CASE REPORT

Combined small-cell carcinoma of the lung with quadripartitedifferentiation of epithelial, neuroendocrine, skeletal muscle,and myofibroblastic type

Giuseppe Pelosi & Angelica Sonzogni & Domenico Galetta & Federica Perrone &

Paola Braidotti & Michela Manzotti & Alessandra Fabbri & Lorenzo Spaggiari &Giulia Veronesi & Giuseppe Viale

Received: 16 October 2010 /Revised: 7 November 2010 /Accepted: 8 November 2010 /Published online: 6 January 2011# Springer-Verlag 2010

Abstract The combined variant of small-cell lung carci-noma (SCLC) refers to the variable admixture of small celland non-small cell carcinoma, whereas the association withsarcoma or sarcoma-like elements is exceedingly rare. A76-year-old Caucasian man underwent right upper lobecto-my with regional lymphadenectomy because of a symp-tomatic 7 cm-sized tumor mass. Formalin fixed-paraffinembedded material was used to highlight several differen-tiation cell lineages by means of immunohistochemistry,

electron microscopy, and mutational assay. The tumor wasdiscovered as being IIB stage (pT2b pN11/51 pM0) andfeatured biphasic appearance with close intermingling ofSCLC (40%) and collagen-rich spindle cell sarcoma (60%).Epithelial (cytokeratins, TTF-1), neural (neurofilaments,GFAP), endocrine (chromogranin, synaptophysin, CD56),and skeletal muscle (desmin, sarcomeric actin, myogenin)markers were variably co-expressed by SCLC elements,whereas mesenchymal (vimentin), smooth muscle (actin,myosin, H-caldesmon, calponin), fibroblastic (CD10), and,more focally, skeletal muscle (desmin, sarcomeric actin andmyogenin) markers were highlighted in the spindle cellsarcoma elements. TP53 codon V274F mutation in exon8 was shared by either cell component. After undergoingadjuvant chemotherapy, the patient is currently alive andwell at the 40-month follow-up. To the best of ourknowledge, this is the first report of combined SCLC withquadripartite differentiation of epithelial, neuroendocrine,skeletal muscle, and myofibroblastic type, somewhere atthe level of the same individual tumor cells. This tumor hadprobably derived for clonal evolution of a p53-mutatedcommon ancestor lesion.

Keywords SCLC . Sarcoma . Immunohistochemistry .

Mutation . Electron microscopy

Introduction

As many as one third of small cell lung carcinomas (SCLC)are associated with non-small cell lung carcinoma(NSCLC) elements, mainly featuring large cell neuroendo-crine carcinoma (LCNEC), adenocarcinoma or squamouscell carcinoma in that order [1]. This association solidifies

G. Pelosi :A. Sonzogni :M. Manzotti :G. VialeDivision of Pathology and Laboratory Medicine,European Institute of Oncology,Milan, Italy

G. Pelosi : P. Braidotti : L. Spaggiari :G. VialeDepartment of Medicine, Surgery and Dentistry,San Paolo Hospital, University of Milan School of Medicine,Milan, Italy

D. Galetta : L. Spaggiari :G. VeronesiDivision of Thoracic Surgery, European Institute of Oncology,Milan, Italy

G. Pelosi : F. Perrone :A. FabbriDepartment of Pathology and Laboratory Medicine,Fondazione IRCCS National Cancer Institute,Milan, Italy

P. BraidottiFondazione IRCCS Policlinico, Mangiagalli and Regina Elena,Milan, Italy

G. Pelosi (*)Dipartimento di Patologia Diagnostica e Laboratorio,Fondazione IRCCS Istituto Nazionale Tumori,Via G. Venezian, 1,20133, Milan, Italye-mail: giuseppe.pelosi@istitutotumori.mi.it

Virchows Arch (2011) 458:497–503DOI 10.1007/s00428-010-1011-8

the so-called combined variant of SCLC under WHO-2004classification criteria on lung cancer [2]. In this frame ofmind, the combination with sarcoma or sarcoma-likeelements is deemed to be exceedingly rare, probablyreflecting the inherent rareness of pulmonary sarcomatoidcarcinomas, which account for by far less than 5% of allNSCLC [3]. While diverse variations on the theme ofcombined small cell carcinoma with sarcoma or sarcoma-like elements have been described in the English literature[4–11], quadripartite differentiation clustering epithelial,neuroendocrine, skeletal muscle, and smooth muscle/myo-fibroblastic features has not thus far been reported in thelung, to the best of our knowledge.

Clinical history

A 76-year-old Caucasian man, former smoker since 30 yearsafter consuming 30 cigarettes per day for 20 years,underwent left upper lobectomy for Aspergillus-relatedfungus ball in 1980. Clinical history also included diabetesmellitus, urolithiasis, polyps of the vocal cords, cataract,subphrenic abscess after spontaneous right pneumothoraxand anal fissures. In 2003, the patient complained ofhemoptysis for granulomatous inflammation of the leftmain bronchus (likely due to the previous surgery), whichwas treated conservatively with LASER cauterization. In2007, he suffered again from hemoptysis with thoracic painand a chest X ray examination showed a huge tumor massin the right upper lobe. A chest CT scan confirmed a 67×48×50-mm-sized tumor mass, which was close to bothpleural layers and azygos vein. Pleural effusion waslacking. As PET scan with radio-labeled [18F]-2-fluoro-2-deoxy-D-glucose (FDG) denied distant metastases, a rightupper lobectomy along with complete hilar-mediastinallymphadenectomy was performed: the final tumor stagewas pT2b pN11/51 pM0 (IIB) according to the seventhedition of TNM system. The patient underwent adjuvantchemotherapy with cisplatin and etoposide. At the 40-month follow-up, he is alive and well with no signs of localrecurrences or distant metastases.

Material and methods

The investigation was carried out upon formalin-fixed,paraffin-embedded material by using the antibodies listed inTable 1 according to previously refined immunohistochem-ical methods. Moreover, an electron microscopic study wasaccomplished upon formalin-fixed tissue fragments, whichwere washed in phosphate buffer, post-fixed in 2.5%glutaraldehyde solution (0.13 M, pH 7.3), reacted with1% buffered osmium tetroxide, dehydrated through graded

alcohols and propylen oxide, embedded in epoxy resin,counterstained with uranyl acetate and lead citrate and thenexamined with a Jeol JEM 1010 (Jeol, Tokyo, Japan)transmission electron microscope.

Results

The tumor measured 7 cm in its greatest dimension, did notattain the pleura layers and azygos vein and featuredbiphasic epithelial/sarcomatous appearance with intimateintermingling of small cell carcinoma (40%) and spindlecell sarcoma (60%) components. Small cells had a variableamount of eosinophilic to fairly clear cytoplasm, ill-definedcell borders and finely granular and even chromatin withinconspicuous nucleoli (Fig. 1). Less than 10% tumor cellsshowed vesicular chromatin and more evident nucleoli.Small cells were round or oval to spindle, somewhere alsoarranged in neuroendocrine rosettes, and clustered intonests, trabeculae or solid aggregates with peripheralpalisading and nuclear molding. The predominant sarcomacomponent comprised spindle to pleomorphic or multinu-cleated cells with abundant collagen deposition. Plentifulwere mitotic figures, as well as abundant the tumor necrosiswith geographic configuration (Fig. 1). Immunohistochem-ical results are detailed in Table 1 and depicted in Fig. 2.The small cell carcinoma component exhibited positivityfor cytokeratins with dot-like quality (both AE1-AE3 cloneand cytocheratin 7), synaptophysin, CD56, TTF-1, and,focally, chromogranin B, S-100 protein, GFAP, neurofila-ments, sarcomeric actin and desmin, whereas immunoreac-tivity for vimentin, smooth-muscle actin and myosin,CD10, calponin, H-caldesmon, desmin, myogenin andCD56 was found to variable extent in the spindle cellsarcoma component, which focally resembled rhabdomyo-blasts (Fig. 2). Completely negative were cytokeratin 5/6,CD34 and chromogranin A immunolabeling in both tumorcomponents. Remarkably, cytokeratins (AE1-AE3 and 7)and myogenin co-localized in the same aggregates of smallcell carcinoma, with minor contribution of desmin andsarcomeric actin that was only seen in scattered tumor cellsinside these aggregates. Proliferative activity evaluated byKi-67 immunoreactivity showed 80–90% labeling index insmall cell carcinoma and 40–50% in spindle cell sarcoma.Finally, p53 staining was detected in almost all tumors cellsof both components as a strong nuclear decoration. Electronmicroscopy study indicated that the spindle cell sarcomaexhibited myofibroblastic differentiation with cytoplasmicprocesses and huge collagen fiber deposition, whereassmall cell carcinoma showed paranuclear cytokeratinfilaments, abnormal rough endoplasmic reticulum, dense-core neuroendocrine granules and, less frequently, abortiveZ bands reminiscent of rhabdomyoblastic differentiation

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(Fig. 3). Mutation analysis showed V274F substitution inexon 8 in both small cell carcinoma and spindle cellsarcoma components, after accurate microdissection undermicroscopic control (Fig. 4).

Discussion

The case described deals with a high-grade malignanttumor with quadripartite differentiation clustering epithelial(cytokeratins, TTF-1), neuro/endocrine (synaptophysin,chromogranin, CD56, GFAP, neurofilaments), skeletalmuscle (desmin, myogenin, sarcomeric actin), and mesen-chymal/myofibroblastic/smooth muscle (vimentin, smoothmuscle actin and myosin, CD10, desmin, calponin, H-caldesmon) cell lineages. The final diagnosis was thus a

descriptive one on the theme of SCLC, combined type, withskeletal muscle differentation and spindle cell sarcoma ofmyofibroblastic type. Worth mention was the widespreadreactivity for CD56 (a sensitive but not specific marker ofneuroendocrine differentiation) in the spindle cell sarcomacomponent, a feature which could be somewhat related tothe reported distribution of the molecule in mesodermduring fetal life, rhabdomyosarcoma [12], leiomyosarcoma[13], sarcomatoid mesothelioma [14], or other biphasictumors [15]. Combinations of small cell carcinoma withspindle cell [9, 11] or giant cell carcinoma [4, 8], small cellcarcinoma plus adenocarcinoma and spindle-shaped celltumor [7], small cell carcinoma plus squamous cellcarcinoma and spindle cell carcinoma [6], or small cellcarcinoma plus sarcomatoid carcinoma with either spindlecell or giant cell carcinoma [5] are exceedingly rare but

Table 1 Antibody panel used in the current study and results of immunostaining in either tumor cell component

Antibodies Clone Source Dilution Pretreatment Small cellcarcinoma

Spindle cellsarcoma

Acidic and basiccytokeratins

AE1-AE3 Novocastra Laboratories,Newcastle upon Tyne, UK

1:50 MWO-CB +++ (dot-like) −

Calponin CALP DAKO, Glostrup, Denmark 1:400 MWO-EDTA − ++

CD10 56C5 Novocastra Laboratories,Newcastle upon Tyne, UK

1:10 MWO-EDTA − +

CD34 QBEnd/10 Novocastra Laboratories,Newcastle upon Tyne, UK

1:400 MWO-CB − −

CD56 123C3.D5 NeoMarkers, Fremont, CA 1:400 MWO-EDTA +++ +++

Chromogranin A LK2H10 DAKO, Glostrup, Denmark 1:40 with and without − −MWO-CB

Chromogranin B polyclonal Santa Cruz Biotechnology, Santa Cruz, CA 1:2,000 MWO-CB + −Cytokeratin 7 OV-TL 12/30 DAKO, Glostrup, Denmark 1:400 pepsin ++ (dot-like) −Cytokeratins 5/6 D5/16 B4 Chemicon International, Temecula, CA 1:400 MWO-EDTA − −Desmin D-33 DAKO, Glostrup, Denmark 1:50 MWO-CB + +

GFAP polyclonal DAKO, Glostrup, Denmark 1:400 none + −H-caldesmon h-CD DAKO, Glostrup, Denmark 1:200 MWO-EDTA − ++

Ki-67 antigen MIB-1 DAKO, Glostrup, Denmark 1:200 MWO-EDTA +++ ++

Myogenin F5D DAKO, Glostrup, Denmark 1:800 MWO-EDTA +++ +

Neurofilaments NF68.04 NeoMarkers, Fremont, CA 1:100 MWO-CB + −P53 protein D07 Novocastra Laboratories,

Newcastle upon Tyne, UK1:400 MWO-EDTA +++ +++

S-100 protein polyclonal DAKO, Glostrup, Denmark 1:1,600 none + −Sarcomeric actin 5C5 Sigma-Aldrich, Saint Louis, MI 1:2,000 MWO-CB + +

Smooth muscle actin 1A4 DAKO, Glostrup, Denmark 1:200 none − +++

Smooth muscle myosin SMMS-1 DAKO, Glostrup, Denmark 1:50 MWO-CB − +

Synaptophysin SY38 DAKO, Glostrup, Denmark 1:20 MWO-EDTA +++ −TTF-1 8G7G3/1 NeoMarkers, Fremont, CA 1:1,000 MWO-EDTA +++ −Vimentin V9 DAKO, Glostrup, Denmark 1:50 MWO-CB − +++

Pepsin digestion with 5% pepsin solution for 5 min;

MWO-CB: microwave oven at 750W for 30 min in citrate buffer pH6

MWO-EDTA: microwave oven at 750W for 30 min in EDTA buffer pH8

- : negative; + : < 10% postive tumor cell; ++ : 11-50% positive tumor cells; +++ : >50% positive tumor cells

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well-known occurrences among combined variants ofSCLC, as well as associations of atypical carcinoid plusrhabdomyosarcoma [10], carcinoid plus hamartoma [16,17], carcinoid plus adenocarcinoma [18, 19], or incidentalsmall neuroendocrine lesions resembling tumorlets inintrathoracic lymph nodes of patients with primary lungadenocarcinoma [20]. Intimate intermingling of small cell

carcinoma and rhabdomyoblasts in the larynx [21], skin,nasal cavity, urinary bladder [22], and anorectal junction[23], as well as tripartite differentation in individual cellscarcinomas with concurrent epidermoid, glandular, andneuroendocrine features in lung [24] or esophagus [25] ordipartite differentiation with rhabdomyogenous and cyto-keratin expression within the same mesenchymal tumor

Fig. 1 a−n The tumor was biphasic (a), with intimate interminglingof both components (a, inset), and comprised small cells with scantcytoplasm (b), ill-defined cell borders (c), finely granular chromatinwith inconspicuous nucleoli (d), which only in <10% tumor cells wasvesicular with prominent nucleoli (e), round-oval shape with neuro-

endocrine rosettes (f, in the center) or spindled appearance (g),plentiful mitoses (h), and evident nuclear molding (i), and geographicnecrosis (l). The spindle cell sarcoma component showed pleomorphiccells (m) and abundant collagen deposition (n)

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cells in pulmonary carcinosarcomas [26] are likely to befurther variants on the theme of multidirectional differen-tiation of common tumor ancestors.

The current case report, the first to highlight quadripar-tite differentiation inside a combined variant of SCLC,focused on epithelial, neuroendocrine and skeletal musclecell lineages even at the level of individual cells, for theconcurrent expression of these markers in the same tumor

cells. Once excluded a collision tumor due to the closeadmixture of either type of components, the existence ofdifferent cell lineages was probably the result of theplasticity of a common proto-epithelial stem cell. Thisassumption was further supported by the strong p53 proteinaccumulation in SCLC and spindle cell sarcoma, as well asthe same amino acidic substitution (V274F) in exon 8 ofTP53 gene in either tumor component. These findings are

Fig. 2 a−n The small cell carcinoma component showed immunoreac-tivity for cytokeratins (a, clone AE1-AE3 with dot-like pattern),synaptophysin (b) and focally chromogranin B (b, inset), TTF-1 (c),GFAP (d), and neurofilaments (d, inset), desmin (e), and myogenin (f),

the latter co-localized with cytokeratins in the same cell clusters (F,inset). The spindle cell sarcoma was immunolabeled for vimentin (g),smooth muscle actin (h), calponin (i), H-caldesmon (l), and, focally,featured rhabdomyoblasts highlighted by desmin (m) and myogenin (n)

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in keeping with the view that sarcomatous or sarcomaelements of pulmonary sarcomatoid carcinomas derive fromcarcinoma elements according to a process of sarcomatousmetaplasia (conversion paradigm) during tumor progressionrather than to be collision tumors [27–29]. In our case, thecomplete lack of epithelial differentiation in the spindle cellsarcoma component, which only focally retained rhabdo-myoblastic features, made us hypothesize an almostcomplete myofibroblastic/smooth muscle transdifferentia-tion of carcinomatous cells rather than early divergence ofthe same ancestor lesion.

The differential diagnosis of this tumor includedpleomorphic carcinoma because of its biphasic appear-ance, carcinosarcoma for the presence of heterologouselements, pulmonary metastasis of mixed mullerianmalignant tumors with neuroendocrine differentiation forthe immunoreactivity for CD10 and smooth musclemarkers in spindle cell sarcoma [30] and the exceedinglyrare primary pulmonary rhabdomyosarcoma in adults [31].It is worth bearing in mind that the occurrence ofneuroendocrine components in the form of SCLC and/orLCNEC in pulmonary carcinomas harboring sarcoma orsarcomatous components should be handled by regardingthem as combined variants of either tumor with associatedsarcoma or sarcoma-like elements rather than classifyingthem as pulmonary sarcomatoid carcinomas exhibitingsmall-cell and/or large cell neuroendocrine components[3]. The term carcinosarcoma should be discourageddespite the presence of a heterologous population, whethera high-grade neuroendocrine carcinoma of any amount is

Fig. 3 a, b Electron microscopic features of epithelial tumor cellsshowing desmosomes (black arrow), dense-core granules of neuroen-docrine type (red arrows) (a) and abortive Z bands reminiscent ofrhabdomyoblastic differentiation (b, black arrowheads)

Fig. 4 Direct sequencing ofPCR-amplified DNA of TP53exon 8 extracted from the SCLCand sarcomatous componentsafter accurate microdissection:the same mutation (GTT>TTT,V274F) supports the tumor originfrom a common ancestor lesion

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recognizable [3]. Albeit more uncommonly, even LCNECmay bear a sarcomatoid component in the form of spindlecell carcinoma [32]: remarkably, however, the associationwith sarcoma featuring rhabdomyosarcoma is mainly limitedto SCLC-containing tumors at least in the lung [33]. Adultprimary pulmonary rhabdomyosarcoma are referred asnegative for epithelial and neuroendocrine markers [31].

Acknowledgments This work is dedicated to the memory ofCarlotta, an extraordinarily lively girl who untimely died of cancerin the prime of life.

Conflict of interest statement The authors declare that they have noconflicts of interest.

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