Extrapulmonary Small Cell Carcinoma: A Pictorial Review

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1 Nuclear Medicine and Molecular Imaging Original Research Howard Extrapulmonary Small ell arcinoma Special rticle Pictorial Essay ownloaded from by on 01/23/18 from IP address opyright RRS. For personal use only; all rights reserved Stephanie Howard 1 Kevin O Regan Jyothi Jagannathan Katherine Krajewski ngela Giardino Nikhil Ramaiya Howard S, O Regan K, Jagannathan J, Krajewski K, Giardino, Ramaiya N Keywords: extrapulmonary small cell, extrapulmonary small cell carcinoma, nonpulmonary small cell, oat cell carcinoma OI: /JR Received September 7, 2010; accepted after revision January 25, ll authors: epartment of Radiology, ana-farber ancer Institute, 44 inney St, oston, M ddress correspondence to S. Howard (sahoward@partners.org). WE This is a Web exclusive article. JR 2011; 197:W392 W X/11/1973 W392 merican Roentgen Ray Society Extrapulmonary Small ell arcinoma: Pictorial Review OJETIVE. Extrapulmonary small cell carcinoma (EPS) is a rare, aggressive neoplasm arising from virtually any organ. Numerous oncologic studies have addressed prognostic indicators and survival rates in EPS, however relatively little has been published regarding the imaging features and metastatic patterns of these uncommon tumors. This article provides a pictorial review of EPS in multiple organs, emphasizing the imaging appearance at presentation and the radiologic patterns of recurrence/metastasis. ONLUSION. lthough the appearance of EPS is often nonspecific, the typical presentation is large aggressive tumors that, similar to small cell carcinoma in the lung, often respond well to local therapy but tend to recur relentlessly at distant sites. T he World Health Organization classifies neuroendocrine tumors into three groups: well differentiated (true carcinoids), moderately differentiated (atypical carcinoids), and poorly differentiated (small cell carcinomas) [1]. lthough small cell carcinomas most frequently occur in the lung, 2 5% arise at extrapulmonary sites, accounting for % of all cancers [2]. Histologically, EPS is identical to pulmonary small cell carcinoma: round to spindle shaped small cells with dense nuclei, inconspicuous nucleoli, and sparse cytoplasm [2]. Given its pathologic similarity to pulmonary small cell carcinoma, it is important to ensure that newly diagnosed tumors are true primary sites of disease and not metastases from a pulmonary tumor. EPS is thought to arise either from a multipotent stem cell that develops neuroendocrine features or as a late-stage phenomenon in the genetic progression of more organ-typical carcinomas [2, 3]. Immunohistochemically, EPS shows both epithelial and primitive neuroendocrine differentiation, often staining positive for markers such as chromogranin and synaptophysin [2]. Given its rarity, epidemiologic data for EPS are limited. Little has been written regarding the T and MRI appearance of these tumors in comparison with other neuroendocrine lesions. The largest series retrospectively reviewed a cancer database in Southeast England over 34 years and found 1600 cases of EPS, with gastrointestinal origin occurring most commonly (33%) followed by genitourinary (20%), head and neck (11%), and breast (10%) [3]. Historically, staging of EPS mirrored the two-stage classification system of pulmonary small cell carcinoma, with disease considered either limited or extensive. lthough limited and extensive disease were defined differently by different groups, the commonly used Veterans dministration Lung Study Group classification defined limited disease as disease that could be contained in a single radiation port [4]. This staging has been in flux, however, with the Union for International ancer ontrol recommending in 2009 that small cell carcinoma and its extrapulmonary equivalents be handled like other pulmonary tumors, using the TNM system [5]. isease stage is the most important prognostic indicator in EPS, with a 3-year survival rate of 28% in patients with limited disease versus 9% in patients with extensive disease [3, 6]. The survival difference between patients with limited and extensive disease is more pronounced in EPS than in pulmonary small cell carcinoma [6]. lthough EP- S often responds initially to local therapy, the tumors differ from more organ-typical tumors by their tendency toward hematologic metastasis, leading to new distant metastases rather than locoregional recurrence [7]. W392 JR:197, September 2011

2 Extrapulmonary Small ell arcinoma ownloaded from by on 01/23/18 from IP address opyright RRS. For personal use only; all rights reserved The aim of this article is to review the imaging features of these tumors in multiple organs and to emphasize the tendency of these tumors to metastasize to distant, and often unusual sites. Gastrointestinal EPSs most commonly arise in the gastrointestinal tract [3, 6], with most (53 71%) gastrointestinal EPSs occurring in the esophagus followed by the colon (13%) [8, 9]. ompared with other organ systems, gastrointestinal EPSs have the worst prognosis, with one study quoting a median survival of 4.4 months and a 3-year survival rate of 7% [3, 6]. These tumors are more likely than nongastrointestinal EPSs to present with extensive disease. meta-analysis of 544 cases of gastrointestinal EPS found that more than 50% of patients presented with distant metastases [8]. This study also suggested that EPSs arising in the gastrointestinal tract share a common pattern of spread: first to the liver, followed by lymph nodes and bone marrow. Previously reported imaging features of gastrointestinal EP- S include exophytic growth pattern, minimal enhancement after contrast administration, and enhancing internal septations [9]. Gastrointestinal EPS often shows a good local response to chemotherapy radiation but tends to relapse at distant sites [8] as illustrated in Figure 1. On PET/T, EPS is typically 18 F-FG avid [10]. PET/T may be useful, therefore, in both staging and detecting and confirming new sites of disease [10]. Figure 2 shows an EPS of the transverse colon. Gynecologic Whereas more than 75% of gynecologic EPSs occur in the cervix, small cell carcinomas of the cervix are less than 3% of cervical cancers [7, 11]. retrospective review of 188 patients with cervical EPS found a median age at presentation of 42 years [11]. This study noted that these tumors tend to be large at presentation, with more than 80% of the tumors measuring greater than 2 cm [11]. ompared with other common extrapulmonary sites, gynecologic EPS has a better prognosis, with one large study reporting a median survival of 54 months [6]. Patients with gynecologic EPSs are more likely than other subsets to present with limited disease, with many studies reporting more than 80% of patients presenting with no distant metastases [6, 7]. lthough the MRI appearance of cervical EPS is nonspecific, most tumors present with locoregional spread, with one study showing 71% of cases presenting with parametrial invasion and 86% of cases having associated pelvic lymphadenopathy [12]. ervical EPS often responds well locally to radiation and chemotherapy but is much more likely than other types of cervical cancer to metastasize to distant sites [11], as seen in Figure 3. Whereas ultrasound in this case showed hypoechoic hepatic metastases, the sonographic appearance of neuroendocrine hepatic metastases is nonspecific, with hypo-, iso-, and hyperechogenic metastases reported [13]. Genitourinary Genitourinary EPS most commonly involves the bladder followed by the prostate [14, 15]. These tumors most commonly occur in men older than 60 years and are associated with a poor prognosis, yielding 5-year survival rates of 8% for bladder EPS and 1% for prostate EPS [14, 15]. On cystoscopy, bladder EPSs cannot be differentiated from more common urothelial neoplasms. It has been observed, however, that bladder EPS more commonly arises from the lateral bladder wall [14]. lthough bladder EPS often responds well to initial therapy with varying combinations of surgery, chemotherapy, and radiation, patients tend to quickly relapse at extrapelvic sites [14]. Figure 4 shows a case of bladder EPS with distant metastatic disease. Figure 5 shows a case of bladder EPS that responded to treatment and to date has not recurred. Prostatic EPS occurs rarely, comprising less than 1% of all prostate tumors [15]. t least 50% of EPSs of the prostate occur in tumors with other histologic subtypes [15]. Unlike prostatic adenocarcinoma, patients with pure small cell histology do not typically have elevated prostate specific antigens [15]. These patients usually present with obstructive urinary tract signs [15]. These tumors tend to be androgen resistant and are characterized by an aggressive course with rapid development of visceral and bone metastases and an early but nondurable response to cisplatin-based chemotherapies [15]. Figure 6 shows a case of EPS arising in the prostate gland. Miscellaneous Sites lthough EPS has been reported to arise from nearly every organ in the body [2], EPS occurring outside of gastrointestinal, genitourinary, and gynecologic sites is rare. Tumors arising from these sites behave similarly to their more common counterparts. They are often locally responsive to treatment; however, they quickly develop distant disease. Figure 7 shows an EPS of the thyroid gland [7]. onclusion This article has reviewed the imaging characteristics of primary EPSs in multiple organs. lthough the appearance of these tumors is often nonspecific, they typically present as large aggressive tumors that, similar to small cell carcinoma in the lung, often respond well to local therapy but tend to recur relentlessly at distant sites. References 1. Solcia E, Kloppel G, Sobin LH. World Health Organization international histological classification of tumours: histological typing of endocrine tumour, 2nd ed. erlin, Germany: Springer-Verlag, 2000: Frazier SR, Kaplan P, Loy TS. The pathology of extrapulmonary small cell carcinoma. Semin Oncol 2007; 34: Wong YN, Jack RH, Mak V, Henrik M, avies E. The epidemiology and survival of extrapulmonary small cell carcinoma in South East England, M ancer 2009; 9: Micke P, Faldum, Metz T, et al. Staging small cell lung cancer: Veterans dministration Lung Study Group versus International ssociation for the Study of Lung ancer what limits limited disease? Lung ancer 2002; 37: Sobin LH, ompton. TNM seventh edition: what s new, what s changed communication from the International Union gainst ancer and the merican Joint ommittee on ancer. ancer 2010; 116: Haider K, Shahid RK, Finch, et al. Extrapulmonary small cell cancer, a anadian province s experience. ancer 2006; 107: rennan SM, Gregory L, Stillie, Hershtal, Mac Manus M, all L. Should extrapulmonary small cell cancer be managed like small cell lung cancer? ancer 2010; 116: renner, Tang LH, Klimstra S, Kelsen P. Small-cell carcinomas of the gastrointestinal tract: a review. J lin Oncol 2004; 22: Lee SS, Ha HK, Kim Y, et al. Primary extrapulmonary small cell carcinoma involving the stomach or duodenum or both: findings on T and barium studies. JR 2003; 180: Gregory L, rennan SM, Stillie, et al. Impact of 18-F-fluorodeoxyglucose positron emission tomography in the staging and treatment response assessment of extra-pulmonary small-cell cancer. J Med Imaging Radiat Oncol 2010; 54: ohen JG, Kapp S, Shin JY, et al. Small cell car- JR:197, September 2011 W393

Howard ownloaded from www.ajronline.org by 37.44.206.3 on 01/23/18 from IP address 37.44.206.3. opyright RRS.

m J Obstet Gyncol 2010; 203:e1 e6 12. Yang H, Kim JK, Kim KW, ae SJ, Kim KH, ho KS.

Neuroendocrine tumors: characterization with contrast-enhanced ultrasonography. Ultraschall Med 2008; 29:506 514 14.

Small cell carcinoma of the urinary bladder: a 15-year retrospective review of treatment and survival in the nglian ancer Network.

Small cell (neuroendocrine) carcinoma of the prostate: etiology, diagnosis, prognosis, and therapeutic implications a retrospective study

1 49-year-old woman who presented with extrapulmonary small cell carcinoma of esophagus.

3 Howard ownloaded from by on 01/23/18 from IP address opyright RRS. For personal use only; all rights reserved cinoma of the cervix: treatment and survival outcomes of 188 patients. m J Obstet Gyncol 2010; 203:e1 e6 12. Yang H, Kim JK, Kim KW, ae SJ, Kim KH, ho KS. MRI of small cell carcinoma of the uterine cervix with pathologic correlation. JR 2004; 182: G E 13. orffel Y, Wermke W. Neuroendocrine tumors: characterization with contrast-enhanced ultrasonography. Ultraschall Med 2008; 29: Mukesh M, ook N, Hollingdale, insworth NL, Russell SG. Small cell carcinoma of the urinary bladder: a 15-year retrospective review of treatment and survival in the nglian ancer Network. JU Int 2009; 103: Stein ME, ernstein Z, bacioglu U, et al. Small cell (neuroendocrine) carcinoma of the prostate: etiology, diagnosis, prognosis, and therapeutic implications a retrospective study of 30 patients from the rare cancer network. m J Med Sci 2008; 336: Fig year-old woman who presented with extrapulmonary small cell carcinoma of esophagus. and, oronal () and axial () contrast-enhanced T images show poorly enhancing lobulated esophageal mass with enhancing internal septations (arrow). and, oronal () and axial () contrast-enhanced T images after treatment with chemotherapy and radiation reveal near complete resolution of esophageal mass. E, xial T1-weighted gadolinium-enhanced MR image of brain obtained at same time as posttreatment T reveals enhancing intracranial lesions (arrows), consistent with metastatic disease. Prior MRI at presentation had been normal. F, Subsequent PET/T reveals new moderately 18 F-FG-avid intramedullary focus at T3 (arrow). Maximum standardized uptake value was 2.3. G, Subsequent sagittal gadolinium-enhanced T1-weighted MR image shows enhancing intramedullary lesion (arrow) at site of prior PET avidity. F W394 JR:197, September 2011

Extrapulmonary Small ell arcinoma ownloaded from www.ajronline.org by 37.44.206.

2 34-year-old man with extrapulmonary small cell carcinoma of transverse colon.

transverse colon (arrow) with multiple T2 hyperintense hepatic metastases (arrowheads).

(arrow) with predominantly peripheral enhancement of hepatic metastases (arrowheads).

hypointense metastases with single lesion containing internal T1 hyperintensity (arrow) suggestive of

3 48-year-old woman with extrapulmonary small cell carcinoma of cervix.

, oronal fat-saturated T2-weighted image reveals lobulated T2 heterogeneous lesion, which extends into

4 Extrapulmonary Small ell arcinoma ownloaded from by on 01/23/18 from IP address opyright RRS. For personal use only; all rights reserved Fig year-old man with extrapulmonary small cell carcinoma of transverse colon., xial T2-weighted MR image reveals T2 isointense to hyperintense mass extending exophytically off transverse colon (arrow) with multiple T2 hyperintense hepatic metastases (arrowheads)., Gadolinium-enhanced axial T1-weighted MR image at same level as shows enhancement of primary mass (arrow) with predominantly peripheral enhancement of hepatic metastases (arrowheads)., xial T1-weighted MR image slightly more superiorly in liver reveals additional predominately T1 hypointense metastases with single lesion containing internal T1 hyperintensity (arrow) suggestive of blood., xial contrast-enhanced T image reveals multiple hypodense hepatic metastases (arrows). Fig year-old woman with extrapulmonary small cell carcinoma of cervix., Sagittal T2-weighted MR image shows large T2 heterogeneous mass arising from posterior cervix (arrow)., oronal fat-saturated T2-weighted image reveals lobulated T2 heterogeneous lesion, which extends into parametrium (arrow); adjacent T2 hyperintense enlarged right internal iliac lymph node is seen (arrowhead)., Sagittal PET/T image reveals intense 18 F-FG avidity in primary uterine mass (black arrow), with maximum standardized uptake value (SUV max ) of 43. White arrow points to urinary bladder., xial PET/T image reveals intense FG avidity in adjacent lymph nodes (black arrows), with SUV max of 54. (Fig. 3 continues on next page) JR:197, September 2011 W395

3 (continued) 48-year-old woman with extrapulmonary small cell carcinoma of cervix.

right lobe of liver posteriorly (arrow), which were biopsy-proven metastatic disease.

lesion is in right lobe of liver (arrows). Fig. 4 71-year-old man with extrapulmonary small cell carcinoma of bladder.

bladder wall with perivesicular extension (arrow).

perivesicular fat. Patient was treated with neoadjuvant chemotherapy and radiation and radical cystoprostatectomy.

5 Howard ownloaded from by on 01/23/18 from IP address opyright RRS. For personal use only; all rights reserved E Fig. 3 (continued) 48-year-old woman with extrapulmonary small cell carcinoma of cervix. E, xial contrast-enhanced T image shows significant decrease in size of pelvic lymphadenopathy (arrow) after treatment with chemotherapy and radiation. F, xial contrast-enhanced T obtained 6 months after diagnosis reveals multiple hypodense hepatic lesions, largest in right lobe of liver posteriorly (arrow), which were biopsy-proven metastatic disease. G, Subsequent sonographic image reveals extremely subtle hypoechoic hepatic metastases, most visible subtle hypoechoic lesion is in right lobe of liver (arrows). Fig year-old man with extrapulmonary small cell carcinoma of bladder., elayed coronal image from contrast-enhanced T urogram reveals irregular area of masslike thickening along right lateral bladder wall with perivesicular extension (arrow)., xial T1-weighted gadolinium-enhanced MR image shows avid enhancement of this lesion (arrow), which extends into perivesicular fat. Patient was treated with neoadjuvant chemotherapy and radiation and radical cystoprostatectomy. Initial T of chest, abdomen, and pelvis performed 1 month postoperatively was negative., xial contrast-enhanced T image of abdomen obtained 2 months postoperatively reveals multiple lowdensity hepatic lesions (arrows), consistent with metastatic disease., Sagittal T1-weighted MR image of spine reveals multiple areas of hypointensity within lower lumbar vertebral bodies (arrows) and enlarged retroperitoneal lymph node (arrowhead). F G W396 JR:197, September 2011

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and, oronal () and axial () gadoliniumenhanced T1-weighted MR images reveal bulky mass arising from left lateral wall of bladder (arrow, ) and extending

Initial biopsy revealed synaptophysin-positive small cell carcinoma of bladder.

Pathology at time of resection revealed no residual viable small cell carcinoma.

6 54-year-old man with extrapulmonary small cell carcinoma of prostate.

, xial chest T reveals diffuse nodularity along pleura and lymphovascular bundles, consistent with lymphangitic carcinomatosis, with multiple tiny

6 Extrapulmonary Small ell arcinoma ownloaded from by on 01/23/18 from IP address opyright RRS. For personal use only; all rights reserved Fig year-old woman with extrapulmonary small cell carcinoma of bladder. and, oronal () and axial () gadoliniumenhanced T1-weighted MR images reveal bulky mass arising from left lateral wall of bladder (arrow, ) and extending anterolaterally into perivesicular fat and posteriorly into anterior wall of vagina (arrowhead, ). Initial biopsy revealed synaptophysin-positive small cell carcinoma of bladder. Patient received neoadjuvant chemotherapy and then underwent radical cystourethrectomy. Pathology at time of resection revealed no residual viable small cell carcinoma. Patient has been followed with T of chest, abdomen, and pelvis every 6 months and is 4 years postsurgery with no evidence of disease. Fig year-old man with extrapulmonary small cell carcinoma of prostate., xial T2-weighted MR image of prostate reveals diffuse hypointensity throughout right peripheral zone of prostate (arrow)., xial chest T reveals diffuse nodularity along pleura and lymphovascular bundles, consistent with lymphangitic carcinomatosis, with multiple tiny nodules in pulmonary parenchyma, consistent with micronodular pulmonary metastases. Wedge resection revealed metastatic disease. Patient initially had mixed response to chemotherapy and radiation but soon developed rapidly progressive disease at multiple visceral sites., ontrast-enhanced axial T image of brain reveals two mildly enhancing lesions in right orbit (arrows)., ontrast-enhanced axial T image at level of parotid gland reveals peripherally enhancing parotid mass (arrow) and small enhancing nodule in subcutaneous fat of posterior cranium (arrowhead). JR:197, September 2011 W397

Howard ownloaded from www.ajronline.org by 37.44.206.

, oronal contrast-enhanced T image reveals large predominantly

involving right aspect of thyroid (arrow).

18F-FG avid mass in right thyroid (arrows), with maximum standardized

bsence of central FG avidity is consistent with necrosis.

axial fused PET/T images reveal near-complete resolution of primary

7 Howard ownloaded from by on 01/23/18 from IP address opyright RRS. For personal use only; all rights reserved Fig year-old man with extrapulmonary small cell carcinoma of thyroid., oronal contrast-enhanced T image reveals large predominantly peripherally enhancing lesion in right lobe of thyroid (arrow) with enhancing internal septations., oronal STIR MR image reveals predominately T2 hyperintense mass involving right aspect of thyroid (arrow). and, oronal () and axial () fused PET/T images reveal intensely 18F-FG avid mass in right thyroid (arrows), with maximum standardized uptake value (SUV max ) of bsence of central FG avidity is consistent with necrosis. E and F, fter patient was treated with chemotherapy and radiation, axial fused PET/T images reveal near-complete resolution of primary mass (E) but new intensely FG-avid hepatic lesion (arrow, F), consistent with metastasis. SUV max was 9.5. G and H, Subsequent unenhanced (G) and contrastenhanced (H) axial T images confirm hypodense metastasis (arrows). G H E F W398 JR:197, September 2011

Recurrent Ovarian Cancer: Spectrum of Imaging Findings

Recurrent Ovarian Cancer: Spectrum of Imaging Findings Recurrent Ovarian Cancer Women s Imaging Pictorial Essay Downloaded from www.ajronline.org by 80.243.130.157 on 03/08/18 from IP address 80.243.130.157. Copyright RRS. For personal use only; all rights