Tumors are like new organs and are made of multiple cell types and components. The tumor competes with the normal microenvironment to overcome antitumorigenic pressures. Before that battle is won, the tumor may exist within the organ unnoticed by the host, referred to as 'occult cancer'. We review how normal tissue homeostasis and architecture inhibit progression of cancer and how changes in the microenvironment can shift the balance of these signals to the procancerous state. We also include a discussion of how this information is being tailored for clinical use.

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Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression

Objectives/Hypotheses: Salvage surgery is widely viewed as a “double-edged sword.” It is the best option for many patients with recurrent cancer of the upper aerodigestive tract, especially when original therapy included irradiation, yet it may provide only modest benefit at high personal cost to the patient. The stakes are high because alternatives are of limited value. The primary objective of this study was to fully assess the value of salvage surgical procedures in the treatment of local and regional recurrence. The following hypotheses were developed to focus the study design and data analysis. 1) The efficacy of salvage surgery correlates recurrent stage, recurrent site, and time to presalvage recurrence. 2) The economic and noneconomic costs of salvage surgery increase with higher recurrent stage. 3) Information relating the value of salvage surgery to recurrent stage and recurrent site will be useful to these patients and the physicians who treat them.



Study Design: Two complimentary methods of investigation were used: a meta-analysis of the published literature and a prospective observational study of patients undergoing salvage surgery for recurrent cancer of the upper aerodigestive tract.



Methods: The meta-analysis combined 32 published reports to obtain an estimate of average treatment effect for salvage surgery with regard to survival, disease-free survival, surgical complications, and operative mortality. The prospective observational study included detailed data in 109 patients who underwent salvage surgery. In addition to parameters studied in the meta-analysis, we obtained baseline and interval quality of life data (Functional Living Index for Cancer [FLIC] scores), baseline and interval performance status evaluations (Performance Status Scale for Head and Neck Cancer Patients [PSS head and neck scores]), length of hospital stay, and hospital and physician charges, and related this data primarily to recurrent stage, recurrent site, and time to presalvage recurrence.



Results: The weighted average of 5-year survival in the meta-analysis was 39% in 1,080 patients from 28 different institutions. In the prospective study, median disease-free survival was 17.9 months in 109 patients, and this correlated strongly with recurrent stage, weakly with recurrent site, and not at all with time to presalvage recurrence. Noneconomic costs for patients and economic costs correlated with recurrent stage, but not with site. Baseline FLIC and PSS head and neck scores correlated with recurrent stage, but not with site. After salvage surgery the percentage of patients reaching or exceeding baseline was 51% for FLIC scores, and this differed significantly with recurrent stage. Postoperative interval “success” in PSS head and neck subscale scores for diet and eating in public also correlated with recurrent stage.



Conclusions: Overall, the expected efficacy for salvage surgery in patients with recurrent head and neck cancer was surprisingly good, but success was limited and costs were great in stage III and, especially, in stage IV recurrences. A strong correlation of efficacy and noneconomic costs with recurrent stage allowed the creation of expectation profiles that may be useful to patients. Additional systematic clinical research is needed to improve results. In the end, the decision to undergo salvage surgery should be a personal choice made by the patient after honest and compassionate discussion with his or her surgeon.

Salvage surgery for patients with recurrent squamous cell carcinoma of the upper aerodigestive tract: when do the ends justify the means?

Few diagnoses in medicine engender as much pessimism as the diagnosis of metastatic cancer of an unknown primary site. Patients with this syndrome often have widespread metastatic disease, with involvement of multiple visceral sites such as the liver, lungs, and bones, and are often debilitated at the time of diagnosis. Early reports of chemotherapy in these patients documented low rates of response and no effect on the dismal median survival of three to four months, thereby strengthening arguments for a nihilistic approach1–4. Recently, however, the treatment of some patients with cancer of an unknown primary site has improved . . .

Treatment of Patients with Cancer of an Unknown Primary Site

• An isolated axillary lymph node metastasis in a woman without an obvious clinical primary site most frequently originates from the breast. Mastectomy has been the historical treatment of choice. A retrospective study of 35 patients was undertaken to evaluate the roles of modern mammography, breast preservation, and adjuvant systemic therapy in the management of these patients. Twenty-eight patients underwent a mastectomy, while 7 were managed by a combination of limited resection and/or axillary dissection and radiation therapy. Twenty-two (67%) of the 33 breast specimens contained carcinoma. Comparison of the pathologic results with the preoperative mammograms showed a specificity of 73%, while the sensitivity was only 29%. Actuarial 5-year survival after mastectomy or breast preservation was similar (77% and 65%, respectively). Patients with more than one positive lymph node benefited from adjuvant therapy. Mammography does not locate the majority of occult stage II breast cancers, and both breast preservation and adjuvant therapy may have roles in the management of these patients. ( Arch Surg . 1990;125:210-215)

Occult breast cancer presenting with axillary metastases. Updated management.

Most squamous cell carcinomas of the oral cavity and oropharynx are not diagnosed until they have attained at least the T2 stage (greater than 2.0 cm). This study identifies factors which may contribute to the delayed diagnosis of these tumors, despite the fact that they frequently arise at sites readily accessible to examination. Personal interviews of 149 patients with oral and oropharyngeal squamous cell carcinoma revealed delays by patients of one day to more than one year (mean, 17 weeks) before seeking care. Furthermore, delay by doctors occurred in 45 instances (30%). Neither short nor long delays had a statistically significant relationship to tumor T stage at the time of diagnosis. The length of patient delay was also not related to age, gender, amount of education, or history of alcohol consumption. The authors concluded that the early carcinomas were probably asymptomatic and subsequent manifestations were commonly misinterpreted as benign or innocuous oral/dental problems. These inconspicuous or misleading perceptions may be primarily responsible for the advanced stages of these tumors at the time of discovery. Emphasis must, therefore, be placed upon gaining access to high-risk individuals for periodic oral and oropharyngeal examinations and upon educational efforts to increase the skill of primary health care providers in recognizing this problem.

Factors delaying the diagnosis of oral and oropharyngeal carcinomas

Twenty-nine cases were reviewed in which carcinoma manifested first as the enlargement of an axillary node from an occult breast carcinoma. A small hidden breast cancer was identified in 16 patients. In the remaining 13, the breast tumor was never discovered. Regardless of whether the primary tumors were discovered, the metastasis-free survival rates were comparable to those of patients with breast carcinoma with axillary nodal metastasis. The authors recommend that carcinoma found in an axillary node should be treated as a breast cancer, even in the absence of the breast tumor. Extensive investigative procedures in an attempt to uncover an extramammary primary site were largely unproductive and should either be omitted or performed selectively. Mammography, if positive or suspicious, can lead to the primary tumor in 75% of the patients, but, when negative, it does not necessarily exclude the breast as the source of the carcinoma. A carcinoma of the breast was found by pathologic examination in 44% of the patients with negative mammograms.

Axillary lymph node metastasis from an occult breast cancer

This is a retrospective study in 279 patients, who were treated for squamous cell carcinoma of the tongue, to evaluate the role of initial modality on survival and recurrence pattern and the salvage rate of the second modality (surgery or radiation therapy) when the first one had failed

Jashbhai K. Patel

Papers

Axillary lymph node metastasis from an occult breast cancer

The role of initial modality in treatment of squamous cell carcinoma of the tongue