Transplacental Transmission of Metastatic Melanoma to the Posterior Fossa:

Case Report

Eric R. Trumble, MD
Ryan M. Smith, MBA
Gary Pearl, MD, PhD
Judith Wall, MD

Arnold Palmer Hospital for Children and Women
Orlando, FL 32806

Corresponding Author
Eric R Trumble, MD
22 Lake Beauty Dr  Suite 204
Orlando, FL  32806
(407) 236-0006
Fax (407) 236-0007
E-mail: etrumble@neurosurgeons4kids.com

Running head:
Transplacental Transmission of Metastatic Melanoma to Brain

Keywords: Melanoma, transplacental metastasis, infratentorial mass, pediatric neurosurgery, brain tumor

Abstract:

The authors describe the first documented case of transplacental transmission of metastatic melanoma to the neural axis.  The patient was a 7 month old boy who presented with signs and symptoms of elevated intracranial pressure.  Magnetic resonance imaging revealed a 5x5x6cm inhomogeneously enhancing posterior fossa mass, filling the fourth ventricle.  Posterior fossa craniotomy was performed.  Pathology confirmed metastatic melanoma, with pathology identical to his mother’s.  He received aggressive chemotherapy with repeat resection.  He also required a ventriculo-peritoneal shunt for treatment of his hydrocephalus.  He lived longer than any other case of trans-placental transmission of metastatic melanoma but ultimately succumbed to the disease, 18 months after his initial presentation.

Introduction:

Pediatric brain tumors are the most common of all pediatric solid malignancies.  However, method of transmission/metastasis is highly variable.  One of the most rare methods of transmission of tumors is trans-placental.  There have been no previously reported cases of trans-placental transfer of metastatic melanoma to the neural axis.  This is also the first case of transplacental transfer of metastatic melanoma confirmed using current molecular markers, including HMB-45 and S100 protein markers and in situ hybridization with X and Y probes.  We report a case where a child whose mother had been diagnosed with melanoma during pregnancy had an infratentorial metastatic melanoma.  The treatment course and response are described.

Case Report:

History and Presentation: 
While pregnant with patient, his mother was diagnosed with cutaneous melanoma, treated post-natally.  She subsequently developed metastases and died due to her disease.  Patient was born without complication and was routinely discharged home.  At 7 months of age, patient presented to the emergency room with a 2 week history of bulging fontanelle, diminished oral intake, and lethargy.
 
Examination:
On admission, physical exam revealed an irritable child with a full fontanelle, bilateral abducens palsy, sunsetting, and papilledema.  His head circumference was 48.5cm and pupils were 3mm and sluggish bilaterally.  The patient was able to move all extremities equally.  An emergent head computerized tomographic scan revealed a large posterior fossa mass with hydrocephalus, leading to emergent external ventricular drain placement and initiation of intravenous dexamethasone treatment.  Magnetic resonance imaging demonstrated a large enhancing mass measuring 5x5x6 cm, which was sharply circumscribed and consistent with malignant melanoma.  In addition, there was significant hydrocephalus with trans-ependymal flow. (Fig 1)

Operation:
Patient was brought to the operative suite, where he underwent general endotracheal anesthesia.  He then underwent a mid-line sub-occipital craniotomy.  During the skin opening, significant scalp vasculature was noted.  Removal of the sub-occipital bone revealed the posterior fossa dura, which was found to be tense.  Upon opening the dura, a vascular tumor was noted to be extruding from the midline.  The tumor was yellowish-tan with black speckling.  Pial planes were respected in most directions, although the lesion appeared to fill the 4th ventricle.  The lesion was extending through bilateral foramina of Luschka and the foramen of Magendie.  Central necrosis of the tumor was appreciated.  Careful, microscopic dissection was performed to remove all visible tumor.  Closure was performed using a superiorly hinged bone flap. 

Pathology:
Pathology revealed a neoplasm composed of large epithelial cells with large nuclei and prominent nucleoli (Fig 2A). Neoplastic cells reacted positively for HMB-45 (Fig 2B) and S100 protein consistent with malignant melanoma. The neoplasm had a similar appearance to the mother’s tumor (Fig 2C).  XX karyotype of the tumor specimen, consistent with a maternal origin, was confirmed by in situ hybridization using X and Y probes.

Treatment Course:
Patient was admitted to the PICU post-operatively.  Patient’s hydrocephalus failed to improve and he ultimately had a ventriculo-peritoneal shunt placed, which required revision for proximal failure.  Aggressive chemotherapy treatment with Temozolomide was followed by repeat resection of residual posterior fossa tumor 15 months after initial resection.  Lumbar drop metastases were noted, and patient ultimately succumbed to his tumor, 18 months after his initial presentation.

Discussion:

Fetal metastasis from maternal melanoma is rare.  Tolar and Neglia reported more than 50 cases of maternal malignancies with metastases to the placenta and 14 cases of maternal-to-fetal metastases by vertical, transplacental transmission.21  Metastatic melanoma accounted for 6 of the 14 transplacental tumors reported to date.  To date, this is the seventh case of malignant maternal melanoma metastasizing to the fetus reported in the literature.2,3,5,6,7,10,13,15,18,21,23  No previous case had the pathology benefit of staging or molecular markers.  All previously reported patients with pathology proven melanoma died within 4 months of diagnosis.  One case had spontaneous regression with a “histological diagnosis of metastasizing malignant melanoma or reticuloendotheliosis” considered.6 (see Table 1)

Maternal melanoma is the most commonly transferred malignancy to the fetus.10,21  The median age at presentation was 2 months with a range of birth to 38 weeks and male dominance.  Skin lesions were the most common finding on initial presentation.  Among the previously reported cases, the skin lesions involved the upper extremities in one case, the lower extremities in two cases, and the buttocks region in one case.1,10 This case reports a 28-week old patient who initially presented with a full fontanelle and papilledema.  This is the first report of an intracranial transplacental metastatic melanoma. 

The exact mechanism of trans-placental fetal metastasis is poorly understood. Current theories state that the fetus may have an inability to recognize the tumor cells as foreign before complete immunologic maturation can take place.5,10,12  In all cases where the placenta was pathologically inspected, there were also metastases to the placenta.  Unfortunately, in this case, the placenta had not been submitted for pathologic evaluation.  The physiologically hyperkinetic state and hormonal modifications associated with pregnancy may also facilitate transplacental spread of tumor.10  Finally, the absence of immunohistochemically detectable hormone receptors in melanomas more common in pregnancy may mask the tumor, reducing the fetus’ ability to recognize the tumor cells as foreign.8,9,14
 
Rapid maternal demise was seen in all cases.  Clearly, the extent of disease spread, including to the placenta and fetus, is a poor prognostic factor.  Development of maternal malignant melanoma during pregnancy is also associated with a significantly worse prognosis.20  The treatment of malignant melanoma is complicated in pregnancy by a relative reluctance on the part of both the medical community and patients to have procedures performed, e.g. biopsy, that may require medications that can cross the placenta and affect the fetus.  Delay in treatment may be the cause of melanomas occurring in pregnancy being thicker than control groups.16,22

Melanoma is the primary malignancy that is most likely to metastasize to the brain.19  The vast majority(98-99%) of melanomas occur in patients older than 16 years of age.11  Standard treatment of malignant melanoma has included surgical resection, followed by whole brain radiation.  Whole brain radiation is rarely used in infants.  Other, newer treatment modalities include radiosurgery and chemotherapy.  Of the chemotherapeutic agents tried for metastatic melanoma, temazolamide has shown the most promise, almost doubling the median survival in responders from 3.6 months to 5.5 months.4  Despite ongoing improvement in the management of malignant melanoma, median survival remains poor.17  Many other novel therapies for metastatic melanoma are under study and in development.  However, a review of these is beyond the scope of this case report.

All of the previously reported patients diagnosed with trans-placental spread of malignant melanoma have ultimately succumbed to the disease within 4 months of diagnosis. In one patient in whom the pathological diagnosis was presumed but not confirmed, the melanoma “disappeared spontaneously.”5  Our reported patient survived 18 months before yielding to the disease.  This is the longest survival from initial diagnosis to demise.  This leads us to believe that aggressive surgical resection and appropriate oncological treatment may help maximize the life span of patients who present with intracranial metastasis.  

References

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TABLE 1: Reported cases of transplacental transmission of maternal melanoma to fetus
AUTHOR	AGE at presentation	LOCATION	SURVIVAL after diagnosis
Weber23	8 Months	Liver	2 Months
Brodsky5	11 Days	Skin	1 Months
Gottron12	7 Weeks	Liver	1 Months
Dargeon7	7 Months	Skin & Liver	3 Months
Cavell6	2 Months	Skin & Lung	Regression
Ferreira10	Birth	Skin	Stillborn
Trumble	7 Months	Brain	18 mo

Figure 1: T1-weighted magnetic resonance image demonstrating enhancing posterior fossa melanoma.

Fig. 2A:  Patient’s malignant melanoma (H&E); 2B: Patient’s tumor showing immunoreactivity for HMB-45; 2C: Mother’s malignant melanoma (H&E).