

Gichuhi S, Irlam JH. Interventions for squamous cell carcinoma of the conjunctiva in HIV-infected individuals. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD005643. DOI: 10.1002/14651858.CD005643.pub3.

Author Information

  1. 1

    University of Nairobi, Department of Ophthalmology, Nairobi, Kenya

  2. 2

    University of Cape Town, Primary Health Care Directorate, Cape Town, Western Cape, South Africa

*Stephen Gichuhi, Department of Ophthalmology, University of Nairobi, P.O Box 347, KNH, Nairobi, 00202, Kenya. sgichuhi@wananchi.com. sgichuhi@uonbi.ac.ke.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 28 FEB 2013

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Definition
Squamous cell carcinoma of the conjunctiva (SCC) is the end stage of a spectrum of conditions called ocular surface squamous neoplasia (OSSN). Histologically, OSSN varies from a benign form that includes papilloma, pseudoepitheliomatous hyperplasia and benign hereditary intraepithelial dyskeratosis, through a pre-invasive form called conjunctival intraepithelial neoplasia (CIN) graded as I,II or III depending on depth of involvement and finally the invasive form that includes squamous cell carcinoma and mucoepidermoid carcinoma (Basti 2003). When the dysplastic changes are confined to the basal one third of the epithelium, this is termed CIN I or mild dysplasia, when they extend into the middle third of the epithelium this is termed CIN II or moderated dysplasia and when they extend into the superficial third of the epithelium this is termed CIN III or severe dysplasia. Full thickness dysplasia is also referred to as carcinoma-in-situ (CIS). Invasive squamous cell carcinoma of the conjunctiva refers to the infiltration through the basement membrane to involve the underlying stroma (Basti 2003; Shields 2004). Clinically, these stages may be indistinguishable except by histology.

Clinical features
The tumour may be asymptomatic or present with redness, irritation, severe pain, and visual loss (Tunc 1999). It commonly affects the visible area between the upper and lower eyelids (interpalpebral conjunctiva), usually on the nasal side at the margin of the conjunctiva and the cornea (limbus). This slow-growing tumour can present as a solitary or diffuse growth. Solitary tumours can be nodular or gelatinous and may have a whitish plaque (leukoplakia). The lesion mimics benign conjunctival degenerations such as pterygium and pinguecula. Most cases are unilateral(Cervantes 2002; Chisi 2006).

The morbidity from squamous cell carcinoma of the conjunctiva relates to the effects of the disease and its treatment. It may extend into the eyeball, orbit, regional lymph nodes, surrounding paranasal sinuses and the brain. Death may result from regional or distant metastases, as well as intracranial spread.

Aetiology
The aetiology of SCC has been associated with HIV infection (Ateenyi-Agaba 1995;Waddell 1996), human papilloma virus (HPV) infection (Waddell 1996; Nakamura 1997; Newton 2002), immunosuppression in organ transplant recipients (Macarez 1999), and exposure to ultraviolet B rays of the sun (Ateenyi-Agaba 2004; Ng 2008; ). Chronic conjunctival diseases, such as allergic conjunctivitis and trachoma, have also been implicated (Poole 1999).

The majority of affected persons in Africa are HIV-positive; 71% in Uganda, 86% in Malawi (Waddell 1996) ,70.6% in South Africa (Mahomed 2002) and 75% in Nigeria (Osahon 2011). In a smaller study in Zimbabwe, 12 out of 13 persons with SCC or CIS (92.3%) were HIV-positive (Porges 2003). Many ophthalmologists in Africa now consider SCC in young adults to be a marker for HIV infection. The relationship between SCC and HPV is less clear. Some case-control studies have found an association (Moubayed 2004; de Koning 2008) while some have not (Sen 2007; Guthoff 2009). Among HIV-infected people with SCC, cutaneous types of HPV are detected more frequently than the mucosal types (de Koning 2008; Ateenyi-Agaba 2010). In another Ugandan study, HPV was detected more frequently in the low-grade conjunctival neoplasias than in more advanced disease (Tornesello 2006). Ultraviolet solar radiation causes tissue damange mediated through mutation of the tp53 tumour-suppressor gene and tissue matrix metalloproteinases (Ateenyi-Agaba 2004; Ng 2008).

It is plausible that the aetiology involves an interaction of these factors in a yet to be determined model.

Epidemiology
The epidemiology of SCC has transformed in the last few decades. It used to be an uncommon slow-growing tumour found in elderly males (Lee 1997; McKelvie 2002), but in Africa it is becoming more common, more aggressive, and more likely to affect young persons, especially females (Ateenyi-Agaba 1995). This pattern is related to the co-existence of the HIV/AIDS pandemic, high HPV exposure, and solar radiation in the region. The HIV pandemic is mainly centered in Africa. In 2009 22.5 million of the 33.3 million infected people worldwide were living in Africa (UNAIDS 2010). Africa also has the highest prevalence of HPV infection in the world, with an age-adjusted prevalence of 25.6% in women of age 15 to 74 years, followed by South America (14.3%), Asia (8.7%) and Europe (5.2%). (Clifford 2005). The equator bissects the continent and over 75% of the continent is within the tropics with consequent high ambient solar exposure all year round.

The Kampala Cancer Registry in Uganda recorded a six-fold increase in the incidence of conjunctival squamous cell carcinoma, from an average of six per million per year between 1970 and 1988, to 35 per million per year in 1992 (Ateenyi-Agaba 1995).

A study in Australia found that 78.5% of affected persons were elderly males with a mean age of 60 years (Lee 1997). Similarly, in Britain, 77% were males and 69% of them were more than 60 years old (McKelvie 2002). In contrast, a study in Zimbabwe found that 70% of patients were young females with a median age of 35 years (Pola 2003), while in South Africa the mean age was 37 years (Mahomed 2002). In Tanzania the tumour has been observed to be more aggressive than it was previously. The mean length of history on presentation is three months (Poole 1999).

SCC is a common tumour of the ocular surface among adults in Africa. Pola 2003 In Tanzania 45.8% of 168 conjunctival biopsies seen between 1996 and 1997 were squamous cell carcinomas, while 35% were pingueculum or pterygium (Poole 1999).

The prevalence of SCC in a hospital-based HIV-positive population in Kenya was 7.8% (Chisi 2006).

Diagnosis
Most cases are diagnosed on clinical impression after a person presents with a growth on the eyeball, which is then excised and sent for histology to get a definitive diagnosis (Shields 1997). Histopathology is the commonest mode of diagnosis in practice. Although regarded as the gold standard, histopathological diagnoses are subject to discordant interpretation (Margo 2002). Cytology has also been used, especially for the follow-up of people treated using chemotherapy or immune therapy to monitor recurrence, since malignant cells are poorly adherent to each other (McKelvie 2001).

Other methods include the use of DNA cytometry to identify tumour-cell regression (Nadjari 1999); immunostaining for certain molecular genetic markers, such as proliferating cells nuclear antigens (PCNA), Ki67 expression, tp53 gene mutations, and argyrophilic nucleolar organiser regions (AgNORs) (Aoki 1998); and toluidine blue staining to mark tumour margins for surgical excision (Kaji 2006).

Treatment options
The treatment of this condition since the pre-HIV era has been simple: surgical excision alone or with additional adjunctive therapy. The main objective of surgical excision is complete removal of the tumour to minimise recurrence (Shields 1997). The resulting surface defect may need reconstruction using amniotic membrane transplantation (Espana 2002; Gunduz 2005) or limbal autografts (Copeland 1990). Adjunctive therapies augment surgical excision. These include cryotherapy, chemotherapy, radiotherapy, immune therapy, and amniotic membrane transplants. They work by killing residual malignant cells at the excision margins or any that may be seeded during excision, although there are also reports of their use as primary therapy (Cerezo 1990; Karp 2001; Barbazetto 2004). Cidofovir, an antiviral active against human papilloma virus, has been described as a primary therapy, and was reported to cause tumour regression (Sherman 2002). It undergoes phosphorylation to active diphosphates independent of viral enzymes, which act as both inhibitors and alternative substrates of viral DNA polymerase, thus inhibiting DNA synthesis (Safrin 2004). A list of these interventions is shown in  Table 1.

Cryotherapy kills malignant cells by repeated cycles of freezing and thawing (Peksayar 1989). Chemotherapy involves using a class of drugs called antimetabolites. They act by interfering with the enzymes involved in the intermediary metabolism of replicating cancer cells. An example is 5-Fluorouracil (5-FU) and mitomycin C. The former (5-FU), is a prodrug, which means it is converted to active molecules. One of them, 5- fluoro-2'- deoxyuridine-5'-monophosphate (FdUMP), binds to the enzyme thymidylate synthetase critical for the synthesis of thymidylate, which results in the inhibition of DNA synthesis. Another one, 5-fluorouridine-5'-triphosphate (FUTP) interferes with RNA synthesis (Chu 2004). It is cell-cycle specific and acts in the S phase of the cell cycle. In one study, 1% 5-FU eyedrops were used alone without concurrent surgery or radiotherapy to treat a recurrent tumour (Midena 2000). Mitomycin C is an antibiotic which acts by interfering with the DNA of tumour cells. It undergoes metabolic activation, which generates an alkylating agent that cross-links DNA, making the cell unable to replicate (Chu 2004). It is a cycle-non-specific agent that is most effective in the G1 and S phases. Radiotherapy destroys the DNA and RNA of dividing cells (Goldberg 1963). The source of beta radiation is strontium 90 (Cerezo 1990). Photodynamic therapy combines a drug (called a photosensitizer or photosensitizing agent) with light of a specific wavelength to produce activated oxygen species that promote tumour destruction (Castano 2005). Another treatment option is amniotic membrane transplantation. It is one of the layers of the placenta and is obtained after elective Caesarean section. It has anti-angiogenic, anti-scarring, and anti-inflammatory properties (Hao 2000). Immune therapy for this condition involves the use of interferon alpha. Interferon alpha is part of a group of proteins called cytokines. It has three-pronged action with antiviral and oncostatic effects and also activates natural killer cells, which are cells of the immune system that are able to recognise and destroy tumour cells (Lake 2004). The exact mechanism of action is not known. Cidofovir, an antiviral that is active against human papilloma virus, has been reported to cause regression of this tumour (Sherman 2002). It undergoes phosphorylation to active diphosphates independent of viral enzymes, which act as both inhibitors and alternative substrates of viral DNA polymerase, thus inhibiting DNA synthesis (Safrin 2004).

Advanced disease where the tumour has spread requires removal of the eyeball (modified enucleation) or the entire orbital contents (exenteration) in an attempt to save life (Shields 1991).

Despite therapy, up to 43% of treated patients experience recurrence at variable times (but usually within two years) (Peksayar 1989; Tabin 1997; Yeatts 2000). Simple excision has a higher rate of recurrence. A study in Australia reported 23% (Lee 1997). In the USA, it was 28.5%, but was 7.7% when combined with cryotherapy (Sudesh 2000). In one series of 17 cases treated with mitomycin C eye drops, 15 of them had undergone one to four surgical procedures before the mitomycin C treatment and six (35%) recurred within six months (Frucht-Pery 1997). The efficacies of treatment reported in the literature need to be interpreted cautiously, since some of the treated cases have recurrences from prior surgical excision (Frucht-Pery 1997; Midena 2000). The recurrence rate may be higher in Africa due to late presentation, exposure to solar radiation, and lack of many of the adjunctive therapies. Only cryotherapy and chemotherapy are likely to be found in advanced centres.

It is not clear whether the efficacy of these interventions is different in people with HIV infection. The effect, if any, of highly active antiretroviral therapy (HAART) on this condition is also not clearly known.

Clinical and public health importance of this review
Although the number of people living with HIV infection worldwide seems to have stabilized Africa remains the global epicentre of the AIDS pandemic (UNAIDS 2010). The region also has the highest prevalence of HPV in the world and high solar ultraviolet exposure year-round (Clifford 2005). If this triad of risk factors remains, the number of cases of conjunctival squamous cell carcinoma is expected to remain high. The effect of HPV vaccination in children on OSSN if any will take a long time to determine.

Recurrences still occur after surgical excision. Most of the current adjunctive therapies described are not readily available in low-income countries. They are expensive and inconvenient to use. Cryotherapy requires special probes and canisters of liquid nitrogen gas that need refilling. Amniotic membrane transplantation requires tissue banks to process and preserve the transplant material. Medications for chemotherapy are not widely available, but are probably the easiest to obtain and use in such settings, since they are packed in small vials and do not require stringent storage conditions.

The cosmetic outcome of advanced disease and its treatment is very poor and leaves patients with an empty socket (Figure 1). Patients who undergo orbital exenteration often experience social problems because of their facial disfigurement leading to limited social interaction (Bonanno 2010). Facilities for cosmetic surgery and orbital implants in low-income countries are often unavailable.

 FigureFigure 1.

With antiretroviral therapy, HIV-infected people can now enjoy an improved physical appearance and quality of life, but unsightly lesions on the face such as those caused by conjunctival squamous cell carcinoma unmask what would otherwise be a 'hidden' HIV infection. This potentially exposes the affected persons to the stigma and discrimination associated with HIV infection.

Effective evidence-based interventions that allow early diagnosis and treatment are therefore needed.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

To evaluate interventions for treating squamous cell carcinoma of the conjunctiva in HIV-infected individuals (see  Table 1 for list of interventions).

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

Randomised controlled trials (RCT).

 

Types of participants

HIV-positive people with ocular surface squamous neoplasia (OSSN), whose diagnosis of HIV infection is based on either antibody or antigen tests, and whose OSSN is determined by histology, conjunctival impression cytology, or immunostaining.

 

Types of interventions

Any intervention used for treating OSSN, including the following:

  • surgical excision, modified enucleation, and exenteration
  • adjunctive therapies such as cryotherapy, chemotherapy, radiotherapy, amniotic membrane transplants , and immune therapies, such as interferon therapy
  • cidofovir
  • different regimens of HAART
  • combinations of the above

We were interested in trials that compared any of the interventions with another intervention or a placebo, or trials comparing different dosages or regimens of the same intervention.

 

Types of outcome measures

Primary outcomes

  • local control, defined as a tumour-free period of two years
  • recurrence at six months, then at six-month intervals thereafter until two years after treatment, diagnosed by histopathology, conjunctival impression cytology, or immunostaining
  • death

Secondary outcomes

  • time to recurrence
  • adverse events

 

Search methods for identification of studies

The HIV/AIDS review group search methods were used. We searched electronic databases and abstracts of conference proceedings. There were no language restrictions. The key words used in the search included:

ocular surface squamous neoplasia, squamous cell carcinoma, conjunctiva, carcinoma in situ, conjunctival intraepithelial neoplasia, HIV, AIDS, excision, enucleation, exenteration, chemotherapy, cryotherapy, interferon, immunetherapy, radiotherapy,
A search had been conducted in December 2009 using search terms from the first edition of this review and found no trials. We conducted an updated search beginning January 2010.

  • Electronic databases

The following electronic databases were searched.
1. PubMed - from January 2010 to 27th January 2012
2. EMBASE - from January 2010 to 10th February 2012
3. The Cochrane Library - from January 2010 to 3rd February 2012

  • Clinical trial registers

We searched the WHO International Clinical Trials Registry Platform (ICTRP) on 10th February 2012 (WHO ICTRP 2012). We also searched the clinical trial register of the US National Institutes of Health (NIH) www.clinicaltrials.gov website (NIH 2012) on 12th February 2012. This database includes trials registered with the US National Eye Institute (NEI) and US National Cancer Institute (NCI).

  • Conference proceedings

We searched abstracts of the proceedings of the HIV/AIDS conferences covered in the AIDS Education Global Education System (AEGIS) database (http://www.aegis.com/search).

This search covered all the following conferences which also shows the latest conference abstracts available in the AEGIS database:

1. International AIDS conference by the the International AIDS Society (IAS) upto the conference held from 18th-23rd August 2010

2. International AIDS Society (IAS) HIV Pathogenesis and Treatment upto the 5th conference held from 19th-22nd July 2009

3. International Congress on Drug Therapy in HIV infection upto the 9th meeting on 9th-13th November 2008

4. International Workshops on Adverse Drug Reactions and Lipodystrophy in HIV upto the 11th workshop on 26th-28th October 2009

5. Conference on Retroviruses and Opportunistic Infections (CROI) upto the 15th conference on 3rd-6th February 2008

6. Centers for Disease Control and Prevention (CDC) National HIV Prevention conference upto the meeting on 12th-15th June 2005

7. The International Workshops on HIV Drug Resistance and Treatment Strategies upto the 5th workshop on 4th-8th June 2001

8. British HIV Association (BHIVA) upto the 17th conference held on 6th to 8th April 2011

9. European AIDS Clinical Society upto the 11th conference held on 24th-27th October 2007

10. National HIV/AIDS Update Conference upto the 17th conference on 10th-13th April 2005

  • Reference lists

We checked the reference lists of all studies identified by the above methods for additional relevant records.

 

Data collection and analysis

We independently screened the results of the search to select potentially relevant studies and to retrieve the full articles ( Table 2). Where there was any uncertainty we obtained the full article. We independently applied the inclusion criteria using a specially designed eligibility form to the potentially relevant studies. No randomised controlled trials met the inclusion criteria.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Description of studies

See: Characteristics of ongoing studies.

No studies were identified that fulfilled the selection criteria. The PRISMA flowchart in Figure 2 summarizes the results (Figure 2). There is an ongoing study in Kenya that was registered in the PanAfrican Clinical Trials Register on 19th July 2012. This register feeds into the WHO International Clinical Trials Registry Platform (ICTRP).

 FigureFigure 2. PRISMA study flow diagram.

 

Risk of bias in included studies

No studies were identified that fulfilled the selection criteria.

 

Effects of interventions

No studies were identified that fulfilled the selection criteria. The search strategy yielded 12 records, which were all excluded (see table of excluded studies).

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

In this review no randomised controlled trials on the effectiveness of interventions against conjunctival squamous cell carcinoma in HIV-infected individuals were identified. No randomised controlled trials were found, even in the HIV-uninfected populations. Current practice is based on the results of interventional case series and case reports ( Table 1). The quality of evidence from these study designs ranks low by various systems for grading evidence. It is graded level four by the Oxford Centre for Evidence-Based Medicine (OECBM) recommendations (Phillips 2001) and low-grade by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group (Atkins 2004). According to GRADE, low means that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. These studies are also mainly from western countries, where the participants are usually elderly males, who have a different disease profile from participants in developing countries. They have a less aggressive form of the disease and few are HIV-infected (Ateenyi-Agaba 1995; Waddell 1996; Lee 1997; Poole 1999; Mahomed 2002; McKelvie 2002). We could not explain why there are no trials, but postulate that perhaps it reflects differences in research priorities, since the prevalence of this tumour is low among HIV-infected individuals living in the western world.

There is a need to conduct randomised controlled trials to provide unbiased evidence for the effectiveness of currently used interventions for treating conjunctival squamous cell carcinoma. Ideally, the disease would be studied in its early stages, before it has spread, since in the later stages the treatment is more costly, can only be provided in tertiary care centres, and would tend to be individually tailored depending on the extent of spread. Studies are needed in the setting where the greatest burden of disease is found. The typical setting involves young HIV-infected individuals, mostly females with aggressive disease and HIV co-infections, in the context of high HIV prevalence, high solar exposure, and limited resources.

Investigating the effectiveness of simple surgical excision versus wide excision with or without adjunctive antimetabolite eye drops would be relevant as these are relatively simple interventions that can be easily translated in developing countries. The effect of new health technologies used in the developed world, such as cryotherapy, amniotic membrane transplants, and photodynamic therapy, should also be assessed in RCTs.

Preventive interventions directed against the mutagenic effects of solar ultraviolet B radiation and the oncogenic viruses associated with this disease also need to be identified.

There is also an important implication for diagnostic tests for early disease. Ethical issues that may arise include, for instance, whether participants should be subjected to the application of potentially dangerous cytotoxic antimetabolites as an adjunct to excision biopsy before there is histological confirmation of tumour. Treatment of conjunctival squamous cell carcinomas with topical mitomycin C and/or radiation has been associated with induction of atypical cell changes, such as conjunctival DNA-polyploidy afterward (Cartsburg 2001). More sensitive diagnostic tests, such as cytology or immunostaining, may thus need to be used pre-operatively.

Treatment of opportunistic tumours in HIV/AIDS, such as squamous cell carcinoma of the conjunctiva, is part and parcel of HIV care. Untreated squamous cell carcinoma of the conjunctiva threatens survival. Not paying attention to this disease may compromise the gains from other care availed to affected individuals.

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

 

Implications for practice

Current clinical practice in treatment of squamous cell carcinoma of the conjunctiva is based on case series and case reports. This is a weak evidence base.

 
Implications for research

RCTs for treatment of this disease are needed in the settings where it occurs most frequently. Preventive interventions, such as HPV vaccination, also need to be identified once scientific knowledge of the serotypes involved is established. HIV/AIDS research has not focused on treatment of this tumour.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Dr S Gichuhi was awarded a Reviews for Africa Programme Fellowship (www.mrc.ac.za/cochrane/rap.htm), funded from the Nuffield Commonwealth Programme, through The Nuffield Foundation. We would like to acknowledge the support provided by the staff at the South African Cochrane Centre and the Cochrane HIV/AIDS Review Group mentoring programme.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

This review has no analyses.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Appendix 1. PubMed search strategy and results

Title:               Interventions for squamous cell carcinoma of the conjunctiva in HIV-infected individuals

Database:     PubMed (2010 – 2012)

Date:              27 January 2012


SearchQueryItems found

#13Search #1 AND #2 AND #11 AND ("2010/10/01"[Date - Publication] : "2012/01/27"[Date - Publication])4

#12Search #1 AND #2 AND #1123

#11Search #9 OR #102290

#10Search conjunctival neoplasms[mh]1729

#9Search #5 AND #81099

#8Search #6 OR #7546016

#7Search carcinoma[tiab] OR carcinomas[tiab] OR neoplasia[tiab] OR neoplasm[tiab] OR neoplasms[tiab]514787

#6Search carcinoma, squamous cell[mh]92643

#5Search #3 OR #423573

#4Search conjunctiva[tiab] OR conjunctivas[tiab] OR conjunctival[tiab]18906

#3Search conjunctiva[MeSH Terms]11829

#2Search (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh])2499392

#1Search HIV Infections[MeSH] OR HIV[MeSH] OR hiv[tw] OR hiv-1*[tw] OR hiv-2*[tw] OR hiv1[tw] OR hiv2[tw] OR hiv infect*[tw] OR human immunodeficiency virus[tw] OR human immunedeficiency virus[tw] OR human immuno-deficiency virus[tw] OR human immune-deficiency virus[tw] OR ((human immun*) AND (deficiency virus[tw])) OR acquired immunodeficiency syndrome[tw] OR acquired immunedeficiency syndrome[tw] OR acquired immuno-deficiency syndrome[tw] OR acquired immune-deficiency syndrome[tw] OR ((acquired immun*) AND (deficiency syndrome[tw])) OR "sexually transmitted diseases, viral"[MH:noexp]282439



 

Appendix 2. EMBASE search strategy and results

Title:               Interventions for squamous cell carcinoma of the conjunctiva in HIV-infected individuals

Database:     PubMed (2010 – 2012)

Date:              10 February 2012


No.QueryResults

#13 #1 AND #2 AND #11 AND [humans]/lim AND [embase]/lim AND [1-2-2012]/sd NOT [10-2-2012]/sd0

#12 #1 AND #2 AND #114

#11 #9 OR #102964

#10 'conjunctiva tumor'/syn1802

#9 #5 AND #81796

#8 #6 OR #7646277

#7 carcinoma:ab,ti OR carcinomas:ab,ti OR neoplasia:ab,ti OR neoplasm:ab,ti OR neoplasms:ab,ti617186

#6 'carcinoma, squamous cell'/syn110025

#5 #3 OR #456567

#4 conjunctiva:ab,ti OR conjunctivas:ab,ti OR conjunctival:ab,ti22041

#3 'conjunctiva'/syn51682

#2 random*:ti OR random*:ab OR factorial*:ti OR factorial*:ab OR cross?over*:ti OR cross?over:ab OR crossover*:ti OR crossover*:ab OR placebo*:ti OR placebo*:ab OR (doubl*:ti AND blind*:ti) OR (doubl*:ab AND blind*:ab) OR (singl*:ti AND blind*:ti) OR (singl*:ab AND blind*:ab) OR assign*:ti OR assign*:ab OR volunteer*:ti OR volunteer*:ab OR 'crossover procedure'/de OR 'crossover procedure' OR 'double-blind procedure'/de OR 'double-blind procedure' OR 'single-blind procedure'/de OR 'single-blind procedure' OR 'randomized controlled trial'/de OR 'randomized controlled trial' OR allocat*:ti OR allocat*:ab1186635

#1 'human immunodeficiency virus infection'/exp OR 'human immunodeficiency virus infection' OR 'human immunodeficiency virus'/exp OR 'human immunodeficiency virus' OR hiv:ti OR hiv:ab OR 'hiv-1':ti OR 'hiv-1':ab OR 'hiv-2':ti OR 'hiv-2':ab OR 'human immunodeficiency virus':ti OR 'human immunodeficiency virus':ab OR 'human immunedeficiency virus':ti OR 'human immunedeficiency virus':ab OR 'human immune-deficiency virus':ti OR 'human immune-deficiency virus':ab OR 'human immuno-deficiency virus':ti OR 'human immuno-deficiency virus':ab OR 'acquired immunodeficiency syndrome':ti OR 'acquired immunodeficiency syndrome':ab OR 'acquired immuno-deficiency syndrome':ti OR 'acquired immuno-deficiency syndrome':ab OR 'acquired immune-deficiency syndrome':ti OR 'acquired immune-deficiency syndrome':ab OR 'acquired immunedeficiency syndrome':ti OR 'acquired immunedeficiency syndrome':ab371108



 

Appendix 3. The Cochrane Library search strategy and results

Title:               Interventions for squamous cell carcinoma of the conjunctiva in HIV-infected individuals

Database:     CLIB (2010 – 2012)

Date:              3 February 2012

 

Appendix 4. WHO International Clinical Trials Registry Platform (ICTRP) search terms and results

Title:               Interventions for squamous cell carcinoma of the conjunctiva in HIV-infected individuals

 Database:     WHO International Clinical Trials Registry Platform (ICTRP) 2010 - 2012

 Date:              10 February 2012

 No results were found for: hiv AND carcinoma AND conjunctiva

 

Appendix 5. National Institutes for Health (NIH) Clinical Trials registry search terms and results

Title:               Interventions for squamous cell carcinoma of the conjunctiva in HIV-infected individuals

Database:     Clinicaltrials.gov

Date:              10 February 2012

Found no studies with search of:   "squamous cell carcinoma" AND conjunctiva AND hiv

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Last assessed as up-to-date: 19 February 2007.


DateEventDescription

11 December 2012New citation required but conclusions have not changedNew comprehensive searches, review updated.

11 December 2012New search has been performedUpdated



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Protocol first published: Issue 1, 2006
Review first published: Issue 2, 2007


DateEventDescription

29 October 2008AmendedConverted to new review format.

19 February 2007New citation required and conclusions have changedSubstantive amendment



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

SG developed the review topic idea. JI looked through search outputs, provided input, guidance and mentoring.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms

Stephen Gichuhi has received funding to conduct a trial in this field (Gichuhi 2012).

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Index terms
 

Internal sources

  • University of Nairobi, Department of Ophthalmology, Kenya.

 

External sources

  • South African Cochrane Centre HIV/AIDS Mentoring Programme, South Africa.

References

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Characteristics of studies
  18. References to ongoing studies
  19. Additional references
Aoki 1998
  • Aoki S, Kubo E, Nakamura S, Tsuzuki A, Tsuzuki S, Takahashi Y, et al. Possible prognostic markers in conjunctival dysplasia and squamous cell carcinoma. Japanese Journal of Ophthalmology 1998;42(4):256-61.
Ateenyi-Agaba 1995
Ateenyi-Agaba 2004
  • Ateenyi-Agaba C, Dai M, Le Calvez F, Katongole-Mbidde E, Smet A, Tommasino M, et al. TP53 mutations in squamous cell carcinomas of the conjuntiva: evidence for UV-induced mutagenesis. Mutagenesis 2004;19(5):399-401.
Ateenyi-Agaba 2010
  • Ateenyi-Agaba C, Franceschi S, Wabwire-Mangen F, Arsian A, Othieno E, Binta-Kahwa J, van Doorn LJ, Kleter B, Weiderpass E. Human papillomavirus infection and squamous cell carcinoma of the conjunctiva. British Journal of Cancer 2010;102:262-7.
Atkins 2004
Barbazetto 2004
Basti 2003
Bonanno 2010
  • Bonanno A, Esmaeli B, Fingere MC, Nelson DV, Randal S, Weber RS. Social challenges of cancer patients with orbitofacial disfigurement. Ophthalmic  Plastic and  Reconstructive Surgery 2010;26:18-22.
Cartsburg 2001
  • Cartsburg O, Kallen C, Hillenkamp J, Sundmacher R, Pomjanski N, Bocking A. Topical mitomycin C and radiation induce conjunctival DNA-polyploidy. Analytical Cellular Pathology 2001;23(2):65-74.
Castano 2005
  • Castano AP, Demidova TN, Hamblin MR. Mechanisms in photodynamic therapy: Part three - photosensitizer pharmacokinetics, biodistribution, tumor localization and modes of tumor destruction. Photodiagnosis and Photodynamic Therapy 2005;2(2):91-106.
Cerezo 1990
  • Cerezo L, Otero J, Aragon G, Polo E, de la Torre A, Valcarcel F, et al. Conjunctival intraepithelial and invasive squamous cell carcinomas treated with strontium-90. Radiotherapy and oncology Journal of the European Society for Therapeutic Radiology and Oncology 1990;17(3):191-7.
Cervantes 2002
Chisi 2006
  • Chisi SK, Kollmann MKH, Karimurio J. Conjunctival squamous cell carcinoma in patients with Human Immunodeficiency Virus infection seen at two hospitals in Kenya. East African Medical Journal 2006;83(5):267-70.
Chu 2004
  • Chu T, Sartorelli AC. Cancer chemotherapy. In: Katzung BG editor(s). Basic and clinical pharmacology. 9th Edition. Boston: McGraw Hill, 2004:898-930.
Clifford 2005
  • Clifford GM, Gallus S, Herrero R, Munoz N, Snijders PJF, Vaccarella S, et al. Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis. Lancet 2005;366(9490):991-8.
Copeland 1990
  • Copeland RA. Limbal autograft for reconstruction after conjunctival squamous cell carcinoma. American Journal of Ophthalmology 1990;4(110):412-5.
de Koning 2008
  • de Koning MN, Waddell K, Magyezi J, Purdie K, Proby C, Harwood C, Lucas S, Downing R, Quint WG, Newton R. Genital and cutaneous human papillomavirus (HPV) types in relation to conjunctival squamous cell neoplasia: a case-control study in Uganda. Infectious agents and cancer 2008;3:12.
Espana 2002
  • Espana EM, Prabhasawat P, Grueterich M, Solomon A, Tseng SCG. Amniotic membrane transplantation for reconstruction after excision of large ocular surface neoplasias. British Journal of Ophthalmology 2002;86(6):640-5.
Frucht-Pery 1997
  • Frucht-Pery J, Sugar J, Baum J, Sutphin JE, Pe'er J, Savir H, et al. Mitomycin C treatment for conjunctival-corneal intraepithelial neoplasia: a multicenter experience. Ophthalmology 1997;104(12):2085-93.
Goldberg 1963
Gunduz 2005
  • Gunduz K, Ucakhan OO, Kanpolat A, Gunalp I. Non-preserved human amniotic membrane transplantation for conjunctival reconstruction after excision of extensive ocular surface neoplasia. Eye 2005;20(3):351-7.
Guthoff 2009
  • Guthoff R, Marx A, Stroebel P. No evidence for a pathogenic role of human papillomavirus infection in ocular surface squamous neoplasia in Germany. Current Eye Research 2009;34:666-71.
Hao 2000
Kaji 2006
Karp 2001
Lake 2004
  • Lake DF, Briggs AD, Akporiaye ET. Immunopharmacology. In: Katzung BG editor(s). Basic and clinical pharmacology. 9th Edition. Boston: McGraw Hill, 2004:931-57.
Lee 1997
Macarez 1999
Mahomed 2002
  • Mahomed A, Chetty R. Human immunodeficiency virus infection, Bcl-2, p53 protein, and Ki-67 analysis in ocular surface squamous neoplasia. Archives of Ophthalmology 2002;120(5):554-8.
Margo 2002
McKelvie 2001
McKelvie 2002
Midena 2000
Moubayed 2004
  • Moubayed P, Mwakyoma H, Schneider DT. High frequency of Human Papillomavirus 6/11, 16, and 18 infections in precancerous lesions and squamous cell carcinoma of the conjunctiva in subtropical Tanzania. American Journal of Clinical Pathology 2004;122:938-43.
Nadjari 1999
  • Nadjari B, Kersten A, Ross B, Motherby H, Krallmann R, Sundmacher R, et al. Cytologic and DNA cytometric diagnosis and therapy monitoring of squamous cell carcinoma in situ and malignant melanoma of the cornea and conjunctiva. Analytical and Quantitative Cytology and Histology 1999;21(5):387-96.
Nakamura 1997
  • Nakamura Y, Mashima Y, Kameyama K, Mukai M, Oguchi Y. Detection of human papillomavirus infection in squamous tumours of the conjunctiva and lacrimal sac by immunohistochemistry, in situ hybridisation and polymerase chain reaction. British Journal of Ophthalmology 1997;81(4):308-13.
Newton 2002
  • Newton R, Ziegler J, Ateenyi-Agaba C, Bousarghin L, Casabonne D, Beral V, et al. The epidemiology of conjunctival squamous cell carcinoma in Uganda. British Journal of Cancer 2002;87(3):301-8.
Ng 2008
  • Ng J, Coroneo MT, Wakefield D, Di Girolamo N. Ultraviolet radiation and the role of matrix metalloproteinases in the pathogenesis of ocular surface squamous neoplasia. Investigative Ophthalmology & Visual Science 2008;49:5295-5306.
NIH 2012
  • U.S. National Institutes of Health. Information on clinical trials and human research studies. www.clinicaltrials.gov (accessed 10 February 2012).
Osahon 2011
  • Osahon AI, Ukponmwan CU, Uhunmwangho OM. Prevalence of HIV seropositivity among patients with squamous cell carcinoma of the conjunctiva. Asian Pacific Journal of Tropical Biomedicine 2011;1(2):150-53.
Peksayar 1989
Phillips 2001
  • Phillips B, Ball C, Sackett D, Badenoch D, Straus S, Haynes B, et al. Levels of evidence and grades of recommendation. www.cebm.net/levels_of_evidence.asp (accessed 14 June 2006).
Pola 2003
  • Pola EC, Masanganise R, Rusakaniko S. The trend of ocular surface squamous neoplasia among ocular surface tumour biopsies submitted for histology from Sekuru Kaguvi Eye Unit, Harare between 1996 and 2000. Central African Journal of Medicine 2003;49:1-4.
Poole 1999
Porges 2003
Safrin 2004
  • Safrin S. Antiviral agents. In: Katzung BG editor(s). Basic and clinical pharmacology. 9th Edition. Boston: McGraw Hill, 2004:801-27.
Sen 2007
  • Sen S, Sharma A, Panda A. Immunohistochemical localization of human papilloma virus in conjunctival neoplasias: a retrospective study. Indian Journal of Ophthalmology 2007;55:361-3.
Sherman 2002
Shields 1991
  • Shields JA, Shields CL, Suvarnamani C, Tantisira M, Shah P. Orbital exenteration with eyelid sparing: indications, technique and results. Ophthalmic surgery 1991;22(5):292-7.
Shields 1997
Shields 2004
  • Shields JA, Shields CL. Tumors of the conjunctiva and cornea. In: McLeod SD editor In: Tasman W, Jaeger EA editor(s). Duane's clinical ophthalmology CD-ROM. Revised 2004. Vol. 4, Philadelphia: Lippincott William and Wilkins, 2004:Chapter 10.
Sudesh 2000
Tabin 1997
Tornesello 2006
  • Tornesello ML, Duraturo ML, Waddell KM, Biryahwaho B, Downing R, Balinandi S, et al. Evaluating the role of human papillomaviruses in conjunctival neoplasia. British Journal of Cancer 2006;94(3):446-9.
Tunc 1999
UNAIDS 2010
  • Joint United Nations Programme on HIV/AIDS (UNAIDS). Global report: UNAIDS report on the global AIDS epidemic 2010. http://www.unaids.org/globalreport/global_report.htm 2010.
Waddell 1996
  • Waddell KM, Lewallen S, Lucas SB, Atenyi-Agaba C, Herrington CS, Liomba G. Carcinoma of the conjunctiva and HIV infection in Uganda and Malawi. British Journal of Ophthalmology 1996;80(6):503-8.
WHO ICTRP 2012
  • WHO ICTRP. WHO International Clinical Trials Registry Platform. www.who.int/ictrp/ (accessed on 10 February 2012).
Yeatts 2000