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CARCINOMA CELLS IN PLEURAL CAVITY WASHINGS HARLAN J. SPJUT, M.D., VELMA J. HENDRIX, GUSTAVO A. RAMIREZ, M.D.,*t AND CHARLES L. ROPER, M.D. MPLANTATION of cancer cells is a recognized I hazard of cancer surgery. Failures of treat- ment include a respectable number of pa- tients in whom there is local persistence of cancer that is probably related to implanta- tion. Haagensen’s studies2 revealed 4.4% to 24.0% local persistence of breast cancers after radical mastectomy. The percentage was de- pendent upon the presence or absence of axil- lary lymph node metastases. Cole and his associates1 reported 16% local persistence of carcinoma after resection for carcinoma of the large bowel. Perhaps implantation of cancer cells contributes to the rather poor long term results in surgery for cancer of the lung. As a means of studying the potential danger of im- plantation accompanying pulmonary cancer surgery. the saline used for detecting air leaks from the bronchial stump after pneumonec- tomy or lobectomy and for rinsing the pleural cavity during exploratory thoracotomy was collected and the sediment studied for cancer cells. MATERIALS AND METHODS Through co-operation with the Thoracic Surgery Service of Barnes Hospital, St. Louis, Mo., 60 specimens of pleural cavity washings were obtained. The fluids were all grossly bloody: some contained blood clots. The vol- ume of the specimens varied from approxi- mately 100 cc to 500 cc. A portion of each sample was used for smears and stained by the Papanicolaou method. The major part of the fluid was used for preparation of a parafin block section and stained with hematoxylin- eosin. Three separate smears were made; from the paraffin block sections 3 slides were made, From the divisions of Surgical Pathology and Tho- racic Surgery, Washington University School of Medi- cine; Barnes Hospital; and the Exfoliative Cytology Laboratory of Barnard Free Skin and Cancer Hospital, St. Louis, Mo. Fellow of the American Cancer Soaety, Inc. +Present address: Calle Las Marias 249, Hyde Park, Rio Piedras, Pueno Rim. The statistical calculations were made by Dr. R. C. Ahlvin of the Department oP Pathology, Washington University School of Medicine. Received for publication March 14, 1958. TABLE 1 SUMMATION OF CYTOLOGICAL FINDINGS FOR PLEURAL CAVITY WASHINGS FROM 49 PATIENTS OPERATED UPON FOR PULMONARY CANCER With excis. Without excis. for frozen for frozen sect., no. sect., no. Operation Pos. Neg. Pos. Neg. Pneumonect. 10 7 3 18 Esplor. only 3 8 or lobect. ... ... - -- - - TOTAL 13 15 3 18 each from a different depth into the block. Among the patients were 49 with cancer and 11 with non-neoplastic diseases. The latter were used as controls, i.e., controls in the sense of establishing a base line for the com- parative study of normal or altered normal cells with the neoplastic cells obtained from the pleural cavity by this technique. Included among the 49 patients were 26 who had pneu- monectomies, 12 who had lobectomies, and 11 who had exploratory thoracotomies. Each of the 11 control patients had either a pneu monectomy or a lobectomy. In the interpretation of the smears and paraffin block sections, a diagnosis of positive or negative for cancer cells was made. Cells of doubtful origin were declared negative. In each of the cancer cases, histological sections of the tissue removed at surgery were studied in order to be certain that the cells in the smears and sections made from the pleural cavity washings that were diagnosed as posi- tive were of neoplastic origin. Again the benefit of the doubt was given to the negative. RESULTS Of special interest to us in this study were the pulmonary resections and exploratory op erations done after excision of a lymph node for biopsy or incision into a lung parenchymal lesion to obtain a specimen for frozen section. It was from this group that we expected to find cancer cells in the pleural cavity wash- ings. Under the circumstance of incising into 1222

Carcinoma cells in pleural cavity washings

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CARCINOMA CELLS IN PLEURAL CAVITY WASHINGS HARLAN J. SPJUT, M.D., VELMA J. HENDRIX, GUSTAVO A. RAMIREZ, M.D.,*t

AND CHARLES L. ROPER, M.D.

MPLANTATION of cancer cells is a recognized I hazard of cancer surgery. Failures of treat- ment include a respectable number of pa- tients in whom there is local persistence of cancer that is probably related to implanta- tion. Haagensen’s studies2 revealed 4.4% to 24.0% local persistence of breast cancers after radical mastectomy. The percentage was de- pendent upon the presence or absence of axil- lary lymph node metastases. Cole and his associates1 reported 16% local persistence of carcinoma after resection for carcinoma of the large bowel. Perhaps implantation of cancer cells contributes to the rather poor long term results in surgery for cancer of the lung. As a means of studying the potential danger of im- plantation accompanying pulmonary cancer surgery. the saline used for detecting air leaks from the bronchial stump after pneumonec- tomy or lobectomy and for rinsing the pleural cavity during exploratory thoracotomy was collected and the sediment studied for cancer cells.

MATERIALS AND METHODS

Through co-operation with the Thoracic Surgery Service of Barnes Hospital, St. Louis, Mo., 60 specimens of pleural cavity washings were obtained. The fluids were all grossly bloody: some contained blood clots. The vol- ume of the specimens varied from approxi- mately 100 cc to 500 cc. A portion of each sample was used for smears and stained by the Papanicolaou method. The major part of the fluid was used for preparation of a parafin block section and stained with hematoxylin- eosin. Three separate smears were made; from the paraffin block sections 3 slides were made,

From the divisions of Surgical Pathology and Tho- racic Surgery, Washington University School of Medi- cine; Barnes Hospital; and the Exfoliative Cytology Laboratory of Barnard Free Skin and Cancer Hospital, St. Louis, Mo.

Fellow of the American Cancer Soaety, Inc. +Present address: Calle Las Marias 249, Hyde Park,

Rio Piedras, Pueno Rim. The statistical calculations were made by Dr. R. C.

Ahlvin of the Department oP Pathology, Washington University School of Medicine.

Received for publication March 14, 1958.

TABLE 1 SUMMATION OF CYTOLOGICAL FINDINGS FOR PLEURAL CAVITY WASHINGS FROM

49 PATIENTS OPERATED UPON FOR PULMONARY CANCER

With excis. Without excis. for frozen for frozen sect., no. sect., no.

Operation Pos. Neg. Pos. Neg.

Pneumonect. 10 7 3 18

Esplor. only 3 8 or lobect.

. . . . . . - -- - -

TOTAL 13 15 3 18

each from a different depth into the block. Among the patients were 49 with cancer and 11 with non-neoplastic diseases. The latter were used as controls, i.e., controls in the sense of establishing a base line for the com- parative study of normal or altered normal cells with the neoplastic cells obtained from the pleural cavity by this technique. Included among the 49 patients were 26 who had pneu- monectomies, 12 who had lobectomies, and 11 who had exploratory thoracotomies. Each of the 11 control patients had either a pneu monectomy or a lobectomy.

In the interpretation of the smears and paraffin block sections, a diagnosis of positive or negative for cancer cells was made. Cells of doubtful origin were declared negative. In each of the cancer cases, histological sections of the tissue removed at surgery were studied in order to be certain that the cells in the smears and sections made from the pleural cavity washings that were diagnosed as posi- tive were of neoplastic origin. Again the benefit of the doubt was given to the negative.

RESULTS

Of special interest to us in this study were the pulmonary resections and exploratory o p erations done after excision of a lymph node for biopsy or incision into a lung parenchymal lesion to obtain a specimen for frozen section. It was from this group that we expected to find cancer cells in the pleural cavity wash- ings. Under the circumstance of incising into

1222

a tumor the opportunity for spilling or for the instrument transfer of tumor cells is great, as has been observed in the reports of Saphil.3 and Smith, Thomas, and Hilberg.4 In their studies, tumor cells were recovered from the knife blades used for cutting into tumorsS and from washings of wounds after operative procedures for cancer.4 Our patients were divided into 3 groups: (1) controls, i.e., those who had resections done for non-neoplastic lesions; (2) those who had resections or ex- ploratory operations for cancer that were preceded by excision of tissue for frozen sec- tion; and (3) those who had resections or ex- ploratory operations for cancer that were not preceded by biopsy. In group 1 there were 11 patients; in group 2, 28 patients; and in group 3, 21 patients.

No malignant cells or cells even suggestive of neoplasm were found in the washings from the 11 control patients (group 1). The results were quite astounding in the other 2 groups taken in themselves and on a comparative basis (Table 1). Of the 28 instances in which tissue was excised for frozen section, I 3 of the patients (47%) had cells identifiable as cancer cells in the pleural washings (Fig. lA, B, and D). Seventeen of the 28 had either a pneu- monectomy or a lobectomy; 10 of the 17, or 59%, had demonstrable cancer cells in the pleural washings. The other 11 patients in this group had only exploratory thoracoto- mies, because inoperable lesions were encoun- tered. In this group, 3 of the 11 patients had cancer cells in the pleural washings. Cancer cells were found in the pleural washings from 3 (14.0%) of the 21 in group 3 who had resec- tions. There were no patients who had ex- ploratory thoracotomies in this group.

T o summarize our results: for the entire group of 49 pleural washings from cancer pa- tients, 16 or 33% of the washings contained cancer cells. Pleural washings from patients who had pneumonectomies or lobectomies performed in conjunction with excision of tissue for frozen section yielded 10 of 17 speci- mens (59%) positive for cancer. On the other hand, pleural washings from 3 of 21 patients (14%) who had pneumonectomies or lobecto- mies done without excision of tissue for frozen section contained cancer cells. The results of the 2 groups are statistically significant with f=8.8 and P=<l%.

From the standpoint of cytology the smears and sections contained only a few to a mod- erate number of cells other than erythrocytes.

No. 6 CARCINOMA CELLS IN PLEURAL CAVITY WASHINGS - Spjut et al. 1223

Pleural washings from the control group dem- onstrated readily recognizable mesothelial cells, few leukocytes, and rare macrophages. Similar cells were seen in the specimens from the cancer patients. The problem of hyper- plastic mesothelial cells that are so often found in pleural effusions was rarely manifest in our groups (Fig. IC). Malignant cells along with other cells were few in number; a few of the smears and sections contained abundant cancer cells. The cells, including the red blood cells, were generally well preserved. The criteria for malignancy were the same as for other fluids and secretions. Cells that could not be certainly classified as malignant but were suspicious for cancer were included in the negative groups. From the pleural washings obtained from patients who had re- sections in conjunction with excision of tissue for frozen section or other biopsy, 5 contained such cells; in the group of patients who had resections without prior excision of tissue for frozen section or other biopsy, 4 of the wash- ings contained cells suspicious for carcinoma. Although it was planned to examine both smears and sections of each pleural washing, through forgetfulness and sometimes scant specimens, only smears were made in 6 cases and only sections in the other 6. Three of these 12 patients were from among the con- trols. In all of the cases interpreted as posi- tive, both sections and smears were examined. Of the positive cases, in 2 there were positive smears only, in 7 there were positive sections only, and in 7 both smears and sections were positive.

The control group included patients with tuberculosis, bronchiectasis, bullous emphy- sema, and organizing pneumonia. In the group that had pleural washings that were positive for cancer, there were 4 who had epidermoid carcinomas, 8 who had undiffer- entiated carcinomas, and 4 who had adeno- carcinomas. In the group that had negative pleural washings, there were 13 who had epi- dermoid carcinomas, 11 who had undiffer- entiated carcinomas, 4 who had adenocarci- nomas, and 5 who had other malignant lesions.

DISCUSSION

The importance to the patient and to the surgeon of the presence of cancer cells in pleural cavity washings after excision of tissue for frozen section or other biopsy is not ap-

1224 CANCER November-December 1958 VOl. 11

parent at this time. Follow-up of the patients, in washings from 31 (25.90/,) of 120 cancer particularly autopsy studies, may provide data operation wounds made in performing opera- as to the significance of our findings. At pres- tions on 11 1 patients. The local recurrence ent we can draw on the experience of Smith rate for the patients who had cancer cells in and his associates.4 Malignant cells were found the wound washings was 40%. When cancer

FIG. 1. A, Malignant cell in the pleural washin s. Tissue had been removed for a frozen section. (WU 58- 802.) (~1,100.) B, A clump of neoplastic cells in 8 e pleural washings recovered after removal of a hilar lymph node containing cancer for frozen section. Histologically, the tumor was a combination of epidermoid carci- noma and adenocarcinoma. (WU 58-387.) (~500.) C, Mesothelial cells and erythrocytes in the pleural washings after a lobectomy for carcinoma. A frozen section examination had not been made. Cancer cells were not de- tected in either the smears or the cell block. (WU 58-804.) (X750.) D, Hype lastic mesothelial cells in the pleural washings after a lobectomy for chronic pneumonitis. (WU 58-803.) (x5TO.)

cells were not found in the wound washings the local recurrence rate was 260/,. The au- thors did not believe, however, that their find- ings were statistically significant. Perhaps our observations will mean no more.

Of interest in the analysis of our findings is the background question concerning the chances for survival or implantation of free- lying or floating cancer cells. The answer at present is not known. Smith and his associates' observed that in experimentally seeded wounds it was impossible to wash all tumor cells from the wound; recurrences could be reduced but never completely prevented. This demonstrates that tumor cells are capable of surviving and growing even after repeated washings and resultant reduction of their numbers. As an indirect method of determin- ing the danger of spilling cancer cells by ex- cising tissue for frozen section or other biopsy during lung cancer surgery, a tabulation was made of the number of patients who had tissue removed for study prior to operation among 40 patients who had had a lobectomy or a pneumonectomy and who had survived 5 years. Ten of the 40 had had biopsy for fro- zen section prior to the resection; 30 had not. To serve as controls, the number of pa- tients who had had biopsy for frozen section among 100 who had pneumonectomy or lobectomy for cancer was tabulated. In 31 pa- tients, tissue had been removed for study; in 69, it had not.

From these 2 groups of cases it would seem that any danger from the procedure as regards survival is minimal. The evidence that there is danger of spilling cancer cells during the procedure of obtaining a biopsy specimen is inconclusive without a study of the pleural cavities of patients dying after lobectomy or pneumonectomy for cancer. In this way evi- dences of recurrence could be ascertained.

The results of our study would indicate that there is a potential danger of implanta- tion of cancer cells during operations for lung

No. G CARCINOMA CELLS IN PLEURAL CAVITY WASHINGS * Spjut et al. 1225

cancer, particularly when the operation is ac- companied by the excision of tissue for study. We do not suggest that the procedure should be discarded, as it is very important that an accurate diagnosis be had beEore a lung or a lobe is sacrificed. We believe that the pro- cedure should be avoided when the preoper- ative work-up demonstrates cancer in a biopsy specimen of bronchial tissue or by exfoliative cytology. Occasionally, under these circum- stances an additional biopsy specimen may be needed to determine resectability. If a defini- tive diagnosis is not at hand preoperatively, then any enlarged hilar lymph node on the side of the parenchymal lesion is selected for biopsy and frozen section study. If this is neg- ative for neoplasm, or if there are no signifi- cantly altered hilar nodes, the parenchymal lesion is incised to obtain a biopsy specimen. The defect is closed by interrupted black silk sutures. For peripheral lesions, depending on their roentgenological appearance, either a lobectomy or a wedge resection is performed for biopsy purposes. Because of the results of our study of pleural washings, it would seem that care should be exercised during the ex- cision of a biopsy specimen so as to hold con- tamination and manipulation to a minimum.

SUMMARY 1. Cancer cells were identified in the pleu-

ral cavity washings of 47% of 28 patients un- dergoing operations for pulmonary cancer that were accompanied by excision of tissue for frozen section.

2. Seventeen of the 28 patients had either a pneumonectomy or a lobectomy. Of this group, 10, or 59%, had cancer cells in the pleural cavity washings.

3. The significance of the findings is not apparent at the present time. There is a po- tential danger of cancer implantation in the pleural cavity, especially when the operation is performed in conjunction with the excision of tissue for histological examination.

REFERENCES

1. COLE, W. H.: PACKARD, D., and SOUMWICR, H. W.: Carcinoma of colon with special reference to preven- tion of recurrence. J . A . M. A . 155: 1549-1553. 1954.

2. HAACENSEN, C. D.: Diseases of the Breast. Phila-

3. SAPHIR, 0.: Transfer of tumor cells by surgical knife. Surg. Cynec. & Obst. 63: 775-776, 1936.

4. SMITH, R. R.; THOMAS, L. B., and HILBERC, A. W.: Cancer cell contamination of operative wounds. Cancer

delphia, Pa. W. B. Saunden Company. 1956; p. 627. 11: 53-62, 1958.