—  SPECIALTY CONFERENCE  —

Gynecologic Pathology

Case 2 - Gliomatosis peritonei (peritoneal gliomatosis)

Kathleen R. Cho
University of Michigan
Ann Arbor, Michigan


Click on each slide thumbnail image for an enlarged view
Clinical History
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.


Case 2 - Figure 1 - Low magnification, ovarian mass.
Case 2 - Figure 2 - Intermediate magnification, ovarian mass.


Case 2 - Figure 3 - Low magnification, omentum.
Case 2 - Figure 4 - High magnification, omental nodule.
Diagnosis
Gliomatosis peritonei (peritoneal gliomatosis)

Pathologic Findings
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 tissue.

Extended History
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.

Discussion
Gliomatosis peritonei (GP) was first described by Neuhä user in 1906 [1] . 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 [2] . 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 [3] . Several theories have been proposed to explain the pathogenesis of GP:

  1. Although all elements of the teratoma metastasize or "implant", only the most robust elements, i.e., glial tissue, survives [4] .
  2. Immature neural elements metastasize and subsequently mature, comparable to the maturation of neuroblastoma to ganglioneuroma [5] .
  3. Mature glial tissue is extruded from the teratoma and "implants" on the peritoneal surfaces [6] .
  4. Glial foci arise independently from pluripotent peritoneal stem cells in response to favorable intraperitoneal conditions, as part of a so-called field effect [7] .
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.

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 [8] . 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 [9] . 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 [10] . 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, respectively [11, 12] . Notably, murine astrocyte cells and teratocarcinoma cell lines have been shown to secrete b -nerve growth factor in vitro [13, 14] . Moreover, GP has been described in children without teratomas who have had ventriculoperitoneal shunts placed early in infancy [15] . 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 [2, 16, 17, 18, 19] . Endometrial tissue is Müllerian in origin and is uncommon in teratomas.

References

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