Multifocal Granular Cell Tumor Presenting as an Esophageal Stricture

Bija K. John - Nlcbahu C. Lhng Syed A. Hussaia. Gner C. H. Ynng Matthew D. Cham . Rhonda Yamtlsa. Atha S. Jorepb -Shah M. CLuluddim. Psul C. he. Robert Flemlng - Kaumodl Somay

FUMmbd onlinn: 2 April 2009 8 Humans Rcsr Inc. 2009

Abrma In&cUon Granular cell tumora are uncommonly found in the plminkainal bact wilh slow progression and are wually benign rhough they may have propensity for malignant iranrfomution. Initially amibuted to n m n a l origin b u g h immunohistochemistty, there has been controversy with increasing reports of granular cell NmOn of n o n e origin. h e Repon We report a case of multifocal granular cell tumor invoking the esophagus and stomach in a young female with history of dysphagia for 9 years with worming symptoms. She had bem managrd at anorha faoilicy with repwed dilations for p r e m e d benign peptic micturc. Radii andosanognphy (EUS) of the pmximal end of saiclnre showed a posterior 6ubmucoul coophqpd mass tha~ was b e w o g ~ and invaded into the muscu- lads plopria. Fieneedle aspidon (FNA) showed large

cells with granular cytoplaaln along with spindle nuclei. Cells w a r initially checked for CD117 stain alone and found to be negative. A follow-up CT-guided core needle biopsy revealed similnr gmukr colk tbst were positive for S-100. She u n d m a l a two-s(agc transhiatel sophagogas- tmtomy as the tumor circumfmnlially involved the m i d esophagus and was adbemt to ihc rrachea and recunent laryngeal nerve bilatcdly. At surgery, there wae two additional foci palpable in the pmxirml stomach. Discwlon and Condusion As these lm~ors may have potential for malignant W d o n and locoregional invasion, they should be considered while evaluating submucosal lesions of the esophagus even in young pationrp. A largt number of gnmular cell hunon may be missed in the a h c o of S-100 staining. which should be requeatcd when granular cells are seen on cytology obtained by EUS FNA as this can be a mmimally invasive

9. K. John (24). R Fkming M. D. Cham e s n t of Mediiine. clepmmt of Radiobgy. New Y d Hospital Quwns and Weill Comell Mcdiul Collep, Weill Comcll M d h l College, New York. NY, USA New Yak. NY, USA email: dbii*hn@yahrn.com

h s. Joseph N. C. Dutg IT. New Yo& Hospksl @mm and Weill Comll M e d i i DspMlronr of Cydiovsrcular md Thoracic Sui-gmy, Colkgs Weill C o d l Mediul Calkge, New Yo&. W, USA New Y o k NY. USA

S. h Hurt.in. K. S o m y S. M. GiPrhuddin apmrrnt of Medicine. Divhiom of G~hntao logy . Departrnenr of Arumnnio Plholw, New Yo& Holpitll Qucms ud Weill Comell Mdca l Colkp. New Ymk Hospital Quoent and Weill Comd Medical W e & Nm Yor4 NY, USA New Yo& NY. USA

G. C. H. Y w ' R. Ymdirr Ikpmlmm of Mmnic Fuholoay, WciU Cancll Mcdial O o l k New w, NY. USA

P. C. La Dcpaamenl of C d r d i o v ~ b r .nd Thaaeio %'gay. New Yak Horpiml QWCN and Weill Candl Medical Colic@u, New Yo*, NY. USA

diagnostic modality for t h e tumors. Other fcci should be drinking. Examination and laboratory tests at time of sought at surgcly as they have a propensity for locoregional presentation were normal. An uppa endoscopy rcvmled a d. nanowing of the lumen at 20 cm fmm the incisors with

smooth and normal appearing overlying m u m a Proximal Kcynards granular cell tumor. multifocal granular cell to this stricture, the small esophageal segment appeared t u m a csuphagogastmctomy dilated but othewise normal. The snicturc had reduced the

lumm to a 4-mm opening. Dilation of this stricnue was ananpted using the scope CUE; Balloons (Boston Scientific, Nanick MA. USA), and the opening war stretched horn 4 to 8 mm. The pmcedun resulted only in marginal dilation. This provided the patient trmporary relief but she r e m e d to the

Onnular cell tumor (GCll was fimt r ep led by Abrikosoff officc 2 weeks later with rearrent and worsmingdysphngia in 1926 when he described five caeca of such ~mors involving the tongue [I]. In 1931, he n- a similar l u m r involving the osq,hagus [2]. Five to nine percent of all these tumors ate now known to occur in the gastro- intestinal tract. Most of k s e tumors are benign. although 2 4 % have a malignant potential. Elecmn microscopy and immunohislochemical investigations in the nemt past have attributed their origin to Schwann cells, although there has been some wnmversy with this regard 13-81. On revicw of lilaature, to datq L s than 300 case8 have been described worldwide. Althaugh relatively rare, these are being increasingly identified in the past decade due to improve men1 in imaging modalitic~ and flexible fibaoptic &- copy. We m t here a rare case of s multifocal granular cell tumor involving the esophagus and stomach in a young female who p& with persistent dyq~hagia and was w a g e d at an outside hospital with w e d dilations for a pmumed benign peptic stricture despite multipk uppa andwcopi with biopsy. The purpose of this article is to discuss the clinical presentation and endoscopic and histological features of CiCTs to emphasize how commonly they may ta misdiaposed and lo aleti one of their multi- focal and malignat potential risks.

case Report

A 3C-yedr-old Africsn American h a l e with a history of dysphagia for 9 yoats was seen in the office for complaints of worsening symptoms over the last 4 weeks. She had her first endoscopy in 1999 at an outside hospital that revealed a smooth stricture at 20 an from the incisors. Multiple repeat EGDs with four quadrant biopsies showed only cvidanw of chronic nonspecific esophagitis on histology. She was mated with serial balloon dilations with which she could tolerate pureed and soft mlid foods. F a u weeks prim to presenting to us, she described symptoms of worsening dysphagia for sofl d i d food associated with occasional regurgitation. She also nportcd an unintentio~l weight 1 0 s of @cr than 10 tb over the laa 6 months. She was a smoker with a flve-pack year history and admitted to social

A repcat endoscopy revealed the same smooth shicture (Fig. I). Serial balloon dilatations wem sttempted again ht this did not m l t in any subslantial efFect, raising the suspicion for a submucosal procclss in esophagus or periesophageal MI. It was not possible to negotiate the scope past the slricture. A CT scan of lhe neck was then performed Bat revealed the presence of a mfl tissue mas in the upper esophagus at the C7n1 level that mm~lsund 2.412.7 cm in size with marked dilation of the pmximal esophagus (Fig. 2a, b and c). A barium swallow was also obtained that showed a 3-cm-long sfrimre with near occlusion oftha lumen (Fig. Zd).

Radial endosonography (EUS) was then pMformcd but as the stricnue was resistant to dilation, scanning was p e r f o d only from of the pmximal end of strictwe. This showed a posterior submumal esophageal mass hat was hekrogwmus, measured 2.4 cm in width, and invaded into the muscularis propria (Fig. 3a). Linear EUS-guided fine- needle aspiration @NA) was done that showed large cells with granular cytoplasm along with spindle nuclei (Fig. 3b). Calls w a r ohecked fw CD117 stain alone and found to bc negative.

A CT-guided con needle biopsy (Fig. 4) was then obtained and sent for special staining (S-100, Ki-67, CD117 and SMA). Ihe speoimen was found to be positive for S-I00 and Ki-67 with 5% proliferation index, which supported the diagnosis of granular a l l m o r with low malignant potential.

The diagnosis and the bvament optima wen discussed at length with the patient. Given the astun, imaging avail- able, extent of the tumor, and lack of alternative ucatmmt, it was decided to surgically nmove the involved segment of the esophagus.

She undnwent a cervical collar incision for a planned local resection. Exploration revealed a fm, whitc, k m - l a g , submucosal Nmor circumferentially involving the cervical esophagus. Antaiorly. the hlmor was adherent to the trachea and the r ecumt lluyngoal nerves bilaterally. The esophagus was carefully dkeued fmm these sfrue- lures, a longihrdid myoromy was made to expose the submucosal bullor, and partial resection of the tumor was

PIC 1 Elophsgeal Ptricano c o n a sndoacopy

GCI; formerly known as granular cell myoblastoma, was first described by Abrikossoff in 1926. Fischcr and Wechsler noted that these tumors have the potential to be multicnlric and more often originate fiurn Schwann cells [I-31. The origin to neural cells was attributed by poritive immunohistachemistty to S-100 and neumn-specific mkv [3. 41. This subscqwntly became a subject of controversy when S-100 was danonatrated in non-Schwann calls. Moreover. several caws of granular cell tumom from the

performed of the anterior curnponent. Care was taken not to enter the underlying esophageal muma, which was

was awakened. and a full discussion was &cd out with denssly adherent to the tumor, Portoprativcly. the patient b..;

her regarding the locally aggtessivc nature of the NInW, as well as Ihc potential for fuNrc growth and recurrent symp-.

She was cxpmled 4 days later md underwent a (ranshiatal mphagngasmctDmy (Fig. 5% b, and c). At surgery, there werc two additional foci palpaled in the proximal stomach, and so, 20.0 cm of the d i l csophagua and a 5 . 5 - a s m m t of pmximJ s(orrmch bearing the additional foci wae removed en bloc. The proximal dilated csoplueus and was divided quite high, at 14 cm horn the incisors. A ccchnically challenging handarwn csophago- gaavosbnny anastomosis was pertormad, and a feeding 1: .

jcjunoaomy was p W . The esophagenl specimen was sent for staining and

immunohistochcmistry, which revealed a tumor with nests of numerous @nular a l l s with small, round, oval, and spindle nuclei and abundant granular cytoplasm. Cell bdm were indistinct and infiltrated into the adjaomt muscle. Histology was most consistent wih granular cell Nmw (Fig. 6a and b). Similar pathology was noted in tho gsmic pan of the tumor, $

Postopmivaly, tho patient developed a small anraior . . m~;.' anastornotic leak on postopmtiw day 9. Hermk incision Svbmd mB .s doauibod in raeiml No was opened, and she undenvent twice-daily dressing inf i l~t irm - d-t mctsrol. b bopbrpoal rrrichln wcll changes. She was maintained on full- entaal lube visualized. c Conuastmhmd CT (sagiMI vkw) danonstmtd a feeds at the time of -e. At the t i m o f h a l - m o h t.5rmvatebnl k n g t h o f h a @ ~ a l hrmcncomplotcly o b l i t o d

by l i te &WOI [ml o m w ) jut above the thoracic ink1 pmtorior fO1'owup, paim"s leak had hukd* 4nd rn the - ( I ) . emesophageal lumen pmximal kwm a a r e r ~ ) she was tolming a clear liquid diet. She was then 4 &I (blue L U ~ ~ ~ S L I lo {he msss a horn. d ~ a r i ~ ~ ,tudy ~ t d advanced o v a the next week to a r(ulsr diet. a cem shicm

A g 3 a BUS: Uppa pat of Dlmar sclnncd ibovo. Emp4ngeal sukturc rhowinp lesion arking h m thc aubmvcou kuLing Utmugh Ulc musentah pmpria, b FNA showing lwge cell. whh p u l s r fytoplam

oral cavity, brain, and pituitary showed no reactivity to S- Despite their fmt description eight decades ago. granular 1W or nm-apeeificaolase. Morerecently, several cases cell nunom m d l1 rare, and diagnosis and management of mtancaua granular cells of nondeural origin have been of thesc NInOrs even today can be challenging. n p o d [S-81. Their pmpmsity for being multricenhic has Most of the tumors are usually located in the. head and been npmccd in ns many as I&I 5% of cases [9-111. neck region. The GI trwl accounts for 54% of all cases.

AL. 4 CT-guided biopry and hhlolagy. 8 CT-guided c o n biopsy (bmwi). UlmRsl hp lahl ~400. e Qmdar cell hlmor (pink) with rhoans biopsy nadk wimin thc mas (4 arrow) elongated cymplmm iafillnting into fibmus tissue. H&E shin. posrmior ~o the trach(1). b Oranulard ~ n m (Mur) with oval ad Hiaololagy, x40. d Gnnulu cell turnor (bmwn) with ex(eluive spindly mlsi ad g m m h cylopl- infillrating inm skaIctal musoh infllmtion into lJroleml m w t e (white). S-100 immwmstain. x4O

0-R~U

multifocal GCTs arc betng reported in the past decade, many authors m m m e n d complete endoscopic examina- tion of upper and lower gastrointestinal hact in patients d~agnosed with gastrointestinal GCTs 124, 251. This is iiuther supported by recent studies showing increased yet unexplained association of gtanular cell tumor and other malignant cancers, namely squamous cell cancers [24, 26- 291.

With the advent of EUS, inctemng cases of granular cell Nmors are being reported. Endosonographically, these tumors appear as hypoechoic. homogenous ksions with smooth border, arising from the mucosa or submucosal layer[30].

Most cases of GCTs can be diagnosed by EUS-guided biopsy. provided that adequate specimen is obtained. Obtaining multiple biopsy specimens from the same site commonly referred to as "well technique" yields better specimen for histology [3l]. Once a diagnosis of GCT has been entertained, it is imperative to send the tissue sample for special staining and ~mmunohistochmistty as it is com- monly missed on routine staining. Endosmptc ultrasonog- raphy helps in staging by determining depth of invasion and

FYr, 5 1 Longitudinal mytomy. b Esophageal Nmor nsectioo. c Snbmucous nodules involving pmximal stomach

of which 30% are seen in the esophagus [12-151. GCTs commonly occur in the 50-60 age group and are more frequent in women. There have been reports of GCT ptesenting in younger patients in their second decade [l l , 16. 171.

Although GCT rnvolving the GI (tact commonly presents as dysphagia, majority of patients with granular cell minor of the esophagus have no symptoms. Other symptoms associated with GCT are reflux esophagitis, rehternal pain or discomfort. nausea, and vomiting [IS- 221. In one smdy, as many as 50% of patients with esophageal GCTs were symptomatic. while half had totally unrelated symptoms, some being found incidentally at upper gastrointestinal endoscopy [23]. As more cases of

Fig. 6 a Esophago~astrectomy specimen, b Esophageal hlrnor showing shcets and nests of granular cells separated by collagenous septat. The cells have uniform small ovcloi and abundant eosinophilio cyaplasrn

-ing for pwihunoral lymph ~ d e involvrment. En& scopic hunor m v a l has ken rcpted to be s d l when the h c o r is small in aim (4 cm) and docs not invade inlo the muscularis propria [32]. In our case, the woor was noted on EUS lo invade into the muoulrris pmpria, and thii was confirmed on the surgical pathology of the rumor specimen.

Histologically, the tumor shows nests of polygonal and spindle-shaped 4 1 s s q m I e d by layers of collagenous material. These eelk have a chaaneristic appearance with abundant eosinophilic cytoplasm and enlarged lysosomes. The granular apparing lyswomm arc PAS positive, stained red with Irkborne stain, and are diastase nsinant.

Acwrding to Fanbutg and Smith, presence of tumor n e w i s , tumor a l l spindling, largs nucleus, h s c d r u c c l ~ p l a s m i c ratio, i n d mitotic d v i t y , plec- morpbim, and high Ki-67 immunoreactivity are suggestive of M i . '~uIIIoR with a minimum of time of the= aitoli. would be clarsified iu malignant [33]. In our patient, apart h m tumor spindling no other, critaia was met for malignmq Similarly, cytological crimis atbiiuted to malignancy described by Wiecwk ct sl. were not met 1341. lheK fmdings faMIsd a diagnosis of grsnular cell nuna with low mnlignancy potential. Malignant p u h dl n u ~ t g UIC rare, awounting for only 1-2% of all rep& GCTs [35, 361. Obidi~h-Msya repomd a 080 of a 23- YULT-OI~ woman with a 10-cm esophageal grmular cell nunor that wwed I month after d o n and metanarizcd to tho regional lymph nodes 6 months lam, at which time the patiem died [In. Its relalionship a squamous cell cancer and other d i i e s still mnains unexplained. which fi~rtha adds a the dilemma in M u managesnmt and surveillance.

Ona identifid a number of tmtment options have brm outlined in the l i t c r a m Tada in hi article has described endompic polpcclomy as a hulmml option if these tumm an small, i.e.. less than 2 crn and localized within b submucosr, without extension into the muscularis propria [37]. Oms modalities like alcohol injection *ser, and removal by diathermy loop have been reviewed in literalure with iirnilar effiw [22, 381. In many cases, local -on is all that is nwded to h u t small non- invasive hrmors. If the m r is, however, significantly symptomatic or apposn to be infilhBfing adjacent structures anaor multicmaic, more rsdical tMbnent is meded. In wr patient, initial core biopsy showed a NmOr having a low malignant potential; ham. the first swgq was planned as a local resection Howem, inbnopcrativcly, it was noted that the tumor was more exlensive than initially thought with dense sdhrrenca to local seuctures appuring invasive and I d l y aggressive. As local rarsetim waa being ansmped. the widm Mha, and extent of the tnmor became appusnt. The remaining segment of the uninvolved

esophagus wav thought to be very thin and teauour for an anastomosis if a wide excision was anempted with a high pomtial risk for postoperative leakage. So, only partial resection for mom detailed pathological review of the hMor was peflbrmed at the firs1 surgety. Moreover, prim to the first surgery, in light of the preoperative imaging and core biopsy results thatwggcded a local ~marwim low malignant potential, we had ob(aincd consent for local excision with s- anastomasis and not for a b-nnshiual esophagognstmmmp It was deemed appropriate to admcss the new findings of the exploration with the patiart, explaining the risks and bma% and obtaining informal consent fora mom radical swgq . To achieve a complete removal of the tumor, ensuxe ekar magins, prevent recurrence, and minimiza posbpxative c o m p l i c a t ~ a trsnrhiacal mophagenmy w performed together with removal of only the pmxirnal portion of the smmach due to addinional foci noted on palpation in the stomach intraopernrively.

The purpose of this case is to cmphasiza consideration of granular call rumor in the differential diygrosis of sub- muwsal lesions found in cha gastmintestinal t m t as thwe can be evident on endoscopy. It must be noted that a lnw! number of granular cell tumors m y be diagnosed by S-100 staining, which must be requeslcd based on clinicalsuspicion. M a q m e n t by endosmpic versus surgical maeo(ion should be based on severity of sympomn, size and exlenl of ttmlor, staging by EUS, and the histology M seen on com biopsy of the tumor.

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