Extrapulmonary small cell carcinoma.

Abstract: This article reviews the recent literature on extrapulmonary small cell carcinomas. Until now, only four cases have been published in the English literature, two of those in the Southern Medical Journal. Sharing the information on diagnosis and treatment of these cases is important for better understanding and treatment of these patients. The differential diagnosis of pleural masses and the relation to asbestos exposure is briefly discussed. In addition, the available literature on other extrapulmonary localizations of small cell carcinoma is reviewed. The focus is on the available larger series of patients. Small cell carcinoma of the skin is included. This form of small cell carcinoma is often excluded from the larger review series, but can be an important alternative in the diagnostic process of patient evaluation.

Key Words: asbestos, chemotherapy, extrapulmonary, pleural disease, small cell carcinoma

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In comparison to the incidence of pulmonary small cell carcinoma (SCC), the incidence of SCC originating from other organs is very low. The available literature on these tumors is predominantly based on case reports and a few reviews of published cases or analysis of institutional data-sets. (1) Extrapulmonary SCC have been reported in several organs such as skin (Merkel cell carcinoma), the gastrointestinal system, salivary glands, genitourinary system, kidney and internal genitalia, upper respiratory system, lymph nodes, the thymus and the peritoneum. (2-7) A primary localization of a SCC in the pleura is very rare. Four case reports have been described. (8-11)

In this review, we will focus on the subject of pleural SCC and compare the findings and results with those described in the available literature on other sites of extrapulmonary SCC. Second, we will focus on skin localization of small cell carcinoma. This form of small cell carcinoma is also known as Merkel cell carcinoma, and this form of small cell carcinoma is not always included in the reviews. This subject is briefly elucidated by two cases from our clinic.

The literature on the subject of extrapulmonary small cell carcinoma is primarily based on case reports. Richardson and Weiland (4) published one of the first summaries of the available literature in 1982. We will focus on the larger series of patients with extrapulmonary localization of SCC, describing or summarizing from 6 to 600 cases published after the publication of the review by Richardson and Weiland in 1982, (4) but we have included two papers published in 1981 that were not included in their review. (2,3)

Sites of Extrapulmonary Small Cell Carcinomas

Extrapulmonary SCC are uncommon. (2,3) It is estimated that approximately 2.5% of all SCC are present in extrapulmonary sites. (5,12) In the United States, the overall incidence of extrapulmonary SCC is estimated to be between 0.1 and 0.4% of all cancers. (12)

The organs in which the primary localization of extrapulmonary SCC was found in the reviewed series of cases are listed in the Table.

In 1981, Levenson et al (2) described eight patients (4%) with exclusive extrapulmonary localization of SCC in a series of 203 consecutive patients with pulmonary SCC presented between 1973 and 1979. The primary site of SCC in these eight patients and of the literature survey (n = 70 cases) reported in this paper showed that the most frequently reported site of extrapulmonary SCC was the esophagus (22%), salivary glands (20%), larynx (17%), skin and cervix (both 13%), and stomach (6%). (2) In 1981, Pazdur et al (3) described 6 cases of primary extrapulmonary localization; the primary localization was found in salivary glands, larynx, thymus, colon, and cervix.

Remick et al (5) described 20 cases of extrapulmonary SCC in 1987. These 18 patients were identified in a database of 2000 cancer patients treated between 1969 and 1985. (5) In this study, they also reviewed the available literature at that moment in which 610 cases were identified. (5) The results from this review are summarized in the Table. Galanis et al (1) described a series of 81 patients with extrapulmonary SCC. These patients were identified in the Mayo Clinic between 1974 and 1994, and treatment and prognosis are described (1) (Table). The relative frequency of primary presentation is more diverse than the one described by Levenson et al. (2) The overall prognosis is poor, with an overall 5-year survival rate of 13%. (1)

In 2000, Ordonez (13) published a series of 28 pulmonary SCC and 54 extrapulmonary SCC cases obtained from a pathology laboratory database. The site of original presentation of these pathology-based studies is also listed in the Table. (13) From a similar source, a second series of patients is presented by Cheuk et al (14,15) in 2001. They describe a series of 52 pulmonary and 50 extrapulmonary SCC cases; this study, however, does not give detailed clinical information and is therefore not listed in the Table. (14) These two studies, (13,14) however, were designed to answer the question of which immunohistochemical patterns can be used to differentiate between pulmonary and nonpulmonary SCC, including Merkel cell carcinomas. The relative incidence of the origin of extrapulmonary SCC is likely to be influenced by this design and is therefore different from the reported data derived from clinical studies such as the study by Galanis et al. (1)

Cutaneous Small Cell Carcinoma: Merkel Cell Carcinoma

In the Mayo Clinic series, a primary localization of SCC in the skin was excluded from the review. (1) Small cell carcinoma of the skin or Merkel cell carcinoma (Figs. 1 and 2) is a form of extrapulmonary SCC but is often excluded in the above-mentioned case reviews. From the series listed in the Table, only Levinson et al (2) and Ordonez (13) included the skin localization in their series. The overall prognosis of Merkel cell carcinoma is better than the prognosis of SCC in other extrapulmonary sites, since the largest number of patients is presented in an earlier stage of disease. The recurrence rate ranges from 55 to 79% within the first 6 to 12 months. (6) This malignancy originates from Merkel cells, which are believed to be primary neural cells expressing neurosecretory (dense core) granules. Approximately 2000 cases have been reported, and recently a comprehensive review has been published. (6) Merkel cell carcinomas usually show expression of cytokeratin 20 and are negative for thyroid transcription factor-1, whereas pulmonary SCC usually express cytokeratin 7 and thyroid transcription factor-1. (13-16) Figures 1 and 2 show a case of Merkel cell carcinoma seen in our clinic during the last year. This 81-year-old female was referred to us for analysis of a possible primary pulmonary localization of SCC in conjunction with the small cell carcinoma found on her left upper arm. The tumor on her left arm had a diameter of 26 mm. The patient complained of hemoptysis and lower respiratory tract infection. She used anticoagulant treatment after a myocardial infarct and coronary bypass surgery. No pulmonary masses were found on chest computed tomography (CT) scan or the fluorodeoxyglucose-positron emission tomography scan, and no abnormalities were found during bronchoscopy. The diagnosis of stage 1 Merkel cell carcinoma was confirmed after resection and sentinel lymph node staging. We advised adjuvant radiotherapy (45 to 50 Gy). (6)

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

A second case of cutaneous small cell carcinoma was presented to our outpatient clinic after resection of a subcutaneous mass localized on the ventral thorax. In this case, pathologic evaluation of the resected lesion showed a localization of an SCC in a 78-year-old patient with concomitant adenocarcinoma of the prostate and a pathologic fracture of the acetabulum. Extensive additional investigation revealed fluorodeoxyglucose-positron emission tomography-positive lesions in the right hilar region and lymphadenopathy in the mediastinum. He was treated with 5 cycles of chemotherapy (cyclophosphamide, doxorubicin, and etoposide). Approximately 18 months after completion of the chemotherapeutic treatment, he was readmitted to our clinic, and a disseminated SCC was diagnosed with bronchoscopy and pleural fluid examination. Because of a rapid decline in performance status, chemotherapeutic treatment was withheld, and the patient died 9 days after the diagnosis of recurrent extensive disease, 22 months after the initial diagnosis obtained from a subcutaneous solitary mass.

Pleural Small Cell Carcinoma

The literature on SCC primarily found in the pleura is entirely based on case reports. In 2002, Satoh et al (8) described the second case of pleural SCC published in Southern Medical Journal. The first recorded case of pleural SCC was reported by Bouvier and Bell (9) in this journal in 1989. They described a case of pleural SCC in a 67-year-old male with a history of heavy smoking and asbestos exposure. (9) He had inappropriate antidiuretic hormone secretion syndrome, and the diagnosis was made after thoracotomy. He was treated with platinum-based chemotherapy and prophylactic cranial irradiation and survived for at least 10 months. (9) A third case of pleural SCC was published by Schinkewitch et al (10) in 1996, describing a 60-year-old male with a smoking history of 40 pack-years and no detectable asbestos exposure. This patient had a history of ipsilateral tuberculosis, lobectomy for bronchiectasis, and postsurgery empyema. Pleural SCC was diagnosed by percutaneous biopsy; no distant metastases were detected on bone scan, cerebral magnetic resonance imaging (MRI), and thoracic and abdominal CT scans. This patient was treated with chemotherapy (cis-platinum, etoposide, cyclophosphamide, and doxorubicin) and survived for more than 26 months. (10)

The fourth case was published in 2002 by our group. (11) This patient was 66 years old and had a smoking history of 40 pack-years. He had a history of asbestos exposure, and pleural plaques were present on his chest radiographs, dating back to 17 years before the diagnosis of pleural SCC. The site at which the mass developed was unchanged until 6 months before referral. The diagnosis of pleural SCC was confirmed by surgical biopsy, no distant metastases were detected by chest CT, bone scan, and after mediastinal lymph node sampling. Chemotherapy was started (cyclophosphamide, doxorubicin, and etoposide). He refused medical treatment after development of fever and died 11 days after the start of cytotoxic chemotherapy. (11)

Differential Diagnosis, Pleural Small Cell Carcinoma

The most important differential diagnosis of pleural masses is malignant mesothelioma, especially since all the reported cases of pleural SCC were found in heavy smokers (range, 30 to 70 pack-years) (8-11) and two of these four cases were found in patients with a history of asbestos exposure. (9,11) Asbestos exposure is related to an increased risk of development of asbestosis (interstitial pulmonary fibrosis) and pleural diseases such as pleural plaques, pleural thickening, and malignant mesothelioma. Pulmonary malignancies of all histologic types including small cell lung carcinoma are found in patients with asbestos exposure. (17,18) In a recent review of 500 cases of malignant mesothelioma, synchronous malignancies were detected in nine patients (1.8%). (19) From these nine patients, six had a pulmonary carcinoma (three adenocarcinomas, two squamous cell carcinomas, and one SCC). (19) Asbestos-induced pleural fibrosis is the most common radiographic finding among those exposed to asbestos. (20) The two major known risk factors for bronchogenic carcinoma are smoking and asbestos exposure, and these risk factors have a synergistic effect. Individuals who are exposed to asbestos and cigarette smoke have an approximate 30- to 50-fold increased risk for development of lung cancer. (21) To our knowledge, no new data have been published after publication of our case report describing other cases of SCC of the pleura in patients with asbestos-related pleural disease. (11) Our case report (11) underlines the need for careful analysis of radiologic alterations in patients with asbestos-related pleural abnormalities.

Another rare disease in the differential diagnosis of malignant pleural masses is a pleural localization of desmoplastic small round cell tumor. (22) Desmoplastic small round cell tumors are characterized by nests of small tumor cells surrounded by a cellular and vascular collagenous stroma, hence the name desmoplastic small round cell tumor. The amount of stroma varies with the progression of the tumor, although stroma is always seen. In the immunohistochemical presentation of this tumor, overlapping staining patterns can be found with SCC and mesothelioma, but WT1, a polyclonal antibody against the amino terminus of the WT1 protein, has shown positive staining in more than 95% of cases of desmoplastic small round cell tumors and can be used to differentiate this tumor from SCC. (22,23)

Treatment

The 3-year disease-free survival and overall survival of extrapulmonary SCC in the Mayo Clinic was reported to by slightly better than pulmonary SCC, with 26 and 38%, respectively. (1) In this analysis, patients with Merkel cell carcinomas and well-differentiated neuroendocrine cell carcinomas were excluded. (1) Extrapulmonary SCC is ultimately a fatal disease, with an overall 5-year survival of only 13%. (1) The median survival declines with progression of the disease and consequently with its treatment options. In the most recent series of patients with extrapulmonary SCC treated in the Mayo Clinic, the median survival for the patients with limited/local disease was 18 months in the surgically treated group (range, 65 days to 9 years). (1) In the combined modality treatment group (surgery and radiotherapy), a median survival of 28 months was reported (range, 13 months to 13 years). The group treated with radiotherapy only had a median survival of 11 months (range, 3 to 15 months). (1)

When the disease is limited to the organ of origin of the SCC, surgery can be curative. In analogy to the treatment of pulmonary SCC, multimodality treatment (combinations of chemotherapy and radiotherapy or surgery) should be considered in all cases of extrapulmonary SCC. Most reported chemotherapeutic regimens are platinum or doxorubicin based.

The median survival of Merkel cell carcinoma is reported to decline from 30 months for stage Ia (localized disease and diameter of skin lesion [less than or equal to]2 cm) to 5 months in stage III disease (distant metastasis). (6) The 5-year survival is approximately 64% for stage I, 47% for stage II, and 0% for stage III Merkel cell carcinoma. (6) The recommended treatment is based on the stage of the disease. For localized disease, surgery with a 2-cm margin and sentinel node biopsy is recommended, followed by adjuvant radiotherapy (45 to 50 Gy). For stage II disease, it is recommended that the radio-therapy is given to the primary site and the region of the involved lymph nodes. The experience with chemotherapy is limited. For stage III Merkel cell carcinoma, palliative radio-therapy and chemotherapy are recommended. (6)

Table. Primary disease site of extrapulmonary small cell carcinoma

                                      Levinson   Pazdur     Remick
Organ system            Organ         et al (2)  et al (3)  et al (5)

No. treated/reviewed                   8/70      6/6         20/610
Head and ear, nose,     Salivary      15 (17%)   1           32 (5%)
  and throat              glands
                        Sinusis                              26 (4%)
                        Thyroid
Upper respiratory       Larynx        12 (14%)   1           74 (12%)
                        Trachea        3                      6 (1%)
Thorax                  Pleura
                        Thymus                   1            6 (1%)
Gastrointestinal tract  Esophagus     17 (20%)               88 (14%)
                        Stomach        4 (5%)                 6 (1%)
                        Pancreas       1 (1%)                15 (24%)
                        Liver
                        Gall bladder
                        Colorectal     1 (1%)    1           73 (12%)
                        Peritoneum
Gynecologic             Cervix         9 (10%)   2          236 (37%)
                        Ovary                                13 (21%)
                        Endometrium                           5 (1%)
Genitourinary tract     Kidney                                1
                        Bladder                               4 (1%)
                        Prostate       1 (1%)                27 (4%)
                        Penis
Central nervous         Brain
  system
Skin                                  10 (11%)
Lymph nodes                            1 (1%)                 1
Other                                  3 (3%)                17 (3%)

                                      Galanis    References  Majhail
Organ system            Organ         et al (1)  8-11        et al (7)

No. treated/reviewed                  81/81      1/0-2        2/22
Head and ear, nose,     Salivary       6 (7%)
  and throat              glands
                        Sinusis        7 (9%)
                        Thyroid        1 (1%)
Upper respiratory       Larynx         4 (5%)
                        Trachea        1 (1%)
Thorax                  Pleura                   4
                        Thymus         3 (4%)
Gastrointestinal tract  Esophagus      8 (10%)
                        Stomach
                        Pancreas       7 (9%)
                        Liver          1 (1%)
                        Gall bladder   1 (1%)
                        Colorectal    13 (16%)
                        Peritoneum     1 (1%)
Gynecologic             Cervix         7 (9%)
                        Ovary          2 (2%)
                        Endometrium    1 (1%)
Genitourinary tract     Kidney                               24
                        Bladder        7 (7%)
                        Prostate       4 (5%)
                        Penis          1 (1%)
Central nervous         Brain          1 (1%)
  system
Skin
Lymph nodes                            5 (6%)
Other

Organ system            Organ         Ordonez (13)

No. treated/reviewed                   0/54
Head and ear, nose,     Salivary       2 (4%)
  and throat              glands
                        Sinusis        8 (15%)
                        Thyroid        2 (4%)
Upper respiratory       Larynx
                        Trachea
Thorax                  Pleura
                        Thymus
Gastrointestinal tract  Esophagus      1 (2%)
                        Stomach
                        Pancreas       1 (2%)
                        Liver
                        Gall bladder
                        Colorectal    11 (20%)
                        Peritoneum
Gynecologic             Cervix         3 (6%)
                        Ovary
                        Endometrium
Genitourinary tract     Kidney
                        Bladder        5 (10%)
                        Prostate       3 (6%)
                        Penis
Central nervous         Brain
  system
Skin                                  18 (33%)
Lymph nodes
Other

Accepted June 22, 2004.

References

1. Galanis E, Frytak S, Lloyd RV. Extrapulmonary small cell carcinoma. Cancer 1997; 79:1729-1736.

2. Levenson RM Jr, Ihde DC, Matthews MJ, et al. Small cell carcinoma presenting as an extrapulmonary neoplasm: sites of origin and response to chemotherapy. J Natl Cancer Inst 1981; 67:607-612.

3. Pazdur R, Bonomi P, Gould VE, et al. Neuroendocrine small cell carcinomas in miscellaneous primary sites: implications for staging and therapy. Anticancer Res 1981; 1:335-340.

4. Richardson RL, Weiland LH. Undifferentiated small cell carcinomas in extrapulmonary sites. Semin Oncol 1982; 9:484-496.

5. Remick SC, Hafez GR, Carbone PP. Extrapulmonary small-cell carcinoma: a review of the literature with emphasis on therapy and outcome. Medicine (Baltimore) 1987; 66:457-471.

6. Goessling W, McKee PH, Mayer RJ. Merkel cell carcinoma. J Clin Oncol 2002; 20:588-598.

7. Majhail NS, Elson P, Bukowski RM. Therapy and outcome of small cell carcinoma of the kidney: report of two cases and a systematic review of the literature. Cancer 2003; 97:1436-1441.

8. Satoh H, Ishikaua H, Ohtsuka M, et al. Small cell carcinoma of the pleura. South Med J 2002; 95:1221.

9. Bouvier DP, Bell B. Small cell carcinoma of the pleura. South Med J 1989; 82:1437-1438.

10. Schinkewitch P, Gasser B, Wihlm JM, et al. Small cell carcinoma of the pleura: a case report. Lung Cancer 1996; 16:87-94.

11. Van der Heijden HFM, Heijdra YF, Bulten J, et al. Pleural small cell carcinoma in pre-existent asbestos related pleural disease. Lung Cancer 2002; 35:91-94.

12. Remick SC, Ruckdeschel JC. Extrapulmonary and pulmonary small-cell carcinoma: tumor biology, therapy, and outcome. Med Pediatr Oncol 1992; 20:89-99.

13. Ordonez NG. Value of thyroid transcription factor-1 immunostaining in distinguishing small cell lung carcinomas from other small cell carcinomas. Am J Surg Pathol 2000; 24:1217-1223.

14. Cheuk W, Kwan MY, Suster S, et al. Immunostaining for thyroid transcription factor 1 and cytokeratin 20 aids the distinction of small cell carcinoma from Merkel cell carcinoma, but not pulmonary from extrapulmonary small cell carcinomas. Arch Pathol Lab Med 2001; 125:228-231.

15. Cheuk W, Chan JK. Thyroid transcription factor-1 is of limited value in practical distinction between pulmonary and extrapulmonary small cell carcinomas. Am J Surg Pathol 2001; 25:545-546.

16. Leech SN, Kolar AJ, Barrett PD, et al. Merkel cell carcinoma can be distinguished from metastatic small cell carcinoma using antibodies to cytokeratin 20 and thyroid transcription factor 1. J Clin Pathol 2001; 54:727-729.

17. Levin JL, O'Sullivan MF, Corn CJ, et al. Asbestosis and small cell lung cancer in a clutch refabricator. Occup Environ Med 1999; 56:602-605.

18. de Klerk NH, Musk AW, Eccles JL, et al. Exposure to crocidolite and the incidence of different histological types of lung cancer. Occup Environ Med 1996; 53:157-159.

19. Attanoos RL, Thomas DH, Gibbs AR. Synchronous diffuse malignant mesothelioma and carcinomas in asbestos-exposed individuals. Histopathology 2003; 43:387-392.

20. Hillerdal G. Nonmalignant pleural disease related to asbestos exposure. Clin Chest Med 1985; 6:141-152.

21. Lee BW, Wain JC, Kelsey KT, et al. Association of cigarette smoking and asbestos exposure with location and histology of lung cancer. Am J Respir Crit Care Med 1998; 157:748-755.

22. Ostoros G, Orosz Z, Kovacs G, et al. Desmoplastic small round cell tumour of the pleura: a case report with unusual follow-up. Lung Cancer 2002; 36:333-336.

23. Syed S, Haque AK, Hawkins HK, et al. Desmoplastic small round cell tumor of the lung. Arch Pathol Lab Med 2002; 126:1226-1228.

RELATED ARTICLE: Key Points

* Malignant tumors of the pleura other than malignant mesothelioma are rare, and small cell carcinoma with a primary localization in the pleura is extremely rare.

* Only four cases have been reported, two of which were published in the Southern Medical Journal.

* Small cell carcinomas in other extrapulmonary sites are also rare but less infrequent as primary pleural localization.

Henricus F.M. van der Heijden, MD, PHD, and Yvonne F. Heijdra, MD, PHD

From the Department of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Reprint requests to Dr. Erik (H.F.M.) van der Heijden, Radboud University Nijmegen Medical Centre, 549 Department of Pulmonary Diseases, PO Box 9101, 6500HB Nijmegen, The Netherlands. Email: [e-mail]