A case of synchronous double primary neuroendocrine lung cancer

Jpn J Clin Oncol1999;29(4 )219-225

A Case of Synchronous Double Primary Lung Cancer withNeuroendocrine FeaturesSeiji Niho1,2, Tomoyuki Yokose2, Kanji Nagai1, Yutaka Nishiwaki1, Tetsuro Kodama3 and Kiyoshi Mukai2

1Division of ThoracicOncology, National Cancer Center Hospital East, Chiba, 2Pathology Division, NationalCancerCenter Research Institute East, Chibaand 3Department of Internal Medicine, National Cancer CenterHospital, Tokyo, Japan

We report a case of unique double primary lung cancers with neuroendocrine features in a63-year-old male smoker. The mass in the left lower lobe (LLL) was a small cell/large cellcarcinoma with spindle cellsarcomatous areasandorganoid structure. Themassinthe leftupperlobe(LUL) was a tubular adenocarcinoma withneuroendocrine features including organoid nestsshowing occasional rosette formation, nuclear palisading intheperiphery ofthe nests andpositiveimmunoreaction for CD56, chromogranin A and synaptophysin. The difference in histologicalstructures between the two masses led us to diagnose double primary lung cancer. Thecombination of small cell lung carcinoma and spindle cell carcinoma is very uncommon. Therelationship between LLL and LUL tumors remains unclear. Multiple lung cancers withneuroendocrine features haveonly rarely been reported in the literature. The patient in our casediedofwidespread cancer2 years and4 months afterthesurgery without adjuvant chemotherapy,a longerpostoperative survival time than in cases of ordinary extensive small cell lung cancer.Multiple lungcancers withneuroendocrine features areextremely rareandsimilarcaseshavenotbeen reported in the literature. Neuroendocrine differentiation hasattracted widespread attentionand, therefore, examining neuroendocrine features in lung cancers is important.

Key words: small cell carcinoma - spindle cell carcinoma - double primary lung cancers - adenocarcinoma- neuroendocrine feature

INTRODUCTION

The classification of neuroendocrine tumors of the lung used tobe complex and confusing. Recent!y, Travis et al. (1) reported thefollowing spectrum of pulmonary neuroendocrine (NE) lesions:(i) minute NE lesions, (ii) common neoplasms with an NE lightmicroscopic appearance, (a) typical carcinoid, (b) atypicalcarcinoid, (c) large cell NE carcinoma and (d) small cell lungcarcinoma, (iii) non-small cell lung carcinoma with NE featuresand (iv) uncommon primary NE neoplasms. The classification ofsmall cell lung carcinoma (SCLC) has changed over time. TheWorld Health Organization (WHO) defined the subtypes ofSCLC in 1981 as oat cell type, intermediate cell type and

Received September 11, 1998; accepted December 21, 1998

For reprints and all correspondence: Seiji Niho, Division of ThoracicOncology, National Cancer Center Hospital East, 5-1, Kashiwanoha6-chome, Kashiwa, Chiba 277-8577, Japan. E-mail: [email protected]

Abbreviations: LLL, left lower lobe; LUL, left upper lobe; NE,neuroendocrine; SCLC, small cell lung carcinoma; WHO, World HealthOrganization; IASLC, International Association for the Study of LungCancer; CEA, carcinoembryonic antigen; MRI, magnetic resonanceimaging; ABC, avidin-biotin complex; Sp-A, surfactant apoprotien A;Sp-D, surfactant apoprotein D; GRP, gastrin-releasing peptide

combined type (2). The International Association for the Study ofLung Cancer (IASLC) redefined the subtypes in 1988 as smallcell carcinoma, mixed small cell/large cell carcinoma andcombined small cell carcinoma (3). Almost all combined SCLCscontain a component of squamous cell carcinoma or adenocarcinoma; however combinations can occur with spindle cellcarcinoma (4) and giant cell carcinoma (5)' We present a case ofdouble primary lung cancers with NE features, one tumorconsisting of small cell/large cell lung cancer combined withspindle cell sarcomatous lesions and the other an adenocarcinomawith NE features in a different lobe.

CASE REPORT

A 63-year-old man was admitted to the National Cancer CenterHospital East in October 1994 because of cough, sputum andhemoptysis. He had smoked 20 cigarettes daily over 40 years. Thepatient's mother died of leukemia at the age of 38. Laboratorydata were within normal limits except for a low serum albumin(2.9 g/dl) and elevated CEA (7.2 ng/ml). Chest radiographyrevealed a round nodule in the left lower lobe (LLL). Bronchoscopic examination showed a white polypoid mass obstructing theLLL bronchus. The biopsy specimen contained malignant cells;however, the cell type could not be determined because of the

© 1999 Foundation for Promotion of Cancer Research

by guest on March 28, 2013

http://jjco.oxfordjournals.org/D

ownloaded from

http://jjco.oxfordjournals.org/

220 Lung cancer with neuroendocrine features

Figure 1. (a) Macroscopic findings for LLL tumors. A yellow- white welldefinedmass measuring 14 x 10.5 x 8 em in the LLL was compressing the surroundingnormal lung parenchyma with formationof a capsule-like structure. (bHe) Microscopic findings for LLLtumor. Small cell component consists of smallcells withlargeN/Cratio,scantycytoplasm andfinely granular nuclearchromatin withhighmitoticactivity (b). Cellsin smallcell/large cellcomponent haveeosinophilic largercytoplasmandvesicular nucleuswithdistinctnucleolus (c).Organoid components formwelldemarcated roundto ovoidclusters resembling atypical carcinoidin thebackground of smallcell/large cellsor 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 chestshowed no enlargement of the mediastinal or hilar lymph nodes.Magnetic resonance imaging (MRI) of the brain showed a 6 x 6mm solitary mass in the right cerebellar hemisphere. The LLLwas resected in December 1994. Part of the left upper lobe (LUL)

of the lung was also resected because another nodule was foundin the LUL during the operation. Radiation therapy to the brainwas performed when the brain mass was found to have grown to14 x 14 mm on MRI in January 1995, suggesting a brainmetastasis. After 50 Gy of radiation to the brain, the nodule could



ownloaded from


Jpn J Clin OncoI1999;29(4) 221

Figure 2. (a)Macroscopicfindings for LLLand LUL tumors. A whiteround nodulemeasuring2.1x 1.7x 1.5em was presentin the LUL(S1+2) with a clearmargin.(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 showingoccasional rosette formation(c). Hematoxylin and eosin stain; original magnifications, x83 (b), x410 (c).

no longer be detected on MRI of the brain. No chemotherapy wasgiven. Left leg pain occurred in February 1997 due to bonemetastasis. Computed tomography of the chest showed multiplepulmonary metastases. Dyspnea developed and the patient diedin February 1997, 2 years and 4 months after the operation. Anautopsy was not performed.

We performed an immunohistochemical analysis to the formalin-fixed, paraffin-embedded sections by the avidin-biotincomplex (ABC) method (6). Biotinylated secondary antibodyand ABC reagents were purchased from Dako Japan (Kyoto,Japan). Primary antibodies used were against keratin (AE1/AE3,Dako, Dakopatts, Glostrup, Denmark; CAM5.2, Becton Dickinson, San Jose, CA, USA), surfactant apoprotien A (Sp-A) (PE-lO,Dako), surfactant apoprotein D (Sp-D) (6B2, Yamasa, Chiba,Japan), CD56 (Lu243, Nippon Kayaku, Tokyo, Japan), chromogranin A (Dako) , synaptophysin (Dako), CDS7 (Leu7, BectonDickinson), gastrin-releasing peptide (GRP) (Dako), serotonin(SHT-H209, Dako), calcitonin (Dako) , CEA (011, Mochida,Tokyo, Japan), vimentin (V9, Dako), myoglobin (Dako), desmin(033, Dako) , alpha-smooth muscle actin (lA4, Dako), S-lOO

protein (Dako), Factor VIII (Dako), p53 (Nichirei, Tokyo, Japan)and Rb (MK-15-1 , MBL, Nagoya, Japan).

A yellow-white, well defined mass measuring 14x 10.5x 8 cmin S10 of the LLL was compressing the surrounding normal lungparenchyma with formation of a capsule-like structure; the centerof the mass revealed extensive hemorrhage and necrosis . (Fig.1a). The LLL showed poor aeration and moderate anthracosis andfibrosis , especially beneath the pleura, but no emphysema.

A round, white nodule measuring 2.1 x 1.7 x 1.5 em and havingwell defined margins was found in Sl+2 of the LUL . The tumorwas solid and there was no evidence of hemorrhage or necrosis.A sharp pleural indentation was detected (Fig. 2a).

The LLL tumor was largely necrotic, but there were viabletumor cells in the periphery. It consisted of four components:small cell, large cell, organoid and sarcomatous . The small cellcomponent was composed of oval to spindle-shaped cells slightlylarger than lymphocytes and having a large N/C ratio, scantycytoplasm and oval nuclei with fmely granular chromatin but nonucleoli (Fig. 1b). The large cell component consisted ofpolygonal to round cells that were larger than the cells in the small



ownloaded from


222 Lung cancer with neuroendocrine features

cell component and they contained abundant eosinophilic cytoplasm and a vesicular nucleus with one or two prominent nucleoli(Fig. 1c). Small cells and large cells were frequently intermingled.Both types of cells had high mitotic activity [22/10 high powerfield (HPF)] and clusters of pure small cell carcinoma cells werealso observed focally. In the organoid component, the neoplasticcells formed well demarcated round to ovoid clusters resemblingatypical carcinoid in the background with small cell/large cells orspindle cells (Fig. 1d). The cells forming the organoid structurewere polygonal to spindle shaped and had a fmely granular nucleuswith one or two prominent nucleoli. Mitotic activity was high(24/10 HPF). The sarcomatous cells were spindle shaped and theirnuclei were variable in size and contained coarse chromatin withone or two prominent nucleoli (Fig. Ie). The small cell/large cellcarcinoma, spindle cell sarcomatous carcinoma and organoidcomponents were highly intermingled with areas of transitionbetween them; the proportions of these components were about 65,30 and 5%, respectively. No lymphatic permeation or vascularinvasion was observed. The remaining non-neoplastic pulmonaryparenchyma showed no evidence of carcinoid tumorlets orneuroendocrine cell hyperplasia.

The LUL tumor had a clear margin and showed expansivegrowth. It consisted of irregular-shaped glands lined by tall

columnar cells. The tumor cells contained relatively abundanteosinophilic cytoplasm and hyperchromatic nuclei with coarsegranular chromatin and distinct eosinophilic nucleoli (Fig. 2b).Mitotic activity was high (25/10 HPF). The stroma was scant. Thetumor had a focal solid growth area with organoid nests showingoccasional rosette formation (Fig. 2c). Nuclear palisading was alsoseen in the periphery of the nests. No lymphatic permeation orvascular invasion was observed. Hilar lymph nodes contained nometastatic tumors. Mediastinal lymph nodes were not explored.

The results of the immunohistochemical analysis are shown inTable 1. The small cell/large cell component. of the LLL wasdiffusely positive for CD56 (Fig. 3a) and chromogranin A andpartially positive for keratin.. The organoid component waspositive for CD56, chromogranin A, synaptophysin (Fig. 3b),GRP and CEA. The sarcomatous component was positive forvimentin (Fig. 3c) and some spindle-shaped also cells showed animmunoreaction for keratin (Fig. 3d). The LUL tumor waspositive for CD56, chromogranin A (Fig. 4), GRP, calcitonin,CEA and keratin. The positive rates for p53 were 79% of the cellsin the small cell/large cell component, 13% in the organoidcomponent, 80% in sarcomatous component and 8% in the LULtumor. Rb was positive only in the LUL tumor (30%) andnegative 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.



ownloaded from



/ .,

'(

; "/

"If.';r" .,-,,"

,-' - . ' /{.

, ~ I

I .

.:' .;'~1.J :~

• > -

." " J; '/

'.

/- l,.:

"

. .." .

,~

I ." ( .'. .. ." 0# .~

{.,

I

I

I

Figure 3. Immunohistochemical findings for LLL tumor. Small cell/large cell component was diffusely positive for CD56 (a), Organoid component was positive forsynaptophysin (b). Sarcomatous component was positive for vimentin (c) but some spindle-shaped cells showed immunoreaction for keratin (d). Originalmagnification, x4 1O.

DISCUSSION

Our 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 smallcell/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 association with giant cell carcinoma and adenocarcinoma, lessfrequently with large cell carcinoma or squamous cell carcinoma

Figure 4. Immunohistochemical findings for LUL tumor. It was positive forchromogranin A. Original magnification, x41O.

and infrequently with small cell carcinoma (7). Tsubota et al. (4)reported a case of combined small cell (pure type) and spindle cellcarcinoma of the lung. The spindle cell carcinoma was predomi-



ownloaded from


224 Lung cancer with. neuroendocrinefeatures

nant and immunoreactive for smooth-muscle actin, but not for NEmarkers, in their case, whereas the small cell/large cell component in our case occupied more of the tumor than the spindle cells.Moreover, the spindle cell sarcomatous area in our case did notshow clear NE features or differentiation to mesenchyme butexhibited epithelial differentiation, indicating poorly differentiated carcinoma or sarcomatoid change of carcinoma. Thespindle cell sarcomatous component was immunohistochemically positive for p53 and the frequency of positive cells wasalmost same as in the small cell/large cell component, suggestingthat although their phenotypes were different, a similar geneticabnormality may have occurred in both.

We considered three possible diagnoses for the LUL mass:(i) moderately differentiatedadenocarcinoma, tubular type, with NEfeatures, (ii) combined adenocarcinomaand largecell NE carcinomaand (iii)metastatic carcinoma from the LLL tumor.The LUL tumorexhibited glandular structures lined by tall columnar cells andorganoid nests of large pleomorphic cells with rosette formation andnuclear palisading. The latter pattern may be seen in large cell NEcarcinoma (1); however, the clear glandular differentiation favoredadenocarcinoma rather than large cell NE carcinoma.

Immunohistochemical testing yielded different characteristicsin the LUL and LLL tumor. Calcitonin and Rb were positive onlyin the LUL tumor. Furthermore, the LLL tumor exhibited noevidence of glandular differentiation, indicating that the LULtumor was not a metastasis of the LLL tumor. Immunohistochemical study showed that both the organoid and the glandularcomponent of the LUL tumor had NE features, indicating that itwas an adenocarcinoma with NE features rather than a combination of adenocarcinoma and NE carcinoma.

The relationship between LLL and LUL tumors is a matter ofcontroversy. The LUL tumor was immunohistochemically positive for p53 the same as the organoid area in the LLL tumor, butpositive cells were less frequent than in the small cell/large cellor spindle cell sarcomatous lesions. The NE marker study showedthat the LUL tumor and the organoid area in the LLL mightdifferentiate with NE feature better than small cell/large cell orspindle lesions. LUL tumor. resembled the organoid componentin the LLL in the immunohistochemical pattern of the NEmarkers (CD56, chromogranin A, synaptophysin, GRP). Thesame genetic change may have occurred in the areas of these twotumors exhibiting NE features, even though their morphologywas different. Genetic analysis might resolve this issue.

The only case of multiple lung cancer with NE features reportedpreviously was a case of bronchial carcinoid, small cell carcinomaand adenocarcinoma of the right lung described by Jung-Legg etal. (8) The series of synchronous double primary lung cancersreported 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 demonstrated by immunohistochemistry. Since these cases were notimmunohistochemically tested for NE markers, some of them mayhave been double cancer, both of which had NE differentiation. Inany event, the occurrence of synchronous double cancers with NEfeatures in both appears to be a rare event.

The survival time in our case was 2 years and 4 months withoutchemotherapy, longer than in ordinary small cell lung cancer (10).The median survival for limited stage small cell lung cancer treatedby surgery alone has been reported to be about 6 months (11).Tsubota et al. did not comment on the outcome of their case of acombined small cell and spindle cell carcinoma of the lung. Smallcell lung cancer has a poor prognosis although it is sensitive tochemotherapy and radiation. In contrast to small cell lung cancer,spindle cell carcinoma is also generally considered to have a poorprognosis and to be resistant to irradiation and chemotherapy(12,13). The metastatic brain tumor in our case was as sensitive toradiation therapy as small cell lung cancer; however, it recurred 2years after surgery, a much longer latent period than in ordinarysmall cell lung cancer. No lymph node metastasis was observed inour case despite the large tumor, a finding also different from usualsmall cell lung cancer. The reason for the comparatively goodoutcome in our case remains unclear. Two-year disease-freesurvivors represented 13% of patients presenting with limitedsmall cell lung cancer but only 2% of those with extensive disease(10). More than 80% of 2-year survivors of small lung cell lungcancer have been found to have received chest irradiation andalmost all extensive disease patients had metastases confmed to asingle organ system (11). In our case, however, the brain was theonly metastatic site at the time of presentation. Hardly anylong-term survivors of resected small cell lung cancer have hadlymph node metastases or distant metastases (14,15). The presentcase was exceptional, because the patient survived for a long timein spite of the brain metastasis and having been treated only byresection of the lung tumors and radiotherapy to the brain. Slowgrowth may have been one of the characteristics of the tumors inour case, despite their high mitotic activity.

In conclusion, we have reported a unique case of synchronousdouble primary lung cancers with a combination of smallcell/large cell carcinoma and a spindle sarcomatous componentin the LLL and adenocarcinoma with NE features in the LUL. Atpresentation the tumor had metastasized to the brain, but not tolymph nodes. Radiation to the brain after resection of the lungtumors was very effective. The survival time in our patient, whodid not receive chemotherapy, was 2 years and 4 months. Multiplelung cancers with NE features are extremely rare and similarcases have not been reported in the literature.

Acknowledgments

This work was supported in part by a Grant from the Ministry ofHealth and Welfare for the 2nd term Comprehensive Strategy forCancer Control and a Grant-in Aid for Cancer Research from theMinistry of Health and Welfare, Japan.

References

1. Travis WD, Linnoila RI, Tsokos MG, Hitchcock CL, Cutler GB Ir,Nieman L,et al. Neuroendocrine tumors of the lung with proposed criteria for large-cellneuroendocrine carcinoma. An ultrastructural, immunohistochemical andflow cytometric study of 35 cases. Am J Surg PathoI1991;15:529-33.

2. Histological typing of lung tumors. International Histological Classificationof Tumors. Geneva: World Health Organization 1981.



ownloaded from


3. HirschFR,MatthewsMJ,AisnerS, Campobasso0, ElemaJD,GazdarAF,etal. Histopathologic classification of small cell lung cancer. Changingconcepts and terminology.Cancer 1988;62:973-7.

4. TsubotaYT,KawaguchiT,HosoT,NishinoE, TravisWD.Acombinedsmallcell and spindle cell carcinoma of the lung. Report of a unique case withimmunohistochemical and ultrastructural studies. Am J SUiX Pathol1992;16:1108-15.

5. Colby TV, Koss MN, Travis WD. Small cell carcinoma and large cellneuroendocrinecarcinoma.In: Tumorsof theLowerRespiratoryTract.Atlasof TumorPathology,Third Series, Fasc. 13.Washington, DC: ArmedForcesInstitute of Pathology 1995;235-57.

6. Hsu S, RaineL, Franger H. Useof avidin-biotin-peroxidasecomplex(ABC)in immunoperoxidase techniques:a comparisonbetweenABCand unlabeledantibody (PAP) procedures.J Histochem Cytochem 1981 ;29:577-80.

7. Fishback NF,Travis WD, Moran CA, Guinee DG Jr, McCarthy WF,KossMN. Pleomorphic (spindle/giant cell) carcinoma of the lung. Cancer1994;73:2936-45.

8. Jung-Legg Y, McGowan SE, Sweeney KG, Zitzman JL, Pugatch RD.Synchronoustriple malignanttumors of the lung. A case report of bronchialcarcinoid,small cell carcinomaand adenocarcinomaof the right lung.Am JClin Patho/1986;85:96-101.


9. Carey FA,DonnellySC, WalkerWS, CameronEWJ, Lamb D. Synchronousprimary lung cancers: prevalence in surgical material and clinical implications. Thorax 1993;48:344-6.

10. Ihde DC, Pass HI, Glatstein E: Small cell lung cancer. In: Devita VT Jr,Hellman S, Rosenberg S, editors. Cancer. Principles and Practice ofOncology,5th ed. Philadelphia: Lippincott-Raven 1997;911-49.

11. Morstyn G, Ihde DC, Lichter AS, Bunn PA, Carney DN, Glastein E, et al.Small cell lung cancer 1973-1983: early progressand recent obstacles. lnt JRadiat Oncol Bioi Phys 1984;10:515-39.

12. Nappi 0, Glasner SD, Swanson PE, Wick MR. Biphasic and monophasicsarcomatoidcarcinomasof the lung: a reappraisal of 'carcinosarcomas' and'spindle cell carcinomas.' Am J Clin Patho/1994;102:331-40.

13. Ro JY, Chen JL, Lee JS, Sahin AA, Ordonez NG, Ayala AG. Sarcomatoidcarcinomaof the lung: immunohistochemical and ultrastructural studiesof 14cases. Cancer 1992;69:376-86.

14. CoolenL, Eeckhout AVD, DeneffeG, DemedtsM, Vansteenkiste 1.Surgicaltreatmentof small cell lung cancer.Eur J Cardiothorac Surg 1995;9:59-64.

15. AngelettiCA, MacchiariniP,MussiA, BasoloF.InfluenceofT and N stageson long-termsurvival in resecteablesmallcell lung cancer.EurJ SUiR Oncol1989;15:337-40.



ownloaded from


A case of synchronous double primary neuroendocrine lung cancer

Health & Medicine

Transcript of A case of synchronous double primary neuroendocrine lung cancer