Correspondence and requests for reprints：Dr. Kuan-Der Lee
Address：Department of Hematology and Oncology, Chang Gung Memorial Hospital, 6 West Sec, Chia-Pu Road, Pu-Tz city, Chiayi 613, Taiwan
Extrapulmonary Small Cell Carcinoma：A Review
Chang-Hsien Lu1, Wen-Chi Chou2, Chih-Chen Chen1, Jen-Tsun Lin1, Chung-Huang Chan1, and Kuan-Der Lee1
1Division of Hematology & Oncology, Department of Internal Medicine, Chang-Gung Memorial Hospital, Chia-yi, Taiwan;
2Division of Oncology, Department of Internal Medicine, Saint Paul's Hospital, Taoyuan, Taiwan
Introduction
Small cell lung cancer (SCLC) accounts for approximately 15-20% of bronchogenic cancers in the United States1. In Taiwan, there are annually 750-800 new cases, which represent about 10% of all lung cancers2. This type of cancer is chara- cterized by an increased propensity for early distant metastases and poor prognosis3. Small cell carcinomas (SCCs) may also originate in non- pulmonary organs. Duguid and Kennedy first reported in 1930 two cases of mediastinal oat cell
tumor where autopsy failed to reveal pulmonary involvement4. Since then, numerous sites of small cell carcinoma have been documented, most commonly seen in the head and neck5, gastro- intestine6,and genitourinary system7. Small cell cancers were occasionally reported in breast, thyroid, skin, and thymus8. Rarely, the primary site is undetermined, making such tumors known as small cell carcinoma of unknown primary9,10. In general, they are classified as "extrapulmonary
Abstract
Extrapulmonary small cell carcinoma (EPSCC) is a relatively rare malignancy accounting for only 2.5~4% of all small cell carcinomas. The head and neck, gastrointestinal tract, genitourinary and gynecologic organs are most common tumor sites. EPSCC behaves aggressively like the small cell lung cancer (SCLC) and its prognosis is dismal. Its tumorigenesis and molecular alternations remain poorly understood. The clinical diagnosis, staging and treatment of EPSCC are challenging. The extent of disease is important for prognosis whereas the tumor location affects the choice of treatment modality. Currently there is no standard guideline as yet. Combined modality (surgery, radiation or chemotherapy) treatment has often been applied to limited-stage EPSCCs in which long-term survivors have ever been reported.
However, the sequence of these combinations is not well-defined. Palliative chemotherapy is used for extensive and recurrent/ metastatic EPSCCs with high response rate but short progression-free interval.
More research is warranted for improving the survival. ( J Intern Med Taiwan 2009; 20:294-300 ) Key Words：Extrapulmonary small cell carcinoma (EPSCC), Small cell lung cancer (SCLC)
small cell carcinoma" (EPSCC), encompassing 2.5-4% of all SCCs11,12.
EPSCC is defined as biopsy-proven small cell carcinoma from non-pulmonary primary site. By definition, a plain chest radiography or computed tomography scan should reveal no evidence of tumor in lung. The sputum cytology and/or bron- choscopy are negative for malignant cells8. Irrespective of the origin, EPSCCs resemble their pulmonary counterpart with regard to morphology, immunohistochemistry and electron microscopic features. Moreover, the cytogenetic and molecular abnormalities detected in EPSCCs are similar to the primary SCLC and other carcinomas typically encountered in the organ involved. The differen- tiation between primary and metastatic EPSCCs as well as other types of neuroendocrine tumors is thus a clinical challenge. Because EPSCCs are rare cancers, there are no well-established clinical trials to establish treatment guideline as yet. Herein, we review the literature in EPSCC in respects to its histology, site of occurrence, cytogenetic and molecular alterations, staging, treatment and prognosis.
Histology
Small cell carcinomas, regardless of the site of origin, share the similarity in their histology. They are characterized as round to spindle-shaped small cells with dense nuclei, inconspicuous nucleoli, and sparse cytoplasm under light microscopy. SCCs have a high mitotic index, grow in sheets and trabecular patterns, and may contain areas of necrosis8. SCCs are classified as part of the neuroendocrine family of tumors containing neurosecretory granules in which only electron microscopy can identify9.
The immunophenotypes of EPSCCs suggest both epithelial and primitive neuroendocrine differentiation. It is not surprising that EPSCC cells possess positive stains for the common neuroen-
docrine markers like neuron-specific enolase (NSE), neurofilament, synaptophysin and the specific marker of neuroendocrine differentiation, chromogranin-A. Besides, ESPCC cells may also be stained diffusely for general epithelial markers such as keratin. Thyroid transcription factor-1 (TTF-1) has been used widely to differentiate primary and metastatic pulmonary adeno- carcinoma13,14, however, it could not differentiate pulmonary from extrapulmonary small cell carcinomas15. TTF-1 is useful for differentiating small cell carcinomas from other types of neuroen- docrine tumors14,16,17 because EPSCC cells generally stain positive for TTF-1 while other extrapulmonary neuroendocrine tumors do not.
EPSCCs were once thought to come from the amine-precursor uptake and decarboxylase (APUD) cells but this theory was questioned by the concomitance of heterogeneous tumor cells composing of both small cells and epithelial cells. It is more accepted that EPSCCs could originate from multipotential stem cell cells with the capability of divergent differentiation18-20.
Site of Occurrence
EPSCC can occur in almost every organ. Most reports were retrospective showing the most common locations were the head and neck, gast- rointestinal tract, genitourinary and gynecologic system8,12,21-24. Galanis et al. reported a series of 81 EPSCC patients treated in Mayo clinic and 36% of the primary disease originate from gastrointestinal tract, 17% from head and neck, 15 % from genitourinary and 12% from gynecologic system8. In a large series of 101 EPSCC patients in Canada, Haider et al. reported that 20% of cases were from gastrointestinal origin, 10% from head and neck, 18% from genitourinary tract, 11% from gynecologic organs, and 31% from the unknown primary site21. Lee et al. reported in a series of 61 patients with EPSCC in South Korea that the most
common primary sites were the gastrointestinal tract (56%) and uterine cervix (18%)22. Lin et al. also reported a series of 90 EPSCC patients in Taiwan23. They found gastrointestinal origin (30%), genitourinary (11%), gynecologic system (30%) and head and neck (19%). Among 544 cases of gastrointestinal SCC, Brenner et al. found appro- ximate 70% arise in the upper gastrointestinal tract where esophagus is the most common location (56%), especially in its lower two thirds6.
Cytogenetic and Molecular Alterations
Despite small cell carcinomas share similar morphology, they differ cytogenetically. For example, loss of chromosome 3p is common in SCLC but rare in EPSCC25. Cytogenetic abnorm- alities, such as microsatellite instability, loss of heterozygosity and chromosome deletion or loss have been reported in EPSCCs from gastrointestinal tract, gallbladder, cervix, urinary bladder and breast20. Additionally, some molecular alterations were shared by SCLC and EPSCC such as p53 over-expression, Rb inactivation, increased bcl-2 expression, c-myc amplification, telomerase activ- ation and k-ras mutation6,20.
Clinical Presentation and Diagnosis
EPSCC was usually found in patients at 60-70 years of age23, with a slight preponderance in males8,21. A significant male predominance (male:
female, 6-7:1) occurs in gastrointestinal SCC6, while a reverse incidence (male: female, 1:3.4) was found in renal SCC26. Smoking and alcohol had been presumed as risk factors for EPSCC but were not verified.
The clinical presentation of EPSCC is associ- ated with the location. SCC shows the tendency of rapid growth, local invasion and early metastases.
Paraneoplastic syndromes, akin to SCLC, may accompany with EPSCC29,30.
The final diagnosis of EPSCC is made only by
biopsy. A careful assessment should include brain CT/MRI and bone scan for exclusion of central nervous system and bone metastases. A bone marrow exam is suggested especially for those patients with cytopenia31. The differential diagnosis of EPSCC should include metastatic SCLC, other types of neuroendocrine or carcinoid tumors, Merkel cell tumors, metastatic melanoma, lymphoma and poorly differentiated carcinoma.
Carcinoid can be easily distinguished from EPSCC by distinct morphological features20. Merkel cell carcinoma is morphologically similar to SCC but lacks TTF-1 expression and also displays a chara- cteristic perinuclear CK-20 immunostaining15,32. Melanoma and lymphoma could be easily identified by their specific markers such as S-100, HMB-45 and CD45. Other small round blue cell tumors, including rhambdomyosarcoma, Ewing's sarcoma, mesenchymal chondrosarcoma, olfractory neuro- blastoma, small cell osteosarcoma should be differ- entiated by immunophenotypes and ultrastructures33.
Staging
There is no established system for EPSCC staging. Most clinicians adopt the two-stage classification used for SCLC. The limited-stage represents SCC confined to the primary site and surrounding organs which can be encompassed within a tolerable radiation therapy port. The extensive-stage applies to SCC that is beyond the extent of limited-stage34. The survival rate is impacted by the extent of disease. Unfortunately, over 50% of EPSCC cases present as extensive- stage at diagnosis6,8,21-23.
Treatment and Prognosis
Currently there is no standard guideline for EPSCC treatment because of its rarity and limited experience in the management. Most concepts of treatment follow the SCLC. For example, chemotherapy is the mainstay of treatment for
extensive-stage. For limited-stage, the sequence of surgery, radiotherapy and chemotherapy, as well as the role of single or combined modality, is still less- defined. In contrast to SCLC, which upfront surgery is uncommon even for limited-stage, the EPSCC has often undergone a curative-intent resection first.
The median survival for those whom received surgical resection followed by adjuvant treatment was longer than those without resection6,8,12,22,28,35-37. Nevertheless, it is still controversial for the role of combined modality with radiotherapy and chemo- therapy. One large study revealed no difference in overall survival for limited-stage EPSCC treated with combined modality versus single treatment21.
Chemotherapy is the treatment of choice for patients with relapse or metastasis and who has the extensive-stage EPSCC. Platinum- or adriamycin- based regimens are the most common protocols with a response rate of 30% to 90%. But the progre- ssion-free interval is usually short. Lin et al. reported that there was no significant difference in patient outcome among different chemotherapy regimens23.
Interestingly, brain metastasis is less common in EPSCC compared to SCLC28. Although prophy- lactic cranial irradiation has been suggested for the complete responder of SCLC38, however, there are insufficient data to suggest prophylactic cranial irradiation for EPSCC8,28.
EPSCC is considered a fatal disease with 3-year survival rate around 30% and 5-year survival rate 11-13%8,12,22,39. Patients with untreated EPSCC have a dismal outcome and the survival ranges from weeks to 3 months21-23. With treatment, patients with EPSCC have the median survival of 8-16 months12,21,22,25,39. The extent of disease is an impo- rtant prognostic factor in which the limited-stage has better survival. Most patients with limited disease survived over 2 years, compared to 2~9 months in patients with extensive disease6,8,21-24,39. EPSCC originated from gynecologic organs, especially the uterine cervix, and the head-and-neck
have more favorable outcome12,21-24. This can be partly attributed by the early detection and intensive treatment in these two areas22-24. ESPCCs from gastrointestinal tract are usually more extensive at diagnosis and have worse survivals8,22,23. EPSCC of unknown origin also has a shorter survival10,21. Combined modality treatment has been found an independent predictor of survival in one study23 but unfortunately it shows no better survival benefit over single treatment in the other study21. The disease characteristics, treatment and survival are summarized in Table 1.
Conclusion
The diagnosis and treatment of EPSCCs remain challenging. Combined modality preferred in the treatment of limited-stage disease but the sequence remains unclear. Concurrent chemoradiation needs to be further explored in this setting. Palliative chemotherapy is the mainstay for extensive-stage and relapse but new agents and targeted therapy should be tested. Prospective trials are warranted to help the establishment of treatment guidelines in the future.
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Table 1
Study Van Der Gaast35 Lo Re G36 Galanis8 Sengoz39 Haider 21 Year (country) 1990 (Netherland) 1994 (Italy) 1997 (US) 2003 (Turkey) 2006 (Canada)
Patient number 11 24 81 16 101
Median age 55 60.5 63 62 72
Primary site
HEENT 1 5 14 1 12
GI 5 1 29 5 20
GU 0 11 12 3 18
GYN 2 2 10 3 11
MUO 3 5 8 4 31
Others 8 (resp. tract & thymus) 9 (breast)
LD/ ED 5 / 6 >50% 54 / 17 9 / 7 51 / 50
Treatment#
Single 7 9 48* 0 48
Multimodality 4 6 6 16 26
No treatment 0 NS NS 0 24
MSAll 12 NS NS 14 9.83
LD 3 year OS: 38% 25 34
ED 5 year OS: 13% 12 2
Study Cicin28 Kim12 Lee22 Huang24 Lin23
Year (country) 2007 (Turkey) 2004 (Korea) 2007 (Korea) 2006 (Taiwan) 2007 (Taiwan)
Patient number 11 24 61 20 90
Median age 56 53 67 56 62
Primary site
HEENT 0 3 5 5 17
GI 5 7 34 3 27
GU 3 7 6 4 10
GYN 1 7 12 7 27
MUO 2 0 4 9
Others 1(thymus)
LD/ ED 3 / 8 16 / 8 37 / 24 12/ 8 49 / 41
Treatment#
Single 9 12 22 2 35
Multimodality 2 11 25 18 45
No treatment 0 1 -- 10
MS All 32 15.3 16 NS NS
LD NS 23 22 No treat (1.1)
ED 9.6 6 3 Single (13.8, 6.7)**
Multimodality(24.9) HEENT = Head, eyes, ears, nose, throat; GI = gastrointestinal; GU = genitourinary; GYN = gynecological; MUO = unknown origin cancer LD = limited disease; ED = extensive disease; MS= median survival, NS= not shown
#Single treatment means surgery, radiotherapy or chemotherapy alone as primary treatment.
Multimodality treatment means combination of more than one single treatment.
*Only limited stage disease patients
**Radiation or chemotherapy alone respectively
肺外小細胞癌
呂長賢1 周文其2 陳志丞1 林正純1 詹宗晃1 李冠德1
1
財團法人長庚紀念醫院嘉義分院 內科部血液腫瘤科
2
財團法人桃園聖保祿修女會醫院 內科部腫瘤科
摘 要
肺外小細胞癌是種少見的惡性腫瘤，占所有小細胞癌的2.5-4%。常見好發部位為頭頸部，
腸胃道，泌尿生殖器官與女性生殖系統。臨床表現與肺小細胞癌類似，相當惡性且預後不 佳。肺外小細胞癌的致癌機轉與其生物分子變化不明。臨床上對於其診斷，分期與治療是一 難題。疾病的分期是最重要的存活因子。治療計畫也需考慮腫瘤原發部位。因其少見與治療 經驗不足，目前尚未發展治療準則。對於局部腫瘤通常採合併治療，偶見長期存活的患者。
但如何併用與治療順序尚待研究。對於廣泛性與復發轉移的患者則使用化學治療。雖其反應 率高，但效果持續短暫。更多的基礎與臨床研究將有助於改善其治療結果。
