CD8+ T cells, natural killer cells, or natural killer T cells have been associated with improved prognosis

for a number of different tumor types.85–88 The initial association between favorable prognosis and TILs

was first observed in melanoma patients where it was reported that patients with higher levels of CD8+

T cell tumor infiltration survived longer than patients with tumors containing lower numbers.85 The

mechanism of TILs and especially CD8+ T-cell–mediated tumor elimination requires tumor antigen

presentation by APCs, typically dendritic cells. Activation of CD8+ T cells occurs following binding of

MHC class I molecules expressed by APCs and costimulatory molecule expression. The most widely

studied costimulatory molecule pathway is the B7-CD28 interaction with B7 expressed on APCs and

CD28 on CD8+ T cells. Following CD8+ T-cell activation, intracellular signaling activation of the NFAT, NF-kb, and AP1 pathways leads to further CD8+ T-cell activation and promotion of tumor cell

death.76

Although the original immune surveillance hypothesis is critical to understanding cancer cell

eradication it is likely that tumor cell tolerance and evasion play a much more important role in tumor

cell growth, thus offering opportunities for development of novel immunotherapies. The most successful

molecules to be targeted in clinical cancer immunotherapy are the immune checkpoint receptors,

cytotoxic T-lymphocyte–associated antigen 4 (CTLA4), and programmed cell death protein 1 (PD1).

Both PD1 and CTLA4 are inhibitory receptors that regulate immune responses at different levels and via

different mechanisms (Fig. 14-5).89

CTLA4, the first immune checkpoint receptor to be clinically targeted, is expressed exclusively on T

cells, where it primarily regulates the amplitude of the early stages of T-cell activation. Although

expressed on activated CD8+ T cells, the major physiologic role of CTLA4 appears to be through effects

on CD4+ regulatory (Treg) and helper cells. Thus, blockade of CTLA4 appears to switch the tumor

microenvironment from immunosuppressive to immunoreactive.90,91 An antihuman CTLA4 antibody,

ipilimumab, was shown in a cohort of patients with advanced melanoma to induce an objective response

rate in tumors previously treated with IL-2. Although there is significant immune-related toxicity

involving skin, liver, or colon, ipilimumab has gained FDA approval for the treatment of advanced

melanoma.92

In contrast to CTLA4, the major role of PD1 is to limit the activity of T cells in peripheral tissues at

the time of T-cell activation to tumor antigen presentation. Similar to CTLA4, PD1 is highly expressed

on Treg cells acting as a suppressor mechanism to effector T cells (CD8+ T cells).93 Currently, two antiPD1 inhibitors, pembrolizumab and nivolumab, have demonstrated efficacy in advanced melanoma

patients with disease progression following ipilimumab treatment.94,95

The Role of the Surgeon in Cancer Management

For many patients, surgeons are the entry point into the healthcare system when managing cancer and

cancer-related illness. For many surgeons, palliative or supportive care for patients with incurable

malignancy comprises a significant portion of their practice. Surgeons are involved in every phase of

cancer care from diagnosis to palliation. Many of the concepts covered in this chapter are covered on a

disease-specific basis elsewhere in the textbook. Understanding the concepts underpinning many of the

treatment approaches can help surgeons understand the rationale for current practice, and can also

potentiate the development of new therapeutic strategies.

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Figure 14-5. A: Upon antigen expression to the T cell receptor on memory or naïve T cells and subsequent stimulation, CTLA4 is

transported to the T cell surface dampening further T cell activation. B: The activity of PD1 is further downstream in the

inflammation process. PD1 is induced by activated T cells within peripheral tissues and signals to dampen further effector T-cell

activation-limiting inflammatory cascade. (Adapted from Pardoll DM. The blockade of immune checkpoints in cancer

immunotherapy. Nat Rev Cancer 2012;22:252–264.)

Surgical Intent

Although a significant portion of oncologic surgery practice focuses on curative resection of disease, the

intent for many surgical situations does not include cure. Recognizing the goals of therapy prior to

initiating a treatment course can help surgeons maintain a patient-centered approach with appropriate

patient preoperative counseling and consent.

Diagnosis and Staging

The role of surgical biopsy to confirm the diagnosis of cancer prior to definitive therapy has been

diminished recently by the advances of image-guided and endoscopic biopsy techniques. These

techniques allow high levels of diagnostic accuracy with reduced patient discomfort, expense, and use of

hospital resources. Procedures such as punch biopsy for suspicious cutaneous lesions or excisional lymph

node biopsy for characterization of lymphoma still remain a common diagnostic procedure for many

surgeons.

A key aspect of these biopsies is a clear communication with the responsible pathologist regarding

specialized tissue handling or preservation prior to initiation of the procedure. Specimen marking and

orientation are critical for subsequent resection needs. Incorrect preservation of the biopsy specimen

may obviate the possibility for flow cytometry when attempting to characterize lymph node suspicious

for lymphoma. Intraoperatively, surgeons need to plan for a subsequent definitive resection when

appropriate. Forethought in the selection of an incision or the extent of tissue plane dissection and

disruption can make a subsequent definitive resection less morbid and less complex for the patient and

surgeon. For instance, on occasion, extremity soft tissue tumors may require excisional biopsy. A

longitudinal incision in the orientation of the affected limb can minimize the size of the incision during

the subsequent definitive resection.

Surgeons may also play a key role in the staging of cancers. As entry points into the healthcare

system for patients dealing with cancer, surgeons are often responsible for distilling the physical

examination, radiologic, endoscopic, and surgical findings into a clinical stage assignation. For cancers,

such as pancreatic adenocarcinoma, gastric adenocarcinoma, and ovarian cancer, the operative

assessment of the peritoneum may identify radiographical occult carcinomatosis 10% to 25% of the

time.96–99 When performed laparoscopically in well-selected patients, this minor procedure can avoid

the patient impact of a nontherapeutic laparotomy in the setting of metastatic, incurable cancer. In

addition, lymphadenectomy, which will be discussed more fully elsewhere, serves an important

prognostic role by allowing for complete staging of the nodal basins. The status of the nodal basins not

only has important prognostic impact, but also defines the role of adjuvant therapy for many different

cancer types.

Curative Resection

The ability to completely resect all viable tumors requires consideration of technical, oncologic, and

functional resectability. A small number of tumor types are associated with surgical survival benefit in

the setting of incomplete resection. Patients with cancers such as ovarian cancer and mucinous

appendiceal cancer may benefit from cytoreduction with the possible addition of intraperitoneal

chemotherapy.100–104 Patients with life-limiting hormonal symptoms related to metastatic

neuroendocrine tumors may gain survival benefit from cytoreduction and the resulting decrease in

circulating hormones, such as insulin and somatostatin.105,106 However, for the vast majority of cancers,

survival benefit of resection is only associated with complete resection.107–110 For that reason, a plan for

resection should include extirpation of all viable tumor for patients with a treatment goal of cure.

The goals for curative resection should include not only complete removal of tumor, but also

preservation of adequate patient function and the possibility of prolonged disease-free survival (DFS).

These functional and oncologic aspects of resectability are the metrics by which any planned resection

can be judged successful. For instance, the role of resection of hepatic colorectal metastases or

hepatocellular cancer is defined to a great degree by the amount of healthy residual liver and not

necessarily the volume of liver tumors.111–113 Conversely, even small-volume hepatic metastasis in the

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setting of pancreas adenocarcinoma precludes resection for curative intent.114 Resectability for patients

with colorectal hepatic metastases relies on functional preservation; resection for patients with pancreas

cancer metastases is limited by oncologic outcomes.

Palliative Surgery

Symptoms related to the progression of malignant disease are a common problem faced by surgeons. A

significant proportion of a surgeon’s oncologic practice can be dedicated to providing palliation for

patients with incurable conditions. This need is not limited to patients with malignancy; however, the

principles associated with surgical palliation of cancer-related symptoms are a sound model for

discussion regarding surgical palliation in general.

The primary concept driving decision-making for patients with palliative needs is the critical starting

point of goal assessment. In order to deliver the most individualized, risk-appropriate, effective

palliation to any given patient, surgeons need to ascertain the goals of therapy for each individual

patient at that given time. This assessment transcends diagnosis-based treatment algorithms or

pathways. Patients with gastric outlet obstruction related to metastatic gastric cancer may seem like a

homogeneous group; however, the primary therapeutic goals of individual patients may vary

dramatically. Treatment goals in that setting may include resolution of nausea, eating independently,

long-term maintenance of nutrition, or improving performance status sufficiently to enter home hospice.

These variable treatment goals can lead to variable treatment strategies, such as placement of a

nasogastric decompression tube, a percutaneous gastrostomy tube, gastrojejunostomy, and/or

antiemetic medications.

A second factor particularly relevant to palliative surgery for patients with cancer is the increased risk

for many procedures in a population with incurable malignancy. Many patients eligible for palliative

operations or procedures have been debilitated by malnutrition, physical deconditioning, prolonged

hospitalization, or cytotoxic chemotherapy.115,116 These factors, as well as the presence of metastatic

disease, have all been associated with poor short-term outcomes following operations. Understanding

the increased risks of even simple operations for this patient population can help the surgeon guide the

patient and family conversations regarding the risks and benefits of a procedure. Making a decision with

a patient and family regarding strategies for surgical palliation requires both an individualized

assessment of the needs of those involved as well as a generalized awareness of the risks for that

procedure based on associated risk factors.

Extent of Resection

For malignancies such as melanoma, breast cancer, or sarcoma, the requirement for radical resection has

decreased significantly over the past several decades.117–121 Conversely, for diseases such as pancreas

cancer and liver tumors, the frequency and safety of radical resections have increased dramatically over

that same time period.122 A key point of judgment for surgeons involved in cancer operations is not

only deciding when to operate, but also how extensive that operation should be.

Pathologic Margins

An important distinction must be made between surgical and pathologic margins. Surgical margins are

the planned lines or planes of resection around a grossly visible tumor. The aim of this strategy is not to

ensure a wide swath of healthy tissue around the tumor specimen, but to ensure a final negative

pathologic margin. Pathologic margins are the histologically assessed borders of uninvolved tissue

around the microscopic tumor. Tumors with infiltrative behavior may extend up to the pathologically

assessed margin even though the grossly assessed surgical margin appears to be uninvolved. An example

of this discrepancy occurs in the management of melanoma. Resection with a 1-cm surgical margin is

generally considered adequate for a nonmetastatic extremity lesion with a tumor thickness of 1 to 2

mm. If the final pathologic margin is only 0.3 mm, this is considered a negative, and adequate,

pathologic margin.

Table 14-9 Terms Typically Used to Describe Pathologic Margins for Cancer

Resections

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