A case of synchronous double primary neuroendocrine lung cancer

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A case of synchronous double primary neuroendocrine lung cancer

  1. 1. Jpn J Clin Oncol1999;29(4 )219-225 A Case of Synchronous Double Primary Lung Cancer with Neuroendocrine FeaturesSeiji Niho 1,2, Tomoyuki Yokose2, Kanji Nagai1, Yutaka Nishiwaki1, Tetsuro Kodama 3 and Kiyoshi Mukai21Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, 2Pathology Division, NationalCancer Center Research Institute East, Chiba and 3Department of Internal Medicine, National Cancer CenterHospital, Tokyo, Japan We report a case of unique double primary lung cancers with neuroendocrine features in a 63-year-old male smoker. The mass in the left lower lobe (LLL) was a small cell/large cell carcinoma with spindle cell sarcomatous areasand organoid structure. The massin the leftupper lobe (LUL) was a tubular adenocarcinoma with neuroendocrine features including organoid nests showing occasional rosette formation, nuclear palisading in the periphery ofthe nests and positive immunoreaction for CD56, chromogranin A and synaptophysin. The difference in histological Downloaded from http://jjco.oxfordjournals.org/ by guest on March 28, 2013 structures between the two masses led us to diagnose double primary lung cancer. The combination of small cell lung carcinoma and spindle cell carcinoma is very uncommon. The relationship between LLL and LUL tumors remains unclear. Multiple lung cancers with neuroendocrine features have only rarely been reported in the literature. The patient in our case diedof widespread cancer2 years and4 months afterthe surgery without adjuvant chemotherapy, a longer postoperative survival time than in cases of ordinary extensive small cell lung cancer. Multiple lungcancers with neuroendocrine features are extremely rareandsimilarcaseshavenot been reported in the literature. Neuroendocrine differentiation hasattracted widespread attention and, therefore, examining neuroendocrine features in lung cancers is important. Key words: small cell carcinoma - spindle cell carcinoma - double primary lung cancers - adenocarcinoma - neuroendocrine featureINTRODUCTION combined type (2). The International Association for the Study of Lung Cancer (IASLC) redefined the subtypes in 1988 as smallThe classification of neuroendocrine tumors of the lung used to cell carcinoma, mixed small cell/large cell carcinoma andbe complex and confusing. Recent!y, Travis et al. (1) reported the combined small cell carcinoma (3). Almost all combined SCLCsfollowing spectrum of pulmonary neuroendocrine (NE) lesions: contain a component of squamous cell carcinoma or adenocarci-(i) minute NE lesions, (ii) common neoplasms with an NE light noma; however combinations can occur with spindle cellmicroscopic appearance, (a) typical carcinoid, (b) atypical carcinoma (4) and giant cell carcinoma (5) We present a case ofcarcinoid, (c) large cell NE carcinoma and (d) small cell lung double primary lung cancers with NE features, one tumorcarcinoma, (iii) non-small cell lung carcinoma with NE features consisting of small cell/large cell lung cancer combined withand (iv) uncommon primary NE neoplasms. The classification of spindle cell sarcomatous lesions and the other an adenocarcinomasmall cell lung carcinoma (SCLC) has changed over time. The with NE features in a different lobe.World Health Organization (WHO) defined the subtypes ofSCLC in 1981 as oat cell type, intermediate cell type and CASE REPORT A 63-year-old man was admitted to the National Cancer CenterReceived September 11, 1998; accepted December 21, 1998 Hospital East in October 1994 because of cough, sputum andFor reprints and all correspondence: Seiji Niho, Division of Thoracic hemoptysis. He had smoked 20 cigarettes daily over 40 years. TheOncology, National Cancer Center Hospital East, 5-1, Kashiwanoha patients mother died of leukemia at the age of 38. Laboratory6-chome, Kashiwa, Chiba 277-8577, Japan. E-mail: siniho@east.ncc.go.jp data were within normal limits except for a low serum albuminAbbreviations: LLL, left lower lobe; LUL, left upper lobe; NE, (2.9 g/dl) and elevated CEA (7.2 ng/ml). Chest radiographyneuroendocrine; SCLC, small cell lung carcinoma; WHO, World Health revealed a round nodule in the left lower lobe (LLL). Bronchos-Organization; IASLC, International Association for the Study of LungCancer; CEA, carcinoembryonic antigen; MRI, magnetic resonance copic examination showed a white polypoid mass obstructing theimaging; ABC, avidin-biotin complex; Sp-A, surfactant apoprotien A; LLL bronchus. The biopsy specimen contained malignant cells;Sp-D, surfactant apoprotein D; GRP, gastrin-releasing peptide however, the cell type could not be determined because of the © 1999 Foundation for Promotion of Cancer Research
  2. 2. 220 Lung cancer with neuroendocrine features Downloaded from http://jjco.oxfordjournals.org/ by guest on March 28, 2013Figure 1. (a) Macroscopic findings for LLL tumors. A yellow- white well definedmass measuring 14 x 10.5 x 8 em in the LLL was compressing the surroundingnormal lung parenchyma with formation of a capsule-like structure. (bHe) Microscopic findings for LLL tumor. Small cell component consists of smallcells withlargeN/Cratio,scantycytoplasm andfinely granular nuclearchromatin withhighmitoticactivity (b). Cellsin smallcell/large cellcomponent have eosinophilic largercytoplasmand vesicular nucleuswithdistinctnucleolus (c). Organoid components form welldemarcated roundto ovoidclusters resembling atypical carcinoidin thebackground of smallcell/large cells or spindlecells(d).Sarcomatous components havespindle-shaped cellsof VaI;OUS sizes(e).Hematoxylin andeosinstain;originalmagnifications, x333 (b, c), x l67 (d), x130 (e).small size of the specimen. Computed tomography of the chest of the lung was also resected because another nodule was foundshowed no enlargement of the mediastinal or hilar lymph nodes. in the LUL during the operation. Radiation therapy to the brainMagnetic resonance imaging (MRI) of the brain showed a 6 x 6 was performed when the brain mass was found to have grown tomm solitary mass in the right cerebellar hemisphere. The LLL 14 x 14 mm on MRI in January 1995, suggesting a brainwas resected in December 1994. Part of the left upper lobe (LUL) metastasis. After 50 Gy of radiation to the brain, the nodule could
  3. 3. Jpn J Clin OncoI1999;29(4) 221 Downloaded from http://jjco.oxfordjournals.org/ by guest on March 28, 2013Figure 2. (a) Macroscopicfindings for LLL and LUL tumors. A white round nodulemeasuring2.1 x 1.7 x 1.5 em was presentin the LUL(S1+2) with a clear margin.(b), (c) Microscopicfindings for LUL tumor. The tumor consists of glandularstructure lined by tall columnar cells with hyperchromatic nucleiand coarse-granularchromatin (b). There were organoid nests showing occasional rosette formation (c). Hematoxylin and eosin stain; original magnifications, x83 (b), x4 10 (c).no longer be detected on MRI of the brain. No chemotherapy was protein (Dako), Factor VIII (Dako), p53 (Nichirei, Tokyo, Japan)given. Left leg pain occurred in February 1997 due to bone and Rb (MK-15-1 , MBL, Nagoya, Japan).metastasis. Computed tomography of the chest showed multiple A yellow-white, well defined mass measuring 14 x 10.5 x 8 cmpulmonary metastases. Dyspnea developed and the patient died in S10 of the LLL was compressing the surrounding normal lungin February 1997, 2 years and 4 months after the operation. An parenchyma with formation of a capsule-like structure; the centerautopsy was not performed. of the mass revealed extensive hemorrhage and necrosis . (Fig. We performed an immunohistochemical analysis to the for- 1a). The LLL showed poor aeration and moderate anthracosis andmalin-fixed, paraffin-embedded sections by the avidin-biotin fibrosis , especially beneath the pleura, but no emphysema.complex (ABC) method (6). Biotinylated secondary antibody A round, white nodule measuring 2.1 x 1.7 x 1.5 em and havingand ABC reagents were purchased from Dako Japan (Kyoto, well defined margins was found in Sl+2 of the LUL . The tumorJapan). Primary antibodies used were against keratin (AE1/AE3, was solid and there was no evidence of hemorrhage or necrosis.Dako, Dakopatts, Glostrup, Denmark; CAM5.2, Becton Dickin- A sharp pleural indentation was detected (Fig. 2a).son, San Jose, CA, USA), surfactant apoprotien A (Sp-A) (PE-lO, The LLL tumor was largely necrotic, but there were viableDako), surfactant apoprotein D (Sp-D) (6B2, Yamasa, Chiba, tumor cells in the periphery. It consisted of four components:Japan), CD56 (Lu243, Nippon Kayaku, Tokyo, Japan), chromo- small cell, large cell, organoid and sarcomatous . The small cellgranin A (Dako) , synaptophysin (Dako), CDS7 (Leu7, Becton component was composed of oval to spindle-shaped cells slightlyDickinson), gastrin-releasing peptide (GRP) (Dako), serotonin larger than lymphocytes and having a large N/C ratio, scanty(SHT-H209, Dako), calcitonin (Dako) , CEA (011, Mochida, cytoplasm and oval nuclei with fmely granular chromatin but noTokyo, Japan), vimentin (V9, Dako), myoglobin (Dako), desmin nucleoli (Fig. 1b). The large cell component consisted of(033, Dako) , alpha-smooth muscle actin (lA4, Dako), S-lOO polygonal to round cells that were larger than the cells in the small
  4. 4. 222 Lung cancer with neuroendocrine features cell component and they contained abundant eosinophilic cyto- columnar cells. The tumor cells contained relatively abundant plasm and a vesicular nucleus with one or two prominent nucleoli eosinophilic cytoplasm and hyperchromatic nuclei with coarse- (Fig. 1c). Small cells and large cells were frequently intermingled. granular chromatin and distinct eosinophilic nucleoli (Fig. 2b). Both types of cells had high mitotic activity [22/10 high power Mitotic activity was high (25/10 HPF). The stroma was scant. The field (HPF)] and clusters of pure small cell carcinoma cells were tumor had a focal solid growth area with organoid nests showing also observed focally. In the organoid component, the neoplastic occasional rosette formation (Fig. 2c). Nuclear palisading was also cells formed well demarcated round to ovoid clusters resembling seen in the periphery of the nests. No lymphatic permeation or atypical carcinoid in the background with small cell/large cells or vascular invasion was observed. Hilar lymph nodes contained no spindle cells (Fig. 1d). The cells forming the organoid structure metastatic tumors. Mediastinal lymph nodes were not explored. were polygonal to spindle shaped and had a fmely granular nucleus The results of the immunohistochemical analysis are shown in with one or two prominent nucleoli. Mitotic activity was high Table 1. The small cell/large cell component. of the LLL was (24/10 HPF). The sarcomatous cells were spindle shaped and their diffusely positive for CD56 (Fig. 3a) and chromogranin A and nuclei were variable in size and contained coarse chromatin with partially positive for keratin.. The organoid component was one or two prominent nucleoli (Fig. Ie). The small cell/large cell positive for CD56, chromogranin A, synaptophysin (Fig. 3b), carcinoma, spindle cell sarcomatous carcinoma and organoid GRP and CEA. The sarcomatous component was positive for components were highly intermingled with areas of transition vimentin (Fig. 3c) and some spindle-shaped also cells showed an between them; the proportions of these components were about 65, immunoreaction for keratin (Fig. 3d). The LUL tumor was Downloaded from http://jjco.oxfordjournals.org/ by guest on March 28, 2013 30 and 5%, respectively. No lymphatic permeation or vascular positive for CD56, chromogranin A (Fig. 4), GRP, calcitonin, invasion was observed. The remaining non-neoplastic pulmonary CEA and keratin. The positive rates for p53 were 79% of the cells parenchyma showed no evidence of carcinoid tumorlets or in the small cell/large cell component, 13% in the organoid neuroendocrine cell hyperplasia. component, 80% in sarcomatous component and 8% in the LUL The LUL tumor had a clear margin and showed expansive tumor. Rb was positive only in the LUL tumor (30%) and growth. It consisted of irregular-shaped glands lined by tall negative in all components of the LLL tumor. Table 1. Immunohistochemical profiles of left lower lobe and left upper lobe tumors Antigens LLL tumor LUL tumor S/L Organoid Sarcomatous Keratin (AEI/AE3) + (partly) ± + Keratin (CAM5.2) ± + + +++ Sp-A + (partly) Sp-D CD56 + + + Chromogranin A + + Synaptophysin + +++ CD57 GRP + + (partly) Serotonin Calcitonin + CEA + + Vimentin + Myoglobin Desmin Alpha-smooth muscle actin S-IOO protein Factor VIII p53* 79% 13% 80% 8% Rb* 30%LLL, left lower lobe; LUL, left upper lobe; S/L, small cell/large cell carcinoma; Sp-A, surfactant apoprotein A; Sp-D, surfactant apoprotein D; GRP, gastrin-releasingpeptide. *The percentage of immunoreactive cells counted in 500 cells.
  5. 5. Jpn J Clin OncoI1999;29(4) 223 I Downloaded from http://jjco.oxfordjournals.org/ by guest on March 28, 2013 I / - l,.: " .. . ; "/ ,~ " I " .: . ~1.J: ; ~ If. ;r" .,- ," , / ., • > ." " J; - / ,- - . /{. , . {. I ." ( . . . . .~ " 0# , ~ I ( . I . Figure 3. Immunohistochemical findings for LLL tumor. Small cell/large cell component was diffusely positive for CD56 (a), Organoid component was positive for synaptophysin (b). Sarcomatous component was positive for vimentin (c) but some spindle-shaped cells showed immunoreaction for keratin (d). Original magnification, x4 1O.DISCUSSIONOur differential diagnosis of the LLL tumor was (i) small cellcarcinoma with spindle cell component, (ii) large cell NEcarcinoma and (iii) atypical carcinoid. The high mitotic activity(22/10 HPF) ruled out atypical carcinoid, although some parts ofthe LLL tumor showed features resembling atypical carcinoid,such as an organoid growth pattern, tumor cells containingmoderately eosinophilic, finely granular cytoplasm and nucleipossessing finely granular chromatin. Small cell carcinoma waspreferred over large cell NE cancer because the LLL tumorconsisted mainly of two kinds of cells, small-sized tumor cellswith a high N/C ratio and large-sized polygonal to round tumorcells with one or two prominent nucleoli . In addition, the smallcells and large cells were highly intermingled and clusters of puresmall cell carcinoma cells were also observed focally, Wetherefore concluded that the LLL tumor was a mixed small Figure 4. Immunohistochemical findings for LUL tumor. It was positive for chromogranin A. Original magnification, x41O.cell/large cell carcinoma, one of the subtypes of small cell lungcarcinoma in the IASLC classification (3), Spindle cell carcinoma has been found most often in associ- and infrequently with small cell carcinoma (7). Tsubota et al. (4)ation with giant cell carcinoma and adenocarcinoma, less reported a case of combined small cell (pure type) and spindle cellfrequently with large cell carcinoma or squamous cell carcinoma carcinoma of the lung. The spindle cell carcinoma was predomi-
  6. 6. 224 Lung cancer with. neuroendocrine features nant and immunoreactive for smooth-muscle actin, but not for NE The survival time in our case was 2 years and 4 months without markers, in their case, whereas the small cell/large cell compo- chemotherapy, longer than in ordinary small cell lung cancer (10). nent in our case occupied more of the tumor than the spindle cells. The median survival for limited stage small cell lung cancer treated Moreover, the spindle cell sarcomatous area in our case did not by surgery alone has been reported to be about 6 months (11). show clear NE features or differentiation to mesenchyme but Tsubota et al. did not comment on the outcome of their case of a exhibited epithelial differentiation, indicating poorly differen- combined small cell and spindle cell carcinoma of the lung. Small tiated carcinoma or sarcomatoid change of carcinoma. The cell lung cancer has a poor prognosis although it is sensitive to spindle cell sarcomatous component was immunohistochemi- chemotherapy and radiation. In contrast to small cell lung cancer, cally positive for p53 and the frequency of positive cells was spindle cell carcinoma is also generally considered to have a poor almost same as in the small cell/large cell component, suggesting prognosis and to be resistant to irradiation and chemotherapy that although their phenotypes were different, a similar genetic (12,13). The metastatic brain tumor in our case was as sensitive to abnormality may have occurred in both. radiation therapy as small cell lung cancer; however, it recurred 2 We considered three possible diagnoses for the LUL mass: years after surgery, a much longer latent period than in ordinary (i) moderately differentiated adenocarcinoma, tubular type, with NE small cell lung cancer. No lymph node metastasis was observed in features, (ii) combined adenocarcinomaand large cell NE carcinoma our case despite the large tumor, a finding also different from usual small cell lung cancer. The reason for the comparatively good and (iii) metastatic carcinoma from the LLL tumor. The LUL tumor outcome in our case remains unclear. Two-year disease-free exhibited glandular structures lined by tall columnar cells and Downloaded from http://jjco.oxfordjournals.org/ by guest on March 28, 2013 survivors represented 13% of patients presenting with limited organoid nests of large pleomorphic cells with rosette formation and small cell lung cancer but only 2% of those with extensive disease nuclear palisading. The latter pattern may be seen in large cell NE (10). More than 80% of 2-year survivors of small lung cell lung carcinoma (1); however, the clear glandular differentiation favored cancer have been found to have received chest irradiation and adenocarcinoma rather than large cell NE carcinoma. almost all extensive disease patients had metastases confmed to a Immunohistochemical testing yielded different characteristics single organ system (11). In our case, however, the brain was the in the LUL and LLL tumor. Calcitonin and Rb were positive only only metastatic site at the time of presentation. Hardly any in the LUL tumor. Furthermore, the LLL tumor exhibited no long-term survivors of resected small cell lung cancer have had evidence of glandular differentiation, indicating that the LUL lymph node metastases or distant metastases (14,15). The present tumor was not a metastasis of the LLL tumor. Immunohisto- case was exceptional, because the patient survived for a long time chemical study showed that both the organoid and the glandular in spite of the brain metastasis and having been treated only by component of the LUL tumor had NE features, indicating that it resection of the lung tumors and radiotherapy to the brain. Slow was an adenocarcinoma with NE features rather than a combina- growth may have been one of the characteristics of the tumors in tion of adenocarcinoma and NE carcinoma. our case, despite their high mitotic activity. The relationship between LLL and LUL tumors is a matter of In conclusion, we have reported a unique case of synchronous controversy. The LUL tumor was immunohistochemically posi- double primary lung cancers with a combination of small tive for p53 the same as the organoid area in the LLL tumor, but cell/large cell carcinoma and a spindle sarcomatous component positive cells were less frequent than in the small cell/large cell in the LLL and adenocarcinoma with NE features in the LUL. At or spindle cell sarcomatous lesions. The NE marker study showed presentation the tumor had metastasized to the brain, but not to that the LUL tumor and the organoid area in the LLL might lymph nodes. Radiation to the brain after resection of the lung differentiate with NE feature better than small cell/large cell or tumors was very effective. The survival time in our patient, who spindle lesions. LUL tumor. resembled the organoid component did not receive chemotherapy, was 2 years and 4 months. Multiple in the LLL in the immunohistochemical pattern of the NE lung cancers with NE features are extremely rare and similarmarkers (CD56, chromogranin A, synaptophysin, GRP). The cases have not been reported in the literature. same genetic change may have occurred in the areas of these twotumors exhibiting NE features, even though their morphology Acknowledgmentswas different. Genetic analysis might resolve this issue. The only case of multiple lung cancer with NE features reported This work was supported in part by a Grant from the Ministry ofpreviously was a case of bronchial carcinoid, small cell carcinoma Health and Welfare for the 2nd term Comprehensive Strategy forand adenocarcinoma of the right lung described by Jung-Legg et Cancer Control and a Grant-in Aid for Cancer Research from theal. (8) The series of synchronous double primary lung cancers Ministry of Health and Welfare, Japan.reported by Carey et al. (9) included cases of combined non-smallcell lung cancer and small cell lung cancer or carcinoid, but therewere no cases of double cancer with NE differentiation demon- Referencesstrated by immunohistochemistry. Since these cases were not 1. Travis WD, Linnoila RI, Tsokos MG, Hitchcock CL, Cutler GB Ir, Nieman L,immunohistochemically tested for NE markers, some of them may et al. Neuroendocrine tumors of the lung with proposed criteria for large-cellhave been double cancer, both of which had NE differentiation. In neuroendocrine carcinoma. An ultrastructural, immunohistochemical and flow cytometric study of 35 cases. Am J Surg PathoI1991;15:529-33.any event, the occurrence of synchronous double cancers with NE 2. Histological typing of lung tumors. International Histological Classificationfeatures in both appears to be a rare event. of Tumors. Geneva: World Health Organization 1981.
  7. 7. Jpn J Clin OncoI1999;29(4) 2253. HirschFR, MatthewsMJ,Aisner S, Campobasso 0, ElemaJD, GazdarAF,et 9. Carey FA,DonnellySC, WalkerWS, Cameron EWJ, Lamb D. Synchronous al. Histopathologic classification of small cell lung cancer. Changing primary lung cancers: prevalence in surgical material and clinical implica- concepts and terminology. Cancer 1988;62:973-7. tions. Thorax 1993;48:344-6.4. TsubotaYT,KawaguchiT,HosoT, NishinoE, TravisWD. A combinedsmall 10. Ihde DC, Pass HI, Glatstein E: Small cell lung cancer. In: Devita VT Jr, cell and spindle cell carcinoma of the lung. Report of a unique case with Hellman S, Rosenberg S, editors. Cancer. Principles and Practice of immunohistochemical and ultrastructural studies. Am J SUiX Pathol Oncology,5th ed. Philadelphia: Lippincott-Raven 1997;911-49. 1992;16:1108-15. 11. Morstyn G, Ihde DC, Lichter AS, Bunn PA, Carney DN, Glastein E, et al.5. Colby TV, Koss MN, Travis WD. Small cell carcinoma and large cell Small cell lung cancer 1973-1983: early progress and recent obstacles. lnt J neuroendocrinecarcinoma.In: Tumorsof the Lower RespiratoryTract.Atlas Radiat Oncol Bioi Phys 1984;10:515-39. of TumorPathology,Third Series, Fasc. 13.Washington, DC: ArmedForces 12. Nappi 0, Glasner SD, Swanson PE, Wick MR. Biphasic and monophasic Institute of Pathology 1995;235-57. sarcomatoid carcinomas of the lung: a reappraisal of carcinosarcomas and6. Hsu S, RaineL, Franger H. Use of avidin-biotin-peroxidasecomplex(ABC) spindle cell carcinomas. Am J Clin Patho/1994;102:331-40. in immunoperoxidase techniques:a comparisonbetweenABCand unlabeled 13. Ro JY, Chen JL, Lee JS, Sahin AA, Ordonez NG, Ayala AG. Sarcomatoid antibody (PAP) procedures. J Histochem Cytochem 1981 ;29:577-80. carcinomaof the lung: immunohistochemical and ultrastructural studiesof 147. Fishback NF, Travis WD, Moran CA, Guinee DG Jr, McCarthy WF, Koss cases. Cancer 1992;69:376-86. MN. Pleomorphic (spindle/giant cell) carcinoma of the lung. Cancer 14. Coolen L, Eeckhout AVD, DeneffeG, DemedtsM, Vansteenkiste 1. Surgical 1994;73:2936-45. treatmentof small cell lung cancer. Eur J Cardiothorac Surg 1995;9:59-64.8. Jung-Legg Y, McGowan SE, Sweeney KG, Zitzman JL, Pugatch RD. 15. AngelettiCA, MacchiariniP,Mussi A, Basolo F. InfluenceofT and N stages Synchronoustriple malignanttumors of the lung. A case report of bronchial on long-term survival in resecteablesmall cell lung cancer. Eur J SUiR Oncol carcinoid,small cell carcinoma and adenocarcinomaof the right lung. Am J 1989;15:337-40. Clin Patho/1986;85:96-101. Downloaded from http://jjco.oxfordjournals.org/ by guest on March 28, 2013

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