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Metastatic Melanoma in Pregnancy: Risk of Transplacental Metastases in the Infant

April Alexander, Wolfram E. Samlowski, Douglas Grossman, Carol S. Bruggers, Ronald M. Harris, John J. Zone, R. Dirk Noyes, Glen M. Bowen, Sancy A. Leachman

From the Departments of Dermatology, Medicine, Division of Oncology, Oncological Sciences, Pediatric Hematology-Oncology and Surgery, and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.

Address reprint requests to Sancy A. Leachman, MD, PhD, Department of Dermatology, University of Utah, 2000 Circle of Hope, Room 5242, Salt Lake City, UT 84112-5550; email: sancy.leachman{at}hci.utah.edu.

	ABSTRACT

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Purpose: Although metastases to the fetus via the placenta are rare, melanoma is the most common culprit. When it occurs, maternally derived melanoma metastasis in the infant is almost invariably fatal.

Patients and Methods: This article reviews current guidelines for placental evaluation in pregnant women with metastatic melanoma and presents surveillance recommendations for their infants. Comprehensive literature reviews were performed on melanoma in pregnancy and melanoma metastasis to the placenta and fetus. The use of interferon alfa in the pediatric population was also reviewed. A comprehensive search of the MEDLINE database (1966 to 2002) was performed. Articles were reviewed and additional references were obtained from the bibliographies. Translation of non-English articles was performed, and authors of previous publications were contacted.

Results: Eighty-seven patients with placental or fetal metastasis were identified. Twenty-seven occurrences were attributed to melanoma (31%). The fetus was affected in six of 27 melanoma patients (22%), with five of six infants dying of disease. The use of high-dose interferon alfa adjuvant therapy in pediatric patients has not been reported.

Conclusion: The placentas of women with known or suspected metastatic melanoma should be carefully examined grossly and histologically by pathologists. With placental involvement, fetal risk of melanoma metastasis is approximately 22%. Neonates delivered with concomitant placental involvement should be considered a high-risk population. The risk-benefit ratio of adjuvant treatment for a potentially affected infant should be carefully weighed.

	INTRODUCTION

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MALIGNANCY IN pregnancy is not uncommon, with an estimated occurrence rate of one per 1,000.^1,2 The types of cancer observed in pregnancy mirror those seen in nonpregnant women of the same age.^1,3–5 In order of decreasing frequency, these cancers include carcinomas of the breast, cervix, and lung, melanoma, lymphoma, and leukemia. The estimated incidence of melanoma complicating pregnancy has ranged from 0.1 to 2.8 per 1,000 pregnancies,^4,6 although data from this population have not been systematically ascertained. Despite the fact that melanoma is not the most common cancer in pregnancy, it is most likely to metastasize to the placenta and fetus.^7,8 The only other cancers that have been reported to affect the fetus are hematopoietic malignancies and lung cancer. Melanoma incidence rates are increasing dramatically, and melanoma is now a major cause of cancer death in women of childbearing age. To facilitate appropriate patient education, clinical and histologic evaluation, and referral, physicians should be familiar with the data regarding fetal complications in a pregnant woman with malignant melanoma. Most published discussions regarding management and treatment of metastatic melanoma in pregnancy have focused on the mother, with no analysis of fetal management published to date.

Previously published reviews focused on assessing the risk of maternal-fetal transmission of melanoma and calculated an approximate 25% mortality risk to babies born to mothers with placental involvement.^7,9–14 Infants developing clinical evidence of maternally derived metastases have an exceptionally poor prognosis, with death typically occurring within 3 months of diagnosis. Thus, neonates delivered with concomitant placental involvement but without clinical evidence of disease should be considered a high-risk population. Adjuvant treatment of infants born to women with placental metastasis of melanoma has not been reported. This critical and comprehensive review of the literature provides clinicians with relevant information on which to base clinical recommendations for this subpopulation of melanoma patients.

	PATIENTS AND METHODS

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Metastasis to the Placenta or Fetus
To evaluate whether the previously published reviews of fetal metastasis of melanoma (and the published mortality rates) included all available reports, a comprehensive review of the literature was performed. Placental involvement of maternal cancer was defined as gross or microscopic evidence of maternal cancer within any section of the placenta. Fetal metastasis was defined as metastasis of maternal cancer developing in the fetus, with no evidence of primary tumor originating in the fetus. Initially, a broad search was performed to obtain an accurate incidence of placental involvement and fetal metastasis caused by any cancer, using a PubMed search of MEDLINE (1966 to July 2002) and the search string [("Neoplasms" AND "Neoplasm Metastasis" AND (pregnancy OR placenta OR placental OR transplacental OR fetal OR fetus OR products of conception OR vertical transmission) NOT (choriocarcinoma OR trophoblastic tumors)]. Individual cancers such as melanoma or breast cancer are contained within the neoplasm Medical Subject Heading term. Initially, expansion of the search through the PubMed related articles option was also attempted, without identification of additional patient cases. Titles and abstracts of 1,147 articles were screened for reports of metastasis of maternal cancer to the placenta or fetus. This search revealed 44 primary case reports of placental or fetal metastasis. The four most comprehensive literature reviews on placental or fetal metastasis secondary to all cancers revealed an additional 40 articles not identified through the literature search, for a total of 84 previously published papers on this topic.^{7,10–12,15–31}

Because of the concern that additional reports might exist in the literature and be missed by the general search strategy above, several additional search strings were performed. Two of these additional search strings revealed additional patient cases. [("Maternal-fetal exchange" AND cancer)] identified 1,236 records and revealed one additional patient case,³² and [("Pregnancy complications, neoplastic" NOT (choriocarcinoma OR trophoblastic)] identified 4,629 records and revealed a second patient case.^8,33 These combined search strings resulted in a total of 86 primary reports of placental or fetal metastasis in the worldwide literature. Our group has identified an eighty-seventh patient case of placental involvement without transmission to the fetus.²¹ Twenty-seven of the 87 patient cases were due to melanoma. These articles were reviewed in detail, including translation of all non-English articles.^{7,14–21,34–55}

	RESULTS

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Incidence of Metastatic Cancer to the Placenta and Fetus
Since the first case report in 1866,⁵⁶ only 87 patient cases of placental or fetal metastasis have been reported (Table 1). It is important to note that the number of patient cases reported in the literature is increasing, with more than 20% of the patient cases being reported in the last decade. Almost any cancer imaginable has been reported to affect the placenta, including carcinomas, sarcomas, leukemias, and lymphomas.⁸ Sixty-nine of the 87 patient cases were noted in earlier reviews. Our search revealed 18 additional reports of placental or fetal metastasis not reviewed previously and includes seven patient cases of melanoma,^15–21 three patient cases of breast cancer,^22–24 two patient cases of lung cancer,^25,32 one patient case of B-cell type lymphoma,²⁶ one patient case of myeloid leukemia,²⁷ one patient case of acute monocytic leukemia,²⁸ one patient case of natural-killer cell lymphoma,²⁹ one patient case of maternal primitive neuroectodermal tumor,³⁰ and one patient case of probable gastrointestinal carcinoma.³¹

Metastatic Cancer in the Fetus
The 15 patient cases of metastasis in the fetus are summarized in Table 2. The rigor with which fetal metastases have been shown to originate from the mother (and not the infant) has varied considerably. Only five of the 15 patient cases demonstrated metastasis in tissues from the mother, placenta, and fetus.^{19,29,32,35,36,46} Most authors have reported maternal origin of the tumor on the basis of circumstantial evidence, including the rarity of the adult cancer in neonates, the lack of identification of a primary tumor in these neonates, and the clinical and histologic similarity of tumor biopsies in mother and infant. Advances in cytogenetic tumor analysis using cellular DNA markers that permit discrimination between maternal and fetal cells now make it possible to establish the maternal origin of the tumor more conclusively. In four of the most recent patient cases, fluorescent in situ hybridization was used in conjunction with karyotyping to identify conclusively maternal tumor cells in the infants. The analysis in these patient cases was facilitated by the fact that the fetuses were male and the karyotype of tumor cells was XX.

Metastatic Melanoma of the Placenta or Fetus
During the period from 1918 to 2002, there were 27 patients with melanoma reported to involve the placenta or fetus (Table 3). Microscopic evaluation was performed in 24 of 27 patients, and placental involvement was documented in all 24 patients. Six of the 27 reports indicated fetal metastasis, but three reports did not document corresponding placental involvement (the same three reports in which microscopic examination was not performed).^{37,38,43–45} Because the primary goal of this investigation is to establish risk to the fetus, and because we believe that the above-described three patient cases of fetal metastasis (without microscopic placental examination) would have likely demonstrated placental involvement with histologic evaluation, we included them for the purpose of our analysis. Maternal characteristics are described in Table 3, and fetal characteristics are summarized in Table 4.

Lack of Guidelines for Infants With Metastatic Melanoma
Because congenital and infantile melanoma are so rare,⁵⁷ there are no existing standardized guidelines for observation or therapy. Recommendations for follow-up include skin inspection,^7,51 abdominal ultrasound,^7,14 and screening for melanogens in the infant’s urine.^7,37,51 Two unsuccessful attempts with novel immune-based therapies have been reported.^38,46

	DISCUSSION

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Data from all available reported patient cases of placental and fetal metastasis, including all types of malignancy, indicate that maternal-fetal transmission of tumor cells is extremely rare. Even in the small subset of women with placental involvement, the probability that the fetus was affected was only about 17% (15 of 87 patients), but 40% (six of 15 patients) of the fetal patient cases were due to melanoma. In fact, this may underestimate the number of melanoma patient cases because the description of the hepatic carcinoma by Friedreich⁵⁶ in 1866 may have also represented a melanoma ("a pigment-containing visceral tumor").^1,11,38 The tendency of melanoma to metastasize to the fetus relative to other tumor types led us to investigate metastasis of melanoma in pregnant women more thoroughly.

A total of 27 patient cases of placental or fetal metastasis of melanoma have been described in the literature worldwide (Tables 3 and 4). There are two potential biases in these reports. First, the placentas were not always examined microscopically in women with metastatic melanoma (a rare event). Second, there has not been systematic follow-up of children derived from these pregnancies to exclude the possibility of delayed onset of metastases. In the past, physicians were only alerted to the occurrence of transplacental metastasis when gross placental involvement or clinically evident fetal metastasis was present. One aim of this article is to increase the awareness of physicians about transplacental transmission of cancer, and to encourage thorough placental examination in all mothers with metastatic disease.

We also sought to determine whether additional factors, either maternal or fetal, were associated with risk to the infant. One factor considered was whether increased tumor burden within the placenta increases the likelihood of fetal transmission. It is unlikely that tumor burden is a prognostic indicator because of the six patients with fetal melanoma metastasis, only three placentas showed gross evidence of disease. In addition, gross placental involvement was seen in six patient cases that showed no fetal melanoma metastasis.

Another potential prognostic factor considered was whether microscopic evidence of invasion into fetal components of the placenta was associated with greater risk of fetal transmission. It should be noted that the variable extent to which microscopic placental examination was performed confounds this analysis. An additional caveat is that even when examined microscopically, metastatic deposits within the placenta may be difficult to localize, given its enormous blood supply. Indeed, multiple placental sections may be necessary to document the true extent of placental invasion.^13,41 However, with these limitations in mind, it does not seem that the extent of invasion correlates with fetal metastasis. In three patient cases of fetal metastasis, placental examination revealed villous invasion, with fetal blood vessel invasion in samples from two patients. However, three unaffected infants also had placental involvement with villous and fetal blood vessel invasion. Furthermore, metastatic cells have been identified in the cord blood of two infants whose mothers had metastatic melanoma and leukemia, respectively, but the fetus was affected only from the mother with melanoma.^46,58 This indicates that fetal metastasis requires two components: maternal tumor invasion of fetal tissues and fetal inability to eliminate metastatic cells. Hence, placental or fetal vessel invasion may be necessary, but not sufficient, for fetal metastasis.

Other maternal factors that have been reported to indicate an unfavorable fetal or infant outcome include maternal age less than 30 years, primiparity, disease onset more than 3 years before current pregnancy, nodal metastasis before pregnancy, more than three sites of metastatic foci during the third trimester, primary site of the leg, and maternal death within 1 month of birth.^7,14 However, data from our review of the literature do not support any of these factors (Table 3). Of interest, three patient cases of maternal diffuse cutaneous melanosis, a rare sign of metastatic melanoma, occurred in the subset of patients with placental metastasis,^41,42,48 but were not associated with fetal metastasis.

Previously reported fetal factors indicating an unfavorable fetal or infant outcome include birth at greater than 36 weeks and male sex.¹⁴ In our review, gestational age at birth did not seem to influence risk of fetal transmission of melanoma. However, male infants seem to be at higher risk than females for developing metastasis of any maternal cancer. Males comprised 80% of all infants with metastasis of melanoma (Table 4) and 75% with metastasis of all cancers (Table 2). Although long-term survival cannot be determined for patients for whom follow-up was limited,^28,32 the only infant to survive without therapy was female, indicating that sex may influence survival.

The tendency of melanoma to metastasize to the fetus relative to other tumor types is intriguing, but poorly understood. As part of the metastatic model recently proposed by Hanahan and Weinberg,⁵⁹ it is clear that metastatic cells must alter their expression of numerous genes, including proteases, cellular adhesion molecules, and integrins, before they are able to invade and establish themselves in an alternative tissue environment. Because melanoma is overrepresented in the number of placental metastases that occur during pregnancy, there must be some unique or dominant feature within melanoma cells relative to other malignancies that allows this process to occur. An additional consideration is the fact that the placenta is a site of production for many growth factors and is exceptionally vascular. In fact, angiogenic factors produced by the placenta, including placental growth factor, hepatocyte growth factor, and vascular endothelial growth factor,⁶⁰ have also been shown to be released by, and to influence the growth of, melanoma cells in culture.^61,62 It is also possible that placental growth factors or shared endothelial adhesion molecules encourage adhesion, survival, and invasion of melanoma cells. This relative affinity of melanoma for placental metastasis, growth, and invasion may account for the increased risk of fetal metastasis (ie, that any tumor, once metastatic to the placenta, has a greater chance of fetal invasion as well).

An inadequate fetal immune response has also been suspected in the pathophysiology of transplacental spread. In infants who present with metastases, immunologic tolerance seems to have been induced. Osada et al²⁸ reported a patient case of acute monocytic leukemia metastatic to the fetus, in which the infant’s lymphocytes failed to respond to both his own and his mother’s leukemic cells in culture. However, his lymphocytes did respond to unrelated acute monocytic leukemia cells. Tolerance may be induced by exposure to tumor antigens at a time when the developing immune system is not yet capable of responding.^{29,44–46,50,52} T- and B-cell responses in the fetus are thought to develop around weeks 7 to 10 and 14 to 20, respectively,⁶³ and many of the incidences of fetal metastasis occurred in women who had metastatic disease before that date. Thus, metastatic cells may localize to the fetus early enough to be considered self by the developing immune system. However, the timing of maternal metastasis of melanoma does not seem to differ in placental versus fetal metastasis.

Alternatively, this may represent an analogous situation to parental to F1 (first generation) tumor transplant growth in animal models, where the progeny have haploidentical HLA types with the parent.⁶⁴ This is supported by HLA typing of both mother and infant in one patient case of infant leukemia, which demonstrated maternal homozygosity at the HLA locus.²⁸ However, in another patient case, HLA typing of the mother and fetus revealed a mother with two distinct HLA alleles.²⁹ The infant’s tumor was not HLA typed. The possibility remains that the metastatic tumor evaded the fetal immune system by eliminating the allogeneic HLA antigen.

Although some level of immunotolerance exists between the mother and fetus, an intact fetal immune response should eradicate maternal cells.⁶⁵ For example, maternal leukemia cells have been identified in the cord blood of a healthy female infant that never manifested disease and did not have leukemia cells in peripheral blood samples at 6 weeks, 3 months, and 6 months after delivery.⁵⁸ This indicates that maternal leukemic cells were appropriately cleared by the infant’s immune system. The ability of the fetus to clear maternal metastatic cells seems to play a role in melanoma as well. As discussed previously, three separate patient cases of placental metastasis that demonstrated metastatic invasion of fetal capillaries did not progress to fetal metastasis, indicating that the fetal immune system can protect the fetus from metastasis, at least some of the time (Table 3). One intriguing possibility exists that female fetuses are better able to eliminate maternally derived melanoma, or that male fetuses are more immunotolerant. This is supported by the report of spontaneous regression in an affected female infant with biopsy-proven metastatic melanoma,^43–45 and by the fact that there is a male predominance of fetal metastasis despite an equal sex distribution in patient cases with placental involvement.

Given the risk of metastasis to the fetus, we recommend that the placentas of all women with suspected metastatic melanoma during pregnancy should be closely evaluated by gross and microscopic examination. Immunohistochemical staining for melanoma antigens should be performed on histologic sections, using S-100, HMB-45, or other appropriate markers. Research tests that may be of value include examination of cord blood buffy coat for the presence of tumor cells using immunohistochemical staining or reverse transcriptase polymerase chain reaction.^58,66–68 Research evaluation to establish the maternal origin of the tumor (including karyotyping, cytogenetics, and HLA typing of the mother, infant, and tumors) may also be useful.

If the neonate does not present with metastases at birth, we would recommend periodic evaluation for development of melanoma for at least 24 months postpartum coinciding with routine well-child checks. Evaluation should include a baseline chest x-ray and liver enzymes, including lactate dehydrogenase, which may be repeated every 6 months. Other studies may be included on the basis of clinical suspicion.

Because of its rarity, studies regarding melanoma treatment are lacking in infants. The use of adjuvant high-dose interferon alfa therapy has not been reported. A low incidence of irreversible spastic diplegia (0% to 11.5%) has been observed with low-dose interferon alfa in infants, and the risk of this complication may be increased in neonates. At this point, there is insufficient information to make a definitive recommendation about adjuvant therapy for infants at risk for maternal melanoma metastases.

A registry is currently being established at the University of Utah within the Tom C. Mathews, Jr. Familial Melanoma Research Clinic at Huntsman Cancer Institute to obtain long-term follow-up of this high-risk infantile melanoma population.

	ACKNOWLEDGMENTS

 
We acknowledge additional members of the Multidisciplinary Melanoma Tumor Board and physicians of Huntsman Cancer Institute for their input: Anna Beck, MD, David Virshup, MD, and Scott Florell, MD. Charles Wiggins, PhD, director of the Utah Cancer Registry, was invaluable in providing melanoma statistics for women of childbearing age. We also thank Karen Albritton, MD, for critical review of the manuscript, and the many people who helped with translation: Boudewijn Santerse, MD, Zaneta Bulej, MD, Joseph Berg, Christopher Hansen, MD, and Peter Clayton.

	NOTES

 
Supported in part by the Doris Duke Charitable Foundation and the Huntsman Cancer Foundation.

	REFERENCES

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1. Potter JF, Schoeneman M: Metastasis of maternal cancer to the placenta and fetus. Cancer 25:380–388, 1970[CrossRef][Medline]

2. Donegan WL: Cancer and pregnancy. CA Cancer J Clin 33:194–214, 1983[Abstract/Free Full Text]

3. Antonelli NM, Dotters DJ, Katz VL, et al: Cancer in pregnancy: A review of the literature—Part I. Obstet Gynecol Surv 51:125–134, 1996[CrossRef][Medline]

4. Villani GM, Goldberg GL: Nongenital malignancies, in Cohen W (ed): Cherry and Merkatz’s Complications of Pregnancy. Philadelphia, PA, Lippincott Williams and Wilkins, 2000, pp 624–627

5. Nicklas AH, Baker ME: Imaging strategies in the pregnant cancer patient. Semin Oncol 27:623–632, 2000[Medline]

6. O’Reilly S, Chakravarthy A: Other cancers in pregnancy, in Trimble E, Trimble C (eds): Cancer Obstetrics and Gynecology. Philadelphia, Lippincott Williams and Wilkins, 1999, pp 249–259

7. Baergen RN, Johnson D, Moore T, et al: Maternal melanoma metastatic to the placenta: A case report and review of the literature. Arch Pathol Lab Med 121:508–511, 1997[Medline]

8. Walker JW, Reinisch JF, Monforte HL: Maternal pulmonary adenocarcinoma metastatic to the fetus: First recorded case report and literature review. Pediatr Pathol Mol Med 21:57–69, 2002[CrossRef][Medline]

9. Borden EC: Melanoma and pregnancy. Semin Oncol 27:654–656, 2000[Medline]

10. Eltorky M, Khare VK, Osborne P, et al: Placental metastasis from maternal carcinoma: A report of three cases. J Reprod Med 40:399–403, 1995[Medline]

11. Ackerman J, Gilbert-Barness E: Malignancy metastatic to the products of conception: A case report with literature review. Pediatr Pathol Lab Med 17:577–586, 1997[CrossRef][Medline]

12. Dildy GA III, Moise KJ Jr, Carpenter RJ Jr, et al: Maternal malignancy metastatic to the products of conception: A review. Obstet Gynecol Surv 44:535–540, 1989[Medline]

13. Rothman LA, Cohen CJ, Astarloa J: Placental and fetal involvement by maternal malignancy: A report of rectal carcinoma and review of the literature. Am J Obstet Gynecol 116:1023–1034, 1973[Medline]

14. Anderson JF, Kent S, Machin GA: Maternal malignant melanoma with placental metastasis: A case report with literature review. Pediatr Pathol 9:35–42, 1989[Medline]

15. Dipaola RS, Goodin S, Ratzell M, et al: Chemotherapy for metastatic melanoma during pregnancy. Gynecol Oncol 66:526–530, 1997[CrossRef][Medline]

16. Marsh RD, Chu NM: Placental metastasis from primary ocular melanoma: A case report. Am J Obstet Gynecol 174:1654–1655, 1996[CrossRef][Medline]

17. Dillman RO, Vandermolen LA, Barth NM, et al: Malignant melanoma and pregnancy ten questions. West J Med 164:156–161, 1996[Medline]

18. Merkus JM, Teepen JL: The indispensable anamnesis: In-vitro fertilization in a woman under treatment for melanoma. Ned Tijdschr Geneeskd 142:2073–2075, 1998[Medline]

19. Ferreira CM, Maceira JM, Coelho JM: Melanoma and pregnancy with placental metastases: Report of a case. Am J Dermatopathol 20:403–407, 1998[CrossRef][Medline]

20. Johnston SR, Broadley K, Henson G, et al: Management of metastatic melanoma during pregnancy. Br Med J 316:848–849, 1998[Free Full Text]

21. Alexander A, Harris RM, Grossman D, et al: Vulvar melanoma Diffuse melanosis and metastasis to the placenta. J Am Acad Dermatol; In press

22. Ben Brahim E, Mrad K, Driss M, et al: Placental metastasis of breast cancer. Gynecol Obstet Fertil 29:545–548, 2001[CrossRef][Medline]

23. Dunn JS Jr, Anderson CD, Brost BC: Breast carcinoma metastatic to the placenta. Obstet Gynecol 94:846, 1999[CrossRef][Medline]

24. Lehner R, Strohmer H, Jirecek S, et al: Placental insufficiency and maternal death caused by advanced stage of breast cancer in third trimester. Eur J Obstet Gynecol Reprod Biol 99:272–273, 2001[CrossRef][Medline]

25. Kochman AT, Rabczynski JK, Baranowski W, et al: Metastases to the products of conception from a maternal bronchial carcinoma: A case report and review of literature. Pol J Pathol 52:137–140, 2001[Medline]

26. Nishi Y, Suzuki S, Otsubo Y, et al: B-cell-type malignant lymphoma with placental involvement. J Obstet Gynaecol Res 26:39–43, 2000[Medline]

27. Honore LH, Brown LB: Intervillous placental metastasis with maternal myeloid leukemia. Arch Pathol Lab Med 114:450, 1990[Medline]

28. Osada S, Horibe K, Oiwa K, et al: A case of infantile acute monocytic leukemia caused by vertical transmission of the mother’s leukemic cells. Cancer 65:1146–1149, 1990[CrossRef][Medline]

29. Catlin EA, Roberts JD Jr, Erana R, et al: Transplacental transmission of natural-killer-cell lymphoma. N Engl J Med 341:85–91, 1999[Free Full Text]

30. Sakurai H, Mitsuhashi N, Ibuki Y, et al: Placental metastasis from maternal primitive neuroectodermal tumor. Am J Clin Oncol 21:39–41, 1998[CrossRef][Medline]

31. Almanza-Marquez R, Jurado-Jurado MB, Steta-Mondragon J, et al: Pregnancy complicated by acute pulmonary lymphangitic adenomatosis, metastasis and disseminated intravascular coagulation: A case report. J Reprod Med 47:421–423, 2002[Medline]

32. Tolar J, Coad JE, Neglia JP: Transplacental transfer of small-cell carcinoma of the lung. N Engl J Med 346:1501–1502, 2002[Free Full Text]

33. Harpold TL, Wang MY, McComb JG, et al: Maternal lung adenocarcinoma metastatic to the scalp of a fetus: Case report. Pediatr Neurosurg 35:39–42, 2001[CrossRef][Medline]

34. Markus N: Gleichzeitige entwicklung melanosarcoma ovarii und carcinoma hep der schwangerschaft, eklampsie, placentarmetastazen. Arch F Gynakol 92:659–678, 1918[CrossRef]

35. Weber FP, Schwarz E, Hellenschmied R: Spontaneous inoculation of melanotic sarcoma from mother to foetus. Br Med J 1:537–539, 1930[Free Full Text]

36. Holland E: A case of transplacental metastasis of malignant melanoma from mother to foetus. J Obstet Gynaecol Br Emp 56:529–536, 1949[Medline]

37. Gottron H, Gertler W: Zur frage des ubertritts von melanogen der mutter au den saugling uber die muttermilch. Arch Dermatol Syph 181:91–98, 1940[CrossRef]

38. Dargeon HW, Eversole JW, Del Duca V: Malignant melanoma in an infant. Cancer 3:299–306, 1950[CrossRef]

39. Byrd BF, McGanity WJ: The effect of pregnancy on the clinical course of malignant melanoma. South Med J 47:196–200, 1954[Medline]

40. Reynolds AG: Placental metastasis from malignant melanoma: Report of a case. Obstet Gynecol 6:205–209, 1955[Medline]

41. Freedman WL, McMahon FJ: Placental metastasis: Review of the literature and report of a case of malignant melanoma. Obstet Gynecol 16:550–560, 1960[Medline]

42. Moschella SI: A report of malignant melanoma of the skin in sisters. Arch Dermatol 84:1024–1025, 1961[Abstract/Free Full Text]

43. Aronsson S: A case of transplacental tumor metastasis. Acta Pediatr Scand 52:123–134, 1963

44. Cavell B: Transplacental metastasis of malignant melanoma: Report of a case. Acta Paediatr Suppl 146:37–40, 1963

45. Cavell B: Transplacental melanoma: One-year survival. Pediatrics 57:978–979, 1976 (letter)[Abstract/Free Full Text]

46. Brodsky I, Baren M, Kahn SB, et al: Metastatic melanoma malignant from mother to fetus. Cancer 18:1048–1054, 1965[CrossRef][Medline]

47. Stephenson HE Jr, Terry CW, Lukens JN, et al: Immunologic factors in human melanoma "metastatic" to products of gestation (with exchange transfusion of infant to mother). Surgery 69:515–522, 1971[Medline]

48. Holcomb BW, Thigpen JT, Puckett JF, et al: Generalized melanosis complicating disseminated malignant melanoma in pregnancy: A case report. Cancer 35:1459–1464, 1975[CrossRef][Medline]

49. Sokol RJ, Hutchison P, Cowan D, et al: Amelanotic melanoma metastatic to the placenta. Am J Obstet Gynecol 124:431–432, 1976[Medline]

50. Smythe AR, Underwood PB Jr, Kreutner A Jr: Metastatic placental tumors: Report of three cases. Am J Obstet Gynecol 125:1149–1151, 1976[Medline]

51. Russell P, Laverty CR: Malignant melanoma metastases in the placenta: A case report. Pathology 9:251–255, 1977[Medline]

52. Gillis H II, Mortel R, McGavran MH: Maternal malignant melanoma metastatic to the products of conception: Report of a case. Gynecol Oncol 4:38–42, 1976[CrossRef][Medline]

53. Looi LM, Wang F: Malignant melanoma metastases in chorionic villi: A case report. Malays J Pathol 2:73–75, 1979[Medline]

54. Moller D, Ipsen L, Asschenfeldt P: Fatal course of malignant melanoma during pregnancy with dissemination to the products of conception. Acta Obstet Gynecol Scand 65:501–502, 1986[Medline]

55. Brossard J, Abish S, Bernstein ML, et al: Maternal malignancy involving the products of conception: A report of malignant melanoma and medulloblastoma. Am J Pediatr Hematol Oncol 16:380–383, 1994[Medline]

56. Friedreich N: Beitrage zur pathologic des krebses. Virchow Arch (Pathol Anat) 36:30–31, 1866

57. Richardson SK, Tannous ZS, Mihm MC Jr: Congenital and infantile melanoma: Review of the literature and report of an uncommon variant, pigment-synthesizing melanoma. J Am Acad Dermatol 47:77–90, 2002[CrossRef][Medline]

58. van der Velden VH, Willemse MJ, Mulder MF, et al: Clearance of maternal leukaemic cells in a neonate. Br J Haematol 114:104–106, 2001[CrossRef][Medline]

59. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 100:57–70, 2000[CrossRef][Medline]

60. Challier JC, Vervelle C, Uzan S: Ontogenesis of villi and fetal vessels in the human placenta. Fetal Diagn Ther 16:218–226, 2001[CrossRef][Medline]

61. Graeven U, Rodeck U, Karpinski S, et al: Expression patterns of placenta growth factor in human melanocytic cell lines. J Invest Dermatol 115:118–123, 2000[CrossRef][Medline]

62. Lacal PM, Failla CM, Pagani E, et al: Human melanoma cells secrete and respond to placenta growth factor and vascular endothelial growth factor. J Invest Dermatol 115:1000–1007, 2000[CrossRef][Medline]

63. Anderson VM, Good RA: Thymus, spleen, lymphoid tissues, and immunodeficiency disorders, in Gilbert-Barness E (ed): Potter’s Pathology of the Fetus and Infant. St Louis, MO, Mosby, 1996, pp 986–987

64. Auchinloss J, H., Sachs DH: Transplantation and graft rejection, in Paul WE (ed): Fundamental Immunology (ed 3). New York, NY, Raven Press, 1993, pp 1101

65. Dawes GS: The fetoplacental circulation, in Redman CWG, Sargent IL, Starkey PM (eds): The Human Placenta: A Guide for Clinicians and Scientists. Oxford, United Kingdom, Blackwell Sciences, 1993, pp 38–39, 320–322

66. Brugger W, Bross KJ, Glatt M, et al: Mobilization of tumor cells and hematopoietic progenitor cells into peripheral blood of patients with solid tumors. Blood 83:636–640, 1994[Abstract/Free Full Text]

67. Pantel K, Izbicki J, Passlick B, et al: Frequency and prognostic significance of isolated tumour cells in bone marrow of patients with non-small-cell lung cancer without overt metastases. Lancet 347:649–653, 1996[CrossRef][Medline]

68. Schlimok G, Funke I, Bock B, et al: Epithelial tumor cells in bone marrow of patients with colorectal cancer: Immunocytochemical detection, phenotypic characterization, and prognostic significance. J Clin Oncol 8:831–837, 1990[Abstract]

69. Berghinz G: Linfosarcomatosi acute della madre: Metasasi milari nel fegato del feto. Gazzetta degli Ospedali Milano 21:606, 1900

70. Priesel A, Winkelbauer A: Placentare ubertragung des lymphogranuloms. Virchow Anat (Pathol Anat) 262:749–765, 1926[CrossRef]

71. Cramblett HG, Friedman JL, Najjar S: Leukemia in an infant born of a mother with leukemia. N Engl J Med 259:727–729, 1958[Medline]

72. Bernard M, Jacquillat C, Chavelet F, et al: Leucemie aigue d’une enfant de 5 mois nee d’une mere atteinte de leucemie aigue au moment de l’accouchement. Nouv Rev Fr Hematol 4:140–142, 1964

Submitted December 26, 2002; accepted March 19, 2003.

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