European Annals of Otorhinolaryngology, Head and Neck diseases 131 (2014) 121–129

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SFORL guidelines

French ENT Society (SFORL) guidelines for the management of immunodeficient patients with head and neck cancer of cutaneous origin C. Bejara , N. Basset-Seguinb , F. Faurec , C. Fieschid , C. Francese , C. Guennef , C. Lebbeb , M.N. Peraldig , J. Rouxb , G. Lamash , E. Maubeca,∗ , SFORL workgroup a

Service de dermatologie, groupe hospitalier Bichat–Claude-Bernard, AP–HP, 46, rue Henri-Huchard, 75018 Paris, France Service de dermatologie, hôpital Saint-Louis, AP–HP, 1, avenue Claude-Vellefaux, 75010 Paris, France c Service d’ORL, clinique Protestante, 1, chemin Penthod, 69300 Caluire et Cuire, France d Service d’immunologie, hôpital Saint-Louis, AP–HP, 1, avenue Claude-Vellefaux, 75010 Paris, France e Service de dermatologie, hôpital Tenon, AP–HP, 4, rue de la Chine, 75020 Paris, France f Service d’ORL, hôpital Édouard-Herriot, 5, place d’Arsonval, 69437 Lyon cedex 03, France g Service de néphrologie, hôpital Saint-Louis, AP–HP, 1, avenue Claude-Vellefaux, 75010 Paris, France h Service d’ORL, hôpital Pitié-Salpêtrière, AP–HP, 47-83, boulevard de l’Hôpital, 75013 Paris, France b

a r t i c l e

i n f o

Keywords: Squamous cell carcinoma Basal cell carcinoma Melanoma Merkel-cell carcinoma Kaposi’s sarcoma Lymphoma Immunodeficiency Transplant HIV infection

a b s t r a c t Objectives: The French ENT Society (SFORL) created a workgroup to draw up guidelines for the management of immunodeficient patients with head and neck cancer of cutaneous origin. The present guidelines cover diagnostic and therapeutic management and prevention of head and neck cancer of cutaneous origin in immunodeficient patients, and in particular in transplant patients and those with HIV infection. Materials and methods: The present guidelines were based on a critical multidisciplinary reading of the literature. Immunosuppression and its varieties are defined. The usual risk factors for skin cancer and those specific to immunodeficiency are presented. The prevention, assessment and management of cutaneous carcinoma, melanoma, Kaposi’s sarcoma and lymphoma are dealt with. The level of evidence of the source studies was assessed so as to grade the various guidelines. When need be, expert opinions are put forward. Results: Immunodeficient patients are at higher risk of head and neck skin tumors. The level of risk depends on the type of deficiency; there is an especially high risk of squamous cell carcinoma in transplant patients and of Kaposi’s sarcoma in HIV-positive subjects. Various viruses are associated with skin cancers. Skin tumors are often evolutive in case of immunodeficiency, requiring rapid treatment. Management is generally the same as in immunocompetent subjects and should be discussed in a multidisciplinary team meeting. Immunosuppression may need to be modulated. In organ transplant patients, the only class of immunosuppressants with proven antitumoral efficacy are mTOR inhibitors, particularly in cutaneous squamous cell carcinoma. The rhythm of clinical surveillance should be adapted according to the risk of recurrence. Preventive measures should be undertaken. Conclusion: Skin cancers in immunodeficiency are highly evolutive, requiring the earliest possible treatment. Immunosuppression may need modulating. As the risk of recurrence may be elevated, careful surveillance should be implemented. Preventive measures should also be undertaken. © 2014 Elsevier Masson SAS. All rights reserved.

1. Introduction The elevated risk of certain forms of cancer in case of immunodeficiency illustrates the importance of the immune system in controlling their development [1,2] (level of evidence 2). Various

∗ Corresponding author. E-mail address: [email protected] (E. Maubec). 1879-7296/$ – see front matter © 2014 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.anorl.2014.02.002

viruses, particularly HPV, HHV-8, EBV and polyomaviruses, are implicated in skin cancer in immunodeficient subjects. The increasing life expectancy of immunodeficient subjects and the increasing frequency of transplantation entail an increasing incidence of cancer. The present guidelines concern the management of head and neck tumor of cutaneous origin in transplant and HIV-infected patients. The levels of evidence and grades employed are those defined by the French HAS health authority. The guidelines are

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based on a detailed review of the literature by experts from various fields: ENT, nephrology, immunology and dermatology. They have been checked by several ENT and dermatology specialists. 1.1. Transplant patients Transplant patients mainly show T- and associated B-cell immunodeficiency. Anti-calcineurin inhibitors, which form a major component of maintenance immunosuppression, are implicated in the onset and dissemination of tumors [3] (level of evidence 1). The increasing lifespan of grafts and age of patients account for the increased incidence of cancer following transplantation. Within some 15 years, cancer can be expected to be the main cause of death following kidney transplantation. The most frequent form of tumor following transplantation is skin cancer, 95% of which is represented by squamous cell carcinoma. Risk of squamous cell carcinoma is elevated 100-fold and risk of basal cell carcinoma and of Kaposi sarcoma about 10-fold; Merkel-cell carcinoma, cutaneous lymphoma and melanoma, are likewise more frequent following transplantation. 1.2. HIV-positive subjects HIV-positive subjects show a 3.5-fold higher relative risk of cancer than the general population [4] (level of evidence 2). The most frequent cancers are those classifying HIV infection as AIDS (39%), although frequency has diminished with the advent of powerful antiretroviral therapies (ART). Elevated viral load is a risk factor. Risk of skin cancer as a whole is elevated. There is a high risk of Kaposi sarcoma, Merkel-cell carcinoma and sebaceous carcinoma. There is also an increased risk of skin carcinoma, melanoma and cutaneous lymphoma. Unlike in transplant patients, basal cell carcinoma is more frequently implicated than cutaneous squamous cell carcinoma. Other factors than CD4 count and viral load seem to be implicated, and HIV-positive subjects should be kept under surveillance even at non-advanced stages. 1.3. Risk factors Virological risk factors include HPV (associated with squamous cell carcinoma), HHV-8 (associated with Kaposi sarcoma), EBV (associated with certain skin lymphomas) and polyomavirus (associated with Merkel-cell carcinoma). Sun exposure [5] (level of evidence 1) and clear phototype [5,6] (level of evidence 1–3) are major risk factors for skin carcinoma and melanoma. Seventy percent of transplant patients with history of skin cancer experience recurrence [6] (level of evidence 2). Factors specific to transplant patients include gender (male), age (advanced) and interval since transplantation [7] (level of evidence 2). Skin carcinoma is also associated with a count of > 50 actinic keratoses [5] (level of evidence 3). 2. Prevention 2.1. Primary prevention of skin tumors associated with sun exposure

2.2. Secondary prevention Secondary prevention consists in early screening of skin tumor, based on self-examination, dermatologic surveillance consultations, treatment of precancerous lesions and, in transplant patients with multiple tumor, reduced immunosuppression or introduction of retinoids. 3. Management of cutaneous squamous cell carcinoma (CSCC) precursors 3.1. Actinic keratosis In immunodeficient subjects, evolution of actinic keratosis is accelerated and more frequently toward squamous cell carcinoma [5] (level of evidence 3).

Guideline 2 In case of thick actinic keratosis liable to malignant transformation, surgical resection is recommended (Expert consensus). In case of non-infiltrated, single or sparse actinic keratosis, cryotherapy is generally recommended. In case of multiple keratoses, local 5-fluoro-uracile (Grade B), diclofenac (Grade A) or photodynamic therapy (PDT) may be considered (Grade B).

3.2. In situ cutaneous squamous cell carcinoma (Bowen’s disease) The clinical aspect comprises a sharply defined erythematous scaly plaque. Histology shows that about one-third of cases of Bowen’s disease are focally invasive, especially in large carcinomas [8] (level of evidence 3).

Guideline 3 Treatment should not be delayed, due to risk of evolution toward an invasive tumor, and should be surgical (Grade B). Topical 5-FU (once daily for 4 weeks) is the only second-line treatment authorized in immunodeficient patients in France. Post-treatment clinical control is mandatory (Grade C).

4. Invasive CSCC 4.1. Indications for biopsy

Guideline 4 Any suspect squamous cell carcinoma should be biopsied if clinical diagnosis is uncertain or non-surgical treatment is planned, or to confirm diagnosis ahead of complex surgery (Expert consensus).

4.2. Histology Guideline 1 Patients should be informed of the increased risk of skin cancer. Primary prevention consists in avoiding sunlight at high-risk times of day, wearing protective clothing and using sunscreen (Grade A).

4.3. Prognostic classification of infiltrating CSCC Tumors being more aggressive in case of immunodeficiency, CSCC is classified in group 2 according to the INCa–HAS 2009 guidelines [9] (Expert consensus) (Table 1). Other negative clinical or

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Guideline 5 The pathology report should include: location, diameter of tumor and of specimen, Clark level, tumor thickness (Breslow index), perineural invasion, vascular and lymphatic emboli, differentiation, histologic type, and resection margins laterally and in depth (Expert consensus).

Table 1 Clinical prognostic classification of cutaneous squamous cell carcinoma according to French INCa–HAS 2009 guidelines [9].

Table 3 AJCC 2010 classification of cutaneous squamous cell carcinoma and risk factors (AJCC Cancer Staging Manual, 2010). TX T0 Tis T1 T2 T3 T4

Clinical criteria

Group 1: Low risk

Group 2: Significant risk

Nx N0 N1

Primary vs. Recurrence Degree of clinical infiltration Neurologic symptoms of invasion Immune status Diameter (according to location)

Primary Absence

Recurrence Adherent to deep plane

N2

No

Yes

Immunocompetent < 10 mm in region R+ < 20 mm in region R−

Immunodeficient ≥ 10 mm in region R+ ≥ 20 mm in region R−

Note: R+ regions comprise:

• peri-orifice regions and scalp; • regions not exposed to sunlight; • chronic dermatoses: radiation burn, burn scars, chronic inflammation or ulcers.

Table 2 Pathologic prognostic criteria for cutaneous squamous cell carcinoma according to INCa–HAS 2009 guidelines [9] (Expert consensus). Pathologic criteria

Group 1: Low risk

Group 2: Significant risk

Perineural invasion Degree of differentiation

No Good

Histologic form

Common, verrucous, spindle-shaped (outside irradiated region), mixed or metatypic CSCC Level ≤ III Thickness ≤ 3 mm

Yes Moderate to undifferentiated Desmoplastic > mucoepidermoid > acantholytic CSCC

Depth (Clark’s level) and thickness

Level ≥ IV Thickness > 3 mm

histological signs are to be taken into account (Expert consensus) (Table 2). The prognostic value of the American Joint Committee on Cancer staging system (AJCC 2010) was confirmed in immunodeficient patients [10] (level of evidence 4). The most important prognostic factor in the AJCC classification is tumor thickness [9,11] (level of evidence 4). The AJCC classification does not take direct account of immunodeficiency (Tables 3 and 4). The lymph node region most frequently involved is the parotid, constituting an independent risk factor not taken account of by the AJCC classification [12] (level of evidence 2). Parotid involvement is classified as: P0, no parotid (only cervical) invasion; P1, ≤ 3 cm metastasis; P2, metastasis > 3 cm and ≤ 6 cm; P3, metastasis > 6 cm or invasion of the base of the skull or facial nerve. 4.4. Clinical and paraclinical assessment 4.5. Sentinel node biopsy 4.6. CSCC without palpable lymph-node involvement The resection margin should be wide (≥ 6 mm, or even ≥ 10 mm), including the peritumoral erythema, with a deep margin into the subcutaneous fat, while sparing adjacent structures

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N2a N2b N2c N3 Mx M0 M1

Non-assessable primary Absence of primary In situ carcinoma Tumor ≤ 2 cm and < 2 high risk factors Tumor > 2 cm or tumor of any size with ≥ 2 high risk factors Tumor with invasion of maxillary, mandible, temporal bone or orbit Tumor with bone invasion (axial or limbs) or perineural invasion of skull base Non-assessable lymph nodes No regional lymph-node metastasis Lymph-node metastasis only in ipsilateral lymph-node area, diameter ≤ 3 cm Lymph-node metastasis only in ipsilateral lymph-node area, diameter > 3 cm but ≤ 6 cm; or multiple ipsilateral lymph-node metastases ≤ 6 cm long axis; or multiple bilateral lymph-node metastases ≤ 6 cm long axis Lymph-node metastasis only in ipsilateral lymph-node area, diameter > 3 cm or ≤ 6 cm long axis Multiple ipsilateral lymph-node metastases ≤ 6 cm diameter Bilateral or contralateral lymph-node metastases ≤ 6 cm diameter Lymph-node metastasis > 6 cm diameter Non-assessable distant metastasis No distant metastasis Distant metastasis/es

Table 4 Risk factors for primary tumor (AJCC 2010 classification). Breslow depth Clark’s level Location Differentiation Perineural invasion

> 2 mm ≥ IV Ear Poorly differentiated or undifferentiated Yes

Guideline 6 Cutaneous squamous cell carcinoma being more aggressive in immunodeficiency (INCa–HAS 2009 group 2: at significant risk of local recurrence and/or metastasis), any CSCC in an immunodeficient subject is to be discussed in a multidisciplinary team meeting (MTM). Management as discussed in MTM should take account of the patient’s other clinical or histological risk factors (Expert consensus).

Guideline 7 Clinical examination should comprise complete cutaneous inspection (to screen for a second skin cancer), regional lymphnode area palpation and comorbidity assessment. Standard imaging (chest X-ray and liver ultrasound, or CT, MRI or PET-CT) adapted to initial AJCC stage, tumor location and general health and comorbidity status is recommended in case of locally advanced tumor or other risk factors (Expert consensus).

(aponeurosis, periosteum, perichondrium) when they are neither in contact nor invaded [9] (Expert consensus). In case of microscopic lymph-node involvement, adjuvant radiation therapy should be discussed, although its contribution in limited microscopic involvement is unproven [9] (level of evidence 4). In transplant patients, reduced immunodepression and conversion to mTOR inhibitors is to be discussed as of CSCC onset [13] (level of evidence 1).

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Guideline 8 The contribution of sentinel node biopsy has not been validated. It may be implemented under certain protocols (Expert consensus).

Guideline 9 There is a severe evolutive risk of CSCC in immunodeficiency. Regardless of location, surgical resection with ≥ 6 mm margins is recommended (Grade B). Margins should be extended to 10 mm in case of supplementary clinical or histological risk factors (Grade B). Single-step resection and closure is preferable when technically feasible (Expert consensus). Two-step resection is recommended if complex graft or flap reconstruction is planned (Expert consensus). If histology finds incomplete resection, surgical re-excision is to be preferred (Expert consensus). As palpebral surgery is difficult in 2 steps, extemporaneous examination is required (Grade C). Mohs surgery has not been proved to be more effective than classical techniques. It is essentially an option for tumors of the eyelid and peri-oral region (Expert consensus). Adjuvant radiation therapy in the resection bed is to be discussed in case of incomplete resection without possibility of re-excision, or in case of histological features of poor prognosis (signs of perineural invasion, involvement of bone and/or adjacent deep structures) (Expert consensus). In transplant patients, reduced immunodepression and conversion to mTOR inhibitors is to be discussed as of first onset of CSCC (Grade B). Topical treatment of the “cancerization field” with 5-fluorouracile or PDT is recommended in case of peritumoral actinic keratosis (cancerization field treatment) (Expert consensus). If surgical resection is not feasible, radiation therapy (external or brachytherapy, depending on location) is an alternative. The tumor should be analyzed on histology (Expert consensus). In non-resectable locally advanced tumor, alternatives comprise: neoadjuvant chemotherapy, basically using cisplatin or taxanes, EGFR inhibitors, immunotherapy (interferon + retinoids), radiation therapy, and modulation of immunosuppression (Grade C).

4.7. Squamous cell carcinoma with regional lymph-node involvement Lymph-node involvement is a negative factor for survival [14,15] (level of evidence 2–4). Extracapsular lymph-node spread is a significant risk factor for recurrence [16] (level of evidence 4). The lymph-node area most frequently involved in head and neck CSCC is the parotid. 4.7.1. Assessment In case of palpable regional lymph-node involvement, cervicofacial CT or MRI assessment and CT or PET-CT remote extension assessment should be undertaken (Expert consensus). 4.7.2. Postoperative adjuvant radiation therapy Adjuvant radiation therapy enhances locoregional control and survival, including in parotid involvement [14,17] (level of evidence 3–4). The usual recommended dose is around 50 Gy in 2.5–3 Gy fractions. Regional lymph-node area radiation therapy is recommended: 1. after cervical lymph-node dissection for palpable lymph-node involvement [17] (level of evidence 2); 2. after positive parotidectomy for a palpable parotid mass [14,18] (level of evidence 2). The contribution of radiation therapy in limited microscopic lymph-node involvement (1 node, without capsule rupture) detected on sentinel lymph-node biopsy is unproven (Expert consensus).

Guideline 12 In palpable cervical or parotid lymph-node involvement, cervicofacial CT or MRI should be performed, with distant extension assessment by CT or PET-CT (Expert consensus). In palpable cervical lymph-node involvement, complete functional, or otherwise radical, cervical lymph-node dissection should be performed (Expert consensus). Any suspect parotid lymphadenopathies require parotidectomy + ipsilateral cervical lymph-node dissection (Grade B). Any proven lymph-node invasion requires postoperative adjuvant radiation therapy of the lymph-node area (Grade B).

4.8. Squamous cell carcinoma with distant metastasis Guideline 10 Keratoacanthoma is difficult to differentiate from squamous cell carcinoma on histology, and should be treated surgically (Expert consensus).

Adjuvant radiation therapy in the lymphatic drainage areas is not recommended in CSCC without lymph node involvement (Expert consensus).

Guideline 11 Given the higher risk of recurrence during the first 2 years, clinical quaterly dermatological surveillance is recommended during this period. Careful subsequent dermatological surveillance is also recommended (Expert consensus).

Guideline 13 In immunodepressed patients with distant metastatic CSCC, surgery is to be considered in case of a single metastasis. The decision should be made only after CT or PET-CT extension assessment (Expert consensus). Medical management is to be considered in inoperable patients if performance status and comorbidity permit. Medical treatment is the same as in immunocompetent subjects: chemotherapy (essentially based on cisplatin/carboplatin), associated interferon and retinoids, or EGFR inhibitors, alone or in association (Grade C). In inoperable patients, palliative radiation therapy may be considered (Expert consensus). In case of regional or distant metastasis, reducing immunosuppression should be considered, and regular follow-up, at least every 3 months, should be implemented (Expert consensus).

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5. Basal cell carcinoma Basal cell carcinoma is the most frequent form of cancer in adults [19,20] (level of evidence 2). Risk is increased 10-fold in transplant patients and 2-fold in HIV-positive subjects. Sun exposure and clear phototype are also major risk factors. In transplant patients, incidence is increased in extracephalic sites [21] (level of evidence 2). The French prognosis classification takes account of size, histologic type, location and primary or recurrent status. Prognosis is similar to that in immunocompetent subjects [22] (level of evidence 1). Management: Management is similar to that for immunocompetent subjects; treatment is surgical. In superficial forms, imiquimod [23] (level of evidence 1) or PDT provide alternatives [24] (level of evidence 2). New skin carcinoma of the same type develops in 50% of cases [25] (level of evidence 2). Education, sun exposure prevention and regular follow-up are key factors in management.

Guideline 14 As in immunocompetent subjects, basal cell carcinoma is classified, according to the guidelines (Grade A) and to size, histologic type, location and primary or recurrent status, as being of good, poor or intermediate prognosis; this determines treatment. Treatment is generally surgical; in superficial forms, however, there are possible alternatives, without risk to the graft: imiquimod (level of evidence 1) or PDT (Grade B).

Guideline 16 Clinical examination should assess lesion diameter and check the absence of transit lesions and regional lymph-node involvement. Diagnosis should be confirmed on histology and immunohistochemistry with analysis of expression of CK20 as marker (Expert consensus).

Adjuvant radiation therapy provides better locoregional control than surgery alone [31,32] (level of evidence 1).

Guideline 17 Surgery: in the absence of any palpable lymph-node, wide resection with 2–3 cm margins should be associated to sentinel node biopsy (Grade C). Positive sentinel node biopsy is an indication for complementary lymph-node dissection, and positive intraparotid sentinel node biopsy for parotidectomy. 50 Gy adjuvant radiation therapy should be applied to the tumor bed. Complementary regional radiation therapy should also be performed in case of lymph-node involvement (Grade A). When extensive resection is not feasible, isolated radiation therapy is an alternative (Grade C). Two years’ 3-monthly surveillance is recommended, due to the elevated risk of relapse during this period. Subsequent dermatological follow-up should be at least annual (Expert consensus). There is no consensus on paraclinical surveillance. Sixmonthly imaging and serum NSE assay may be considered (Expert consensus).

6. Merkel-cell carcinoma Merkel-cell carcinoma is a rare neuroendocrine tumor. Risk is elevated 5-fold in transplant patients and 11-fold in HIV-positive patients [26] (level of evidence 2). Polyomavirus has been demonstrated to be implicated [27] (level of evidence 1–3). Merkel-cell carcinoma is aggressive, and immunodepression is a negative factor for survival. Location is usually in regions exposed to sunlight, including the face and neck (44%). Presentation is typically a single evolutive erythematous or purple nodule, but may also be subcutaneous.

Guideline 15 Initial imaging should be adapted to tumor stage and comorbidities. PET-CT is sensitive in detecting lymph-node locations and distant metastases (Grade C). Pre-operative neuron-specific enolase (NSE) serum assay may be considered (Expert consensus).

The present classification is that of the AJCC 2010: stage I,  2 cm; stage II, > 2 cm; stage III, lymph-node involvement; stage IV, remote metastasis. Survival is 50% in stage III and 9 months in stage IV [28] (level of evidence 2). Polyomavirus seems to be associated with better prognosis [29] (level of evidence 2).

6.2. Merkel-cell carcinoma with regional lymph-node involvement (stage III)

Guideline 18 Adenectomy should be followed by lymph-node dissection if lymph-node involvement is confirmed. Local plus regional adjuvant radiation therapy is recommended (Expert consensus).

6.3. Merkel-cell carcinoma with remote locations (stage IV) In remote metastasis, chemotherapy may be undertaken as in immunocompetent subjects [33] (Expert consensus).

The two usual protocols associate either carboplatinetoposide or cyclophosphamide-doxorubicin-vincristine (Expert consensus).

6.1. Treatment of primary tumor without palpable lymph-node 7. Kaposi sarcoma In all stages, extensive resection of the primary should be performed whenever possible. In all cases without clinical lymphadenopathy, it is important to resect the sentinel node to detect infraclinical lymph-node metastasis [30] (level of evidence 3).

Kaposi sarcoma (KS) is an opportunistic tumoral proliferation of cells derived from the lymphatic endothelium. HHV-8 infection and immunodepression are necessary preconditions for KS.

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7.1. Post-graft KS KS is much more frequently secondary to reactivation of pregraft HHV-8 infection than to primary HHV-8 infection transmitted from the donor [34] (level of evidence 2). Male subjects are more often affected (2:40). Black skin and age at transplantation seem to be associated to post-graft KS [34] (level of evidence 2). Risk is highest in the 2 years following graft [35] (level of evidence 2). KS has been reported in most immunosuppression regimens. Antilymphocyte serum is a risk factor. mTOR inhibitors probably exert a preventive effect [34,36] (level of evidence 2–4).

Table 5 The TIS classification of the AIDS Clinical Trial Group (ACTG) of the National Institute of Health. TIS classification

Good risk 0

Poor risk 1

T: Tumor

Limited to Skin and/or

Associated with Edema and/or skin ulcer Non-flat mouth lesions Other visceral locations

Lymph nodes and/or Flat palate lesion I: Immune system

CD4 > 200/mm3

CD4 < 200/mm3

S: Systemic symptoms

No history of opportunistic infection No history of oropharyngeal candidosis No fever or weight-loss Karnovsky index > 70%

History of opportunistic infection Fever or weight-loss

7.2. Epidemic KS Epidemic KS more frequently affects homosexual or bisexual males. The main risk factor is CD4 level. 7.3. Clinical characteristics There is cutaneo-mucosal involvement in more than 80% of cases, with maculae forming progressively infiltrating erythematous and purple plaques that do not disappear under vitropressure and tend to show an ecchymotic, hemorrhagic or pigmented aspect. Mucosal, digestive, lymph-node and pulmonary involvement is frequent in immunodeficient subjects [37] (level of evidence 4), but the frequency of digestive and pulmonary involvement has fallen by 50–30% since the introduction of ARTs [38,39], (level of evidence 2).

Karnovsky index < 70% Neurologic involvement, lymphoma, etc.

7.6. Classifications 7.6.1. Post-graft KS The Khader classification is of limited interest, as prognosis in post-graft KS is independent of the extent of skin involvement. 7.6.2. Epidemic KS The TIS classification of the AIDS Clinical Trial Group (ACTG) of the National Institute of Health (Table 5) is of real prognostic value (level of evidence 2). 7.7. Interest of virological examination

7.4. Diagnosis Diagnosis should always be confirmed on histology. Endothelial cell markers such as CD31 and CD34 and the HHV-8 latencyassociated nuclear antigen (LANA) are positive. 7.5. Initial assessment/prognostic classifications Initial clinical assessment should include examination of the whole cutaneo-mucosal cover and ENT and conjunctive tissue examination.

Guideline 19 In transplant patients, extension assessment comprises thoraco-abdominopelvic CT and upper digestive tract endoscopy. Bronchoscopy and lavage are recommended in case of thoracic CT abnormalities. Colonoscopy may be performed, depending on the presenting symptomatology (Expert consensus). In epidemic KS, visceral involvement is explored by interview and clinical examination as well as biological analysis (anemia, blood in stool). Lung X-ray is systematic, without first-line thoraco-abdominopelvic CT (Expert consensus).

Guideline 20 Opportunistic infection liable to aggravate immunodeficiency should be systematically screened for, as KS may resolve when this is treated (Expert consensus).

Serum HHV-8 assay is usually positive during KS. Elevated viremia is significantly associated with evolutive KS, but the prognostic value of HHV-8 viral load on PCR remains to be established. 7.8. Treatment of Kaposi sarcoma Simply attenuating immunosuppression may stabilize or cure KS, and is the first-line attitude. 7.8.1. Post-graft KS The objective is not full remission but control and conserving graft function (Expert consensus). Specific complementary treatment is justified only in case of esthetic or functional concerns or life-threatening risk. Local treatment (cryotherapy, radiation therapy) does not affect evolutivity but may be useful for limited lesions. Without awaiting stabilization or regression of KS, after simple reduction of immunosuppression, calcineurin inhibitors are often replaced by mTOR inhibitors. In severe forms, liposomal anthracyclines (doxorubicin or daunorubicin) may be used in first-line chemotherapy. In case of failure, paclitaxel or docetaxel may be used. Antiherpes agents have proved disappointing [34] (level of evidence 2). Hopes have been raised by the advent of targeted therapies: antiangiogenics, NF␬B pathway inhibitors, anti-IL6, anti-STAT3. 7.8.2. Epidemic Kaposi sarcoma ART should be initiated, and may prove sufficient, although in some 7% of patients KS remains active despite ART and good immunovirological control [40] (level of evidence 2). Specific treatment may be required, given the 3–6-month interval to ART efficacy or to prevent or manage an immune restoration syndrome [41,42] (level of evidence 2).

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Guideline 21 The keystone in the management of KS after organ transplantation is to minimize immunosuppression so as to control proliferation and conserve graft function (Expert consensus). Any concomitant opportunistic infection liable to increase immunodeficiency should be systematically treated. In severe forms, liposomal anthracyclines or taxanes may be considered (Expert consensus).

Guideline 22 Initiation of ART is recommended when epidemic KS is diagnosed (Grade C). After multidisciplinary team meeting, systemic chemotherapy (liposomal anthracycline or taxane) should be initiated in parallel to ART in evolved KS in patients resistant to antiretrovirals, especially in case of visceral (notably, pulmonary) lesions or severe exacerbation accompanying immune restoration (Grade B).

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Guideline 23 Sentinel node biopsy is, like in immunocompetent subjects, an option in transplant patients with melanoma (Expert consensus).

8.3. Treatment

Guideline 24 The treatment of melanoma in an immunodeficient patient is to be discussed in a multidisciplinary team meeting comprising at least a dermatologist, a surgeon specializing in oncology and, if necessary, an infectologist or transplantation team physician (Expert consensus). The recommended resection margins are the same as in immunocompetent subjects (Expert consensus). Although the current attitude favors reducing immunosuppression in organ transplant patients, especially for stage ≥ II melanoma, the interest remains to be established by prospective studies (Expert consensus).

8. Melanoma Melanoma is more frequent in immunodeficient subjects, including organ transplant, HIV-positive and lymphoma patients. Relative risk compared to the general population was significantly higher in transplant patients (RR = 2.34; 95% CI, 1.98–2.77) than HIV-positive patients (RR = 1.24; 95% CI, 1.04–1.48) in a metaanalysis [43] (level of evidence 1). Prognosis is poorer than in immunocompetent subjects. 8.1. Melanoma in transplant patients 8.1.1. Melanoma transmitted by donor Melanoma is the tumor most frequently acquired in transplantation. Surgical treatment consists in removing the affected transplanted organ and resecting all secondary locations accessible to surgery. Cessation or reduction of immunodepression is recommended. Specific treatment of melanoma will be discussed. In case of remission, clinical and imaging surveillance should be implemented. 8.1.2. Melanoma with pre-transplantation onset In situ melanoma is not a contraindication to transplantation. In stage I melanoma (Breslow’s depth < 1 mm, non-ulcerated), transplantation is generally allowed after 2 years’ surveillance; in stage II, it is allowed 5 years after diagnosis, but is not recommended in case of lymph-node or distant metastasis [44] (Expert consensus). Sentinel node biopsy can be performed as in immunocompetent subjects (Expert consensus).

8.4. Surveillance The surveillance rhythm for organ transplant patients depends on prognosis in terms of AJCC stage.

Guideline 25 The rhythm of clinical surveillance of transplant patients with stage I melanoma is at least the same as for immunocompetent subjects: 6-monthly for 5 years, then annually. Transplant patients with stage II melanoma should have 3monthly dermatologic surveillance for 5 years, then at least annually (Expert consensus).

8.5. Melanoma in HIV-positive patients Time to relapse and overall survival are poorer in HIV-positive patients than in immunocompetent subjects [45] (level of evidence 3), suggesting that those with history of melanoma should have careful surveillance with preventive measures for those with risk factors for skin melanoma. In advanced unresectable melanoma requiring medical treatment, antiretrovirals should be continued. 9. Lymphoma

8.1.3. Melanoma with post-transplantation onset This is the more frequent situation. Prognosis in stage T1 or T2 melanoma is similar in transplant patients and the general population, but is less good in transplant patients with T3 or T4 melanoma or Breslow depth > 1.5 mm or Clark’s level III, IV or V (level of evidence 2). 8.2. Interest of sentinel node biopsy Sentinel node biopsy is basically of prognostic value. It may select patients for reduction of immunosuppression or possible adjuvant treatment within protocols. Some authors recommend extending indications to transplant patients in stage T1b melanoma [44] (level of evidence 4).

In immunodeficient subjects, lymphoma is basically type B, often associated with EBV, and less often type T. Skin lymphoma accounts for only 5% of lymphomas in transplant patients [46] (level of evidence 2). They are mainly aggressive typeB lymphomas [47,48] (level of evidence 4) and are associated with a risk of extra-lymph-node involvement and involvement of the transplanted organ [49] (level of evidence 2). Data are scarce for skin lymphoma in HIV-positive patients. The French Cutaneous Lymphoma Study Group (Groupe Franc¸ais d’Étude des Lymphomes Cutanés) conducted a retrospective study of 21 cases of skin lymphoma in HIV-positive patients (representing 2.6% of all registered cases in the GFELC data-base). Mycosis fungoides, the most frequent skin lymphoma in immunocompetent

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subjects, was rare (3 cases). There was a high rate of type-B skin lymphoma (10/21) and type T CD30+ and ALK1− (8/21) lymphoma [50] (level of evidence 4). To improve management, it seems important to enter lymphomas occurring in immunodeficient patients in registries such as that of the Groupe Franc¸ais d’Étude des Lymphomes Cutanés.

Guideline 26 Initial assessment of skin lymphoma in an immunodeficient patient should rule out secondary cutaneous location of systemic lymphoma, requiring hematologic management (Expert consensus).

Guideline 27 Reduced immunodepression in transplant patients or change in antiretroviral treatment should be discussed in HIVpositive patients. Hematologic tolerance for chemotherapy requires particular surveillance in these patients. Chemotherapy regimens are the same as for immunocompetent subjects (Expert consensus).

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