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Solitary neurofibroma of the Mesentery: Report of a Case and review of the literature
PATlIOLOGY RESEARCH AND PRACTICE
Tead\ing Ca~
© Urban & Fischer Verlag http://w.m.l.urbanfischer.deJjournalsJprp
Solitary Neurofibroma of the Mesentery: Report of a Case and Review of the Literature Gaetano Magro" Maria Piana " Carmelo Venti 2 , Arcangelo Lacagnina 2 and Martino Ruggieri 3 'Institute of Anatomical Pathology and ' Division of Paedriatic Neurology, University of Catania, ' Division of General Surgery, Hospital M. Raimondi, San Cataldo, Ca ltanissetta, Italy
Summary Neurofibromas of the gastrointestinal tract are usually associated with neurofibromatosis type I (Nfl), or they are exelusi ve manifestations of the so-called "familial intestinal neurofibromatosis". Gastrointestinal neurofibromas can rarely occur as sporadic lesions in the jejunum and stomach, and only exceptionally in the mesentery. A critical review of the literature revealed that only seven cases of solitary neurofibromas (SNFs) of the mesentery (six in the ileal mesentery; one in the gastrocolic mesentery) have been reported in patients without stigmata of Nfl. We report the clinicopathologic features of an additional case of SNF of the ileal mesentery, incidentally found in a patient with an ad-
mesentery. To the best of our knowledge, only seven cases of SNF of the mesentery have previously been reported in the literature (Table I). We report an additional case of SNF of the ileal mesentery, review the literature on this topic. and discuss the possible links between this entity and Nfl.
Case Report A 71-year-old man was referred to a hospital elsewhere in Italy because of a 6-month hi story of irrepressible vomiting. Hc was well until first gastrointestinal symptoms appeared. and there was no family history of gastrointestinal diseases or genetic di sorders. Hi s two otherwi s~
vanced gastric carcinoma.
sons were
Since there is increasing evidence that some patients may have some features of Nfl, including dermal or nodular SNFs alone - limited to onc or more body segments - (segmental Nfl), the possibility that SNFs of the mesentery may also represent a segmental manifestation of Nfl is postulated.
remarkable. except for a mass on the left hypogastrium. Endoscopy revealed a pyloric stenosis. Histology of a punch biopsy taken from the gastric wall demonstrated a moderately differentiated adenocarcinoma of the intestinal type. At laparotomy, the posterior gastric wall was stuck to the pancreas. Multiple omental metastatic nodules and a large nodular mass in the ileal mesentery werc observed. A gastric-jejunum anastomosis was performed: peri-pancreatic adipose tissue, two omental nodules and a 15 Clll tract of ileum, including the mesenteric mass, were also excised.
Key words: Solitary neurofibroma - Mesentery - Neurofibromatosis type I
well. General examination was un-
Introduction The term solitary neurofibroma (SNF) refers to a localized neurofibroma occurring in patients without other stigmata of neurofibromatosis type I (Nfl) [3 J. SNF is usually a dermal or nodular skin lesion [3 J that is only rarely found at other sites, including the ileal Pathol. Res. Pract. 196: 7 13-7 18 (2000)
Address for correspondence: Gaetano Magro, Istituto di Anatomia Patologica, Universita' di Catania, Via Bibliotcca 4, 95 124. Catania. Italy. Phone: ++95-310241. Fax: ++95316045. E-mail: magrog.@ dimtel.nli.il 0344-0338/2000/ 196110-713 $15 .00/0
714 . G. Magro el a!. Table I. SNFs of the mesentery reported in the literature Authors
Age (yr)
Sex
Symptoms
Mesentery
Size
Treatment
Leach 1957
22
M
Painful mass
Ileum
24cm
Surgical excision
Follow-up
Alive with no recurrence after 7 years
Lahbabi H 1960
24
M
Painful mass
Ileum
Huge?
Surgical excision
Yannopoulos et al. 1963
17
F
Mass
Ileum
Small?
Biopsy
M
Painful mass
I1eumjejunum
24cm
Surgical excision
Yannopoulos et a!. 1963 22
?
Alive with disease
after 1 year
Alive with no recurrence after 11 years
Yannopoulos et a!. 1963
54
M
Incidental finding
Gastro-colic
?
Surgical excision
Gusarenko et a!. 1978
57
M
Painful mass
Ileum
23cm
Surgical excision
Lanzafame et aI. 1994
32
F
Painless mass
Ileum
8cm
Surgical excison
'!
Prescnt case
71
M
Incidental finding
Ileum
10 cm
Surgical excison
Died of advanced gastric carcinoma
?
Alive with no re-
currence after 5 years
Materials and Methods The surgical specimens were fixed in 10% neutrally buffered formalin. Sections were cut and stained with hematoxylin-eosin. van Gieson's for collagen. and Gomori's silver impregnation for reticulin. Immunohistochemistry was performed using a labeled streptavidin-biotin technique (LSAB, Dakopatts) and incubating tissue sections with antibodies to vimentin (mouse monoclonal; prediluted: Immunotech), asmooth muscle actin (mouse monoclonal; dilution 1:500; Dakopaus), desmin (mouse monoclonal; dilution 1:500; DakopaUs), CD34 antigen (mouse monoclonal; prcdiluted; Immunotcch). EMA (epithelial membrane antigen; mouse monoclonal; dilution I: 100; Dakopalts), neuron specific enolase (NSE; mouse monoclonal; prediluted; Immunotech), synaptophysin (mouse monoclonal; dilution: I: I 00; Dakopatts), chromogranin A (mouse monoclonal: dilution: 1.300; Dakopalts), PGP 9.5 (mouse monoclonal; dilution 1:800; Biogenex), c-kit (CDI17; polyclonal antibody; dilution LillO; Biogenex), and S-IOO protein (rabbit polyclonal; dilution 1:800; Dakopalts). Bound peroxidase was visualized using 0.05% 3,3'-diaminobenzidine tetrahydrochloride (Sigma Chemical Co., USA) as a chromogenic substrate for 10 min at room temperature. Negative conlrois excluding primary and secondary antibodies from the staining procedure as well as positive controls were used when appropriate.
Results Pathological findings
The mesenteric mass was well circumscribed, with a smooth surface mcasuring 10.5 x 9.5 x 6.5 Col (Fig. lA). The cut surface rcvealed a firm, solid mass, whitish in color, and confined to the mesentery without involvement of the gut wall (Fig. 1B).
Fig. I. Gross appearence of SNF of the mesentery. A: Uninodular mass with smooth external surface arising from the mesentery. B: The cut surface reveals a firm and solid mass, whitish in color
Solitary Neurofibroma of Ileal Mesentery
715
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Fig. 2. A: Hypocellular, collagenized spindle cell tumor with pushing borders, B: Bundles of spindly celis scattered among wire-like collagen fibres are typical of neurofibroma. C: Spindle cells showing focal immunoreactivity for S-l OO-protein
716 . G. Magro et al. Histological examination confirmed the metastatic nature of the omental nodules and revealed three lymph node metastases in peri-pancreatic adipose tissue. Notably, the mesenteric mass had the typical morphological features of a collagenized neurofibroma: a well-circumscribed hypocellular tumor (Fig. 2A) composed of wavy bundles of bland-looking spindle-shaped cells, closely associated with wire-like, fibrotic collagen bands (Fig. 2B). Only focally showed the stroma myxoid changes. Cellular pleomorphism and mitoses were absent. The tumor was limited to the mesentery compressing the adjacent gut wall, resulting in an expansive growth pattern. Immunohistochemistry revealed a diffuse positivity for vimentin, while S-IOO protein was detected only focally (Fig. 2C). Staining was negative with all the other antibodies tested. Gross, microscopic and immunohistochemical findings were consistent with the diagnosis of neurofibroma of the mesentery. Follow-up
Soon after surgery, the patient was re-examined, and there were no circumscribed or segmental features of Nfl. Slit-lamp examination revealed no Lisch nodules, and fundoscopy was otherwise normal. Clinical and slit-lamp examinations of both patient's sons were unremarkable. There was no history of neurofibromatosis in any other member of the family. The patient died of cancer-related complications nine months after laparatomy.
Discussion Neurofibromas of the gastrointestinal tract are usually associated with Nfl. Although an old hospital-based series estimated that gastrointestinal neurofibromas occurred in up to 25% of patients with Nfl, the reported frequency is estimated to be around 2.0% or less in most recent population-based studics [6, 11]. These tumors are located in the jejunum followed by the stomach, but multiple sites of involvement as well as unusual locations, including the ileal mesentery, have also been reported {l8J. Visceral neurofibromas are usually situated in the serosa, and some have hyperplasia of Auerbach's plexus, suggesting a disturbance of neuronal proliferation. Only rarely arc neurofibromas limited to the intestine in patients without any other clinical sign of Nfl. Onc possibility is the "familial intestinal neurofibromatosis", a rare dominant disorder, phenotypically distinct from Nfl, and characterized by multiple intestinal neurofibromas restricted only to the intestine {l2, 13J; the other possibility is the sporadic occurrence of multiple or SNFs in patients without any kind of familial neuro-
fibromatosis. In the latter condition, neurofibromas occur primarily in the small bowel, el ss frequently in the large bowel and stomach {l5, 191, and only exceptionally at other sites, including the ileal and gastrocolic mesenteries (Table I). To our knowledge, only seven cases of primary SNFs of the mesentery, all but one occurri ng in the ileal mesentery, have been reported as single case repOtts or as a small series in the literature (Table I). Leach and Vancouver, in 1957 {9J, reported on a giant plexiform neurofibroma of the ileal mesentery in a 22-year-old man who, at the time of diagnosis and after a three year follow-up, had no clinical signs of Nfl. Later, Lahbabi {7 J described an additional case in a 24-year-old man without any clinical sign of Nfl at surgical excision. However, Yannopoulos and Stout {l7 J, reporting their own experience of three well documented eases of mesentery SNFs (Table I), cited hut excluded the two cases mentioned above from the list of the SNF of the mesentery, because in their opinion Nfl could not be completely ruled out, given that cafe' -aulait (CAL) spots appeared seven years after surgical excision, while follow-up data was not available. In the last two decades, knowledge of the natural history and the genetics of the different forms of neurofibromatosis has changed [6, 11- 13/. It is known that there is a 100% penetrance of the Nfl gene (which is located on chromosome 17q 11 .2) by the age of 5 years, and CAL spots in Nfl manifest before the age of two years or not at all {6, 12, 13]. Thus, we believe that the cases of SNF of the ileal mesentery reported by Leach and Vancouver [9 J and Lahbabi [7/ occurred in nonNfl patients, since there were no clinical signs of Nfl at the age of22 and 24 years, respectively. An extensive MEDLINE-based search on SNFs of the mesentery revealed two further cases of SNFs of the ileal mesentery [4, 8/, including one previously reported by one of us (GM) {8J. A review of all the cases recorded in the literature reveals that SNFs of the ileal mesentery may reach a large size (cm 24 in greatest diameter), and that they are usually diagnosed only after histological examination, since, preoperatively, they are interpreted as ovarian cysts or unclassified symptomatic or asymptomatic abdominal masses (Table I). The present case was incidentally found at laparotomy, performed as surgical treatment for an advanced gastric carcinoma. The association between SNF of the ileal mesentery and gastric cancer seems to be incidental, as the literature search revealed no significant coexistence of SNF, irrespective of its location, with malignant epithelial tumors {3, 4, 7-9, 17/. In the present case, the diagnosis of SNF was made on clinical grounds due to the absence of stigmata of Nfl in the patient and lack of Nfl history in the patient's first degree relatives. From the pathological point of view, the differential diagnosis included a wide spectrum of benign spindle
Solitary Neurofibroma of Ileal Mesentery . 717 cell tumor or tumor-like lesions, such as fibromatosis, inflammatory pseudotumor (inflammatory myofibroblastic tumor), solitary fibrous tumor, perincurioma, and the wide spectrum of gastrointestinal stromal tumors (GISTs), including the autonomic nerve tumors (GANTs). Fibromatosis may occur in the mesentery as a sporadic disease or in the context of genetic syndromes, such as Gardner's syndrome [3J. Unlike our case, the peripheral margins of fibromatosis are infiltrating, and it is characterized by a typical growth pattern consisting of interlacing long bundles and fascicles of uniform spindle-shaped cells in parallel array [3]. In addition, immunohistochemistry reveals a variable degree of immunoreactivity for smooth muscle markers (especially a-smooth muscle actin), a tinding that is in line with the myoftbroblastic nature of the cells {3/. Although the inflammatory pseudotumor of the ileal mesentery may present as a uninodular mass and shows a pauciccllular fibroblastic proliferation with prominent hyalinized stroma, it usually contains a conspicuous inflammatory component consisting of lymphocytes, plasma cells and histiocytes [l6J, which is lacking in our casco Furthermorc, the spindlc cells of the inflammatory pseudotumor usually exhibit a myofibroblastic phenotype (variable degree of expression of a-smooth muscle actin and, surprisingly, cytokeratins) [16/. Solitary fibrous tumor is currently considered as a ubiquitous neoplasm arising from the CD34+ interstitial cells of connective tissues [IJ, which may rarely involve the mesentery [5]. Unlike our case, solitary fibrous tumor exhibits a variety of growth patterns, including storiform , hemangiopericytoma-like, and angiofibroma-like patterns; its cellular component is strongly positive for CD34 [I]. Perincurioma is a rare benign spindle cell nerve sheath tumor which may show a variable degree of cellularity and sclerosis. However, it is usually composed of EMA-positive fusiform cells arranged in a fascicular, lamcllar, whorled or storiform pattern /3/. The term GISTs covers a widc morphological and immunophenotypical spectrum of spindly to epithelioid cell neoplasms occurring in the gastrointestinal tract, including the peritoneum, omentum and mesentery [10]. These tumors usually show a higher degree of cellularity than that observed in our case, and most neoplastic cells are immunoreactive for CD 117, CD34. and less frequently exhibit a focal expression of a-smooth muscle actin [10]. Tumors with morphological features overlapping those observed in GISTs, but showing immunohistochemical and ultrastructural features of gastrointestinal autonomic nerve differentiation. are currently termed GANTs [2, 10, 14J. Unlikc neurofibroma, GANTs are usually positive for NSE, synaptophysin, cromogranin A, and PGP 9.5 [2, 14J, although their expression level varies. Notably, the recent literature contains an increasing number of rcports on paticnts having featurcs of Nfl
limited to one or more body segments, the so-called segmental/mosaic Nfl [12, 13]. Its frequency appears to be 1 in 70,000-80,000 or 0.014% [12,13/. Although not proven at the molecular level thus far, somatic mutations of the Nfl gene [12 , 13J are the most likely mechanisms underlying this phenomenon. From the clinical point of view, it is well established that patients with segmental/mosaic Nfl may only have pigmentary anomalies (CAL spots and/or freckling), only neurofibromas (dermal and/or nodular), or only a combination of pigmentary lesions and neurofibromas and plexiform neurofibromas [12, 13 J. Thus, the current opinion that isolated dermal or nodular neurofibromas or isolated plexiform neurofibromas, without any other stigmata of Nfl, occur in circumscribed areas of the body as segmental manifestations of the Nfl, leads to the hypothesis that SNFs of the ileal mesentery could also be an expression of segmental/mosaic Nfl. In conclusion, thc present case, along with those rcpotted previously, supports the possibility that ileal mesentery, although rarely, may be the site of origin of sporadic neurofibromas. Therefore, this tumor should be also considered in the preoperative and intra-operative differential diagnosis of mesenteric masses in patients lacking clinical evidence of Nfl. Finally, we hypothesize that SNFs of the mesentery might be reconsidered and tentatively regarded as mosaic manifestations of the Nfl gene. Acknowledgements. We wish to thank Mrg. Antonella Corsaro for her excellent technical assistance
References I. Chan JKC (1997) Solitary fibrous tumour-everywhere,
and a diagnosis in vogue. Histopathology 31: 568-576
2. Dhimes P. Lopez-Carreira M, Ortega-Serrano MP, Gar-
cia-Munoz H, Martinez.-Gonzalez MA, Ballestin C (1995) Gastrointestinal autonomic nerve tumours and their separation from other gastrointestinal stromal tumours: an ultrastructural and immunohistochemical study of seven caSes . Virchows Arch 426: 27-35 3. Enzinger F & Weiss SW (1995) Soft Tissue tumors. 3rd
cd, CV Mosby Company, St. Louis, Washington, Toronto 4. Gusarenko VF. Belonozhko ID (1978) Neurofibroma of the mesentery of the small intestine. Vestn Khir 12/: 65--66 5. Hardisson D, Limeres MA, Jimenez-Heffernan JA. De la Rosa P, Burgos E (1996) Solitary fibrous tumor of the mesentery. Am J Gastroenterol 91: 810-811 6. Huson SM. Hughes RAC (1994) The neurofibromatoses. A pathogenetic and clinical overview. Chapman & Hall,
London 7. Lahbabi H (1960) A propos de deux cas de tumeurs du mesentere. Maroc med 39: 262-263 8. Lanzafamc S. Villari L. Viola S. Magro G (1994) Solitary neurofibroma of the mesentery: a case report with irn-
718 . G. Magro el a!.
9. 10.
II.
12. 13. 14.
munohistochemical study of extracellular matrix. Pathologica 86: 304-306 Leach WB, Vancouver BC (1957) Giant neurofibroma of the mesentery. Arch Surg 74: 438-441 Miettinen M, Sarlomo-Rikala M, Lasota J (1999) Gastrointestinal stromal tumors:recent advances in understanding of their biology. Hum Pathol30: 1213-1220 Ri ccardi VM (1992) Neurofibromatosis. Phenotype, Natural History, and Pathogenesis, 2" ed. Johns Hopkins University Press, Baltimore Ruggieri M, Huson SM (1999). The neurofibromatoses. An overview. Ital J Neurol Sciences 20: 89-108 Ruggieri M, Moss C, Upadhyaya M, Huson SM (1999) Mosaic-segmental neurofibromatosis type I: a clinical study. J Neurol246 (supp!. I) 162 Shanks JH, Harris M , Banerjee SS, Eyden BP (1996)
Gastrointestinal autonomic nerve tumours: a report of nine cases. Histopathology 29: 111 - 121 15. Sivar MV, Sullivan BH, Farmer RG (1975) Neurogenic
tumors of the small intestine. Review ofthe literature and
report of a case with endoscopic removal. Gastroenterol -
ogy 68: 374-380 16. Treissman Sp, Gillis DA, Lee CL, Giacomantonio M, Resch L (1994) Omental-mesenteric innammatory pseudotumor. Cytogenetic demonstration of genetic changes and monoclonality in one tumor. Cancer 73: 1433-1437 17. Yannopoulos K, Stout AP (1963) Primary solid tumors of the mesentery. Cancer 16: 914-927 18. Yano K, Okamura T, Yoshida Y, Osaki T, Ichiyoshi Y, Yasumoto K (1998) Mesenteric neurofibroma with von Recklinghausen's disease: a case report. Hepatogastroenteralogy 45: 456-458 19. Watanuki F, Ohwada S, Hosomura Y, Okamura S, Kawashima Y, Tanahashi Y, Nakamura S, Iino Y, Johshita T, Morishita Y (1995) Small ileal neurofibroma causing intussusception in a non-neurofibromatosis patient. J Gastroenterol30: 113- 116 Received: November II, 1999 Accepted in revised version: April 25 , 2000
Tead\ing Ca~
© Urban & Fischer Verlag http://w.m.l.urbanfischer.deJjournalsJprp
Solitary Neurofibroma of the Mesentery: Report of a Case and Review of the Literature Gaetano Magro" Maria Piana " Carmelo Venti 2 , Arcangelo Lacagnina 2 and Martino Ruggieri 3 'Institute of Anatomical Pathology and ' Division of Paedriatic Neurology, University of Catania, ' Division of General Surgery, Hospital M. Raimondi, San Cataldo, Ca ltanissetta, Italy
Summary Neurofibromas of the gastrointestinal tract are usually associated with neurofibromatosis type I (Nfl), or they are exelusi ve manifestations of the so-called "familial intestinal neurofibromatosis". Gastrointestinal neurofibromas can rarely occur as sporadic lesions in the jejunum and stomach, and only exceptionally in the mesentery. A critical review of the literature revealed that only seven cases of solitary neurofibromas (SNFs) of the mesentery (six in the ileal mesentery; one in the gastrocolic mesentery) have been reported in patients without stigmata of Nfl. We report the clinicopathologic features of an additional case of SNF of the ileal mesentery, incidentally found in a patient with an ad-
mesentery. To the best of our knowledge, only seven cases of SNF of the mesentery have previously been reported in the literature (Table I). We report an additional case of SNF of the ileal mesentery, review the literature on this topic. and discuss the possible links between this entity and Nfl.
Case Report A 71-year-old man was referred to a hospital elsewhere in Italy because of a 6-month hi story of irrepressible vomiting. Hc was well until first gastrointestinal symptoms appeared. and there was no family history of gastrointestinal diseases or genetic di sorders. Hi s two otherwi s~
vanced gastric carcinoma.
sons were
Since there is increasing evidence that some patients may have some features of Nfl, including dermal or nodular SNFs alone - limited to onc or more body segments - (segmental Nfl), the possibility that SNFs of the mesentery may also represent a segmental manifestation of Nfl is postulated.
remarkable. except for a mass on the left hypogastrium. Endoscopy revealed a pyloric stenosis. Histology of a punch biopsy taken from the gastric wall demonstrated a moderately differentiated adenocarcinoma of the intestinal type. At laparotomy, the posterior gastric wall was stuck to the pancreas. Multiple omental metastatic nodules and a large nodular mass in the ileal mesentery werc observed. A gastric-jejunum anastomosis was performed: peri-pancreatic adipose tissue, two omental nodules and a 15 Clll tract of ileum, including the mesenteric mass, were also excised.
Key words: Solitary neurofibroma - Mesentery - Neurofibromatosis type I
well. General examination was un-
Introduction The term solitary neurofibroma (SNF) refers to a localized neurofibroma occurring in patients without other stigmata of neurofibromatosis type I (Nfl) [3 J. SNF is usually a dermal or nodular skin lesion [3 J that is only rarely found at other sites, including the ileal Pathol. Res. Pract. 196: 7 13-7 18 (2000)
Address for correspondence: Gaetano Magro, Istituto di Anatomia Patologica, Universita' di Catania, Via Bibliotcca 4, 95 124. Catania. Italy. Phone: ++95-310241. Fax: ++95316045. E-mail: magrog.@ dimtel.nli.il 0344-0338/2000/ 196110-713 $15 .00/0
714 . G. Magro el a!. Table I. SNFs of the mesentery reported in the literature Authors
Age (yr)
Sex
Symptoms
Mesentery
Size
Treatment
Leach 1957
22
M
Painful mass
Ileum
24cm
Surgical excision
Follow-up
Alive with no recurrence after 7 years
Lahbabi H 1960
24
M
Painful mass
Ileum
Huge?
Surgical excision
Yannopoulos et al. 1963
17
F
Mass
Ileum
Small?
Biopsy
M
Painful mass
I1eumjejunum
24cm
Surgical excision
Yannopoulos et a!. 1963 22
?
Alive with disease
after 1 year
Alive with no recurrence after 11 years
Yannopoulos et a!. 1963
54
M
Incidental finding
Gastro-colic
?
Surgical excision
Gusarenko et a!. 1978
57
M
Painful mass
Ileum
23cm
Surgical excision
Lanzafame et aI. 1994
32
F
Painless mass
Ileum
8cm
Surgical excison
'!
Prescnt case
71
M
Incidental finding
Ileum
10 cm
Surgical excison
Died of advanced gastric carcinoma
?
Alive with no re-
currence after 5 years
Materials and Methods The surgical specimens were fixed in 10% neutrally buffered formalin. Sections were cut and stained with hematoxylin-eosin. van Gieson's for collagen. and Gomori's silver impregnation for reticulin. Immunohistochemistry was performed using a labeled streptavidin-biotin technique (LSAB, Dakopatts) and incubating tissue sections with antibodies to vimentin (mouse monoclonal; prediluted: Immunotech), asmooth muscle actin (mouse monoclonal; dilution 1:500; Dakopaus), desmin (mouse monoclonal; dilution 1:500; DakopaUs), CD34 antigen (mouse monoclonal; prcdiluted; Immunotcch). EMA (epithelial membrane antigen; mouse monoclonal; dilution I: 100; Dakopalts), neuron specific enolase (NSE; mouse monoclonal; prediluted; Immunotech), synaptophysin (mouse monoclonal; dilution: I: I 00; Dakopatts), chromogranin A (mouse monoclonal: dilution: 1.300; Dakopalts), PGP 9.5 (mouse monoclonal; dilution 1:800; Biogenex), c-kit (CDI17; polyclonal antibody; dilution LillO; Biogenex), and S-IOO protein (rabbit polyclonal; dilution 1:800; Dakopalts). Bound peroxidase was visualized using 0.05% 3,3'-diaminobenzidine tetrahydrochloride (Sigma Chemical Co., USA) as a chromogenic substrate for 10 min at room temperature. Negative conlrois excluding primary and secondary antibodies from the staining procedure as well as positive controls were used when appropriate.
Results Pathological findings
The mesenteric mass was well circumscribed, with a smooth surface mcasuring 10.5 x 9.5 x 6.5 Col (Fig. lA). The cut surface rcvealed a firm, solid mass, whitish in color, and confined to the mesentery without involvement of the gut wall (Fig. 1B).
Fig. I. Gross appearence of SNF of the mesentery. A: Uninodular mass with smooth external surface arising from the mesentery. B: The cut surface reveals a firm and solid mass, whitish in color
Solitary Neurofibroma of Ileal Mesentery
715
.
A
lIIo ' .
;~~.~.
,
t . • .. ~ .
.. ,
-
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.
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Fig. 2. A: Hypocellular, collagenized spindle cell tumor with pushing borders, B: Bundles of spindly celis scattered among wire-like collagen fibres are typical of neurofibroma. C: Spindle cells showing focal immunoreactivity for S-l OO-protein
716 . G. Magro et al. Histological examination confirmed the metastatic nature of the omental nodules and revealed three lymph node metastases in peri-pancreatic adipose tissue. Notably, the mesenteric mass had the typical morphological features of a collagenized neurofibroma: a well-circumscribed hypocellular tumor (Fig. 2A) composed of wavy bundles of bland-looking spindle-shaped cells, closely associated with wire-like, fibrotic collagen bands (Fig. 2B). Only focally showed the stroma myxoid changes. Cellular pleomorphism and mitoses were absent. The tumor was limited to the mesentery compressing the adjacent gut wall, resulting in an expansive growth pattern. Immunohistochemistry revealed a diffuse positivity for vimentin, while S-IOO protein was detected only focally (Fig. 2C). Staining was negative with all the other antibodies tested. Gross, microscopic and immunohistochemical findings were consistent with the diagnosis of neurofibroma of the mesentery. Follow-up
Soon after surgery, the patient was re-examined, and there were no circumscribed or segmental features of Nfl. Slit-lamp examination revealed no Lisch nodules, and fundoscopy was otherwise normal. Clinical and slit-lamp examinations of both patient's sons were unremarkable. There was no history of neurofibromatosis in any other member of the family. The patient died of cancer-related complications nine months after laparatomy.
Discussion Neurofibromas of the gastrointestinal tract are usually associated with Nfl. Although an old hospital-based series estimated that gastrointestinal neurofibromas occurred in up to 25% of patients with Nfl, the reported frequency is estimated to be around 2.0% or less in most recent population-based studics [6, 11]. These tumors are located in the jejunum followed by the stomach, but multiple sites of involvement as well as unusual locations, including the ileal mesentery, have also been reported {l8J. Visceral neurofibromas are usually situated in the serosa, and some have hyperplasia of Auerbach's plexus, suggesting a disturbance of neuronal proliferation. Only rarely arc neurofibromas limited to the intestine in patients without any other clinical sign of Nfl. Onc possibility is the "familial intestinal neurofibromatosis", a rare dominant disorder, phenotypically distinct from Nfl, and characterized by multiple intestinal neurofibromas restricted only to the intestine {l2, 13J; the other possibility is the sporadic occurrence of multiple or SNFs in patients without any kind of familial neuro-
fibromatosis. In the latter condition, neurofibromas occur primarily in the small bowel, el ss frequently in the large bowel and stomach {l5, 191, and only exceptionally at other sites, including the ileal and gastrocolic mesenteries (Table I). To our knowledge, only seven cases of primary SNFs of the mesentery, all but one occurri ng in the ileal mesentery, have been reported as single case repOtts or as a small series in the literature (Table I). Leach and Vancouver, in 1957 {9J, reported on a giant plexiform neurofibroma of the ileal mesentery in a 22-year-old man who, at the time of diagnosis and after a three year follow-up, had no clinical signs of Nfl. Later, Lahbabi {7 J described an additional case in a 24-year-old man without any clinical sign of Nfl at surgical excision. However, Yannopoulos and Stout {l7 J, reporting their own experience of three well documented eases of mesentery SNFs (Table I), cited hut excluded the two cases mentioned above from the list of the SNF of the mesentery, because in their opinion Nfl could not be completely ruled out, given that cafe' -aulait (CAL) spots appeared seven years after surgical excision, while follow-up data was not available. In the last two decades, knowledge of the natural history and the genetics of the different forms of neurofibromatosis has changed [6, 11- 13/. It is known that there is a 100% penetrance of the Nfl gene (which is located on chromosome 17q 11 .2) by the age of 5 years, and CAL spots in Nfl manifest before the age of two years or not at all {6, 12, 13]. Thus, we believe that the cases of SNF of the ileal mesentery reported by Leach and Vancouver [9 J and Lahbabi [7/ occurred in nonNfl patients, since there were no clinical signs of Nfl at the age of22 and 24 years, respectively. An extensive MEDLINE-based search on SNFs of the mesentery revealed two further cases of SNFs of the ileal mesentery [4, 8/, including one previously reported by one of us (GM) {8J. A review of all the cases recorded in the literature reveals that SNFs of the ileal mesentery may reach a large size (cm 24 in greatest diameter), and that they are usually diagnosed only after histological examination, since, preoperatively, they are interpreted as ovarian cysts or unclassified symptomatic or asymptomatic abdominal masses (Table I). The present case was incidentally found at laparotomy, performed as surgical treatment for an advanced gastric carcinoma. The association between SNF of the ileal mesentery and gastric cancer seems to be incidental, as the literature search revealed no significant coexistence of SNF, irrespective of its location, with malignant epithelial tumors {3, 4, 7-9, 17/. In the present case, the diagnosis of SNF was made on clinical grounds due to the absence of stigmata of Nfl in the patient and lack of Nfl history in the patient's first degree relatives. From the pathological point of view, the differential diagnosis included a wide spectrum of benign spindle
Solitary Neurofibroma of Ileal Mesentery . 717 cell tumor or tumor-like lesions, such as fibromatosis, inflammatory pseudotumor (inflammatory myofibroblastic tumor), solitary fibrous tumor, perincurioma, and the wide spectrum of gastrointestinal stromal tumors (GISTs), including the autonomic nerve tumors (GANTs). Fibromatosis may occur in the mesentery as a sporadic disease or in the context of genetic syndromes, such as Gardner's syndrome [3J. Unlike our case, the peripheral margins of fibromatosis are infiltrating, and it is characterized by a typical growth pattern consisting of interlacing long bundles and fascicles of uniform spindle-shaped cells in parallel array [3]. In addition, immunohistochemistry reveals a variable degree of immunoreactivity for smooth muscle markers (especially a-smooth muscle actin), a tinding that is in line with the myoftbroblastic nature of the cells {3/. Although the inflammatory pseudotumor of the ileal mesentery may present as a uninodular mass and shows a pauciccllular fibroblastic proliferation with prominent hyalinized stroma, it usually contains a conspicuous inflammatory component consisting of lymphocytes, plasma cells and histiocytes [l6J, which is lacking in our casco Furthermorc, the spindlc cells of the inflammatory pseudotumor usually exhibit a myofibroblastic phenotype (variable degree of expression of a-smooth muscle actin and, surprisingly, cytokeratins) [16/. Solitary fibrous tumor is currently considered as a ubiquitous neoplasm arising from the CD34+ interstitial cells of connective tissues [IJ, which may rarely involve the mesentery [5]. Unlike our case, solitary fibrous tumor exhibits a variety of growth patterns, including storiform , hemangiopericytoma-like, and angiofibroma-like patterns; its cellular component is strongly positive for CD34 [I]. Perincurioma is a rare benign spindle cell nerve sheath tumor which may show a variable degree of cellularity and sclerosis. However, it is usually composed of EMA-positive fusiform cells arranged in a fascicular, lamcllar, whorled or storiform pattern /3/. The term GISTs covers a widc morphological and immunophenotypical spectrum of spindly to epithelioid cell neoplasms occurring in the gastrointestinal tract, including the peritoneum, omentum and mesentery [10]. These tumors usually show a higher degree of cellularity than that observed in our case, and most neoplastic cells are immunoreactive for CD 117, CD34. and less frequently exhibit a focal expression of a-smooth muscle actin [10]. Tumors with morphological features overlapping those observed in GISTs, but showing immunohistochemical and ultrastructural features of gastrointestinal autonomic nerve differentiation. are currently termed GANTs [2, 10, 14J. Unlikc neurofibroma, GANTs are usually positive for NSE, synaptophysin, cromogranin A, and PGP 9.5 [2, 14J, although their expression level varies. Notably, the recent literature contains an increasing number of rcports on paticnts having featurcs of Nfl
limited to one or more body segments, the so-called segmental/mosaic Nfl [12, 13]. Its frequency appears to be 1 in 70,000-80,000 or 0.014% [12,13/. Although not proven at the molecular level thus far, somatic mutations of the Nfl gene [12 , 13J are the most likely mechanisms underlying this phenomenon. From the clinical point of view, it is well established that patients with segmental/mosaic Nfl may only have pigmentary anomalies (CAL spots and/or freckling), only neurofibromas (dermal and/or nodular), or only a combination of pigmentary lesions and neurofibromas and plexiform neurofibromas [12, 13 J. Thus, the current opinion that isolated dermal or nodular neurofibromas or isolated plexiform neurofibromas, without any other stigmata of Nfl, occur in circumscribed areas of the body as segmental manifestations of the Nfl, leads to the hypothesis that SNFs of the ileal mesentery could also be an expression of segmental/mosaic Nfl. In conclusion, thc present case, along with those rcpotted previously, supports the possibility that ileal mesentery, although rarely, may be the site of origin of sporadic neurofibromas. Therefore, this tumor should be also considered in the preoperative and intra-operative differential diagnosis of mesenteric masses in patients lacking clinical evidence of Nfl. Finally, we hypothesize that SNFs of the mesentery might be reconsidered and tentatively regarded as mosaic manifestations of the Nfl gene. Acknowledgements. We wish to thank Mrg. Antonella Corsaro for her excellent technical assistance
References I. Chan JKC (1997) Solitary fibrous tumour-everywhere,
and a diagnosis in vogue. Histopathology 31: 568-576
2. Dhimes P. Lopez-Carreira M, Ortega-Serrano MP, Gar-
cia-Munoz H, Martinez.-Gonzalez MA, Ballestin C (1995) Gastrointestinal autonomic nerve tumours and their separation from other gastrointestinal stromal tumours: an ultrastructural and immunohistochemical study of seven caSes . Virchows Arch 426: 27-35 3. Enzinger F & Weiss SW (1995) Soft Tissue tumors. 3rd
cd, CV Mosby Company, St. Louis, Washington, Toronto 4. Gusarenko VF. Belonozhko ID (1978) Neurofibroma of the mesentery of the small intestine. Vestn Khir 12/: 65--66 5. Hardisson D, Limeres MA, Jimenez-Heffernan JA. De la Rosa P, Burgos E (1996) Solitary fibrous tumor of the mesentery. Am J Gastroenterol 91: 810-811 6. Huson SM. Hughes RAC (1994) The neurofibromatoses. A pathogenetic and clinical overview. Chapman & Hall,
London 7. Lahbabi H (1960) A propos de deux cas de tumeurs du mesentere. Maroc med 39: 262-263 8. Lanzafamc S. Villari L. Viola S. Magro G (1994) Solitary neurofibroma of the mesentery: a case report with irn-
718 . G. Magro el a!.
9. 10.
II.
12. 13. 14.
munohistochemical study of extracellular matrix. Pathologica 86: 304-306 Leach WB, Vancouver BC (1957) Giant neurofibroma of the mesentery. Arch Surg 74: 438-441 Miettinen M, Sarlomo-Rikala M, Lasota J (1999) Gastrointestinal stromal tumors:recent advances in understanding of their biology. Hum Pathol30: 1213-1220 Ri ccardi VM (1992) Neurofibromatosis. Phenotype, Natural History, and Pathogenesis, 2" ed. Johns Hopkins University Press, Baltimore Ruggieri M, Huson SM (1999). The neurofibromatoses. An overview. Ital J Neurol Sciences 20: 89-108 Ruggieri M, Moss C, Upadhyaya M, Huson SM (1999) Mosaic-segmental neurofibromatosis type I: a clinical study. J Neurol246 (supp!. I) 162 Shanks JH, Harris M , Banerjee SS, Eyden BP (1996)
Gastrointestinal autonomic nerve tumours: a report of nine cases. Histopathology 29: 111 - 121 15. Sivar MV, Sullivan BH, Farmer RG (1975) Neurogenic
tumors of the small intestine. Review ofthe literature and
report of a case with endoscopic removal. Gastroenterol -
ogy 68: 374-380 16. Treissman Sp, Gillis DA, Lee CL, Giacomantonio M, Resch L (1994) Omental-mesenteric innammatory pseudotumor. Cytogenetic demonstration of genetic changes and monoclonality in one tumor. Cancer 73: 1433-1437 17. Yannopoulos K, Stout AP (1963) Primary solid tumors of the mesentery. Cancer 16: 914-927 18. Yano K, Okamura T, Yoshida Y, Osaki T, Ichiyoshi Y, Yasumoto K (1998) Mesenteric neurofibroma with von Recklinghausen's disease: a case report. Hepatogastroenteralogy 45: 456-458 19. Watanuki F, Ohwada S, Hosomura Y, Okamura S, Kawashima Y, Tanahashi Y, Nakamura S, Iino Y, Johshita T, Morishita Y (1995) Small ileal neurofibroma causing intussusception in a non-neurofibromatosis patient. J Gastroenterol30: 113- 116 Received: November II, 1999 Accepted in revised version: April 25 , 2000