CANCER DE FARINGE CNNC

 

Cancer of the Oropharynx

The oropharynx includes the base of the tongue, tonsils, soft palate, and

posterior pharyngeal wall. The oropharynx is extremely rich in lymphatics.

Depending on the subsite involved, 15% to 75% of patients present with

lymph node involvement. Oropharyngeal cancer that is p16-positive (ie,

HPV-mediated) is a different disease than p16-negative cancer. For

example, patients with HPV-associated H&N cancer tend to be

younger13,16 and have an improved response to treatment when compared

with patients with HPV-negative tumors.29-33,341 To take into account these

differences, separate staging criteria were published for p16-negative and

p16-positive oropharyngeal cancer in the 8th edition of the AJCC Cancer

Staging Manual.318 In 2018, the panel created separate algorithms for p16-

positive (HPV-mediated) oropharyngeal cancer. See the section below on

Staging.

 

Workup and Staging

A multidisciplinary consultation is encouraged including a registered

dietitian and a speech-language/swallowing therapist as clinically indicated

(see Principles of Nutrition in this Discussion and in the NCCN Guidelines

for Head and Neck Cancers). Accurate staging (see Table 3 for p16-

negative oropharyngeal cancer and Table 4 for p16-positive

oropharyngeal cancer) depends on a complete H&N examination and

appropriate imaging studies (see Workup in NCCN Guidelines for Cancer

of the Oropharynx).318,342

Skipping examination under anesthesia (EUA) with confirmation biopsy for

oropharyngeal cancer that presents as a metastatic lymph node may introduce error based on lack of rigor and precision. There may be

situations in which the EUA is undesirable or could be bypassed. These

include patients at high risk for general anesthesia and those who undergo

a thorough examination including tongue base palpation. Those who

require systemic therapy/RT will not have their treatment plan affected,

regardless of surgical evaluation. These situations remain the minority of

cases. Therefore, the panel recommends EUA with biopsy confirmation for

patients presenting with a p16-positive cervical lymph node prior to

treatment decision-making.

Tumor HPV testing through p16 immunohistochemistry (IHC) is required

for cancers of the oropharynx, because prior HPV infection is related to

the development of a significant proportion of oropharyngeal cancers (see

the following section on HPV Testing).

 

HPV Testing

The attributable fraction for HPV in newly diagnosed oropharyngeal cancer

is estimated at 60% to 70% in the United States and parts of the European

Union.15,343-346 There are currently no diagnostic tests with regulatory

approval. A few HPV testing options are available for use in the clinical

setting. Expression of p16 as detected by IHC is a widely available

surrogate biomarker that has very good agreement with HPV status as

determined by HPV E6/E7 mRNA expression.347-350 Other tests include

HPV detection by polymerase chain reaction (PCR) and in situ

hybridization (ISH).347,349 Sensitivity of IHC staining for p16 and PCRbased

assay is high, though specificity is highest for ISH.349 Analyses of

HPV testing methods have shown that sensitivity and specificity of p16

IHC range from 94% to 97% and 83% to 84%, respectively, with sensitivity

and specificity of HPV16 ISH ranging from 85% to 88% and 88% to

95%.347,350 The reduced specificity for p16 IHC may be due to the

presence of p16-positive tumors that do not have evidence of HPV DNA,

while the reduced sensitivity for HPV16 ISH may be due to the presence  of other high-risk HPV types in the tumor. Due to variations in sensitivity

and specificity values of testing options, multiple methods may be used in

combination for HPV detection.13,349-352 Sufficient pathologic material for

HPV testing can be obtained by fine-needle aspiration (FNA).13,353

Guidelines for HPV testing have also been published by the College of

American Pathologists.354 HPV testing may prompt questions about

prognosis (ie, a favorable or a less favorable forecast) and sexual history

that the clinician should be prepared to address.

 

Staging

The algorithms in the NCCN Guidelines for Oropharyngeal Cancer reflect

the new staging criteria published in the 8th edition of the AJCC Cancer

Staging Manual for p16-negative oropharyngeal cancer and p16-positive

oropharyngeal cancer.318 In the updated staging criteria for p16-negative

oropharyngeal cancer, separate pathologic criteria are now presented for

involvement of regional lymph nodes, since extranodal extension is difficult

to accurately capture through the imaging workup that is routinely done for

clinical staging.355 The treatment algorithm for p16-negative disease is

divided into three staging categories: 1) T1–2, N0–1; 2) T3–4a, N0–1; and

3) any T, N2–3. Of note, the following categories are treated as advanced

cancer: T4b, any N; unresectable nodal disease; unfit for surgery; or M1

disease at initial presentation (see the NCCN Guidelines for Very

Advanced Head and Neck Cancers).

A clinical staging system for p16-positive oropharyngeal cancer was

developed using data from 1907 patients with non-metastatic HPV-positive

oropharyngeal cancer from seven cancer centers in Europe and the

United States.356 OS did not significantly differ between T4a and T4b

disease (P = .41). Five-year OS rates did not significantly differ in patients

with N1, N2a, or N2b disease, based on the AJCC 7th edition N

classification,357 so the study investigators reasoned that these patients could be grouped into one category (ie, at least one ipsilateral metastatic

node ≤6 cm).

An analysis of 704 patients with resected p16-positive oropharyngeal

squamous cell carcinoma from five cancer centers showed that the Nclassification

system for oropharyngeal cancer that was described in the

7th edition of the AJCC Cancer Staging Manual357 was not significantly

associated with OS.358 However, patients with 4 or fewer pathologically

confirmed metastatic nodes had a higher 5-year OS rate, compared to

patients with five or more pathologically confirmed metastatic nodes (89%

vs. 71%, respectively). The results from this analysis were used to

construct a pathologic staging system for patients with p16-positive

disease: 1) pT1–T2 and fewer than five metastatic nodes; 2) pT1–T2 and

more than four metastatic nodes, or pT3–T4 and fewer than five

metastatic nodes; and 3) pT3–T4 and more than four metastatic nodes.

The 5-year OS rates for these staging groups were 90% (95% CI, 87%–

93%), 84% (95% CI, 77%–90%), and 48% (95% CI, 30%–66%),

respectively. Five-year DFS rates for the three staging groups were 86%

(95% CI, 82%–90%), 72% (95% CI, 64%–79%), and 40% (95% CI, 24%–

56%), respectively. The results from this analysis are consistent with an

earlier study that showed that the presence of five or more metastatic

nodes, but not N-classification, was associated with disease recurrence

and survival in 220 patients with surgically resected p16-positive

oropharyngeal cancer.359

The modifications to the NCCN Guidelines for p16 (HPV)-positive

oropharyngeal cancer accommodate the new staging system for p16-

positive oropharyngeal cancer. However, the changes are relatively

modest, since the staging system changes are based on prognostic

models and are not based on prospective data from clinical trials that

guide clinical decision-making. Based on differences in features

associated with prognosis,356,358 the staging criteria for p16-positive oropharyngeal cancer differs from staging for p16-negative oropharyngeal

cancer in the following ways:318

• T4b disease has been removed from the staging criteria for

defining the primary tumor.

• Criteria for defining nodal involvement (both clinical and pathologic)

have been simplified for p16-positive disease. Clinical N staging for

p16-positive oropharyngeal cancer is based on lymph node size

and laterality, while pathologic N staging is based on number of

lymph nodes. Further, pN3 disease has been removed for

pathologic N.

The treatment algorithms for p16-positive disease have been divided by

the panel into four staging categories:

1) cT1–2, cN0

2) cT1–2, cN1 (single node ≤3 cm)

3) cT1–2, cN1 (single node >3 cm, or 2 or more ipsilateral nodes

≤6 cm); or cT1–2, cN2; or cT3, cN0–2

4) cT4 or cN3

The algorithms in the NCCN Guidelines for p16 (HPV)-positive

oropharyngeal cancer incorporate the staging criteria presented in the

revised 8th Edition of the AJCC Cancer Staging Manual318 based on

clinical staging criteria. This is to acknowledge that decision-making is

currently frequently based on data from trials that included oropharyngeal

as well as other anatomic sites that were staged utilizing AJCC 7th edition

nodal staging criteria.357

 

Treatment

Consensus is increasing that HPV status should be used as a stratification

factor or should be addressed in separate trials (HPV-related vs. unrelated

disease) for which patients with oropharyngeal cancer are eligible.360-362 Some clinicians have suggested that less-intense treatment may be

adequate for HPV-positive oropharyngeal cancers (ie, deintensification).48

However, the available data supporting this assertion are limited by

retrospective analyses, single-institution phase 3 trials, variability in HPV

testing method used, and short follow-up periods.48,363-365 Deintensification

treatment protocols for HPV-associated locally advanced oropharyngeal

cancer are being investigated in ongoing clinical trials (eg, NCT01154920,

NCT01706939, NCT01855451, NCT01687413, NCT01898494,

NCT02215265). Strategies under active investigation include reducing or

using response-stratified RT dose, using RT alone versus chemoradiation,

using less invasive surgical procedures such as transoral robotic surgery

(TORS), using sequential systemic therapy/RT, and using immunotherapy

and targeted therapy agents such as cetuximab.365-367

Results from multiple phase II trials show that RT deintensification is

associated with promising PFS rates in patients with p16-positive

oropharyngeal cancer.368-372 Analyses of quality-of-life outcomes from one

of these trials showed that RT deintensification was associated with a

quicker and more robust return to baseline-level functioning.373 In a subset

analysis from the EORTC 24971 study,374 p16 status was not significantly

associated with survival outcomes in this analysis, but the investigators

pointed out that the planned analysis was powered to detect a large

treatment by marker interaction.375

With some exceptions, which are noted in this section below, the

treatment algorithms for p16-negative and p16-positive oropharyngeal

cancer are identical. There is currently no evidence that the new staging

criteria published in the 8th edition of the AJCC Cancer Staging Manual318

should drive clinical decision-making. The difference between p16-positive

and p16-negative oropharyngeal cancer is mainly prognostic. Panel

members urge that patients with HPV-related cancers be enrolled in

clinical trials evaluating biological and treatment-related questions.365,367,376Early-stage (T1–2, N–1 for p16-negative disease; T1–2, N0 or single node

≤3 cm for p16-positive disease) oropharyngeal cancers may be treated

with: 1) resection of the primary with neck dissection; or 2) definitive

RT.87,90,377,378 Results from the randomized phase II ORATOR trial, which

included 68 patients with early-stage oropharyngeal cancer, showed that

quality-of-life outcomes were generally better for patients treated with RT,

compared to patients who received TORS with neck dissection.379 Tumors

at or approaching the midline (ie, tumors in the base of the tongue,

posterior pharyngeal wall, soft palate, and tonsil invading the tongue base)

are at risk of contralateral metastasis and warrant bilateral treatment.

Based on results from the phase III randomized GORTEC trial155 and

retrospective analyses from the National Cancer Database (NCDB),380,381

systemic therapy/RT is a treatment option for patients with p16-negative

N1 disease. However, this is a category 2B option, since the number of

patients with T1–T2, N1 disease enrolled in the GORTEC trial is small,

and more data from prospective trials are needed. For patients with p16-

positive disease, systemic therapy/RT is also a category 2B option for T1–

T2 disease and the involvement of a single node ≤3 cm.

Research on the impact of adverse features such as extranodal extension

and number of involved nodes on outcomes in patients with p16-positive

disease who have undergone resection is rapidly evolving. Currently, data

from only retrospective trials are available,45,359,360,382-385 and clinical trials

are being conducted to validate the revised AJCC staging318 for clinical

decision-making. Analyses from the RTOG 9501105 and EORTC 22931

trials104 showed that extranodal extension is associated with poor

prognosis in patients with locally advanced H&N cancer who have

undergone surgical resection.106 However, in a review of published data

from these RCTs, it was noted that these studies did not investigate the

impact of HPV or p16 status.386 In response to this review, the

investigators from RTOG 9501 and EORTC 22931 pointed out that the prevalence of HPV-positive/p16-positive tumors was likely to be low in

these trials.387 Other limitations noted in this review included unplanned

subgroup analyses, the grouping of multiple H&N subsites, inconsistent

quantitative reporting and lack of reporting on tumor and lymph node

classification, treatment effect sizes, multivariable analyses, and quality-oflife

outcomes. Therefore, the investigators who carried out this review

argued that these trials lack the generalizability necessary to rationalize

the use of adjuvant systemic therapy/RT in patients with p16-positive

disease. Based on this controversy and a lack of high-quality, prospective

clinical evidence, this recommendation is a category 2A option for both

patients with p16-positive disease and p16-negative disease. Adjuvant

systemic therapy/RT remains a category 1 recommendation for patients

with other types of H&N cancer who have extranodal extension. Since

patients with p16-positive oropharyngeal cancer have a generally

favorable prognosis and may live longer, toxicity and quality of life are

concerns for these patients.365,367 On the other hand, recent retrospective

analyses including 4,443 patients with HPV-positive oropharyngeal cancer

from the NCDB showed that deintensification by using a single primary

treatment modality such as definitive RT may be associated with worse

treatment outcomes in the long-term.388 Omitting systemic therapy and

administering radiotherapy alone is a category 2B option for patients with

p16-positive cT1–2, cN0–1 disease (single node ≤3 cm) who have

extranodal extension following surgery.

For patients with positive or close margins, re-resection (if feasible), RT,

and systemic therapy/RT are treatment options.127 For patients with other

risk features, options include RT or systemic therapy/RT. For patients with

p16-positive disease and other risk features such as pT3 or pT4 primary,

one positive node >3 cm or multiple positive nodes, nodal disease in

levels IV or V, perineural invasion, vascular invasion, or lymphatic

invasion, systemic therapy/RT is a category 2B option For locally advanced resectable disease (T3–4a, N0–1, or N2–3 for p16-

negative disease; T1–2, cN1 [single node >3 cm, or 2 or more ipsilateral

nodes ≤6 cm] or N2, or T3, N0–3, or T4 for p16-positive disease), three

treatment options are recommended (see the NCCN Guidelines for

Cancer of the Oropharynx), in addition to enrollment in clinical trials. The

three options are: 1) concurrent systemic therapy/RT;127,155 2) resection of

the primary and neck dissection (with appropriate adjuvant therapy

[systemic therapy/RT or RT]); or 3) induction chemotherapy (category 3)

(followed by RT or systemic therapy/RT).87,90,389 As with early-stage

disease, tumors at or approaching the midline should be strongly

considered for bilateral treatment of the neck. An NCDB analysis including

3,063 patients with cT1, N2 or cT2, N1–2 HPV-positive oropharyngeal

cancer showed no statistically significant difference in 3-year OS between

patients who received upfront surgery and patients who received definitive

systemic therapy/RT.390 However, concurrent systemic therapy/RT is

preferred in patients with locoregionally advanced HPV-positive disease

who have clinical evidence of fixed or matted nodes or obvious extranodal

extension in patients, as surgery is not recommended for these patients.

Panel recommendations regarding adjuvant therapy for locally advanced

disease do not differ between p16-positive and p16-negative

oropharyngeal cancer.

Concurrent systemic therapy/RT—with high-dose cisplatin as the preferred

systemic agent—is recommended for treatment of locoregionally

advanced p16-positive and p16-negative cancer of the oropharynx (see

Principles of Systemic Therapy in the NCCN Guidelines for Head and

Neck Cancers). Patients with cN2–3 disease have a higher likelihood of

needing triple-modality therapy because of poor-risk factors present

pathologically after resection, which can be associated with increased

toxicity. Beginning treatment with concurrent systemic therapy/RT may

help decrease the need for triple modality therapy and additional

treatment-induced morbidity. Therefore, definitive concurrent systemic therapy/RT is preferred over upfront surgery for p16-positive T4 or N3

oropharyngeal cancer.

Many panel members did not agree that induction chemotherapy should

be recommended for locally or regionally advanced cancer of the

oropharynx. This disagreement is reflected by the category 3

recommendations for oropharyngeal cancer (see The Induction

Chemotherapy Controversy in this Discussion and the NCCN Guidelines

for Cancer of the Oropharynx).155,374,391-398

The Induction Chemotherapy Controversy

Defining the role of induction chemotherapy in the management of locally

or regionally advanced H&N cancers has generated considerable

discussion within the NCCN Panel. The algorithm for the management of

advanced p16-positive and p16-negative oropharyngeal cancer (see the

NCCN Guidelines for Cancer of the Oropharynx) illustrates the lack of

consensus among NCCN Member Institutions despite the extensive

discussion. Thus, induction chemotherapy has a category 3

recommendation (ie, major disagreement) for the management of

locoregionally advanced p16-negative and p16-positive oropharyngeal

cancer. However in other sites, category 2A and 2B recommendations for

induction chemotherapy are common based on the update from RTOG 91-

11 (see Cancer of the Glottic Larynx, Cancer of the Supraglottic Larynx,

and Cancer of the Hypopharynx in the NCCN Guidelines for Head and

Neck Cancers).399 For selected patients with hypopharyngeal and

laryngeal cancers less than T4a in extent (for which total laryngectomy is

indicated, if managed surgically), induction chemotherapy—used as part

of a larynx preservation strategy—is listed as a category 2A designation.

Panel members feel that induction chemotherapy should only be done in

centers with expertise in these regimens because of challenges

associated with appropriate patient selection and management of

treatment-related toxicities.391 Residual toxicity from induction chemotherapy may also complicate the subsequent delivery of definitive

RT or systemic therapy/RT.

A summary of the data helps provide some perspective on the NCCN

Panel’s recommendations. Most randomized trials of induction

chemotherapy followed by RT and/or surgery compared to locoregional

treatment alone, which were published in the 1980s and 1990s, did not

show an improvement in OS with the incorporation of chemotherapy.396

However, a change in the pattern of failure with less distant metastases

was noted in some studies.400 Also, a correlation was noted between

response to induction chemotherapy and subsequent durable response to

radiation.400,401 Thus, the concept developed that, in selected patients,

induction chemotherapy could facilitate organ preservation, avoid morbid

surgery, and improve overall quality of life of the patient even though OS

was not improved. Because total laryngectomy is among the procedures

most feared by patients,402 larynx preservation was the focus of initial

studies.

Two randomized studies—the Veterans Affairs (VA) Laryngeal Cancer

Study Group trial in advanced laryngeal cancer and the EORTC trial

predominantly in advanced hypopharynx cancer—established the role of

induction cisplatin/5-FU chemotherapy followed by definitive RT in

responding patients as an alternative treatment to primary total

laryngectomy and postoperative radiation, offering potential larynx

preservation without compromise in survival (see Cancer of the Larynx

and Cancer of the Hypopharynx in this Discussion).400,401 Yet even in this

setting, the role of induction chemotherapy decreased with time.

Randomized trials and related meta-analyses indicated that concurrent

systemic therapy/RT (with cisplatin being the best-studied agent) offered

superior locoregional tumor control and survival compared to radiation

alone,403-411 and shorter duration of therapy compared to induction therapy

followed by radiation. Meta-analyses reported that concurrent systemic therapy/RT was more efficacious than an induction chemotherapy

strategy.396,398 In the larynx preservation setting, Intergroup 91-11

compared radiation alone, concurrent cisplatin/radiation, and induction

cisplatin/5-FU followed by radiation; all arms had surgery for

relapsed/refractory disease. The concurrent cisplatin/radiation arm had the

highest larynx preservation rate (see Cancer of the Larynx in this

Discussion).412 A long-term follow-up of 91-11 confirmed that concomitant

systemic therapy/RT improved the larynx preservation rate and that

induction chemotherapy was not superior to RT alone.399 However, OS did

not differ among the treatment arms.

Nonetheless, interest in the role of induction chemotherapy endures for a

few reasons. Advances in surgery, RT, and concurrent systemic

therapy/RT have yielded improvements in locoregional control; thus, the

role of distant metastases as a source of treatment failure has increased

and induction chemotherapy allows greater drug delivery for this

purpose.413,414 Clinicians have increasing concern regarding the long-term

morbidity of concurrent systemic therapy/RT, and thus have increasing

interest in exploring alternative approaches that might have a more

favorable side effect profile.415 Finally, a more effective triplet

chemotherapy regimen has been identified for induction chemotherapy

compared to the standard cisplatin/5-FU used in induction trials of the

1980s and 1990s, and in the related meta-analyses. Three phase III trials

compared induction cisplatin plus infusional 5-FU with (or without) the

addition of a taxane (docetaxel or paclitaxel) followed by the same

locoregional treatment. Results showed significantly improved outcomes

(response rates, DFS, or OS, depending on the trial) for patients in the

three-drug induction group compared to those receiving two drugs

(cisplatin plus 5-FU).374,394,395,397 A randomized phase III trial in the larynx

preservation setting similarly showed superior larynx preservation

outcome when induction docetaxel/cisplatin/5-FU (TPF) and cisplatin/5-FU

were compared.416,417 A meta-analysis including five RCTs (N = 1772) showed that the TPF induction chemotherapy regimen was associated

with reduced risk of death (HR, 0.72; 95% CI, 0.63–0.83; P < .001) and

greater reductions in progression (HR, 0.78; 95% CI, 0.69–0.87; P < .001),

locoregional failure (HR, 0.79; 95% CI, 0.66–0.94; P = .007), and distant

failure (HR, 0.63; 95% CI, 0.45–0.89; P = .009) compared with cisplatin

plus 5-FU.418

Whether adding induction chemotherapy to concurrent chemoradiation

results in a clear advantage in OS continues to be unclear.393,419,420 Both

the DeCIDE and the PARADIGM trials did not convincingly show a

survival advantage with the incorporation of induction chemotherapy.419,420

In patients with stage III or IV squamous cell H&N cancers, a randomized

phase II study compared induction TPF followed by concurrent

cisplatin/5-FU with RT versus concurrent cisplatin/5-FU with RT alone. A

higher radiologic complete response rate was reported with the

incorporation of induction chemotherapy.421 Results from a larger follow-up

study suggest a survival advantage.422

Other induction chemotherapy regimens have been evaluated in phase II

trials. The ECOG-ACRIN trial (E2303) showed promising results in terms

of primary site response and survival for cetuximab, paclitaxel, and

carboplatin as induction chemotherapy, followed by systemic therapy/RT

with the same drug regimen in patients with stage III or IV squamous cell

H&N cancers (N = 74),423 but the incremental benefit of induction

chemotherapy requires further validation using randomized design. Two

phase II studies have evaluated the feasibility of TPF with cetuximab

followed by systemic therapy/RT or RT alone.424,425 The DeLOS-II trial

showed that TPF followed by RT, with cetuximab administered throughout,

was feasible but not superior to TPF and subsequent RT without

cetuximab.424 An EORTC trial evaluating this induction regimen followed

by systemic therapy/RT was stopped prematurely due to numerous

serious adverse events.425 There is currently a lack of consensus regarding the most appropriate

regimen to be administered following induction chemotherapy.426 Of note,

investigators in the DeCIDE trial used the combination of

docetaxel/hydroxyurea/5-FU with RT after induction chemotherapy in this

setting.420 Panel members agree that weekly cetuximab or carboplatin are

reasonable agents to use with concurrent radiation.419,427-429 Results of the

phase III GORTEC 2007-02 trial, in which 370 patients with bulky nodal

disease (N2b, N2c, or N3) were randomized to receive carboplatin/5-FU

with concurrent RT or TPF followed by cetuximab/RT, showed no

significant differences between the study arms for survival outcomes and

local control.430 There was a trend towards a lower rate of distant

metastases in the TPF arm (HR, 0.54; 95% CI, 0.30–0.99; P = .05).

Weekly cisplatin with RT following induction chemotherapy is a category

2B option, based on extrapolation.419,428,429 However, because of toxicity

concerns, high-dose cisplatin (100 mg/m2 every 21 days × 3) is not

recommended after induction cisplatin-based chemotherapy.393,428 Thus,

this highlights concerns that any efficacy gains of induction may be offset

by the use of better-tolerated—but potentially less effective—concurrent

regimens or poorer patient compliance with the radiation-based part of

treatment. Because of these uncertainties, enrollment of patients in

appropriate clinical trials is particularly encouraged. Outside of a clinical

trial, proceeding directly to concurrent systemic therapy/RT—high-dose

cisplatin preferred—is considered the gold standard by many NCCN Panel

Members in several settings (see Principles of Systemic Therapy in the

NCCN Guidelines for Head and Neck Cancers).104-107,403,431 When

induction chemotherapy is used, data show that the addition of a taxane to

cisplatin/5-FU, of which TPF is the most extensively studied, is more

efficacious than cisplatin/5-FU.418,426 Therefore, when used as induction

chemotherapy for squamous cell H&N cancer, this regimen is a category 1

preferred recommendation. Paclitaxel, cisplatin, and 5-FU is also an option

for induction chemotherapy.394 Radiation Therapy Fractionation

The recommended schedules are shown in the algorithm (see Principles

of Radiation Therapy in the NCCN Guidelines for Cancer of the

Oropharynx). IMRT is preferred, as it may be useful for decreasing

toxicity.432,433 A fractionation schedule of 69.96 Gy at 2.12 Gy/fraction daily

(Monday–Friday) for 6 to 7 weeks is recommended for patients with highrisk

subclinical disease, consistent with the fractionation schedule used for

these patients in RTOG 0615.120 Moderate acceleration of treatment is

acceptable in patients with early-stage oropharyngeal cancer.127,434

Despite the evidence that RT dose deintensification may improve longterm

function while preserving PFS in patients with p16-positive

disease,368-370,373 more studies are needed in this area.

Follow-up/Surveillance

Recommendations for surveillance are provided in the algorithm (see

Follow-up Recommendations in the NCCN Guidelines for Head and Neck

Cancers).

 

 

Cancer of the Hypopharynx

The hypopharynx extends from the superior border of the hyoid bone to

the lower border of the cricoid cartilage and is essentially a muscular, lined

tube extending from the oropharynx to the cervical esophagus. For staging

purposes, the hypopharynx is divided into three areas: 1) the pyriform

sinus (the most common site of cancer in the hypopharynx); 2) the

posterior pharyngeal walls; and 3) the postcricoid area.

Workup and Staging

A multidisciplinary consultation is encouraged. Accurate staging (see

Table 3) depends on a complete H&N examination coupled with

appropriate studies (see Workup in the NCCN Guidelines for Cancer of

the Hypopharynx).318 For patients with cancer of the hypopharynx, the prognosis can be quite poor despite aggressive combined modality

treatment.

Treatment

Patients with resectable disease are divided into two groups based on the

indicated surgical options: 1) those with early-stage cancer who are

amenable to larynx-preserving (conservation) surgery (most T1, N0;

selected T2, N0); and 2) those with advanced resectable cancer who

require pharyngectomy with total or partial laryngectomy (T1–4a, any N).

The surgery and RT options for the former group (see the NCCN

Guidelines for Cancer of the Hypopharynx) represent a consensus among

the panel members.

Patients with T1–3, any N disease, for whom the indicated surgical option

is partial or total laryngopharyngectomy, may be managed with three

approaches (see the NCCN Guidelines for Cancer of the Hypopharynx) in

addition to enrollment in clinical trials: 1) induction chemotherapy followed

by additional treatment, depending on the response; 2) surgery with neck

dissection, lymph node dissection, and postoperative radiation or

chemoradiation as dictated by pathologic risk features; or 3) concurrent

systemic therapy/RT. When using concurrent systemic therapy/RT, the

preferred systemic agent is high-dose cisplatin (category 1) (see Principles

of Systemic Therapy in the NCCN Guidelines for Head and Neck

Cancers). Given the functional loss resulting from this surgery and the

overall poor prognosis, participation in clinical trials is encouraged.

The recommendation of the induction chemotherapy/definitive RT option is

based on an EORTC randomized trial.400 This trial enrolled 194 eligible

patients with stage II to IV resectable squamous cell carcinoma of the

pyriform sinus (152 patients) and aryepiglottic fold (42 patients), excluding

patients with T1 or N2c disease. Patients were randomly assigned either

to laryngopharyngectomy and postoperative RT, or to systemic therapy  with cisplatin and 5-FU for a maximum of 3 cycles, followed by definitive

RT. In contrast to a similar approach used for laryngeal cancer, a

complete response to induction chemotherapy was required before

proceeding with definitive RT. The published results showed equivalent

survival, with median survival duration and a 3-year survival rate of 25

months and 43% (95% CI, 27%–59%), respectively, for the surgery group

versus 44 months and 57% (95% CI, 42%–72%), respectively, for the

induction chemotherapy group.400 A functioning larynx was preserved in

42% of patients who did not undergo surgery. Local or regional failure

rates did not differ between the surgery-treated patients and

chemotherapy-treated patients, although the chemotherapy recipients did

show a significant reduction in distant metastases as a site of first failure

(P = .041).

For induction chemotherapy as part of a larynx preservation strategy,

inclusion of only patients with the specified TNM stages is recommended.

Success on larynx preservation with an induction chemotherapy strategy

is best established for patients who had a complete response to induction

therapy at the primary site and stable or improved disease in the neck. A

randomized trial showed that an alternating regimen of cisplatin/5-FU with

RT yielded larynx preservation, progression-free interval, and OS rates

equivalent to those obtained with induction platinum/5-FU followed by

RT.435,436 However, a long-term update from this trial showed that larynx

preservation rate was higher in patients who were randomized to receive

the alternating regimen (32%), compared to patients who received the

sequential regimen (25%).436 Given available randomized data

demonstrating the superiority of TPF compared with PF for induction

chemoradiation, the triplet is now recommended as induction for this

approach.416,417

As noted in the algorithm, surgery is recommended if a partial response or

less occurs after induction chemotherapy (see the NCCN Guidelines for

Cancer of the Hypopharynx). The nature of the operation will depend on

the stage and extent of the tumor. Partial laryngeal surgery may still be

considered, although most patients will require total laryngectomy, and at

least a partial pharyngectomy. In this situation, or when primary surgery is

the selected management path, postoperative systemic therapy/RT is

recommended (category 1) for the adverse pathologic features of

extranodal extension and/or positive or close mucosal margin. For other

risk features, clinical judgment should be used when deciding to use RT

alone or when considering adding systemic therapy to RT (see the NCCN

Guidelines for Cancer of the Hypopharynx). Severe late toxicity appears to

be associated with the amount of RT415 and treatment with radiosensitizing

systemic therapy.

Options for patients with T4a, any N disease include: 1) total

laryngopharyngectomy plus neck dissection(s) followed by adjuvant

systemic therapy/RT or RT; 2) enrollment in clinical trials; 3) induction

chemotherapy (category 3); or 4) systemic therapy/RT (category 3) (see

the NCCN Guidelines for Cancer of the Hypopharynx, and Newly

Diagnosed Locoregionally Advanced Disease under Very Advanced Head

and Neck Cancers in the Discussion, below).

Radiation Therapy Fractionation

Fractionation for RT is discussed in the algorithm (see Principles of

Radiation Therapy in the NCCN Guidelines for Cancer of the

Hypopharynx).

Follow-up/Surveillance

Recommendations for surveillance are provided in the algorithm (see

Follow-up Recommendations in the NCCN Guidelines for Head and Neck

Cancers). 

 

 

 

 

 

Cancer of the Nasopharynx

NPC is an uncommon cancer, accounting for 0.7% of all cancers

diagnosed worldwide in 2018.437 However, there are areas of the world

with endemic disease; global incidence rates are highest in Southeast

Asia (especially southern China), Micronesia/Polynesia, Eastern Asia, and

North Africa.438 Rates are two to three times higher in men than in

women.439 Among H&N cancers, NPC has one of the highest propensities

to metastasize to distant sites, affecting up to one-third of patients in the

highest-risk subgroups.440 On the other hand, with modern radiotherapy

techniques, locoregional recurrences are uncommon, occurring in fewer

than 10% among all but the most locally advanced patients.441The NCCN

Guidelines for the evaluation and management of NPC provide

recommendations aimed at addressing the risks for local, regional, and

distant disease.

Workup and Staging

The workup of nasopharyngeal cancer includes a complete H&N

examination and other studies (see the NCCN Guidelines for Cancer of

the Nasopharynx). These studies are important to determine the full extent

of tumor in order to assign stage appropriately and to design radiation

ports that will encompass all the disease with appropriate doses.

Multidisciplinary consultation is encouraged. The 2017 AJCC staging

classification (8th edition) is used as the basis for treatment

recommendations (see Table 2).318

Epstein-Barr virus (EBV) DNA testing may also be considered (see

Epstein-Barr Virus, below). HPV infection has been associated with World

Health Organization type I NPC in case reports and very small case

series, but the limited data regarding the impact on chemoradiation

outcomes are conflicting.442-444 Therefore, routine testing for HPV in NPC

is not recommended by the NCCN Panel Epstein-Barr Virus

Infection with EBV is an etiologic factor in the development of NPC.445,446

Workup for NPC may include EBV testing of both the tumor itself and the

blood, particularly in the presence of nonkeratinizing and undifferentiated

histology.447-449 Testing methods for detection of EBV in tumor include ISH

for EBV-encoded RNA (EBER)450 and IHC staining for LMP1.451 ISH for

EBER tends to be a more sensitive testing method for carcinomas, relative

to LMP1 IHC staining.452 Real-time PCR may be used to evaluate EBV

DNA load in serum or plasma. Sensitivity and specificity values range from

53% to 96%, and 88% to 100%, respectively.453 Testing for plasma EBV

DNA has been used in select centers as a means of residual disease

monitoring. It should be noted as an important caveat that no standardized

testing procedure has been established worldwide, and there is little

consensus on sample preparation or assay specifications.454 For patients

with locoregionally confined NPC, studies have shown that high initial

levels of plasma EBV DNA, or persistently elevated levels near or at the

end of RT, are associated with a significantly poorer outcome following RT

or chemoradiation.455-460 A meta-analysis including 13 studies showed that

plasma EBV DNA levels assessed pre-treatment were independent

prognostic factors for mortality (HR, 2.81; 95% CI, 2.44–3.24; P < .001)

and distant metastasis (HR, 3.89; 95% CI, 3.39–4.47; P < .001), though

these studies were significantly heterogeneous (P = .03).461 Plasma EBV

DNA has also been studied as an indicator of disease response to

chemotherapy or chemoradiation prior to additional treatment462,463 and in

the setting of distant metastases.464 Most of these studies have been

based on real-time PCR assays amplifying the BamHI-W fragment.

Treatment

Patients with T1, N0, M0 nasopharyngeal tumors should be treated with

definitive RT alone, including elective RT to the neck. Advanced radiation

techniques are needed for the appropriate treatment of NPC and to

minimize the long-term side effects that are common in survivors. IMRT is preferred due to its ability to encompass all areas of cancer spread, which

can be located in close proximity to the brainstem, cochleae, and optic

nerves; proton therapy is considered if the normal tissue constraints

cannot be met by IMRT. Population-based studies have indicated that

high-volume radiation centers have better outcomes when treating this

disease.465,466

Locoregionally Advanced Disease

The Intergroup trial 0099, which randomly assigned patients to EBRT with

concurrent cisplatin plus adjuvant chemotherapy with cisplatin and 5-

fluorouracil (PF) for three cycles versus EBRT alone, closed early when an

interim analysis disclosed a highly significant survival advantage favoring

the combined chemotherapy and radiation group.431 The addition of

chemotherapy also decreased local, regional, and distant recurrence

rates. Subsequent phase III randomized trials in Asia confirmed that

concurrent chemoradiation without adjuvant PF increased survival when

compared with RT alone.467-470 In one of these trials, 5-year OS was 70%

for the chemoradiation group versus 59% for the RT group.467 A

randomized study conducted in Singapore, which was modeled after the

Intergroup 0099 treatment regimen, confirmed the benefit of adding

concurrent platinum to RT with adjuvant PF, using a multiday infusion of

platinum instead of a single bolus high-dose approach.469 However, one of

the largest phase III randomized trials ever conducted in NPC comparing

concurrent cisplatin/RT with (or without) adjuvant PF showed that adjuvant

chemotherapy did not significantly improve survival following

chemoradiation (HR, 0.74; 95% CI, 0.49–1.10; P = .13).471

An individual patient data meta-analysis by Blanchard et al,472 which

included 19 trials and 4806 patients with non-metastatic NPC, showed that

both adjuvant chemotherapy following chemoradiation and chemoradiation

without adjuvant chemotherapy were associated with better OS (HR, 0.65;

95% CI, 0.56–0.76 and HR, 0.80; 95% CI, 0.70–0.93, respectively) and

PFS (HR, 0.62; 95% CI, 0.53–0.72 and HR, 0.81; 95% CI, 0.71–0.92,

respectively). However, differences between the included studies

assessing chemoradiation with and without adjuvant chemotherapy (eg,

different length of follow-up, fewer patients with stage II disease in trials

assessing adjuvant chemotherapy) limited the ability to make a firm

conclusion regarding the efficacy of one treatment modality over the other.

A network meta-analysis based on this individual patient data

meta-analysis472 (including 20 trials and 5,144 patients) showed that the

addition of adjuvant chemotherapy to chemoradiation was associated with

better PFS (HR, 0.81; 95% CI, 0.66–0.98), compared to chemoradiation

only.473 The authors argued that more chemotherapy, in addition to

concurrent chemoradiation, could reduce recurrence rates. The

NRG-HN001 trial (NCT02135042) is currently in progress to further

investigate the role of adjuvant chemotherapy following chemoradiation in

patients with locoregionally advanced NPC. This phase II/III study aims to

investigate whether delivery of adjuvant chemotherapy can be

individualized based on EBV DNA plasma levels after chemoradiation.

Results from three systematic reviews suggest that induction

chemotherapy prior to systemic therapy/RT in patients with locally

advanced NPC may potentially impact tumor control, compared to

systemic therapy/RT without additional chemotherapy.473-475 However,

these reviews had inconsistent results when evaluating the impact on

survival. Two reviews showed that induction chemotherapy prior to

systemic therapy/RT had superior OS and PFS rates, compared to

systemic therapy/RT alone,474,475 while another review showed that

induction chemotherapy prior to systemic therapy/RT did not have better

survival outcomes than systemic therapy/RT alone or systemic therapy/RT

followed by adjuvant chemotherapy.473 Expert groups (eg, ESMO, NCI)

differ in their clinical practice guidelines regarding use of induction

chemotherapy for these patients,476 and the NCCN expert panel could not

reach uniform consensus in this regard. Clinical trials are continuing to  investigate the role of induction chemotherapy prior to systemic

therapy/RT for patients with locoregionally advanced NPC, and two

recently published randomized phase III trials from China show a survival

benefit for induction chemotherapy followed by concurrent systemic

therapy/RT, compared to concurrent systemic therapy/RT alone.477,478

Currently available evidence shows trends favoring the addition of

chemotherapy to concurrent systemic therapy/RT in patients with

locoregionally advanced NPC;473-475 however, it remains unclear whether

to administer chemotherapy to these patients before or after systemic

therapy/RT.

For patients with locoregionally advanced NPC (T1, N1–3; T2–T4, any N),

enrollment in a clinical trial is preferred. The panel recommends

concurrent systemic therapy/RT (cisplatin) with either induction or adjuvant

chemotherapy for locoregionally advanced NPC. Concurrent systemic

therapy/RT (cisplatin) alone is a category 2B recommendation. Concurrent

cisplatin with radiation is recommended for all patients who do not have a

contraindication to the drug, because the vast majority of randomized trials

support the use of cisplatin in this setting.431,467 If using adjuvant

chemotherapy, the standard remains PF. The substitution of carboplatin

for cisplatin in induction, concurrent, and adjuvant regimens, while studied

to some extent, should be limited to cisplatin-ineligible patients.429,479,480

Induction chemotherapy (followed by systemic therapy/RT) is also a

recommended option for patients with NPC with either T1, N1–3 or T2–T4,

any N lesions. Gemcitabine/cisplatin is a category 1 preferred option,478

and modified TPF is also a category 1 option, but only for EBV-associated

disease, as panel members observed that the dosing schedule used in the

study by Sun et al481 (docetaxel 60 mg/m2 every 3 weeks, cisplatin 60

mg/m2 every 3 weeks, and 5-FU 600 mg/m2 as a continuous 120-hour

infusion on days 1–5, 22–26, and 43–47) may not be effective for non–

EBV-associated disease in patients in the United States. Besides TPF,

several other induction/sequential chemotherapy regimens are lower-level

recommendations included in the algorithm for NPC.395,429,467,477,482

Radiation Therapy Fractionation

Radiation dose-fractionation schedules may vary slightly depending on

institutional preference (see Principles of Radiation Therapy in the NCCN

Guidelines for Cancer of the Nasopharynx). Radiation doses of 66 to 70.2

Gy given in standard fractions of 1.8 to 2.0 Gy/fraction are recommended

for control of the gross primary tumor and involved lymph nodes; an

alternative schedule consists of 2.12 Gy/fraction daily (Monday–Friday) for

33 to 35 fractions to all areas of gross disease to a total dose of

approximately 70 Gy.120 Low- to intermediate-risk subclinical disease, such

as in the low neck, is often treated with 44 to 50 Gy at 2.0 Gy/fraction or

can be treated simultaneously with the main plan for the gross disease to

54 to 63 Gy at 1.6 to 1.8 Gy/fraction. For areas considered to be at

intermediate risk, slightly higher doses such as 59.4 to 63 Gy in 1.8 to 2.0

Gy/fraction can be given to different regions of the skull base and neck.

The total doses and fractionation should be prescribed in relationship to

each other and the overall schedule as part of an integrated plan to

address the varying areas at risk.

Follow-up/Surveillance

Recommendations for surveillance are provided in the algorithm (see

Follow-up Recommendations in the NCCN Guidelines for Head and Neck

Cancers). Since the deep areas of the skull base are inaccessible to

clinical examination, periodic cross-sectional imaging may be necessary.

The clinical benefit of blood EBV DNA monitoring is currently uncertain

(see Epstein-Barr Virus, above), but it may be considered in centers with

experience (category 2B). 

Asymptomatic Cholelithiasis: Is Cholecystectomy Really Needed? A Critical Reappraisal 15 Years After the Introduction of Laparoscopic Cholecystectomy

Asymptomatic Cholelithiasis: Is Cholecystectomy Really Needed?
A Critical Reappraisal 15 Years After the Introduction
of Laparoscopic Cholecystectomy
George H. Sakorafas · Dimitrios Milingos ·
George Peros
Received: 13 December 2005 / Accepted: 12 January 2006 / Published online: 28 March 2007
C
Springer Science+Business Media, Inc. 2007
Abstract Asymptomatic cholelithiasis is increasingly
diagnosed today, mainly as a result of the widespread use of
abdominal ultrasonography for the evaluation of patients for
unrelated or vague abdominal complaints. About 10–20%
of people in most western countries have gallstones, and
among them 50–70% are asymptomatic at the time of
diagnosis. Asymptomatic gallstone disease has a benign
natural course; the progression of asymptomatic to symptomatic
disease is relatively low, ranging from 10–25%.
The majority of patients rarely develop gallstone-related
complications without first having at least one episode of
biliary pain (“colic”). In the prelaparoscopy era, (open)
cholecystectomy was generally performed for symptomatic
disease. The minimally invasive laparoscopic cholecystectomy
refueled the discussion about the optimal management
of asymptomatic cholelithiasis. Despite some controversy,
most authors agree that the vast majority of subjects should
be managed by observation alone (expectant management).
Selective cholecystectomy is indicated in defined subgroups
of subjects, with an increased risk for the development of
gallstone-related symptoms and complications.Concomitant
cholecystectomy is a reasonable option for good-risk patients
with asymptomatic cholelithiasis undergoing abdominal
surgery for unrelated conditions. Routine cholecystectomy
for all subjects with silent gallstones is a too aggressive
management option, not indicated for most subjects with
asymptomatic cholelithiasis. An in-depth knowledge of the
natural history of gallstone disease is required to select the
optimal management option for the individual subject with
G. H. Sakorafas ( ) · D. Milingos · G. Peros
4th Department of Surgery, Athens University, Medical School,
“ATTIKON” University Hospital, Arkadias 19–21,
GR-115 26 Athens, Greece
e-mail: georgesakorafas@yahoo.com
silent gallstones.Management options should be extensively
discussed with the patient; he or she should be actively
involved in the process of therapeutic decision making.
Keywords Silent gallstones . Laparoscopic
cholecystectomy . Porcelain gallbladder . Incidental
cholecystectomy . Concomitant cholecystectomy .
Gallbladder carcinoma . Cancer
Introduction
Cholelithiasis constitutes one of the most common causes
of hospitalization due to gastrointestinal problems in
developed countries and accounts for an important part of
health care expenditure. It shows a worldwide distribution
and a high incidence. especially among particular nations
and geographic areas in the world. The definite treatment
of choice for gallstone disease is cholecystectomy. Until the
introduction of laparoscopy, surgery (open cholecystectomy)
was generally indicated only for patients with symptomatic
and complicated disease [1, 2]. However the establishment
of laparoscopic cholecystectomy as the gold standard for the
treatment of cholelithiasis has created new interest for the
management of patients with silent gallstones. As a minimally
invasive technique, with many well-known advantages
over open cholecystectomy, laparoscopic cholecystectomy
renewed the interest and fueled the discussion regarding the
optimal management of asymptomatic gallstone disease.
Today, asymptomatic cholelithiasis is a very common
clinical entity; the surgeon sees an increasing number of
such subjects, owing to the widespread availability and
use of abdominal ultrasonography for the investigation
of a variety of abdominal diseases or vague abdominal
complaints and in cases of routine checkup. Management of such incidentally discovered gallstones poses a real dilemma
for both the physician and the patient; conclusive evidence
of benefits of cholecystectomy is lacking [3].
The aim of the present study was to critically discuss and
summarize currently available data regarding optimal management
of asymptomatic patients, taking into account the
natural history of asymptomatic cholelithiasis, the potential
for the development of complicated gallstone disease, and
the potential morbidity and mortality of cholecystectomy.
Asymptomatic cholelithiasis: the extent
of the problem
When discussing asymptomatic cholelithiasis, the first priority
is to define this entity. Asymptomatic cholelithiasis exists
when gallstones are detected in the absence of gallstonerelated
symptoms, such as history of biliary pain (pain in the
epigastrium or right upper abdominal quadrant that may radiate
to the patient’s back or to the right scapula), or gallstonerelated
complications such as acute cholecystitis, cholangitis,
or pancreatitis (Rome Group for the Epidemiology and Prevention
of Cholelithiasis [GREPCO]) [4]. Other nonspecific
symptoms or vague dyspeptic problems, such as epigastric
discomfort, dyspepsia, flatulence, nausea, abdominal gurgling
noises, or pain outside the right hypochodrium, cannot
be considered as symptomatic cholelithiasis and could easily
be attributed to other gastrointestinal diseases (such as peptic
ulcer disease, irritable bowel syndrome) [5, 6]. Therefore,
and when discussing surgery under this situation, the patient
should understand that these symptoms may persist following
cholecystectomy. However, the fact that patientswith that
kind of nonspecific symptomatology may sometimes benefit
from cholecystectomy could indicate that cholelithiasis
contributes, at least to some extent, to that vague clinical
picture (see Selective Cholecystectomy—Vague Dyspeptic
Symptoms) [7].
In 1992, it was estimated that 10–15% of the adult population
in the USA had gallstones (which amounted to more
than 20 million people),withwomen suffering twice asmuch
as men [4, 5, 8–10]. About one million patients are newly diagnosed
annually (10) and among them 50–70% are asymptomatic
at diagnosis (6, 8). Approximately 600,000 patients
underwent cholecystectomy in 1991 in the USA [11] and
about 4–7% of those operated had asymptomatic cholelithiasis
[12]. The annual cost for the treatment of those patients
had been estimated to be around $5 billion (estimates from
1993) [10].
Similar results have been reported in Europe. The Rome
Group for the Epidemiology and Prevention of Cholelithiasis
found gallstones in 8% of Roman male civil servants
between the age of 20 and 69 years. Fewer than 8% had
a history of symptoms compatible with biliary colic [13,
14]. The same group found a prevalence of as high as 25%
in female civil servants in the 60- to 64-year age group
[13, 14]. One third reported at least one episode of biliary
pain over a period of 5 years [4]. In the Italian Multicenter
Italian Study on Cholelithiasis, 29,739 participants were
examined by ultrasound and questionnaire with respect to
the presence of gallstones and related symptoms [15]. The
prevalence of gallstones for women was 10.5% and for men
6.5%. This increased to 18.9% and 9.5%, respectively, when
subjects who had already undergone cholecystectomy were
added. A linear increase in prevalence was noted with age in
both genders. The vast majority of subjects with gallstones
were asymptomatic (84.9% of women and 87% of men).
Similar numbers were found in a Scandinavian study, where
the overall prevalence of gallstones was 15%, with women
having a higher prevalence both at 40 and at 60 years of age
as compared with men (11% and 25% versus 4% and 15%,
respectively) [16]. In the United Kingdom, around 5,500,000
people have gallstones and more than 50,000 cholecystectomies
are performed each year [17].
It therefore appears that the overall prevalence of gallstone
disease in industrialized countries is between 10% and 20%.
The prevalence rises with age in both genders (close to 10
per 1,000 subjects per year) [18]. At the age of 65, about
30% of women have gallstones, and by the age of 80, 60%
of both men and women have them [19]. These data confirm
the high prevalence of gallstone disease and also shows that
most patients are unaware of it.
Natural history of asymptomatic gallstones
There is no innocent gallstone
—William J. Mayo, MD, 1904
It is unfortunate that so few appreciate from what small
causes diseases come.
—Charles H. Mayo, MD, 1902
About 100 years after the above-noted Mayo dictum about
gallstones, there is now enough evidence that most incidentally
discovered, clinically silent gallstones rarely have
clinical significance [3, 20–24]. In most Western countries,
the majority of patients with asymptomatic cholelithiasis
remain asymptomatic throughout their life, and do not require
any treatment [25]; in fact, these subjects live and
die with their gallstones having never caused pain or other
medical problems. Autopsy studies showed that more than
90% of autopsied patients with gallstone disease died from
unrelated causes. Death as the ultimate complication from
asymptomatic gallstones is very rare (∼3–7% of deaths),
usually in the elderly as a consequence of biliary or postoperative
complications [26–28].

According to the 1992 NIH Consensus Conference report
[10], 10% of patients develop symptoms during the first 5
years after diagnosis and 20% by 20 years. Similar findings
were reported by Zubler et al. [29], who found that only 10-
18% of asymptomatic patients ever become symptomatic;
the annual risk for developing biliary pain (misnamed as
biliary colic) is 1–4% [17, 30] (Table 1). One could extrapolate
that after 20 years, approximately two thirds of patients
will remain symptom free [25]. These rates are in sharp
contrast with those in symptomatic cholelithiasis, where the
annual rates of developing complications and biliary pain
are 1.2% and 50%, respectively [17]. According to the Italian
GREPCO study, the annual complication rate of initially
asymptomatic patients is 0.3–1.2% [31]. In this study, 151
subjects identified to have gallstones during the GREPCO–
1984 study [4] were followed over a period of 10 years. At
the beginning of the study, 118 patients were asymptomatic.
The cumulative probability of developing complications after
10 years was 3% in the initially asymptomatic group and
7% in the symptomatic group.
In the significant study by Gracie and Ransohoff [32],
123 Michigan University faculty members (110 men and 13
women) found to have gallstones through routine screening
were followed for 15 years. At 5, 10, and 15 years of followup,
10%, 15%, and 18%, respectively, became symptomatic.
The approximate rate at which the subjects developed biliary
pain was 2% per year for the first 5 years without a
subsequent decrease over time. Three patients in this study
developed biliary complications, all of which were preceded
by biliary colic. Based on these results, the authors concluded
that prophylactic cholecystectomy for asymptomatic
cholelithiasis is not justified.
A longitudinal follow-up study of asymptomatic gallstones
showed that over a 20-year period only18%of patients
developed biliary pain and that the mean yearly probability
of the development of biliary pain is 2% during the first
5 years, 1% during the second 5 years, 0.5% during the third
5 years, and 0% during the fourth 5 years. None of these
individuals died because of gallstone disease [33].
According to Hermann [34], 40–60% of persons with
cholelithiasis remain asymptomatic, 60–70% present with
mild symptoms of chronic cholecystitis (among them, 20%
have manifestations that are difficult to interpret), 20% develop
acute cholecystitis, and 10% develop complicated
acute cholecystitis (i.e., cholecystitis accompanied by jaundice,
cholangitis, or pancreatitis). Hermann concluded that
the longer patients live with gallstones, the more likely they
are to experience pain or complications [34].
In Japan, Wada and Imamura [35] found that 20% of patients
with asymptomatic cholelithiasis turned symptomatic
after a median follow-up of 13 years. Patients over the age
of 70 were more likely to become symptomatic than patients
under 70. McSherry et al. [36] followed 135 asymptomatic
men and women with gallstones who were subscribers to the
Health Insurance Plan of Greater New York. Ten percent developed
symptoms and only 7% required cholecystectomy
over a median follow-up of 46.3 months. Cucchiaro et al.
[37] followed 125 asymptomatic patients for a period of
5 years. Fifteen patients developed symptoms during that
time and two underwent emergency surgery for gallstone
complications. Fifty-four patients died during that period
because of unrelated causes (malignancies, cardiovascular
disease, renal insufficiency).
Friedman et al. [38] observed 123 asymptomatic patients
over 25 years in a prepaid health plan; serious or mild events
(acute cholecystitis, acute biliary pancreatitis, obstructive
jaundice) occurred in 4% of these asymptomatic patients.
Wacha and Ungeheuer in their review [39] reported higher
rates of conversion from asymptomatic to symptomatic state;
according to these authors, as many as 50% of individuals
with asymptomatic gallstones will be operated on or develop
symptoms within 10–20 years after the initial diagnosis.
Aging is found to be associated with the development of
symptoms or complications, and in particular if the followup
is long enough, in an increasing percentage of patients,
up to 30–50% [34, 36, 40, 41]. The incidence of choledocholithiasis
at the time of cholecystectomy is directly related
to age (9% in those 31–40 years old to 96% in those 80–90 years old) [5]. As is well known, choledocholithiasis
may be associated with potentially serious complications,
such as acute cholangitis and/or pancreatitis. This is of particular
practical importance for the patient and the physician,
because patients with advanced age exhibit higher morbidity
and mortality rates, whereas themanagement of complicated
gallstone disease may require more complicated procedures
than simple laparoscopic cholecystectomy. However, this issue
remains controversial; other authors observed that the
probability of developing symptoms and/or complications
fell steadily over time [10, 25, 31–33]; according to these investigators,
the longer patients were asymptomatic, the less
likely they were to develop symptoms.
In summary,most studies (conducted mainly in the 1980s)
indicate that the progression of asymptomatic to symptomatic
disease is relatively low, ranging from 10–25% [42–
45]. The major concern when discussing the natural history
of asymptomatic cholelithiasis is the possible development
of a severe, potentially life-threatening complication, such as
severe (necrotizing) pancreatitis or acute suppurative cholangitis.
Existing data show, however, that the majority of patients
rarely develop complications without first having at
least one episode of biliary colic pain [5, 10, 17, 32, 36];
biliary colic usually occurs within the first 5 years of the initial
diagnosis [20]. From a practical point of view, it would
be very important for both the patient and the physician if
we could recognize the subgroup of asymptomatic patients
who will become symptomatic. Unfortunately, it is impossible,
using local (such as number, size, nature, alteration in
wall thickness or gallbladder contractility) or general factors
(such as age, gender, associated comorbidities) to predict
who—among asymptomatic patients—will ever develop
symptoms or complications and when [3]. Some authors tried
to classify asymptomatic patients into two groups: a low-risk
group and a high-risk group. The low-risk patients are those
with a functioning gallbladder whose calculi are >3 mm
but <2 cm in diameter and radiolucent, and who are free
of concomitant serious disease [5]. The high-risk patients
are those more likely to develop acute cholecystitis, acute
pancreatitis, or other complications of cholelithiasis and include
those with large stones (>2.5 cm) and those with small
multiple calculi (microlithiasis, stones <3 mm in diameter),
biliary sludge, or both, who tend to develop acute cholangitis
or pancreatitis [46–48]. The risk of complicated cholelithiasis
is admittedly higher when the cystic duct is chronically
obliterated [5].
Management of asymptomatic cholelithiasis
Treatment options for asymptomatic cholelithiasis include
expectant management (observation alone) and cholecystectomy
(laparoscopic), which can be performed either selectively
(for selected subgroups of patients with asymptomatic
cholelithiasis), routinely (for all patients with asymptomatic
cholelithiasis), or concomitantly during another intraabdominal
operation for an unrelated pathologic condition (e.g.,
cancer of the colon).
Expectant management (observation alone)
Because the majority of patients with asymptomatic
cholelithiasis remain asymptomatic throughout their life,
most authors agree that expectant management (watchful
waiting) is the most reasonable treatment for the majority of
these patients [3, 17, 20–23, 49–51). This approach avoids
overtreatment (an unnecessary surgical procedure under general
anesthesia) in the vast majority of asymptomatic patients
who will never develop symptoms. The disadvantage of this
approach is that no one can guarantee the patient that he
or she will never suffer a potentially severe or even lethal
complication of gallstone disease, such as gallbladder cancer
or severe acute pancreatitis, usually at a more advanced
age (Table 2). In this case, emergency surgery for a serious
complication of cholelithiasis may be needed at a later date.
Moreover, in such a setting, the operation ismuch more complicated
and it is performed more frequently by laparotomy,
which may increase morbidity and mortality, especially in
older patients with comorbidities [5]. However, the patient
should recognize that this theoretical possibility is rare. Usually
the conversion from the asymptomatic to symptomatic
state happens by the occurrence of a biliary colic, thereby
indicating the need for surgery in the—then symptomatic—
patient. In conclusion, and considering that the vast majority
of asymptomatic patients remain asymptomatic throughout
their life and that most asymptomatic patients develop symptoms
before the occurrence of complications, prophylactic
surgical therapy is not justified—with a few exceptions (see
Selective Cholecystectomy). According to the NIH Consensus
Conference report [10] “the availability of laparoscopic
cholecystectomy should not expand the indications for gallbladder
removal.”
Surgical management (cholecystectomy)
Currently, laparoscopic cholecystectomy is the gold standard
in the management of cholelithiasis, given the safety
and ease of performance and the many well-known advantages
of this approach over the conventional open cholecystectomy,
including short hospital stay, lesser need for
postoperative analgesia, better cosmetic results, fast recovery
to full preoperative activity, and avoidance of long-term
complications (i.e., incisional hernia) [52, 53]. Conversion to
open cholecystectomy may be required for a small percentage
of patients when the laparoscopic approach is associated
with operative difficulties or when the operating surgeon feels at surgery that laparoscopic cholecystectomy cannot be
performed safely for a variety of reasons (e.g., presence of
firm adhesions owing to previous abdominal operations, difficulty
in identifying vital anatomical structures, etc). About
15 years after its introduction, laparoscopic cholecystectomy
is considered to be a safe operation, with low morbidity and
overall mortality ranging from 0.14–0.50% in different studies,
depending on the age and fitness of the patients [54].
However, despite the fact that morbidity has decreased as the
years go by, as more operative experience is gained, and experienced
in laparoscopy surgeons are involved in the training
of the new generation of surgeons [55], complications—
potentially severe—do exist and should not be neglected
(Table 3).
Routine cholecystectomy
As discussed previously, most authors agree that routine
cholecystectomy is not indicated for asymptomatic cholelithiasis. Some, however, maintain that all asymptomatic
patients should routinely be operated. The main argument
is that surgery can be performed much more safely
before the development of potentially serious or even fatal
complications (such as acute cholecystitis, cholangitis, pancreatitis),
something that usually occurs at a more advanced
age and may demand urgent surgery in older patients, with
higher morbidity and mortality [5, 40–43, 56]. In contrast,
in young, low-risk patients, laparoscopic cholecystectomy
is an almost innocuous procedure with low morbidity and
practically no mortality [5]. According to this surgical philosophy,
precluding or postponing laparoscopic cholecystectomy
may be more risky than undertaking an elective operation
[5]. Even in the prelaparoscopic cholecystectomy era,
Glenn stated that “It is reasonable to strongly recommend
an early (open) cholecystectomy for gallstones, whether or
not they cause symptoms, unless there is a contraindication
to operation. The optimum treatment for asymptomatic
cholelithiasis is elective cholecystectomy without undue
delay” [40, 41]. Laparoscopic cholecystectomy is easier in
asymptomatic than in symptomatic patients, with lesser operative
time (92.1 versus 106 minutes), lower conversion rate
to open cholecystectomy (1.57% versus 4.6%), and lesser
morbidity (4.72% versus 8.80%) (p < 0.05) [57]. Although
mortality after laparoscopic cholecystectomy is 0.6% for all
age groups, it increases with aging, mainly because of the
presence of significant comorbidities in older patients (0.14–
0.4% in patients <50 years, and 4.5% in those >65 years)
[19, 58]. Operative mortality also increases after a “difficult”
cholecystectomy (defined as an operation performed
after a biliary complication, usually acute cholecystitis or
choledocholithiasis, has occurred, even if the acute event has
subsided) compared to a “simple” cholecystectomy (prophylactic
cholecystectomy or cholecystectomy after an episode of uncomplicated biliary pain) (mortality, 0.4% for patients
with chronic cholecystitis, 1.2% for those with acute cholecystitis,
1.2–1.6% after choledochotomy and common bile
duct exploration) [5, 32, 58]. Interestingly, in the study by
Morgenstern et al. [59] all the deaths after cholecystectomy
occurred in patients older than 66 years (mean age, 80.5
years). These authors confirmed also that the mortality increased
threefold when choledochotomy become necessary
[59]. Table 4 summarizes the advantages and disadvantages
of elective (routine) cholecystectomy in patientswith asymptomatic
cholelithiasis.
Selective cholecystectomy
Laparoscopic cholecystectomy can be performed in selected
subgroups of patients with asymptomatic cholelithiasis, who
are at greater risk for the development of symptoms or complications
(Table 5) [5, 11, 50–52, 60].
Chronic hemolytic syndromes
Patients suffering from chronic hemolytic syndromes (such
as sickle cell disease [SCD]) are at risk for gallstone development
at a young age (as a result of repeated hemolytic
crises). Pigment gallstones are reported in 58% of patients
with homozygous SCD and in 17% of patients with heterozygous
types of hemoglobinopathies [61, 62]. Two thirds
of patients with gallstones have symptoms, although it is
often difficult to distinguish between a sickle cell crisis and
acute cholecystitis [63]. Patients with other hemolytic anemias
are also at risk for gallstone development and many
will become symptomatic [64]. Laparoscopic cholecystectomy
should be considered for asymptomatic patients with
chronic hemolytic syndromes for many reasons [65, 66]:
Biliary complications of gallstone disease and vasoocclussive
crisis both present with similar manifestations (nausea, abdominal pain, fever, leukocytosis, and
cholestatic jaundice) and therefore differential diagnosis
may be difficult.
The onset of gallstones at a young age in SCD raises
the lifetime risk of biliary complications, and therefore,
cholecystectomy following the diagnosis of asymptomatic
gallstones in patients with SCD is advisable and justified.
Interestingly, the approach of elective cholecystectomy
for asymptomatic cholelithiasis in SCD patients was not
generally accepted until recently; in the past, surgery in SCD
was associated with a high morbidity and mortality owing
to vaso-occlusive crises [61, 67]. However, with the introduction
of laparoscopic cholecystectomy, the establishment
of its safety in patients with SCD and cholelithiasis, and
the significant improvement of anesthetic techniques, more
patients (adults and children) are being referred for laparoscopic
cholecystectomy [68, 69]. Pediatricians have started
screening their patients for gallstones and referring them
for laparoscopic cholecystectomy before the development
of symptoms and/or complications of the disease [70]. Reduction
of Hb-S to a level lower than 50% by preoperative
partial exchange transfusion is believed to be associated with
a lower risk of veno-occlusive crises [61, 71]. Avoiding open
cholecystectomy during acute crises or acute cholecystitis
has been advocated [65]. In the laparoscopic era, although
surgery should be avoided during veno-occlusive crises, laparoscopic
cholecystectomy for acute cholecystitis is not a
contraindication provided that all the precautions to guard
against a veno-occlusive crisis are taken [3].
Transplantation
Prophylactic cholecystectomy should be strongly considered
for patientswith asymptomatic gallstoneswaiting to undergo
solid organ transplantation [72, 73]. Prophylactic cholecystectomy
can be performed either during the pretransplant
period or—when appropriate—at the time of transplantation.
The theoretical basis for this recommendation is that
these patients are more likely to become symptomatic, especially
in the first 2 years after transplantation [73].Moreover,
because of immunosuppression, diagnosis of complications
of cholelithiasis may be more difficult; these complications
are associated with increased morbidity and mortality. The
aim of prophylactic cholecystectomy is to remove of a possible
septic focus that carries a high potential for severe
complications in immunosuppressed patients [72, 73]. The
mortality rate associated with emergency cholecystectomy
in patients who have received a heart transplant is high,
up to 36% in the review by Begos et al. [74]. Finally, cyclosporine
and tacrolimus (FK 506), used as immunosuppressive
agents, are prolithogenic because of decreased bile
salt export pump function [19]. Episodes of acute cholecystitis
during episodes of maximum immunosuppression or
during rejection episodes have been reported.
Not all authors, however, concur with this aggressive surgical
philosophy in transplant patients [75–79]. Greenstein
et al. [76] follow 21 renal transplant patients with silent
gallstones for 4 years. Thirteen patients (87%) remained
asymptomatic, and 3 patients (1 had diabetes) developed
acute cholecystitis and underwent laparoscopic cholecystectomy
with no complications. Similarly, Courcoulas
et al. [79] followed up 26 transplant patients (including
renal, heart, double lung, and heart–lung recipients) who
underwent laparoscopic cholecystectomy; 73% of these
patients had symptomatic gallstones. These authors found
that laparoscopic cholecystectomy is as safe in the transplant
population as in the general population and the advantages of
short hospital stay, low morbidity and early return to preoperative
routines remain equivalent. Melvin et al. [78] found
that in renal transplant patients, when surgery for gallstones
is needed, it was associated with a low risk and does not
represent an increased rate of complications in renal transplant
patients with 1-, 2-, and 5-year graft survival or 98%,
96%, and 80%, respectively. According to these authors,
expectant policy should be exercised in transplant patients
with silent gallstones. Once gallstones become symptomatic,
laparoscopic cholecystectomy can be safely performed
with no adverse effect on morbidity, mortality or graft
survival.
Gallbladder carcinoma
Gallbladder cancer, although rare in most Caucasian populations,
is amongst the most frequently observed cancers
in native populations of North and South America, and in
the Maori population of New Zealand, possibly as a result
of early onset of gallstones [80–83]. The increased incidence
of gallstones (at an early age) in these ethnic groups
may be due to the presence of cholesterol lithogenic genes
that are highly prevalent in these populations [83]. North
American Indianwomen develop gallbladder carcinomawith
a greater frequency than heavy smokers develop pulmonary
cancer [5, 84]. In all populations, there is a strong correlation
between gallstones and gallbladder cancer. The risk
of gallbladder cancer is approximately four times higher in
cases with than in those without gallstones. It is estimated
that about 80% of patients developing gallbladder carcinoma
have gallstones, especially large stones (≥3 cm) [27]. The
risk of underlying malignancy is also high in patients with
gallbladder polyps larger than 10 mm in diameter [81, 85–
87]. Calcified or porcelain gallbladder is associated with
carcinoma in 13–25% of patients [8, 88–90]. Recently, some
authors questioned the association of porcelain gallbladder
with gallbladder carcinoma [91, 92]. According to these authors,
a calcified gallbladder is indeed associated with an increased risk of gallbladder cancer, but at a much lower
rate than previously estimated [91]. Interestingly, Stephen
et al. [91] found that the incidence of cancer depends on
the pattern of calcification, with selective mucosal calcification
being associated with a greater risk compared to diffuse
intramural calcification.
When examining the role of cholecystectomy as a therapeutic
strategy to prevent the development of gallbladder
carcinoma, the surgeon and the patient should acknowledge
that—despite the association of gallstones with gallbladder
carcinoma—the risk of developing cancer in all patients
with asymptomatic gallstones is less than 0.01%, less than
the mortality associated with cholecystectomy [12, 17].
Therefore, prophylactic cholecystectomy is not indicated
for the general population with asymptomatic cholelithiasis
to prevent future gallbladder cancer [12, 17, 27, 64, 93,
94]. Nevertheless, based on the above data, prophylactic
cholecystectomy to prevent gallbladder carcinoma should
be strongly considered in selected subgroups of patients
with silent gallstones, such as in patients of some ethnic
groups living in areas where gallbladder carcinoma is
prevalent (American Indians and Mexican Americans,
Colombia, Chile, Bolivia) [33, 80–83, 95, 96]. Indications
for cholecystectomy should be liberalized in these high-risk
populations [5]. The increasing frequency of laparoscopic
cholecystectomy in these geographic areas, and the lower
threshold for referral, probably will lower the incidence and
mortality rates for this lethal disease [81, 97]. Moreover,
prophylactic cholecystectomy is indicated in patients with
gallbladder polyps larger than 10 mm in diameter and in patients
with large gallstones (>3 cm) (see above) [27, 33, 81,
85–87, 97] (Table 5). Finally, and despite some controversy
[91, 92], most authors recommend selective prophylactic
cholecystectomy for patients with porcelain gallbladder to
prevent the development of gallbladder carcinoma [8, 11, 12,
88–90].
Diabetes mellitus
Prophylactic cholecystectomy has been recommended for
diabetic patients with silent gallstones [5]. This approach
has been based on the belief that diabetic patients belong to
the high-risk group for the development of complications of
gallstone disease (such as infected bile, gangrenous changes
and perforation of the gallbladder), that are more severe than
in the general population [98, 99]. Earlier reports found that
the risk of acute cholecystitis and subsequent perioperative
morbidity and mortality was significantly higher in diabetic
compared to nondiabetic patients [5, 100, 101]. It is believed
that the autonomic neuropathy in diabeticsmay mask the pain
and other clinical signs associated with acute cholecystitis
[102], thereby delaying accurate diagnosis and appropriate
management. Therefore, in the past surgeons were urged to
consider a diabetic as a high-risk group and prophylactic
cholecystectomy was recommended [5, 94, 100].
Recent evidence, however, has shown that the natural history
of gallstones in diabetics is generally more benign than
thought in the past, with a low risk of a major complications
[103]. The cumulative percentage of initially asymptomatic
non–insulin-dependent diabetic patients who presented with
symptoms and complications was small (14.9% and 4.2%,
respectively) [103]. Also, diabetes as an independent risk
factor for the formation of gallstones has been questioned
[104] and the prevalence of gallstones was found to be similar
among diabetic patients (14.4%) and control subjects
(12.5%), in a case-control analysis [105, 106]. Moreover,
the rates of operative morbidity and mortality for biliary
surgery in diabetics currently are comparable, with rates
in nondiabetics once other comorbidities such as cardiovascular
and renal disease are taken into consideration [98,
107–109]. Therefore, there is no clear benefit to prophylactic
cholecystectomy in diabetic patients with asymptomatic
gallstones, because surgery does not appear to increase either
the duration or quality of life, but may in fact reduce
it [11, 32, 98, 103, 107, 109–111]. Consequently, diabetic
patients should be managed expectantly with the same criteria
as the general population [3, 98, 110, 112]. However,
early elective cholecystectomy is advocated once symptoms
develop [105].
Vague dyspeptic symptoms
Although patients with gallstones who complain of nonspecific
dyspeptic symptoms (such as vague abdominal pain,
bloating, fullness, and/or belching) without biliary colic are
less likely to improve following cholecystectomy, a large
percentage (up to 70%) of them still benefit from surgery
[6, 113]. This suggests that indeed these vague, dyspeptic
symptoms may be caused by gallstones; therefore, laparoscopic
cholecystectomy is expected to improve significantly
the quality of life in patients with asymptomatic
cholelithiasis who reported vague symptoms [6]. An important
practical question, however, is if these patients are truly
“asymptomatic” and if gallstones are really “silent.”
Other indications for selective cholecystectomy
in asymptomatic cholelithiasis
Asymptomatic cholelithiasis in association with stones in
the common bile duct is another indication for selective prophylactic
surgery, because the presence of ductal stones predispose
to potentially severe complications in a significant
percentage of patients (up to 50%) [114, 115].
Selective cholecystectomy should also be considered for
patients with silent gallstones living in a part of the world
very remote from medical facilities. These patients may be at risk for an adverse outcome should a complication of
gallstone disease develop.
Incidental, concomitant cholecystectomy
for asymptomatic cholelithiasis during another
abdominal operation
Concomitant cholecystectomy for asymptomatic cholelithiasis
(diagnosed either preoperatively or intraoperatively) during
a planned abdominal operation is a common clinical
scenario. Several studies showed a high (up to 70%) incidence
of symptoms and/or complications from the biliary
system (such as biliary colic, acute cholecystitis, jaundice)
in patients with asymptomatic cholelithiasis following laparotomy
for unrelated conditions; cholecystectomy was required
in a large percentage (up to 40%) of these patients
within 1 year of the initial operation [116–121]. The aim of
incidental cholecystectomy in this case is to prevent postoperative
cholecystitis or the later development of symptoms.
Of course the addition of cholecystectomy should not
add risks to the patient. In most patients, cholecystectomy
“en passant” can be performed safely [119, 121]; therefore,
concomitant cholecystectomy during another intraabdominal
procedure is a reasonable option for the vast majority of
patients [116, 121], unless specific contraindications exist.
Ideally, gallstones should be detected preoperatively by ultrasonography;
this allows the discussion with the patient before
surgery to obtain his or her consent for cholecystectomy. The
discussion should emphasize the safety and purpose of the
procedure and not dismiss the possible complications, albeit
rare, as with any additional surgical procedure. In addition,
preoperative diagnosis of silent gallstone disease allows a
better planning of the incision [121].
Cholecystectomy-related complications can be avoided
by using the proper surgical technique, including proper exposure,
by performing an uncomplicated primary operation,
and by proper patient selection taking into account comorbidities
and general health [122]. Obviously, this strategy
is not recommended for high-risk patients, with significant
comorbidities, where a minimal operating and anesthesia
time is required for an uneventful recovery. Clinical judgment
at the time of surgery and caution are required from
the part of surgeon to select the optimal management option
for the individual patient. Local conditions (eg, presence
of a shrunken or scarred gallbladder, cirrhosis, extensive
firm adhesions, and/or tissue scarring) should be taken
into consideration. Incidental cholecystectomy for asymptomatic
cholelithiasis is contraindicated when a prosthetic
material (such as vascular graft, mesh for incisional hernia
repair) is used during surgery [123]. The performance
of concomitant cholecystectomy may be more difficult in
the case of a pelvic (gynecologic) procedure, because it
may require an additional or extended incision. However,
this poses no problem if the pelvic procedure is conducted
laparoscopically [3].
Comments
Laparoscopy not only simplified the treatment of cholelithiasis,
because of the many and clear advantages of the minimally
invasive approach compared to the open method, but
also resulted in a broadening of the indications of cholecystectomy
and in a decrease of “the surgical threshold”
for the surgical management of patients with asymptomatic
cholelithiasis. This caused a worldwide increase of the number
of cholecystectomies by 18.7% between 1989 and 1993,
with an increase of 25% in the age group of 45–64 years
[17, 99, 124–125]. This may reflect a change in surgeons’
attitude toward some of the indications for cholecystectomy,
including asymptomatic gallstones [99, 124]. Surgeons may
be treating asymptomatic gallstone disease or resorting to
laparoscopic cholecystectomy as a “diagnostic therapeutic
test” [127]. This liberal surgical attitude has been further
promoted by a lower referral threshold by general practitioners
and gastroenterologists asking for surgical treatment
by laparoscopic cholecystectomy, as a result of the enhanced
perceived benefits of laparoscopic cholecystectomy. These
referring physicians often warn patients that they are at an
increased risk for the development of severe and potentially
lethal complications, causing an unnecessary anxiety to them
and suggesting surgery despite the lack of sufficient data to
support such an aggressive management approach. Based on
existing evidence, physicians should frame their discussions
with patients in such a manner as to inform them of the relative
risk of an expectant approach versus cholecystectomy,
thereby allaying unfounded fears of the expectant management
approach. Another significant reason for the increase
of the number of (laparoscopic) cholecystectomies is the
increased acceptability and demand of minimally invasive
surgery by patients, so that few patients refuse surgical treatment,
especially after the diagnosis of a “potentially lethal”
disease is discussed with the referring physician [124].
Minilaparotomy (open) cholecystectomy is another alternative,
but worldwide most surgeons (and patients) prefer
the laparoscopic approach. Unfortunately, often both the referring
physician and the patient do not take into account
the natural history of asymptomatic cholelithiasis and the
operation/anesthesia-related potential morbidity and mortality.
The end result is the unnecessary overtreatment of a
large percentage of subjects with asymptomatic cholelithiasis
and the very long lists of patients waiting to undergo
cholecystectomy [52]. Among these, of course, are included
patients who are symptomatic and who have absolute indication
for surgery; the long waiting lists may delay surgery
for these symptomatic patients with potential adverse effects  (development of complications, higher conversion rates to
open cholecystectomy, increased morbidity/mortality, prolonged
hospitalization, etc) [128, 129]. The increased cost
and workload for the health system, because of a costly and
unnecessary operation not indicated for most patients with
asymptomatic cholelithiasis, is another factor that should be
taken into consideration when discussing such a controversial
issue [130]. Given the high prevalence of gallstones, the
cost of prophylactic cholecystectomy is almost four times
that of expectant management. It has been estimated that the
average cost in Britain is about 5.89 million euros/10,000
patients with asymptomatic cholelithiasis [30]. Considering
these numbers and the limited financial resources in health
care, and taking into account the natural history of asymptomatic
cholelithiasis, it appears unreasonable to treat every
patient diagnosed with silent gallstones with cholecystectomy
[11].
All patients with asymptomatic cholelithiasis should be
fully informed about the natural history of silent gallstone
disease and about management options. Existing data support
a conservative approach for the large majority of patients
with asymptomatic cholelithiasis. Surgery should be
offered to selected subgroup of asymptomatic patients with
gallstone disease (see Table 5). A careful analysis of hepatobiliary
and systemic risk factors (such as advanced age
and significant comorbidity) should precede any decision
regarding cholecystectomy for asymptomatic cholelithiasis.
Patient preferences should be taken into consideration by
the surgeon, because the decision for surgery remains an
individual decision. Patients unwilling to accept the minimal
but real possibility of complications of gallstone disease
may prefer to undergo laparoscopic cholecystectomy, but—
at the same time—they should acknowledge the morbidity
and mortality of the procedure and general anesthesia, albeit
minimal. The surgeon should emphasize to the patient
that the majority of patients with asymptomatic cholelithiasis
rarely develop complications without having at least
one episode of biliary colic. Consequently, laparoscopic
cholecystectomy can be performed as an elective procedure
for the—then symptomatic—cholelithiasis, allowing a
more optimal and reasonable timing for surgery. With modern
surgical and anesthetic techniques, cholecystectomy—
after symptoms develop—results in a mortality rate almost
equivalent to elective cholecystectomy.
In conclusion, the evolution of laparoscopy should not alter
the indications of cholecystectomy. Becausemost asymptomatic
gallstones remain clinically “silent,” routine laparoscopic
cholecystectomy is not indicated for the vast majority
of subjects with asymptomatic cholelithiasis. Laparoscopic
cholecystectomy is a costly procedure performed under general
anesthesia and is associated with the potential of morbidity
(sometimes serious) and mortality. The risks of the
operation outweigh the complications if stones are left in
situ. However, laparoscopic cholecystectomy should be performed
in selected subgroups of patients with asymptomatic
cholelithiasis (see above). Patients should be fully informed
about the natural history and available management options,
their advantages and disadvantages, and be actively involved
in the decision making.



Advantages
Natural history of asymptomatic gallstones is benign
Only 1–4% of patients per year develop symptoms (biliary “colic”)
Only 10 and 20% of patients will develop symptoms 5- and 20-years after the initial diagnosis
Acute biliary symptoms occur in 3%
Almost all patients develop some symptoms (usually biliary colic) before complications arise
Avoidance of a procedure that represents overtreatment for the majority of asymptomatic patients
Avoidance of surgery/anesthesia-related morbidity and mortality
Avoidance of unnecessary cost/workload for the health system
The patient can be operated if and when he or she becomes symptomatic (usually after an episode of biliary colic)
Avoidance of unnecessary surgery/anesthesia in patients with significant comorbidity/advanced age
Disadvantages
Theoretical potential (albeit small) for the development of serious complications of gallstone disease (such as pancreatitis or development of
gallbladder cancer)
About 20% of patients will develop symptoms after 20 years
Compared to elective, emergency surgery is associated with increased morbidity and mortality; mean operating time, mean hospitalization
and conversion (to open cholecystectomy) rates are higher in emergency surgery
Expected management is contraindicated for selected subgroups of patients with asymptomatic cholelithiasis (see Table 5)


Table 3 Complications of laparoscopic cholecystectomy
Common bile duct injury (1%)
Bile leak (3%)
Bleeding (as in open cholecystectomy)
Retained (undetected) stones and/or bile and stone spillage (with the
potential for abscess formation)
Wound infection (1–2%)
Injury to organ/vessels during trocar insertion or during surgery
(very rare)
Complications due to pneumoperitoneum (i.e., gas embolism,
subcutaneous emphysema) (very rare)
General postoperative complications (ie, deep vein thrombosis,
pulmonary embolus, pneumonia, myocardial infarction,
atelectasia—pneumonia, stroke) (as in open cholecystectomy)


TABLA 4
Advantages
Definitive cure of the patient from a disease with a “benign” natural history, but with the potential for
the development of serious and even fatal complications (albeit rare) (including the development of
gallbladder cancer)
Very safe procedure, with low morbidity and virtually no mortality among low-risk patients. Patient’s
problem can be relieved by undergoing a safe operation, which becomes even safer for patients with
asymptomatic cholelithiasis, owing to favorable local conditions (ie, absence of inflammation,
adhesions)
Disadvantages
Overtreatment of a large number of asymptomatic patients who will never develop symptoms or
complications
Potential morbidity and even mortality of surgery/anesthesia
Increased cost/workload for the health system

TABLA 5
Clear indications
Suspicion/risk of malignancy
Gallstones associated with gallbladder polyps >1 cm in diameter
Calcified (porcelain) gallbladder
Some ethnic groups or subjects living in areas with high prevalence of gallbladder cancer associated
with gallstones (American Indians, Mexican Americans; Colombia, Chile, Bolivia, Maori
population of New Zealand)
Presence of large (≥3 cm) gallstones
Asymptomatic cholelithiasis associated with choledocholithiasis
Transplant patients (before or during transplantation)
Chronic hemolytic conditions (sickle cell anemia)
Relative indications
Increased risk of conversion from asymptomatic to symptomatic disease
Life expectancy >20 years
Calculi >2 cm in diameter
Calculi <3 mm and patent cystic duct
Nonfunctioning gallbladder
Diabetes mellitus
Vague dyspeptic symptoms in the presence of gallstones
Questionable indications
Patient living in an area remote from medical facilities
Incidental (concomitant) cholecystectomy during another abdominal operation