Neonatal solid tumors

Accepted Manuscript Neonatal solid tumors Dr. Aravindan Chandrasekaran PII:

S1875-9572(17)30409-6

DOI:

10.1016/j.pedneo.2016.12.007

Reference:

PEDN 682

To appear in:

Pediatrics & Neonatology

Received Date: 22 August 2016 Revised Date:

25 November 2016

Accepted Date: 30 December 2016

Please cite this article as: Chandrasekaran A, Neonatal solid tumors, Pediatrics and Neonatology (2017), doi: 10.1016/j.pedneo.2016.12.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Title:

Neonatal solid tumors

Type:

Original article

Corresponding Author: Dr. Aravindan Chandrasekaran

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Title Page

Madurai, India. First Author: Aravindan Chandrasekaran

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Order of Authors: Aravindan Chandrasekaran

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Corresponding Author's Institution: Meenakshi Mission Hospital and Research Centre,

Neonatal tumors are defined as tumors which are diagnosed before the first month of life.

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Some of them can be congenital(present at birth). Neonatal tumors are different from tumors in older children in terms of etiopathogenesis, behavior and response to therapy as

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well as long-term outcomes.

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Introduction: Tumor is a rare but important cause of mortality and morbidity in neonates. Only 2 percent of all childhood malignancies occur during the neonatal period.1 There is a wide spectrum of tumors, both benign and malignant, that can occur in a neonate. For a

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small baby even benign tumors can be be lifethreatening because of their relative size and location, as with a large cervical teratoma and malignant potential, as with a

scarococcygeal teratoma or congenital mesoblastic nephroma(CMN). Tumors that are

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clearly malignant may show unpredictable behaviour in the neonatal period. Benign conditions like haemangioma and lymphangioma which form major differential

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diagnoses also have a spectrum of clinical course from benign to lethal. The British Paediatric Pathology Society estimated the prevalence of congenital neoplasia (benign and malignant) to be between 1:12,500 and 17,300 live births.2 Neonatal tumors accounted for 2 to 3 percent of tumors diagnosed in all age groups put together and

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malignancies for about 1 to 2 percent. Malignant tumors represented forty to fifty percent of all diagnosed neonatal tumors.1,3

Etiology of cancer in a child is multifactorial and includes both environmental and

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genetic factors.3 Neonates are characterized as a separate entity as environmental interference is minimal.The aim of this study is to know the exact incidence of the

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various neonatal tumors, their clinical presentations and management options from our own data along with review of the relevant literature.

Materials and methods: All babies from 0 to 3 months of age admitted to our hospital with tumors from January 2011 to January 2016 were studied. Conditions like haemangioma, lymphangioma and hamartomas were included in order to estimate the

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actual distribution of each. The age, sex distribution, type of tumor and management were studied. Most tumors were diagnosed by clinical examination and imaging studies and tumor markers wherever appropriate. Final diagnosis was made with histopathology in

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most cases.

Though congenital tumors are tumors which are present at birth, it is reasonable to

suppose that any tumor presenting in the first three months of life was congenital and

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conditions like hemangiomas are not actual tumors but hamartomas. Therefore the word 'tumor' is used here in its literal sense to mean a mass or swelling.4 The haemangiomas

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were diagnosed by their typical appearance and clinical presentation and involution around the first year of life. Some required therapy with propranalol and a small number required excision. All lymphatic malformations were excised either in the newborn period due to their size and symptoms or later in childhood. Melanocytic nevi are being followed

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up. All the other cases had histological proof of their diagnoses. Management is discussed in detail for individual tumors.

Results: In this series of 51 cases, 43 out of 51 (84.3%) lesions were tumor-like

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conditions and benign masses and eight(15.6%) were malignant ( see TABLE). Haemangiomas and lymphatic malformations accounted for most benign tumors (67.4%).

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If these are excluded and only true neoplasms are considered, malignant tumors represent 36.3% of the total of 22 neoplasms. Neuroblastoma and congenital fibrosarcoma were the commonest malignant tumors. Ovarian cysts were the commonest (22.7%) of the true neoplasms (after excluding haemangiomas and lymphatic malformations) in the series, followed by teratomas (18.1%). There were three sacrococcygeal teratomas and one cervical teratoma.

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A total of 18 (35.2%) cases were diagnosed antenatally, of which 6 were lymphatic malformations, 5 ovarian cysts, 2 scarococcygeal teratomas, one cervical germ cell tumor, one each of congenital

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mesoblastic nephroma, congenital fibro sarcoma, haemangio endothelioma of liver and hamartoma. Only two (11%) tumors diagnosed antenatally were malignant.

The neuroblastomas presented after the newborn period, two cases at two months and one

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at 3 months of age. Considering the large size of the tumor, they were included as neonatal tumors as they must have been present at the time of or soon after birth.

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Similarly, all three fibrosarcomas were diagnosed after birth, two after four months of age, though the parents noticed the swelling soon after birth, and one baby was brought to the hospital on second day of life with the chest wall swelling.

Of the eight malignant tumors in the present series, 4 received chemotherapy. No

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irradiation was given to any of the cases. Of the two neuroblastomas, one had very advanced disease and succumbed in spite of chemotherapy, whereas the child with recurrent fibrosarcoma of the chest wall and the child with Wilms' tumor received

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chemotherapy with very good response and good tolerance to the same with dose-adjusted regimes.

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Discussion:

As we see from our results, tumors in the neonatal period are extremely rare. Many tumors of infancy are unique to that age group but virtually all childhood neoplasms have been reported in the perinatal period also. Although there is no clear difference between the type of tumors that present at birth and those in early infancy, there appears to be some distinction due to the in utero influence of the congenital tumors by the maternal

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hormones and immunoglobulins. The pattern of metastasis is also different due to fetal circulation.4

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Although literature reported about 20 percent incidence of congenital malformations

associated with neonatal tumors, in our series we had none.5 There have been reports of transplacental spread of maternal tumors like choriocarcinoma,6 but there were no

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hereditary tumors in our cases.There were isolated reports of probable association

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between maternal drug intake and tumors.7, 8 We found no such association, however.

In our series of 22 actual neoplasms, the distribution of tumors was as follows. Germ cell tumors 18% , Neuroblastomas 13.6%, Mesenchymal tumors 13.6% and renal tumors 9%,

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which is similar to Barson's series.2

Neuroblastoma and Congenital fibrosarcoma were the most common malignant tumors each forming about 37% of the malignant tumors. Other larger series had significant

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numbers of CNS tumors and leukemias.1,10 We did not encounter brain tumors or leukemaias of the neonatal period in the small number of malignant tumors in our series.

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Our results are similar if we exclude these two neoplasms,however.

Ovarian cysts are the most common benign tumors if we exclude venous and lymphatic lesion. Four of five cases of ovarian cyst were antenatally diagnosed. Three cases resolved spontaneously during the one year follow up. Two cases, one with complex

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nature (both solid and cystic areas) and one large cyst of size 4x4cm were laparoscopically excised and proven to be benign follicular cysts. Simple cysts of the ovary tend to resolve spontaneously and can be treated conservatively. Serial

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ultrasonogram follow up may prevent unnecessary oophorectomy. Patients with cysts

larger than 4 cm need percutaneous aspiration or surgical removal since they are at risk for torsion. Complex cystic masses, symptomatic ovarian cysts and cysts that do not

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resolve should also be removed.16

There were three sacro coccygeal teratomas in our series.These are the most frequent

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perinatal neoplasms, accounting about one third of cases. The risk of malignancy is small but increases substantially in those diagnosed later in infancy.9Solid tumors and solid areas of mixed solid and cystic tumors are more likely to contain malignant elements.3 Total excision of the tumor along with coccyx is mandatory as histologically benign

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residual tissue may recur as malignant tumor.9

Other benign tumors include a female baby with antenatally diagnosed congenital mesoblastic nephroma (CMN) presenting on fourth day of life, who underwent

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nephrectomy (Figure1)The child has continued follow up for 3 years. CMN is the most common type of renal tumor in newborns and infants under three months of age and 90%

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of cases are less than one year old. There are three histological subtypes – classic, spindle cell and mixed variant. Histologically,

classic CMN has uniform fascicles of spindled

cells resembling fibroblasts, which were also observed in the present study. The mitotic rate is low . In cellular CMN, fusiform to ovoid spindle cells give a sarcomatous appearance. An increased number of mitotic cells are also observed and the cells are more densely arranged.17 Generally it is a benign tumor

but can metastasize very rarely,

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usually to lung.(18)A differential diagnosis between CMN and Wilms’ tumor is very important to decide the treatment. The examination of clinical symptoms and imaging characteristics shows that Wilms’ tumor is similar to CMN, particularly the cellular

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variant, but fewer than 2% patients with Wilms’ tumor present before three months of age. Tumors with congenital syndromes or anomalies and the presence of bilateral tumors are clearly more suggestive of Wilms’ tumor.

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One case of infantile hepatic haemangioendothelioma(IHE) was brought to the hospital with cardiac failure and diagnosed as having large(10x10cm) vascular mass in the left

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lobe of liver.(Figure2) The child had normal-for-age AFP and low platelets. The child underwent left hepatic lobectomy. The child developed adhesive intestinal obstruction requiring extensive bowel resection one month later and died due to sepsis. Infantile haemangioendothelioma is a rare benign vascular lesion different from cavernous

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haemangioma. Up to 50 percent of the cases have associated skin lesions. AFP may be mildly elevated and may be associated with hypothyroidism. There are two histological varieties, type 2 has sarcomatous-appearing histological picture and is slightly more

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aggressive. Mesenchymal hamartoma is the important differential diagnosis, but on imaging mesenchymal hamartoma has more cystic areas and presence of calcification is

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more suggestive of IHE.20 Many medical treatment options like corticosteroids, sirolimus, vincristine and

interferon-2-alpha exist, although no single treatment has been shown to

be universally effective. Duration of treatment and cost may be constraints. Surgical excision for a fairly localized lesion is probably the best option. Other rare but interesting tumors include a one-month-old female baby who presented with a 2x2cm firm palatal swelling which was growing rapidly according to the mother.

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The lesion was excised due to high suspicion for rhabdomyo sarcoma but proved to be a pure myxoma from hard palate. The excision left a palatal fistula which was repaired after one year of age. Myxomas arising from oral cavity and palate are very rare and some of

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them can be malignant.21,22

In the present study there were three fibrosarcomas - one male and two female babies, all arising from trunk(two cases) and neck forming about 37% of the malignant tumors of

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neonates.Other studies show predominance of limb lesions (66%).11 One female baby

presented with 4 x 4cm mobile chest wall mass at birth , which was excised and reported

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by pathologist as hamartoma, but it recurred within two months with involvement of rib and pleura (figure 3). The baby received chemotherapy (Vincristine, Adriamycin and Cyclophosphamide at half the usual dose )with good response. The tumor was excised after 3 cycles of chemotherapy and chemotherapy was continued for 5 more cycles. The

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other two children underwent incisional biopsies with proven fibrosarcoma. In one female baby with tumor in the scapular region

and the other male baby with tumor in the neck,

chemotherapy was refused despite medical advice.

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Tumors of fibrous tissue predominate in neonatal age and account for perhaps two-thirds of soft tissue neoplasms in this age group, consisting mainly of the fibromatoses (infantile

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fibromatosis and myofibromatosis).15 Fibrosarcomas are malignant tumors that predominantly arise in soft tissues. They are characterized by a cellular proliferation reproducing fibroblasts, in children. They are classified in the heterogeneous group of nonrhabdomyosarcoma malignant mesenchymal tumors. They represent 5% to 10% of all sarcomas in infants younger than 1 year of age.12 They are locally aggressive and hardly metastasize.(15)Overall, infantile fibrosarcoma has a good prognosis with an 80% cure

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rate. Though surgery is the mainstay of treatment, chemotherapy has been reported to be a very effective adjuvant treatment, clearly more effective than in the adults.13,14 Rhabdomyosarcoma, the most common soft tissue malignancy in older children, is very

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rare in the neonatal period, although presentation, prognosis, and treatment are similar.15 We had three cases of neuroblastoma, representing about 37% of neonatal malignant tumors. One girl who presented at 4 months of age was diagnosed to have this large

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tumor (8cm x 9cm) while being evaluated for fever. The child had liver nodules at

diagnosis. She received chemotherapy(3 cycles). The tumor regressed in size, liver

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nodules disappeared and the infant had the mass resected and chemotherapy was completed. The child has maintained follow up for 2 years. The second case was a boy presenting to our hospital at 5 months of age, diagnosed elsewhere 3 months before, who had with extensive local disease, bony metastasis and poor general condition. The third

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case was a female child who came for a

second opinion. This child had 4S disease for whom we advised surgery, since the primary tumor was small and resectable, but the parents refused. Neuroblastoma is the

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most common type of malignant tumor in neonates in the literature accounting for 30 50% of cases in most series. An abdominal mass is the most common presentation either

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from the primary tumor or liver metastases. Most neonates with disseminated neuroblastoma have stage 4S disease (a localized primary with metastatic disease confined to liver, skin and bone marrow). The prognosis is good, and disease may even undergo spontaneous regression. The mode of treatment can be controversial but should be restricted to the minimum necessary to prevent life-threatening complications.24 The unusually good prognosis of neuroblastoma in very young children is not restricted to

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those with 4S disease and patients with stage 2 ( microscopic tumor residue after resection) also benefit from a conservative approach. The unusual biology of neuroblastoma is explained by neuroblastoma in situ. This entity is presence of nests of

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neuroblastoma tissue in an otherwise normal adrenal medulla, unassociated with gross

tumor or metastases and it has an incidence of between 1:200 and1:500 fetal and infant

postmortem examinations.25 It is thought to represent a potentially malignant neoplasm

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which can regress spontaneously. Surgery should be done at some point of time either immediately or after chemotherapy. According to one study, about fifty percent of the

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children who did not undergo resection ultimately died. The CE (carboplatin, etoposide) regimen is now being proposed as first-line therapy for infants with stage 4S neuroblastoma who require medical intervention.26

Among the malignant tumors, one baby with Wilms’ tumor presented at 2 months of age,

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diagnosed with 7 X 7cm mass in the right kidney while being evaluated for progressive abdominal distension. The baby underwent nephroureterctomy and received half-dose chemotherapy, for stage 2 favorable histology tumor as per COG protocol. The patient is

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doing well 18 months after treatment. According to various studies, Wilms’ tumor is much rare, with an incidence in the range of 3% of all renal tumors diagnosed in this age

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group.22,23 Careful histopathologic examination will give the details of the tumor, presence or absence of anaplasia, and also reveal the related tumors like clear cell sarcoma. Paraneoplastic syndromes such as hypertension and hypercalcemia are common in infants. Infants with Wilms’ tumor have an excellent prognosis overall. SIOP and COG both agree upon immediate nephrectomy and low-dose chemotherapy for infants with Wilms’ tumor.22,23

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A male baby diagnosed with polyhydramnios and cervical swelling was received on first day of life and was intubated due to airway obstruction.(figure 4) The initial diagnosis was cystic hygroma since the mass was predominantly cystic on CT scan. The mass was

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totally resected. It was encapsulated and multi-loculated. Histopatholgical examination

revealed clearly malignant foci though the tumor was predominantly teratomatous and the tumor markers were high for age. The child was put on follow up without chemotherapy

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and is recurrence-free after 4 years.

Cervico facial teratomas account for 5% to 6% of teratomas, which generally present in

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the neonatal period with large tumors and come to light in antenatal scans done for poly hydramnios. Most are mature or immature teratomas, but up to 20% are malignant.27

In adult tumors, the typical histological features of malignancy include high nuclear

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cytoplasmic ratio, increased mitotic activity, anaplasia and local and distant spread of tumor. In a neonate, the tumor with many of these features can still behave in a benign manner. Examples of which include congenital fibro sarcoma and congenital mesoblastic

cellularity.28

both relatively less aggressive tumors in spite of the high mitotic rate and

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nephroma,

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Four of eight malignant tumors received chemotherapy in our institution and three responded well and were disease-free after 2 years of follow up. Hospital policy dictated that radiation was not used for small babies. Although the broad principles of managing malignant disease are the same as in older children neonatal tumors require clinical acumen and close monitoring during therapy. The special behavior of neonatal neuroblastoma enables a conservative approach. Surgery plays a central role in the

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management of benign and many malignant tumors as chemotherapy can be very toxic to the small babies and irradiation is prohibited. Drug doses should be calculated according to body weight rather than surface area and started at reduced levels, and increased as

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tolerated.29 The use of radiation treatment is of great concern in view of the extreme

immaturity of normal tissues and the potential for late effects on growth and the risk of secondary malignancy.30

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Conclusion: Neonatal tumors are very rare and diagnosing a tumor in a neonate poses

many difficulties. The neonate with its rapid growth, development and maturation of all

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organs and tissues may be adversely affected by therapies generally given to older children. Treatment with the best chance for cure and the risk of irreversible damage to the rapidly growing organs need to be balanced. Our analysis of data of tumor and tumor-like conditions in the neonatal period showed a 2.2 percent incidence of

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malignancy in all pediatric malignant tumors, and 36.3 percent of the tumors in the neonates in the series were malignant. Malignant tumors are less likely to be diagnosed antenatally according to this series (only 11 percent of all antenatally diagnosed tumors),

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probably due to the rapid growth after birth. The study also emphasized the central role of surgery in most neonatal tumors and showed that careful use of chemotherapy in neonates

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is well tolerated. We conclude that, the neonates diagnosed with a malignant tumors may have a better prognoses than colder children with cancer. The author has no conflicts of interest relevant to this article.

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vascular anomalies in children. Pediatr Blood Cancer

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TABLE ILLUSTRATING INCIDENCE OF NEONATAL TUMORS

PRESENT STUDY

A. BENIGN

43(84.3%)

1. Haemangioma 2. Lymph.malformations 3. Ovarian cysts 4. Teratoma 5. Melanocytic nevus 6. Hamartoma 7. Palatal myxoma 8. CMN* 9. Hemangioendothelioma

22 7 5 3 2 1 1 1 1

B. Malignant

8(15.6%)

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1. Neuroblastoma 2. Cong. Fibro sarcoma 3. Wilms' tumor 4. Mixed germ cell tumor Total

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DIAGNOSIS

3 3 1 1

51

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*CMN-Congenital mesoblastic nephroma

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Figure 2 Infantile hemangio endothelioma of the left lobe of the liver.

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Figure 1 Congenital mesoblastic nephroma - nephrectomy specimen.

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Figure 3 Congenital fibrosarcoma chest wall - X ray showing soft tissue mass.

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Figure 4 Cervical teratoma.