Case 2 -
Gliomatosis peritonei (peritoneal gliomatosis)
Kathleen R. Cho
University of Michigan
Click on each slide thumbnail image for an enlarged view
A 16 year-old girl presented with non-specific
abdominal pain and a two week history of flu-like symptoms. A CAT scan demonstrated a large left ovarian
mass with solid and cystic components. Exploratory laparotomy revealed a 25 cm ovarian tumor focally
adherent to the omentum, but without obvious rupture. Multiple small white nodules on the peritoneal
surface of the right hemi-diaphragm and cul de sac were also observed. A left salpingo-oophorectomy,
omentectomy, and biopsies of the right ovary and peritoneal nodules were performed.
Gliomatosis peritonei (peritoneal gliomatosis)
The left ovary was
largely replaced by a heterogeneous mass with both cystic and solid areas, extending to the ovarian
surface. Regions of hemorrhage and necrosis were grossly evident. Microscopic examination of the
ovarian neoplasm revealed an immature teratoma, Grade 3, without other germ cell tumor elements. In
addition to tissue types characteristic of mature teratomas, primitive neuroectodermal elements were
prominent. The cul-de-sac and diaphragm biopsies and omentum showed small "implants" of mature glial
The patient developed a left peri-renal mass shortly
after her initial surgery. Biopsies of the peri-renal mass and rectal serosa revealed immature
teratoma. She was treated with 4 cycles of PEB chemotherapy (cisplatin, etoposide, and bleomycin) and
subsequently underwent resection of the kidney, appendix, and left colon. Pathologic examination of the
peri-renal mass revealed mature cystic teratoma. "Implants" of mature glial tissue were observed on the
bowel serosa. The patient is alive and well four years following her initial diagnosis.
Gliomatosis peritonei (GP) was first described by Neuhä user
in 1906  . It is defined as "implantation" of nodular, predominantly mature, glial tissue on
the peritoneal surfaces of patients with ovarian teratomas. Müller and colleagues recently reported two
cases of GP and reviewed 86 additional published cases  . Based on this review, they found
that the glial nodules associated with GP are usually composed of mature glial tissue 1-3 mm in diameter,
but may be significantly larger (up to 3.5 cm). The average age at diagnosis is 15.4 years (range 10
months to 46 years). In nearly 80% of the cases reviewed, adhesions of the tumor or tears in the capsule
were present, although in a subset of cases these findings were definitively absent. The associated
ovarian teratoma can be mature or immature (any grade), but GP was most frequently observed in
association with mature teratomas. All fatal cases (11 of 86) occurred in conjunction with immature
teratomas. The glial tissue associated with GP can persist for many years or spontaneously regress.
Malignant transformation (glial or teratomatous) has also been reported  .
Several theories have been proposed to explain the pathogenesis of GP:
The first three theories lead to the prediction that the glial tissue in GP is genetically related to
the associated teratoma, having been extruded from the primary neoplasm or disseminated through
angiolymphatic channels. The fourth theory would predict that the glial foci are genetically unrelated
to the teratoma and arise from non-neoplastic cells.
- Although all elements of the teratoma metastasize or "implant", only the most robust elements, i.e., glial tissue, survives  .
- Immature neural elements metastasize and subsequently mature, comparable to the maturation of neuroblastoma to ganglioneuroma  .
- Mature glial tissue is extruded from the teratoma and "implants" on the peritoneal surfaces  .
- Glial foci arise independently from pluripotent peritoneal stem cells in response to favorable intraperitoneal conditions, as part of a so-called field effect  .
Molecular Genetic Analysis of GP
To address whether glial implants are genetically related to the associated ovarian teratoma or
whether they arise independently, we exploited the unique genetic make-up of many ovarian teratomas
 . Approximately 65% of teratomas are derived from a single germ cell after the first
meiotic division with subsequent failure of meiosis 2 or endoreduplication of a haploid ovum 
. Teratomas arising through these mechanisms show homozygosity at most, if not all, polymorphic
microsatellite (MS) loci. We used MS loci demonstrating a heterozygous pattern in normal tissue and a
homozygous pattern in the ovarian teratoma from the same patient to determine the origin of glial
implants in GP. We presumed that if the glial implants showed a homozygous pattern similar to the
teratoma, they were most likely related to the teratoma and arose via capsular rupture or angiolymphatic
dissemination. If they demonstrated a heterozygous pattern, similar to normal tissue, they most likely
arose via metaplasia of normal cells within the peritoneum.
DNA samples extracted from paraffin-embedded normal tissue, ovarian teratoma and three individual
laser-dissected glial implants were studied in two cases of GP. In one case, all three implants and
normal tissue showed heterozygosity at each of three MS loci on different chromosomes, whereas the
teratoma showed homozygosity at the same MS loci. Similar results were observed in the second case. Our
findings indicate that glial implants in GP often arise from cells within the peritoneum, presumably
pluripotent Müllerian stem cells, and not from the associated ovarian teratoma. Given that we analyzed
only two cases of GP and a limited number of implants, it is possible that some glial foci result from
true implantation, whereas others arise via metaplasia of normal stem cells within the peritoneum.
Why some intraperitoneal stem cells (or tissues) differentiate along a glial pathway whereas others
do not requires some speculation. The remarkable ability of stem cells derived from various organs to
differentiate along divergent pathways has been the subject of multiple recent articles, including
reports of studies demonstrating that bone marrow-derived stem cells can undergo glial differentiation
 . It has been suggested that a stem cell's microenvironment can induce a specific
differentiation pathway or pathways, and it is possible that some teratomas with an abundant glial
component secrete factors that induce glial differentiation in the peritoneum. Protein secretion by
teratomas is a well-recognized phenomenon. For example, teratomas with a prominent thyroid component,
such as struma ovarii and struma-carcinoid, have been shown to secrete thyroid hormone and calcitonin,
. Notably, murine astrocyte cells and teratocarcinoma cell lines have been
shown to secrete b -nerve growth factor in vitro
. Moreover, GP has been described in children without teratomas who have had
ventriculoperitoneal shunts placed early in infancy  . Neural growth factors normally
present in cerebrospinal fluid may enter the peritoneum through the shunt and induce glial
differentiation in the same manner.
Our findings may have important implications for more common gynecological entities with debatable
pathogenesis, such as endometriosis, endosalpingiosis, and non-invasive implants associated with serous
borderline tumors, by definitively demonstrating the metaplastic potential of stem cells within the
peritoneal cavity. Interestingly, the combination of glial tissue with endometriosis has also been
observed in five reported cases of GP
. Endometrial tissue is Müllerian in origin and
is uncommon in teratomas.
- Neuhäuser, H. Ueber die teratoiden geschwülste des eierstocks. Arch Gynaek 79, 696-719. 6.
- Müller, A. M., Söndgen, D., Strunz, R., and Müller, K. M. Gliomatosis peritonei: a report of two cases and review of the literature. Eur J Obstet Gynecol Reprod Biol, 100: 213-22, 2002.
- Dadmanesh, F., Miller, D. M., Swenerton, K. D., and Clement, P. B. Gliomatosis peritonei with malignant transformation. Mod Pathol, 10: 597-601, 1997.
- Robboy, S. J. and Scully, R. E. Ovarian teratoma with glial implants on the peritoneum. An analysis of 12 cases. Hum Pathol, 1: 643-53, 1970.
- Dyke, P. C. and Mulkey, D. A. Maturation of ganglioneuroblastoma to ganglioneuroma. Cancer, 20: 1343-9, 1967.
- Gocht, A., Lohler, J., Scheidel, P., Stegner, H. E., and Saeger, W. Gliomatosis peritonei combined with mature ovarian teratoma: immunohistochemical observations. Pathol Res Pract, 191: 1029-35, 1995.
- Dallenbach-Hellweg, G. Critical commentary to "gliomatosis peritonei combined with mature ovarian teratoma". Pathol Res Pract, 191: 1037, 1995.
- Ferguson, A. W., Katabuchi, H., Ronnett, B. M., and Cho, K. R. Glial implants in gliomatosis peritonei arise from normal tissue, not from the associated teratoma. Am J Pathol, 159: 51-5, 2001.
- Surti, U., Hoffner, L., Chakravarti, A., and Ferrell, R. E. Genetics and biology of human ovarian teratomas. I. Cytogenetic analysis and mechanism of origin. Am J Hum Genet, 47: 635-43, 1990.
- Kopen, G. C., Prockop, D. J., and Phinney, D. G. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci U S A, 96: 10711-6., 1999.
- Blaustein, A. Calcitonin secreting struma-carcinoid tumor of the ovary. Hum Pathol, 10: 222-8, 1979.
- Simkin, P. H., Ramirez, L. A., Zweizig, S. L., Afonso, S. A., Fraire, A. E., Khan, A., Dunn, A. D., Dunn, J. T., and Braverman, L. E. Monomorphic teratoma of the ovary: a rare cause of triiodothyronine toxicosis. Thyroid, 9: 949-54, 1999.
- Dicou, E., Houlgatte, R., and Brachet, P. Synthesis and secretion of beta-nerve growth factor by mouse teratocarcinoma cell lines. Exp Cell Res, 167: 287-94, 1986.
- Furukawa, S. , Furukawa, Y., Satoyoshi, E., and Hayashi, K. Synthesis and secretion of nerve growth factor by mouse astroglial cells in culture. Biochem Biophys Res Commun, 136: 57-63, 1986.
- Hill, D. A., Dehner, L. P., White, F. V., and Langer, J. C. Gliomatosis peritonei as a complication of a ventriculoperitoneal shunt: case report and review of the literature. J Pediatr Surg, 35: 497-9, 2000.
- Calder, C. J., Light, A. M., and Rollason, T. P. Immature ovarian teratoma with mature peritoneal metastatic deposits showing glial, epithelial, and endometrioid differentiation: a case report and review of the literature. Int J Gynecol Pathol, 13: 279-82, 1994.
- Harms, D., Janig, U., and Gobel, U. Gliomatosis peritonei in childhood and adolescence. Clinicopathological study of 13 cases including immunohistochemical findings. Pathol Res Pract, 184: 422-30, 1989.
- Bassler, R., Theele, C., and Labach, H. Nodular and tumorlike gliomatosis peritonei with endometriosis caused by a mature ovarian teratoma. Pathol Res Pract, 175: 392-403, 1982.
- Dworak, O., Knopfle, G., Varchmin-Schultheiss, K., and Meyer, G. Gliomatosis peritonei with endometriosis externa. Gynecol Oncol, 29: 263-6, 1988.