Squamous Cell Carcinoma of the Lung* Clinicopathologic Study Patrick C. MarabeUa, M.S.; Hiroshi Taldta, M.D.;

Wa"en W. Lane, Ph.D.; and Frederic I. Prefler

1NI lllldermkela to IDvesdpte the ~ tlaenpeldie, _ . pi'OIIlOidc f..._es of 111J ...,.. eel ardlloma of abe ..... 'l1le ovenl lve-yar ...m.t na for 734 ,..._..,... 5 peraat, wldla ....... ....m.J of 5.9 moatiiL Stqieal esdlloa for arty~.-,... partleularly •edlve tllenpy. lal51 of 201 ,..._.. liP•

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J carcinoma has been well established that squamous cell of the lung has the best prognosis of t

the major cellular types of lung canoer. 1_. Previously, wet·• have observed the clinicopathologic features of small cell carcinoma and adenocarcinoma of the lung. In this report, we present a retrospective study of patients with squamous cell carcinoma of the lung who were treated at the Roswell Parle Memorial Institute. PATIENTS

During a ten-year period between 1960 and 1970, a total of 734 patients with lq1I8IDOUS ceD carciDoma of the long were seen at Roswell Parle Memorial IDstftute. Tbere were f115 men ( 92 pemmt) and 59 women, ( 8 perceot), a ~ex ratio of 11.4/1. The average age for men was 81 yean and for women 55 )'ears. The largest number of cases ( 279 or 38 percent) occurred in the siDh decade of life. S.,apfom8

In 551 patients ( 75 percent), the symptoms prompting medical attention were ~ hemoptysis, sbortDea of breath, chest pain, and other respiratory symptoms. In 38 patients, pain due to osseou metastasis was the primary symptom. Other symptoms iDduded those of the ceDtral

nervous system in 11 patieDts, lois of weight in nine patients, aud superiol" veaa cava syndrome in four patients ( 34 patients with vague history had unbown initial symptoms). Eighty-seven patients ( 12 percent) were diagnosed incidentally during routine eumjnafion In 368 cases (50 percent), diagnosis was coo&rmed within two months of the first symptoms.

DIAGNosiS

Sputum cytologic &ndings were positive for malignant disease in 255 ( 46 percent) of 554 cases. B~nchoscopic examination was done in 579 cases; •Fnm the ~ of Thoracic Surgery and the Compute!' Omter, Roswell Parle Memorial Institute Buffalo, NY. Manuscript received June 4; revision accep~ August 19. Reprint reqvem: Dt-. Toldla, Honoell Ptri: Medlctlllnditute, Buffalo 14263

CHEST, 71: 4, APRIL, 19n

1111 -atca1 adiiiOII, tile raectioas were dealed eaildte.

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in 213 cases ( 37 percent) the tumor was visualized, and positive findings were obtained on biopsy; and in 143 cases (25 percent), bronchial washings yielded positive cytologic &ndings. Extrathoracic metastases were the source of the histologic diagnosis in 117 cases ( 16 percent), 93 biopsies of lymph nodes and 24 biopsies of other lesions. In the remaining six instances the source of diagnosis was unknown, due to incomplete information from other institutions.

Stage at Time of Diagnosis At the time of diagnosis, the disease was classified according to a TNM system recommended by the Lung Cancer Worlcing Party7 (T, extent of primary lung tumor; N, extent of metastasis to lymph nodes; and M, extent of hematogenous metastasis). One hundred eighty-seven patients ( 26 percent) were classified as stage 1, a total of 43 ( 6percent) as stage 2, and 484 ( 68 percent) as stage 3. Six patients had an occult carcinoma, in which malignant cells were discovered in bronchopulmonary secretions without evidence of a primary tumor or metastasis (lack of accurate data from outside sources of diagnosis in the remaining 14 patients made staging impossible). The patients in this study were also classified by a "special staging" method as to whether the disease was limited to the hemithorax, as in 544 cases ( 75 percent); had extended to the supraclavicular lymph nodes, as in 103 cases ( 14 percent); or had disseminated, as in 79 cases ( 11 percent). There was insuHicient information at the. time of diagnosis to stage the other eight patients.

Survival from Time of Diagnosis The overall median survival for 726 patients was 5.9 months. Due to a questionable time of diagnosis,

SQUAMOUS CD.L CARCIIOIIA Of THE LUIII 417

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SURVIVAL IN MONTHS eight patients were excluded from the data on survival Two hundred eleven patients ( 29 percent) survived for one year, 95 ( 13 percent) for two years, and 56 ( 8 percent) for three years. There were 35 patients ( 5 percent) who survived for 6ve years, and six patients lived longer than ten years from the date of diagnosis (Fig 1). The median survival for the 233 patients ( 33 percent) who responded to therapy was 12.2 months. A total of 332 patients ( 45 percent) did not respond to any treatment. The median survival for this group was 5. 7 months. A total of 150 patients ( 21 percent) died before therapy could be started.

FIGURE 1. Survival of total group of tients.

pa-

The five-year rate of survival appeared to be closely related to the extent of the disease; 187 patients with stage 1 disease survived for a median time of 9.7 months, with 15 percent surviving for more than five years and four ( 2 percent) for ten years after diagnosis. Forty-three patients with stage 2 disease survived for a median time of 15 months, with two 6ve-year survivors (5 percent). Four hundred eightyfour patients with stage 3 disease survived a median time of 5.1 months, with seven ( 1 percent) surviving for more than five years and two living at least ten years after diagnosis (Fig 2). In 544 cases where the disease was limited to the

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488 IARAB£UA ET lL

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SURVIVAL IN MONTHS CHEST, 71: 4, APRIL, 1977

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36 48 60 72 84 96 SURVIVAL IN MONTHS

thorax, the median survival was 7.4 months. Thirtyfour patients ( 6 percent) survived for five years or longer, with five patients living for at least ten years after diagnosis. When the disease had spread to the supraclavicular lymph nodes, as in 103 cases, the median survival was 5.1 months. There was one fiveyear survivor in this group. The median survival for 79 patients with disseminated disease was 3.2 months, with one five-year survivor (Fig 3). FINDINGS AT AUTOPSY

Autopsy was performed on 296 patients at our institution. The incidence of metastasis by organ is shown in the following tabulation, giving numbers of cases (numbers within parentheses indicate percentages): Lymph nodes Mediastinal nodes Hilar nodes Retroperitoneal nodes Adrenal glands Liver Bone

199 (67) 152 161 78 (27) 76 (26) 68 (24)

64 (22)

Contralateral Ipsilateral Bilateral Kidney Pleura/pericardium Brain Heart Gastrointestinal tract Skeletal muscle Pancreas Spleen Skin

69 35 20 55 (19)

45 (15) 42 30 23 19 18

(15) (10) (8) (7) (6)

11 (4) 10 (3)

9 7 5 3 27

Peritoneum Thyroid gland Spinal cord Gonads

Other

(3) (2) (2) (I) (9)

The most frequent site of metastasis WaS the lymph node; such metastases were seen in 67 percent of all autopsies. Metastases to the mediastinal or hilar nodes were observed in over one-half of all autopsies. Metastases were also frequent in the adrenal glands, liver, bone, kidney, and pleura. Nearly twice as many metastases were found in the contralateral lung as in the ipsilateral lung. Invasion of the great vessels and invasion of the pleura were seen in 58 cases and 54 cases, respectively. The chest wall was invaded in 47 cases, while both the esophagus and pericardium were invaded in 34cases.

64

Lun~

CHEST, 71: 4, APRIL, 1977

108 120

REsuLTS OF

THERAPY

In our study, 22 patients are alive, with no evidence of disease. Twenty-one of these patients underwent surgery (alive in range of one year to 21 years and ten months), and one patient underwent a combination of chemotherapy and radiation therapy (alive 11 years and three months later). Surgery

Thoracotomy was performed on 464 ( 64 percent) of all patients, 201 ( 43 percent) of these procedures leading to surgical excision. This group had a median survival of 14.1 months. In 151 of these 201 SQUAMOUS CRL CARCINOMA OF THE LUNG 499

cases, resection was thought to be curative. The median survival of this group was 18.2 months, with 34 patients ( 23 percent) surviving for more than 6ve years and five patients surviving for at least ten years. The effectiveness of surgical excision seemed closely related to the stage of the disease. Eightyfour (55 percent) of the curative resections were in patients classified as having stage-1 disease, with a median survival of 23.2 months and with Z1 patients ( 33 percent) surviving for more than five years. Thirty-four ( 23 percent) of the curative resections were in patients classi6ed as having stage 2 disease, with a median survival of 15.5 months and with one 8ve-year survivor ( 3 percent). Thirty-three ( 2.3 percent) of the curative resections were performed in patients with stage 3 disease, with a median survival of 9.5 months and with six patients ( 19 percent) living longer than 6ve years (Table 1). Thirty-three patients who underwent palliative surgery alone survived for a median time of 5.9 months (range, 0 to 48 months). Seventeen patients who received adjuvant therapy along with palliative surgery survived for a median time of 8.3 months (range, 0 to 30 months). In 121 ( 16 percent) of all 726 cases, only an exploratory thoracotomy and biopsy were performed, as the disease was deemed beyond the scope of surgery. Twenty-two of these patients received no adjuvant therapy, while 99 did receive therapy. The median survival was 3.5 months and 8.3 months, respectively. Thirty-three patients (33 percent) of those who received adjuvant therapy survived for over one year.

Radiation Therapy One hundred eleven patients received radiation therapy to the primary tumor as initial treatment. This group had a median survival of 5.9 months. There were 19 patients who were considered to respond favorably to radiation therapy. These 19 patients survived for periods ranging from 5 to 30 months. Two patients had a favorable response consisting of greater than 50-percent reduction in the size of the tumor, with survival times of 24 and 30 Table l~aradtJe

.Reaeedon.., Slqe ol DUeae ld

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Group

Total No. of caaes No. resected

8tap 1 Stage 2 Stage 3

187

43

48

84

34

33

84 (56)

84 (23)

33 (22)

1 (3)

6 (19)

No. with curative resection (percent) Fiv~year

-

survivon (percentage) 'r1 (33)

MARABEllA ET AL

months, respectively. Two patients had an apparent 100-percent reduction in the size of the primary tumor; one survived for eight months, and the other lived for six months, with no evidence of the primary lesion at autopsy but with di&use metastases. Ninety-two patients were considered nonrespondent to radiation therapy (therapy palliative), and they survived a median time of 5.3 months. Twentyone of these patients survived for one year, the longest living for two years and two months.

Radiation and Chemotherapy A total of 39 patients received a combination of radiation therapy and chemotherapy as initial treatment. This group had a median survival of 6.8 months. Chemotherapeutic agents used were methotrexate (three patients), meturedepa ( AB-132; 21 patients), dactinomycin (actinomycin D; four patients), 5-fluorouracil ( 6ve patients), mechlorethamine (nitrogen mustard; four patients), methylglyoxal his( guanylhydrazone) (methyl GAG; one patient); and cyclophosphamide ( Cytoxan; one patient). Twenty-nine patients ( 74 percent) showed no response to this therapy. Nine patients had 50-percent regression of their tumors, with a survival range of 3 to 15 months, and with two patients living longer than one year ( 14 and 15 months). One patient treated with radiation and meturedepa ( AB-132) exhibited 100-percent regression of his tumor and is still alive today after 11 years and three months (this patient had stage 3 disease).

Chemotherapy A total of 115 patients received chemotherapy as initial treatment. The median survival was 5.2 months, with only 13 patients surviving for one year. Only three patients showed a favorable response (50-percent regression of tumor), with survival times of 8, 10, and 11 months. The drugs employed were dichloromethotrexate, methylglyoxal his ( guanylhydrazone ), and methotrexate, respectively. Other drugs used are listed in Table 2. DISCUSSION

Our study revealed that squamous cell carcinoma of the lung is more common in older men. The lesion is usually located proximally in the longitudinal tree and therefore was visualized more often at bronchoscopy. Previously, we6•8 have reviewed small cell carcinoma and adenocarcinoma of the lung. By comparison, more squamous cell lesions are localized, as classified by staging system, and thus are operable at the time of diagnosis (Table 3).

CHEST, 71: 4, APRIL, 1977

Table 4---ILt.lu of No. of No. with Patients Response Methotrexate

52

2

Treatment

Noruar.,_ T._.,.,-

Rate of Response (percent)

Median Surviving More than 1 yr Survival, (percent) mo

Radiation

19/111 (17)

25/111 (23)

5.9

8

Radiation and chemotherapy

10/39 (26)

3/39 (8)

6.8

Methylglyoxal bia(guanylhydruone)

6

Chemotherapy

3/115 (3)

13/115 (11)

1, (2-chloroethyl)3-cyclohexyl-l-nitroeourea (CCNU)

2

Diaminodichloromethylpyrimidine (DDMP)

5

Bleomycin

4

Myoophenolic acid

4·

Bensodepa (AB-103)

3

Hydroxyurea

3

Doxorubicin hydrochloride (Adriamycin) and bleomycin

3

Mechlorethamine

2

Hexamethylmelamine (HXM)

2

Results of nonsurgical therapy were not impressive. Only in 17 percent of the Ill patients who received radiation therapy was regression of the tumor oJ>served; and, moreover, the longest survival was only two years. Addition of chemotherapy to radiation therapy increased the rate of response to 26 percent (10/39). All39 patients except one died within 15 months, and that one patient is alive, without evidence of disease for ll years. The results of chemotherapy were extremely poor, and in only three (3 percent) of 115 patients was regression of the tumor observed (Table 4). According to our previous studies, the median survival of patients with adenocarcinoma was 9.3 months and with small cell carcinoma was 4.5 months. It is known that squamous cell carcinoma of the lung is a less rapidly progressing tumor with a better prognosis. Surprisingly, the median survival of our 734 patients was found to be 5.9 months, and only 35 patients ( 5 percent) survived longer than &ve years. Our present study indicated that squamous cell carcinoma may be curable ( 33 percent as the five-year survival rate) only when it is in stage 1. For unresectable cases, combined radiation therapy and chemotherapy may be explored further, as chemotherapy seemed to increase the rate of response to radiation therapy, and there was one cure.

Dichloromethotrexate

9

Meturedepa (AB-132)

-The following drugs or oombinatioDS of drugs were used only once, with no response noted: dactinomycin; 5-fluorouracil; thiocarzolamide; mitomycin C and dactinomycin; imidazolyl thioguanine; bleomycin and dibromodulcitol; acetylenic carbamate; mitomycin C; triethylenethiophosphoramide (Thiotepa); cyclophosphamide (Cytoxan); CCNU 1,(2-ehloroethyl)3-cyclohexyl-1-nitroeourea (CCNU) and cyclophoephamide (Cytoxan); guanosole; Methyl-CCNU; doxorubicin hydrochloride (Adriamycin) and cyclophosphamide (Cytoxan); glucosamine; doxorubicin hydrochloride (Adriamycin); cytosine arabinoside; heumethylmelarnine and cyclophosphamide (Cytoxan); 1, (2-cbloroethyl)3-cyclohexyl-1-nitrosourea (CCNU) and BIC; epipodophyllotoxin; cytarabine (Cytoxar), 5-fluorouracil, cyclophosphamide (Cytoxan), 6thioguanine, and vincristine; and IC-140.

The incidence of hematogenous metastases to the adrenal glands, liver, bone, and brain was about half that of small cell carcinoma and adenocarcinoma. Consequently, a greater proportion of the patients underwent surgical resection. In patients with stage 1 disease (with no metastases to the lymph nodes), the five-year survival rate after curative resection was 33 percent; however, in patients with stage 2 disease, the five-year survival rate was only 3 percent ( l/34) (Table 1 ) . Table 3-Bstena of D&e.e .a Time of

m,.,.-.

Percent

Type of Cancer

Stage 1

Stage 2

Stage 3

0

1

99

Adenocarcinoma

15

5

80

Squamous cell carcinoma

26

6

68

Small cell carcinoma

CHEST, 71: 4, APRIL, 1977

5.2

lb:n:RENCES 1 Kirklin JW, McDonald JR, Clagett OT, et al: B~ genic carcinoma: Qill type and other factors relating to prognosis. Surg Gyoecol Obstet 100:429-438, 1955 2 Collins P: Bronchogenic carcinoma. Arch Surg 11:925-932, 1958 3 Taylor AB, Shinton NK, Waterhouse JAB: Histology of broochial carcinoma in relation to prognosis. Thorax 18: 178-181, 1963 4 Goldman KP: Histology of lung cancer in relation to prognosis. Thorax 20:298-302, 1965 5 Takita II, Bl'11glll0las A, MarabeDa P: Small cell carcinoma of the lung: Clinicopathological studies. J Thorac Cardiovasc Surg 66:472-477, 1973 6 Marabella P, Takita H: Adenocarcinoma of the lung: Clinicopathological study. J Surg Oncol7:205-212, 1975 7 Carr DT: A report on the development of the staging system for cancer of the lung. Proc Natl Cancer Con£ 6:817, 1970

SQUAMOUS CnL CARCINOMA OF THE LUNG 501