Composite signet-ring cell/neuroendocrine carcinoma of the stomach with a metastatic neuroendocrine carcinoma component: a better prognosis entity.

Abstract

Mixed (composite) exocrine-neuroendocrine cell carcinomas are defined as an intimate admixture of neoplastic glandular exocrine and neuroendocrine cell types. Although gastric adenocarcinoma containing a small number of neuroendocrine cells is a relatively frequent occurrence, gastric neoplasms containing equal proportions of both cell types are rare.
We present a case of composite exocrine (signet-ring cell)-neuroendocrine cell carcinoma, in which the neoplastic signet-ring cell exocrine and neuroendocrine constituents occurred in fairly equivalent amounts, whereas only the neuroendocrine carcinoma portion of the tumor represented the metastatic component. Light microscopy, immunohistochemical and electron microscopic findings are described, and the literature is reviewed.
This study confirms the ability of pluripotent precursor cells to differentiate into either adenocarcinoma or neuroendocrine tumor and, justifying the designation of composite exocrine-neuroendocrine cell carcinoma as the appropriate classification for this tumor. The protracted clinical course further supports the notion that composite signet-ring cell/neuroendocrine carcinoma tumors behave relatively less aggressively than the pure forms of the former cell type.

Full text

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BioMed Central
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Diagnostic Pathology
Open Access
Case Report
Composite signet-ring cell/neuroendocrine carcinoma of the
stomach with a metastatic neuroendocrine carcinoma component:
a better prognosis entity
Summer L Nugent†1, Steven C Cunningham†2, Borislav A Alexiev1,
Emily Bellavance2, John C Papadimitriou*1 and Nader Hanna2
Address: 1University of Maryland Medical Center, Department of Pathology, NBW43, 22 S Greene Street, Baltimore, MD 21201, USA and
2University of Maryland Medical Center, Department of Surgical Oncology, 419 West Redwood Street, Baltimore, MD 21201, USA
Email: Summer L Nugent - summerlindsay@gmail.com; Steven C Cunningham - scunningham@smail.umaryland.edu;
Borislav A Alexiev - balexiev@umm.edu; Emily Bellavance - EBellavance@smail.umaryland.edu;
John C Papadimitriou* - Jpapa001@umaryland.edu; Nader Hanna - NHanna@smail.umaryland.edu
* Corresponding author †Equal contributors
Abstract
Background: Mixed (composite) exocrine-neuroendocrine cell carcinomas are defined as an
intimate admixture of neoplastic glandular exocrine and neuroendocrine cell types. Although
gastric adenocarcinoma containing a small number of neuroendocrine cells is a relatively frequent
occurrence, gastric neoplasms containing equal proportions of both cell types are rare.
Case Presentation: We present a case of composite exocrine (signet-ring cell)-neuroendocrine
cell carcinoma, in which the neoplastic signet-ring cell exocrine and neuroendocrine constituents
occurred in fairly equivalent amounts, whereas only the neuroendocrine carcinoma portion of the
tumor represented the metastatic component. Light microscopy, immunohistochemical and
electron microscopic findings are described, and the literature is reviewed.
Conclusion: This study confirms the ability of pluripotent precursor cells to differentiate into
either adenocarcinoma or neuroendocrine tumor and, justifying the designation of composite
exocrine-neuroendocrine cell carcinoma as the appropriate classification for this tumor. The
protracted clinical course further supports the notion that composite signet-ring cell/
neuroendocrine carcinoma tumors behave relatively less aggressively than the pure forms of the
former cell type.
Background
Adenocarcinoma and neuroendocrine carcinomas (NEC)
are each well known to occur in the background of
atrophic gastritis, but the concurrence of both adenocarci-
noma and NEC (malignant carcinoid) together in the gas-
trointestinal tract (GI) is extremely rare [1,2]. Over the
past several years, classification of these tumors has been
a subject of debate. As described by Lewin and Appelman
[3], mixed neuroendocrine and conventional carcinomas
of the stomach should be classified in one of five distinct
groups. These include: carcinomas with interspersed neu-
roendocrine cells, composite glandular-endocrine carci-
nomas, collision tumors, amphicrine tumors, and
combinations of the above [1,3]. More recently, Fujiyoshi
Published: 7 November 2007
Diagnostic Pathology 2007, 2:43doi:10.1186/1746-1596-2-43
Received: 25 September 2007
Accepted: 7 November 2007
This article is available from: http://www.diagnosticpathology.org/content/2/1/43
© 2007 Nugent et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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et al [4] reclassified the mixed endocrine and nonendo-
crine epithelial tumors by subdivision into six categories:
1) neuroendocrine cells interspersed within carcinomas;
2) carcinoids (neuroendocrine tumors/NET) with inter-
spersed nonendocrine cells; 3) composite glandular-neu-
roendocrine cell carcinomas containing both areas of
carcinoid and conventional carcinoma; 4) collision
tumors in which neuroendocrine tumors and conven-
tional carcinomas are closely juxtaposed but not admixed;
5) amphicrine tumors predominantly composed of cells
exhibiting concurrent neuroendocrine and nonendocrine
differentiation; and 6) combinations of the previous
types. A variety of terms have been utilized in the designa-
tion of tumors along this continuum based on the pre-
dominant form of differentiation [5]. The occurrence of a
composite tumor in the setting of atrophic gastritis has
seldom been reported in the literature [6]. In adenocarci-
nomas of the gastrointestinal tract, the presence of both
neuroendocrine and nonendocrine cells is a well-recog-
nized finding [7]. However, mixed exocrine-neuroendo-
crine cell carcinomas are exceptionally rare. To our
knowledge, only 15 cases of gastric mixed exocrine-neu-
roendocrine cell carcinomas have been reported in the lit-
erature (Table 1). Composite, or mixed glandular-
neuroendocrine cell carcinomas, are defined as an intri-
cate admixture of both elements which are present in
equal proportions, unlike amphicrine tumors which dem-
onstrate dual differentiation (exocrine and neuroendo-
crine) within the same cell. Moreover, collision type
neoplasms occur as exocrine and neuroendocrine tumors
that arise adjacent to one another and do not originate
from the same cell type [8]. We review this literature, and
present a case of a composite glandular-neuroendocrine
carcinoma of the stomach emphasizing the light micros-
copy, immunohistochemical and electron microscopic
characteristics of the tumor as well as the clinicopatholog-
ical correlations.
Case presentation
A 64-year-old Caucasian woman with a history of a
resected gastric carcinoid 38 years ago presented to the
Department of Gastroenterology at the University of Mar-
yland with symptoms of early satiety and a progressive, 6-
months weight loss of 20 pounds. The patient had no
other complaints. Her past medical history was significant
for trigeminal neuralgia which had been surgically
treated. She did not take any medications and denied a
family history of cancer. On exam the patient was a thin,
well-appearing woman without remarkable abnormal
physical findings. Laboratory values revealed a mild ane-
mia with a hemoglobin of 10 mg/dL. Her electrolytes,
liver function tests, and coagulation panel were within the
normal ranges.
The patient underwent upper endoscopy and endoscopic
ultrasound (EUS), which revealed the following findings:
an area of nodular mucosa in the distal esophagus at the
gastroesophageal junction, an erythematous patch in the
stomach, a 2-cm gastric polyp, which was then resected,
and an extragastric mass, consistent with a group of mat-
ted lymph nodes, located between the left lobe of the liver
and the anterior wall of the stomach. The pathology
results of the biopsied sites showed that the gastric polyp
and nodular mucosa represented tubular adenomas, the
latter containing focal intramucosal adenocarcinoma. The
fine needle aspiration (FNA) of the gastric mass was con-
sistent with metastatic NEC (malignant carcinoid), and
the erythematous patch in the stomach at 40-cm showed
invasive poorly differentiated/signet-ring cell carcinoma.
The patient underwent a staging computed tomography
(CT) scan of the abdomen and pelvis that demonstrated
two large enhancing masses between the left lateral lobe
of the liver and the anterior wall of the stomach corre-
sponding to the extragastric mass seen on endoscopic
ultrasound. There was no evidence of distant metastases
on CT scan.
The patient was then referred to the Department of Surgi-
cal Oncology, for evaluation for surgical resection. Intra-
operatively, there was no evidence of distant metastases. A
D2 total gastrectomy with omentectomy and regional
lymph node dissection with a Roux-en-Y J-pouch
esophagojejunostomy was performed. There were no pal-
pable masses in the stomach. However, there were two
palpable masses in the gastrohepatic ligament, consistent
with metastatic lymph nodes. The spleen and distal pan-
creas were preserved.
Postoperative recovery was uneventful with the exception
of one urinary tract infection. The patient was discharged
to a rehabilitation facility on the fifteenth postoperative
day.
Materials
The use of paraffin blocks for this study meets Institu-
tional Review Board and Health Insurance Portability and
Accountability Act requirements, and has been approved
by the Institutional Review Board at the University of Mar-
yland Protocol Number: H-29227.
Histology
The resected tissue was fixed in 10% buffered formalin
and embedded in paraffin. The tissue was sectioned in 5
micron thick slices and stained with hematoxylin and
eosin (H and E), mucicarmine and Periodic Acid-Schiff
(PAS).

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Table 1: Review of gastric composite tumor literature
First Author (ref)Year TypeCa typeOut-comeSize (cm) LN (+ of total) EMSynpChrE-cadany CKKi-67
Nagoaka [13]1996 CmpNR DOD8 NRNRNR A-; NE+ NRNRNR
Fujiyoshi [4]2004 CmpsignNED @ 9 y NR 0 of 13NR A-; NE-A+; NE+A- NE+ A-; NE-NR
Fujiyoshi [4]2004Cmpsign NED @ 8 y 10.5 0 of 9NR A-; NE- A+; NE+A- NE+ A-; NE- NR
Adhikari [6]2002 Cmpint NED @ 1 y6 NRNRA+f; NE+ A+f; NE+A+f; NE+A+; NE-NR
Caruso [7] 1989CmpintNR 1.5NR NRNRA+; NE+ NR NRNR
Yang [10]1991 Cmp/AmpintNED @ 6 mo3 18 of 19 NE/M same NR+ NRNR NR
Ulich [14]1988 Cmp intNR 3.6 NR NRNRA+f; NE+ NR NRNR
Wheeler [15]1983 Cmpint DOD @ 3 mo5 NR NRNR NRNR NRNR
Ali [16]1984 Cmpsign DOD22 0 of 5NE/M sameNRNRNR NRNR
Brouland [17] 2001 Cmp/Ampsign NED @ 6 moNRNRNE/M same NR+NRNR NR
Jain [18]2005 Cmpint LTFU 1.5 NRNRA+f; NE+ A+f; NE+NRA+; NE-NR
Jain [18] 2005 Cmp intNED @ 2 y3.3 NR NRA+f; NE+A+f; NE+ NRA-; NE-NR
Jain [18]2005 Cmp int DUC @ 4 moNRNR NRA+f; NE+A+f; NE+ NRNRNR
Klappenbach [5]1985Cmp NRNR NRNR NRNRNR NRNRNR
Pasquinelli [19] 1993Cmp/AmpNRDOD3 NRNE/M same++NRNRNR
Present case 2007CmpsignNED @ 6 mo 3.53 of 12 NE/M diffA+; NE+ A+; NE+ A+; NE-A+; NE- A+; NE-
Abbreviations: +, positive immunolabeling; -, negative; A, adenocarcinoma; Amp, amphicrine; Ca, carcinoma; Chr, chromogranin A; CK, cytokeratin; Cmp, composite; DOD, dead of disease;
DUC, dead of unrelated causes; E-cad, e-cadherin; EM, electron microscopy; f, focal; diff = different. intest = intestinal; LN, lymph nodes; LTFU, lost to follow up; M, mucous; NE,
neuroendocrine; NED, no evidence of disease; NR, not reported; sign = signet; Synp, synaptophysin;

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Immunohistochemistry
Immunohistochemical staining was performed using
Ventana Enhanced DAB Detection Kit and Biotin-StreptA-
vidin (B-SA) amplified methodology (Ventana, Tucson,
AZ) and commercially available prediluted monoclonal
antibodies against the following antigens: neuron specific
enolase (NSE), synaptophysin, chromogranin, E-cad-
herin, pancytokeratin, CAM 5.2, and Ki-67 (all Ventana,
Tucson, AZ).
Electron microscopy
Fragments of formalin fixed gastric mucosa were also
processed for evaluation by electron microscopy. Repre-
sentative tissue samples (1-mm cubes) were fixed in 4F1G
for 4 hours, postfixed in osmium tetroxide, dehydrated in
graded alcohols, and embedded in epoxy resin. The sec-
tions were stained with uranyl acetate and lead citrate and
examined on a JEM 1200 transmission electron micro-
scope.
Pathologic findings: gross appearance
Macroscopically, the gastrectomy specimen contained a
tan-white plaque-like mass measuring 3.5 × 3.4 × 0.5 cm
located in the body of the stomach (lesser curvature),
approximately 10.5 cm from the proximal margin and
approximately 15.2 cm from the distal margin, which
appeared to invade both the mucosa and the submucosa.
The uninvolved gastric mucosa was tan with pinpoint
hemorrhages, with absence of folds. Also present were
multiple, well-circumscribed, firm, yellow nodules (rang-
ing in size 0.4–0.7 cm in greatest diameter) scattered
throughout the mucosa and submucosa of the cardia and
body of the stomach. There were also two larger extragas-
tric nodules (5.5 × 2.7 × 3.1 cm and 7.2 × 3.8 × 2.9 cm
respectively) consistent with matted lymph nodes that
were tan, firm, and well-circumscribed and grossly abut-
ting the wall of the lesser curvature. These two nodules
were located 9.1 cm from the proximal margin and 13.2
cm from the distal margin respectively. The cut surfaces of
the extragastric nodules were firm, pale tan to pink, and
hemorrhagic. The attached adipose tissue contained mul-
tiple lymph nodes, ranging from less than 0.1 × <0.1 cm ×
<0.1 cm to 1.1 × 0.4 × 0.2 cm. Ten resected lymph nodes,
in addition to the two large collections of matted lymph
nodes, were submitted.
Results
Light microscopic appearance
Microscopically, routine hematoxylin-eosin-stained sec-
tions from the tumor showed two distinct neoplastic phe-
notypes. The first type was composed of gastric-type
epithelial cells with a high nuclear to cytoplasm ratio that
diffusely permeated the mucosa and wall in an "infiltra-
tive" growth pattern. The cytomorphology of these cells
was characterized by large cytoplasmic mucin vacuoles
and hyperchromatic eccentrically displaced nuclei. This
component of the tumor was diagnosed as signet-ring cell
adenocarcinoma (Figure 1). The second type was com-
posed of smaller neoplastic cells located within the
mucosa and submucosa that formed discrete islands,
trabeculae, strands, glands, or solid sheets. These tumor
cells were small and uniform with scant, eosinophilic
granular cytoplasm and a centrally located round nucleus
with finely dispersed ("salt and pepper") chromatin. This
second component was diagnosed as NEC (malignant car-
cinoid) (Figure 2). Single neuroendocrine cells were noted
to contain cytoplasm displaying a vacuolated appearance.
Both components of the tumor invaded the subserosal
layer. Lymphatic invasion was present but neither venous
nor perineural invasion was noted. Metastatic NEC
(malignant carcinoid) was found in three of the twelve
lymph nodes. No evidence of metastatic signet-ring cell
adenocarcinoma was found. Diffuse neuroendocrine cell
hyperplasia and chronic gastritis with associated intestinal
metaplasia were additional pathologic findings noted in
the surrounding nonneoplastic mucosa of the stomach.
Proximal and distal margins were negative for tumor.
Special stains
The results of these studies demonstrated that signet-ring
adenocarcinoma cells were, to varying degrees, positive
for mucopolysaccharides with mucicarmine and PAS
stains, while the NEC component, including the neuroen-
docrine cells containing vacuolated cytoplasm, were com-
pletely negative (Figure 3).
Representative section of the tumor showing the signet-ring cell adenocarcinoma component
Figure 1
Representative section of the tumor showing the signet-ring
cell adenocarcinoma component. H and E. Original magnifica-
tion, × 400.

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Immunohistochemistry
Immunohistochemistry studies demonstrated that the
NET was strongly positive for chromogranin-A, synapto-
physin and NSE, while the majority of signet-ring cells
were negative (Figure 4). Pancytokeratin, E-cadherin, and
CAM 5.2 immunolabeling was present in both the signet-
cell adenocarcinoma and the neuroendocrine tumor com-
ponents. Occasional scattered signet-ring carcinoma cells
and goblet cells in the nonneoplastic metaplastic gastric
mucosa stained positive for synaptophysin and chrom-
ogranin A (Figures 5 and 6). Ki-67 immunolabeling
revealed a significant proliferation index (>70%) in the
signet-ring cell carcinoma component of the tumor. In
contrast, only rare neoplastic neuroendocrine cells
expressed Ki-67 (<2%). The lymph node metastases
stained diffusely and strongly positive for synaptophysin
and chromogranin A (Figures 7 and 8), consistent with
the light microscopic classification of these as neuroendo-
crine carcinoma exclusively.
Representative section of the tumor showing single synapto- physin positive signet-ring carcinoma cells
Figure 5
Representative section of the tumor showing single synapto-
physin positive signet-ring carcinoma cells. Anti-synapto-
physin. Original magnification, × 400.
Representative section of the tumor showing PAS positive signet-ring carcinoma cells and PAS negative neuroendocrine tumor cells
Figure 3
Representative section of the tumor showing PAS positive
signet-ring carcinoma cells and PAS negative neuroendocrine
tumor cells. PAS. Original magnification, × 400.
Representative section of the tumor showing the neuroen-docrine carcinoma component
Figure 2
Representative section of the tumor showing the neuroen-
docrine carcinoma component. Intestinal metaplasia is noted
in the upper left of the photo. H and E. Original magnifica-
tion, × 200.
Representative section of the tumor showing synaptophysin positive neuroendocrine cells and synaptophysin negative sig-net-ring carcinoma cells
Figure 4
Representative section of the tumor showing synaptophysin
positive neuroendocrine cells and synaptophysin negative sig-
net-ring carcinoma cells. Anti-synaptophysin. Original magni-
fication, × 100.

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Electron microscopy
Electron microscopically, the signet-ring carcinoma cells
possessed a hyperchromatic nucleus peripherally dis-
placed and compressed by moderately electron-dense
mucous granules. The cytoplasmic organelles were
decreased and could be seen at the periphery of the cell or
between mucous granules. Intracellular lumens lined by
microvilli were frequently observed (Figure 9).
The nuclei of the neuroendocrine cells were oval or round.
A narrow-to-chunky border of chromatin along the
nuclear periphery was seen to surround small nucleoli.
Endoplasmic reticulum, Golgi complex, free ribosomes,
mitochondria and lysosomes occurred quite regularly.
The neuroendocrine granules were round or oval, and
consisted of homogeneous, electron-dense areas tightly
surrounded by a membrane. Also present were single neu-
roendocrine cells containing lipid deposits, but no mucin,
which corresponded to the clear cell signet-ring like vacu-
olated appearance of the tumor cell cytoplasm previously
Representative section of signet-ring carcinoma cell
Figure 9
Representative section of signet-ring carcinoma cell. Note
the presence of intracellular lumen lined with microvilli. EM.
Original magnification, × 5000.
Representative section of neuroendocrine carcinoma com-ponent lymph node metastasis
Figure 7
Representative section of neuroendocrine carcinoma com-
ponent lymph node metastasis. H and E. Original magnifica-
tion, × 100.
Representative section of gastric mucosa with intestinal metaplasia
Figure 6
Representative section of gastric mucosa with intestinal
metaplasia. Neuroendocrine cells and single goblet cells stain
positive for synaptophysin. Anti-synaptophysin. Original mag-
nification, × 400.
Representative section of lymph node metastasis
Figure 8
Representative section of lymph node metastasis. Note
strong expression of synaptophysin in tumor cells. Anti-syn-
aptophysin. Original magnification, × 100.

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evident in some NEC cells in the H and E stained section
(Figure 10). Although immunohistochemical stains dem-
onstrated a minute number of cells displaying amphicrine
features, i.e. cells that had both neuroendocrine and
mucous granules, ultrastructural examination showed no
evidence of cells containing both exo- and neuroendo-
crine features within the same cell.
Conclusion
In the present study it was determined by light microscopy
that the neoplastic cell population contained equal
amounts of both tumor components, displaying on the
one hand a typical signet-ring cell adenocarcinoma pat-
tern admixed with clusters of small cells consistent with
neuroendocrine differentiation on the other. The signet-
ring cell carcinoma component showed positivity for pan-
cytokeratin and CAM 5.2, as well as mucopolysaccharides
but was negative for endocrine markers in the majority of
neoplastic cells. The NEC portion of the neoplasm was
positive for synaptophysin, chromogranin, NSE, pancy-
tokeratin, and CAM 5.2. Only scattered rare single signet-
ring cell carcinoma cells demonstrated amphicrine fea-
tures (i.e. expression of both neuroendocrine immunohis-
tochemical markers as well as positive mucicarmine and
PAS staining), this being inconsistent with the diagnosis
of a true amphicrine tumor. Furthermore, on ultrastruc-
tural examination, concurrence of mucous and endocrine
granules within the same cell was not observed, whereas
the presence of pure exocrine features e.g. intracellular
lumina, was observed in the majority of the signet-ring
cells with only a minority of them reaching the signet-ring
cell morphology through lipid accumulation within an
otherwise typical neuroendocrine cell. We thus concluded
that the neoplasm contained two distinct cell types and
therefore represents a composite signet-ring cell-neuroen-
docrine carcinoma.
The histiogenesis of these composite tumors remains
unclear. It has recently been proposed that signet-ring cell
carcinomas originate from the gradual dedifferentiation
from enterochromaffin-like (ECL) cells through signet-
ring cells with endocrine immunoreactivity [9]. In addi-
tion, two other hypotheses have been proposed, the first
suggesting coincidental neoplastic changes in two differ-
ent cell types and the second proposing a single common
precursor cell that undergoes a bidirectional neoplastic
change [10]. In the current case, the latter hypothesis
appears to be better suited in accounting for the intimate
admixture of the different cell types and patterns in this
tumor. An interesting finding, supporting the above men-
tioned hypothesis, was the appearance of amphicrine cells
in the signet-ring cell carcinoma component as well as in
the adjacent nonneoplastic gastric mucosa.
Four types of "pure" neuroendocrine tumors (NET) can be
distinguished in the stomach. Type 1 is the most com-
mon, occurring in 70–80% of all cases. In most cases, type
1 NETs of the stomach are small (0.1–1 cm in diameter),
multifocal tumors, affecting women more than men, and
always occurring in the background of chronic atrophic
gastritis. Type 3 (sporadic and solitary) is the second most
common, whereas types 2 (occurring in association with
multiple endocrine neoplasia type 1) and 4 (undifferenti-
ated solid neuroendocrine carcinoma) are considered rare
[11]. The clinical setting and morphologic features of the
NEC component in our case resemble the previously
described clinicopathologic findings in type I gastric NETs
[11]. Due to the fact that the NET component in the cur-
rent case was significantly larger than 2 cm and had metas-
tasized to a group of matted lymph nodes located adjacent
to the lesser curvature of the stomach, we can hypothesize
that this tumor would behave similar to a well-differenti-
ated neuroendocrine carcinoma based on the WHO clas-
sification [11]. This was a very unusual finding, given that
the NEC (malignant carcinoid) component was meta-
static without any participation of the signet-ring cell
component, even if the latter is typically the more malig-
nant tumor. Previous studies have shown that regional
lymph-node metastases occurred in very rare cases of type
1 NET in which the tumors were larger than 2 cm and
infiltrated the muscularis propria [11]. One of the latest
studies on gastrointestinal NETs demonstrated that small,
low-grade NETs with low proliferation index may behave
in a highly aggressive fashion, i.e. with multiple lymph
node and hematogeneous metastases [12].
Representative section of neuroendocrine carcinoma cells
Figure 10
Representative section of neuroendocrine carcinoma cells.
Note the presence of electron-dense endocrine granules
tightly surrounded by a membrane and the presence of focal
lipid deposits. EM. Original magnification, × 8000.

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The general biologic behavior of gastric mixed exocrine-
neuroendocrine neoplasms is unknown. A recent study
suggests that composite tumors have a better prognosis
than common gastric adenocarcinomas [2]. Certainly the
course in our case represents a much less aggressive pat-
tern than a classical signet-ring cell carcinoma. As recently
emphasized in cases of advanced signet-ring cell carci-
noma with better prognosis than expected [2], the diagno-
sis of composite glandular/neuroendocrine tumor needs
to be considered.
Competing interests
The author(s) declare that they have no competing inter-
ests.
Authors' contributions
SLN processed the specimen, evaluated the immunohisto-
chemical stains, confirmed the diagnosis, designed the
report and drafted the manuscript.
BAA evaluated the immunohistochemical stains, con-
firmed the diagnosis, designed the report and drafted the
manuscript.
SCC provided surgical intervention, relevant information
and review of the literature.
NH and EB provided surgical intervention and relevant
information.
JCP provided consultation.
All authors read and approved the final manuscript.
Acknowledgements
The use of paraffin blocks for this study meets Institutional Review Board
and Health Insurance Portability and Accountability Act requirements, and
has been approved by the Institutional Review Board at the University of
Maryland Protocol Number: H-29227.
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