CLINICAL AND LABORATORY INVESTIGATIONS
Cutaneous Metastases in Neonates: A Review
Hart Isaacs, Jr., M.D .* , +
*Department of Pathology, Rady Children’s Hospital San Diego, San Diego, California, ¡University of California San Diego School of Medicine, La Jolla, California
Abstract: Two hundred eight neonates with malignant tumors and cutaneous metastases were reviewed. Malignancies most often associated with cutaneous metastases, in order of rank, were leukemia, multisystem Langerhans cell histiocytosis, neuroblastoma, rhabdoid tumor, rhabdo- myosarcoma, primitive neuroectodermal tumor, choriocarcinoma, and adrenocortical carcinoma. Bluish skin nodules producing the “blueberry muffin baby”-like appearance were the most common dermatologic finding in 171, or 82% of 208 neonates. The tendency of newborns to present with skin nodules is one of the significant differences between malignancies in younger and older children. Patients with rhabdoid tumor and rhabdomyo- sarcoma had the lowest survival rates, 4% and 15%, respectively, compared with leukemia, 37.5%, and neuroblastoma, 58%. Overall survival was 39%.
Tumors and tumor-like conditions of the skin are not uncommon in newborns and include a wide variety of entities. The vascular lesions, hemangioma and lymph- angioma, are by far the most prevalent, but other conditions such as melanocytic nevi, cutaneous hamartomas, and neoplastic-like infiltrations occur also (1-7). Malignant tumors should be considered also in the differential diagnosis of a cutaneous nodular infiltrate in neonates.
MATERIALS AND METHODS
The purpose of this review was to examine the findings and outcomes of neonates diagnosed with malignancies presenting with skin metastases. Two hundred eight study cases were collected from the literature and from personal files and recorded only when adequate clinical, dermatologic, pathologic, and follow-up data were given. Most of the database was derived from the archives of the
National Library of Medicine (PubMed MEDLINE). Diagnosis of the various tumors was established in all patients included in the study by histopathological confirmation of biopsy or surgical or postmortem spec- imens. Only patients with skin lesions appearing at birth or in the first month of life were accepted for review. The period of patient accrual was from 1955 to 2010.
RESULTS
Two hundred eight neonates with malignancies and cutaneous metastases were reviewed. Leukemia was the leading malignancy with this association (80 or 38.5%), followed by multisystem Langerhans cell histiocytosis (LCH) (43 or 20.7%), neuroblastoma (36 or 17.3%), rhabdoid tumor (24 or 11.5%), rhabdomyosarcoma (13 or 6.3%), primitive neuroectodermal tumor (PNET) (5 or 2.4%), choriocarcinoma (4 or 1.9%), and adreno- cortical carcinoma (ACC) (3 or 1.4%) (Table 1A).
Address correspondence to Hart Isaacs, Jr., M.D., Rady Children’s Hospital San Diego, Department of Pathology, MC 5007, 3020 Children’s Way, San Diego, CA 92123 or e-mail: hisaacs@ucsd.edu.
DOI: 10.1111/j.1525-1470.2011.01372.x
TABLE 1. Cutaneous Metastases in Neonates
A. Distribution of Cutaneous Metastases in Neonates (n = 208)
| Tumor | Incidence, n (%) | Survival, n/N (%) |
|---|---|---|
| Leukemia | 80 (38.5) | 30/80 (37.5) |
| Multisystem Langerhans cell histiocytosis | 43 (20.7) | 23/43 (53.5) |
| Neuroblastoma | 36 (17.3) | 21/36 (58.3) |
| Rhabdoid tumor | 24 (11.5) | 1/24 (4.2) |
| Rhabdomyosarcoma | 13 (6.3) | 2/13 (15) |
| Primitive neuroectodermal tumor | 5 (2.4) | 1/5 (20) |
| Choriocarcinoma | 4 (1.9) | 1/4 (25) |
| Adrenocortical carcinoma | 3 (1.4) | 2/3 (67) |
| Overall survival | 81/208 (39) |
B. Incidence of the Various Types of Neonatal Tumors (n = 607)*
| Tumor | n (%) |
|---|---|
| Neuroblastoma | 158 (26.0) |
| Teratoma | 152 (25.0) |
| Leukemia | 74 (12.2) |
| Brain tumors | 63 (10.4) |
| Sarcoma | 58 (9.6) |
| Renal tumors | 30 (4.9) |
| Liver tumors | 37 (6.1) |
| Retinoblastoma | 35 (5.8) |
| Total | 607 (100) |
*Abstracted from Isaacs H Jr. Tumors of the fetus and infant: An atlas. Springer-Verlag, 2002: page 2.
Cutaneous nodules giving the patient the “blueberry muffin baby”-like appearance were the most common initial skin finding in 171 or 82% of 208 (Tables 2-9). Most lesions displayed the characteristic histologic fea- ture observed in skin metastases, which consisted of a dermal-situated nodule. Patients with metastatic rhabd- oid tumor had the lowest survival (4.2%), and adreno- cortical carcinoma had the highest (67%). (The significance of this with such few cases is questionable.) The overall survival rate was 39%.
DISCUSSION
Malignant neoplasms may appear in neonates as cuta- neous metastases, which may be the first manifestation of the tumor. Usually it portends a poor prognosis for the affected child (2,6-8). The tendency for newborns to present with skin nodules is one of the significant differ- ences between the same cancers in younger and older children (7,8). The differential diagnosis of bluish skin nodules producing “blueberry muffin baby” is divided roughly into two main groups: neoplastic and non-neo- plastic (Table 10). The non-neoplastic group included infections (“TORCH” infectious agents) and blood dyscrasias such as hemolytic disease of the newborn and twin-twin transfusion. In fetal life, the skin functions as a hematopoietic organ and may revert back to this func- tion in neonates in the form of dermal nodules of hematopoiesis when there is a demand to increase blood
cell production. This may occur when tumor cells infiltrate the bone marrow or when there is severe anemia (1,7,8). The neoplastic category includes leukemia and other malignancies that manifest in the formation of cutaneous malignant tumor nodules.
Leukemia
Leukemia cutis occurs in more than half of neonates born with leukemia (9,10). With extensive involvement of the skin, it may have a nodular, indurated bluish appearance (4,5,11,12). Histological examination reveals infiltrates of immature lymphoid or myeloid cells, depending on the type of leukemia, within the dermis and subcutaneous tissues. The diagnosis of a small blue cell tumor may not be possible on a routine bone marrow examination; immunocytochemical and ultrastructural studies may be required to distinguish leukemia from other malignant tumors (5). The infant’s leukemia and leukemia cutis may resolve spontaneously (4,9,10,12).
Acute leukemia, accounting for 80, or 38.5% of cases, was the most common malignancy presenting with cutaneous metastases. Acute myelocytic, FAB M5, monocytic leukemia was the leading subtype of leuke- mia. Most neonates had a high leukocyte count and hepatosplenomegaly. The interval between appearance of skin lesions and diagnosis of leukemia was the same in 68 of 80, or 85% of patients. The blueberry muffin baby appearance was present initially in 68 of 80, or 85% of
| Characteristic | Value |
|---|---|
| Sex, n | |
| Male | 43 |
| Female | 37 |
| Type of leukemia, n | |
| AML | 63 |
| ALL | 12 |
| AML and ALL | 4 |
| Type not specified | 1 |
| French-American-British leukemia classification, n | |
| M4 | 11 |
| M5 | 32 |
| M4,5 | 2 |
| M6 | 5 |
| M7 | 1 |
| L1 | 2 |
| L2 | 0 |
| Type not stated | 27 |
| Initial white blood cell count | |
| Average (range) | 124 × 109 (4-650) |
| Median | 47 x 109 |
| Interval between appearance of skin lesions and diagnosis of | |
| leukemia, n (range) | |
| Same time | 68 |
| Leukemia diagnosis followed skin nodules | 10 |
| (1 wks-3 mos) | |
| Leukemia diagnosis preceded skin nodules | 2 (1-8 wks) |
| Location of skin nodules, n | |
| Trunk | 30 |
| Generalized | 25 |
| Extremities | 17 |
| Head | 14 |
| Face | 13 |
| Size, cm | 0.1-6 |
| Hepatosplenomegaly, n (%) | 47 (59) |
| Central nervous system findings, n (%) | 22 (27.5)* |
| Survival, n | |
| Alive, in remission | 30 |
| Dead of disease | 50 |
| Survival rate, % | 37.5 |
*Presence of blasts in the cerebrospinal fluid.
AML, acute myelocytic leukemia; ALL, acute lymphocytic leukemia.
neonates. Other skin lesions occurring to a lesser degree were macules of various sizes and colors, papules, ve- siculopustules, petechiae, purpura, and ecchymoses. Survival rate was 37.5%; 30 of the 80 patients were alive in remission.
Langerhans Cell Histiocytosis
Skin lesions are an important manifestation of LCH in fetuses and infants (2,5,6,13-15). Typically, the patient presents with a rash refractory to therapy accompanied by anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and generally failure to thrive.
| Sex, n | |
|---|---|
| Female | 22 |
| Male | 21 |
| Presenting findings, n | |
| Skin lesions | 43 |
| Hepatomegaly | 10 |
| Splenomegaly | 10 |
| Lymphadenopathy | 9 |
| Lung infiltrates on imaging studies | 6 |
| Diarrhea | 5 |
| Respiratory distress | 5 |
| Thrombocytopenia | 2 |
| Miscellaneous* | 5 |
| Interval between the appearance of skin lesions and presence of | |
| multi-system disease, n | |
| Same timet | 12 |
| Other (average; range) | 31 |
| (90 days; 1-20 mos) | |
| Location of skin nodules, n | |
| Generalized | 24 |
| Scalp | 17 |
| Trunk | 17 |
| Extremities | 15 |
| Face | 13 |
| Site not specified | 9 |
| Gingiva | 6 |
| Neck | 3 |
| Ears | 2 |
| Size of nodules, cm | 0.2-5 |
| Other types of skin lesions, n | |
| Vesiculopustules | 18 |
| (with or without | |
| crusting or hemorrhage) | |
| Eczematous (seborrhea-like) dermatitis | 7 |
| Sites involved other than skin, n | |
| Lung | 25 |
| Liver | 25 |
| Bone marrow | 23 |
| Spleen | 22 |
| Lymph nodes | 20 |
| Gastrointestinal tract | 8 |
| Mucosa, not otherwise specified | 7 |
| Thymus | 7 |
| Ear | 6 |
| Brain | 5 |
| Nose | 5 |
| Pituitary | 4 |
| Pancreas | 4 |
| Eye | 3 |
| Heart | 3 |
| Kidney | 2 |
| Treatment, n | |
| Patients treated | 34 |
| Alive | 22 |
| Patients not treated | 9 |
| Alive | 1 |
| Overall survival, n (%) | 23 (53.5) |
*One each stillbirth, fetal hydrops, jaundice, oral ulcer, otitis media.
¡Twelve patients had skin lesions and multisystem disease at birth and 15 in the first week of life.
| Sex, n | |
| Male | 18 |
| Female | 12 |
| Not stated | 6 |
| Tumor primary site, n | |
| Adrenal | 24 |
| Adrenal, bilateral | 5 |
| Retroperitoneum | 4 |
| Neck | 3 |
| Stage, n | |
| 4S | 30 |
| 4 | 4 |
| Not stated | 2 |
| Interval between the time of appearance of skin metastases and | |
| diagnosis, n | |
| Same time as diagnosis | 31 |
| 2-3.5 mos before diagnosis | 4 |
| Nodules noted 3 mos after diagnosis | 1 |
| Sites of cutaneous metastases, n | |
| Extremities | 10 |
| Trunk | 8 |
| Generalized | 8 |
| Face | 2 |
| External genitalia | 2 |
| Not specified | 15 |
| Size of skin nodule metastases, cm | 0.2-6 |
| Metastatic sites other than skin, n | |
| Liver | 29 |
| Bone marrow | 15 |
| Pancreas | 3 |
| Lungs | 2 |
| Placenta | 1 |
| Retroperitoneum | 1 |
| Mediastinum | 1 |
| Lymph nodes | 1 |
| Treatment, n | |
| Patients treated | 26 |
| Patients not treated | 10 |
| Outcome, n | |
| Alive | 21 |
| Dead | 15 |
| Survival rate, % | 58.3 |
The disease is regarded as a proliferation of Langerhans cells that normally reside in small numbers in the skin and other organs. Approximately half of infants with dis- seminated (multisystem) LCH (Letterer-Siwe disease) die within a year of diagnosis, frequently from extensive histiocyte infiltration of the lung (3,5,14,15). Involvement of two or more organ systems are the criteria required for the diagnosis of multisystem LCH (14). Examples of spontaneous regression or “self-healing” congenital LCH (Hashimoto-Pritzger disease) are well documented (2,6,13-15). In a recent review of 104 fetuses and neo- nates with LCH, the number with LCH limited to the skin and those with multisystem disease were approxi- mately equal in number (15).
The diagnosis of LCH is made by skin biopsy of a representative lesion, which microscopically shows variable numbers of Langerhans histiocytes infiltrating
| Sex, n | |
|---|---|
| Male | 15 |
| Female | 8 |
| Not stated | 1 |
| Primary site, n | |
| Kidney | 3 |
| Mediastinum | 3 |
| Chest | 3 |
| Neck and upper chest | 2 |
| Paraspinal | 2 |
| Extremities | 2 |
| Medulloblastoma | 1 |
| Orbit | 1 |
| Neck and face | 1 |
| Liver | 1 |
| Palate | 1 |
| Scalp | 1 |
| Subcutaneous tissue | 1 |
| Bone | 1 |
| Paratesticular | 1 |
| Interval between diagnosis and appearance of skin metastases, n | |
| Same time | 16 |
| Other | |
| 5 days-7 wks | 7 |
| 1 mo before discovery | 1 |
| Location of skin metastases, n | |
| Extremities | 10 |
| Multiple sites | 7 |
| Face | 6 |
| Neck | 5 |
| Back | 5 |
| Chest | 4 |
| Head | 3 |
| Scalp | 3 |
| Shoulder | 2 |
| Abdomen | 1 |
| Genitalia | 1 |
| Buttock | 1 |
| Size of skin nodule metastases, cm | 1.5-5.5 |
| Sites of organ metastases other than skin, n | |
| Liver | 10 |
| Lungs | 9 |
| Brain | 6 |
| Lymph nodes | 6 |
| Adrenals | 6 |
| Heart | 5 |
| Soft tissue | 5 |
| Placenta | 4 |
| Thymus | 4 |
| Pleura | 3 |
| Bones | 3 |
| Mediastinum | 2 |
| Intestines | 2 |
| Orbit | 1 |
| Pancreas | 1 |
| Spleen | 1 |
| Spinal cord | 1 |
| Larynx | 1 |
| Dura | 1 |
| Diaphragm | 1 |
| Treatment, n | |
| Patients treated | 16 |
| Patients not treated | 8 |
| Outcome, n | |
| Alive | 1 |
| Survival, % | 4.2 |
| Sex, n | |
| Female | 10 |
| Male | 3 |
| Tumor primary site, n | |
| Extremity | 5 |
| Neck | 2 |
| Orbit | 2 |
| Trunk | 2 |
| Retroperitoneum | 1 |
| Iliac fossa | 1 |
| Histology, n | |
| Alveolar | 13 |
| rhabdomyosarcoma | |
| (Stage IV) | |
| Interval between diagnosis and appearance of skin metastases, n | |
| Same time | 11 |
| Other: Few weeks-2 | 2 |
| mos after discovery | |
| Sites of cutaneous | |
| metastases, n | |
| Multiple | 10 |
| Extremities | 4 |
| Trunk | 4 |
| Scalp | 1 |
| Face | 1 |
| Neck | 1 |
| External genitalia | 1 |
| Perineum | 1 |
| Size of skin | 1.5-5 |
| nodule metastases, cm | |
| Metastatic sites | |
| other than skin, n | |
| Brain | 5 |
| Kidney | 3 |
| Bones | 3 |
| Lungs | 2 |
| Lymph nodes | 2 |
| Mediastinum | 1 |
| Cranial fossa | 1 |
| Adrenal | 1 |
| Spleen | 1 |
| Thymus | 1 |
| Orbit | 1 |
| Treatment, n | |
| Patients treated | 12 |
| Patients not treated | 1 |
| Outcome, n | |
| Alive | 2 |
| Dead | 11 |
| Survival rate, % | 15 |
*One patient was alive at age 6 mos and the other at age 14 mos with metastases. It is not known whether the two children are still alive at the time of writing.
the subcutaneous tissue and dermis and extending through the epidermis into the stratum corneum, a helpful diagnostic feature (4,5,13-15). The Langerhans cell has a characteristic coffee bean-shaped nucleus, a small nucleolus, and an eosinophilic cytoplasm. Ultra- structural studies reveal the presence of diagnostic, but often difficult to find, tennis racket-shaped Birbeck granules in the cytoplasm of the Langerhans cells, which
| Sex, n | ||
| Male | 4 | |
| Female | 1 | |
| Tumor primary site, n | ||
| Chest wall | 1 | |
| Brain (thalamus) | 1 | |
| Subcutaneous tissue | 1 | |
| Paraspinous muscle | 1 | |
| Abdominal cavity | 1 | |
| Interval between appearance of skin metastases | and diagnosis, n | |
| Same time | 3 | |
| Other: Diagnosis of primary | 2 | |
| tumor 9 days and 8 mos after | ||
| skin metastases | ||
| Sites of cutaneous metastases, n | ||
| Generalized | 3 | |
| Extremities | 2 | |
| Scalp | 1 | |
| Face | 1 | |
| Neck | 1 | |
| Back | 1 | |
| Size of skin nodule metastases, cm | 0.3-2 | |
| Metastatic sites other than skin, n | ||
| Lungs | 2 | |
| Lymph nodes | 2 | |
| Liver | 1 | |
| Soft tissues | 1 | |
| Orbit | 1 | |
| Treatment, n | ||
| Patients treated | 4 | |
| Patients not treated | 1 | |
| Outcome, n | ||
| Alive* | 1 | |
| Dead | 4 | |
| Survival rate, % | 20% | |
*One patient was alive at age 16 mos after “spontaneous regression of tumor nodules.”
are S-100 protein and CD 1a thymocyte antigen immunoreactive (4,5,13).
Multisystem or generalized LCH was the second most common malignancy presenting with skin lesions (43/208 or 20.7%). Only 18 (42%) infants with this dis- ease presented with blue nodules. A generalized poly- morphous eruption was more common initially in the other 25, or 58% of neonates; 18 had vesiculopustules with or without crusting or hemorrhage and seven an eczematous (seborrhea-like) dermatitis. Some of the 18 patients developed skin nodules later in the course of their disease. The interval between the appearance of skin lesions and time of diagnosis varied considerably in patients with LCH and those with other malignancies in the study. Appearance of skin lesions and diagnosis was the same in 12 neonates, including one stillborn who had skin lesions and evidence of multisystem disease at birth. The interval ranged from 1 to 20 months (average 90 days) in the other 31. Overall survival was 23 of 43, or 53.5%, which is similar to that reported in other studies (15,16).
TABLE 8. Neonatal Choriocarcinoma with Skin Metastases (n = 4)
Sex, n
Male
3
Female
1
Tumor primary site, n Placenta 4
Interval between appearance of skin metastases and diagnosis, n Same time
2
Other
Few days
1
Few weeks
1
Sites of cutaneous metastases, n
Scalp
3
Neck
2
Extremities
1
Trunk
1
Perineum
1
Generalized
1
Size of skin nodule metastases, cm
Metastatic sites other than skin, n
Liver
3
Brain
2
Lungs
2
Lymph nodes
2
Diaphragm
1
Treatment, n
Patients treated
2
Patients not treated
2
Outcome, n
Alive
1
Survival rate, %
25
Neuroblastoma
Neuroblastoma is the leading malignant tumor of neo- nates (3,6,7,17). The tumor is unique because of its dis- tinctive biologic behavior and many different clinical manifestations. Multiple bluish cutaneous nodules pro- ducing the “blueberry muffin baby” appearance occur in more than one-third of patients younger than 1 year old, and it may be the initial presentation of metastatic neu- roblastoma (5,6). Most infants with this finding are classified as stage IV-S. In addition to their skin lesions, IV-S patients typically have a small tumor, usually situ- ated in the adrenal gland, with multiple metastases to the liver and bone marrow that tend to resolve spontane- ously (18). Histologic examination of the cutaneous nodule reveals a uniform, small cell, malignant tumor with or without Homer-Wright pseudorosette forma- tion. The tumor cells show neurone-specific enolase and synaptophysin reactivity and neurosecretory (dense core granules) and neurotubules under electron microscopy (5).
Neuroblastoma ranked third in incidence in this review. The adrenal gland was the most common pri- mary site (29/36, 80%); five were bilateral. The majority of neonates were classified as stage IV-S. The interval
| Sex | |
| Males | 2 2:1 |
| Females | 1 |
| Presenting findings | |
| Skin lesions | 3 |
| Adrenal mass on imaging | 2 |
| Cerebral lesions | 1 |
| Lymphadenopathy | 1 |
| Interval between appearance of skin lesions and | |
| diagnosis of tumor | |
| Same time | 0 |
| Other | 8, 22 days |
| and 5.5 mos | |
| Distribution of skin lesions | |
| Scalp | 2 |
| Trunk | 2 |
| Neck | 2 |
| Generalized | 2 |
| Type of skin lesions | |
| Red-purple papules & nodules - | 2 |
| "blueberry muffin baby" | |
| Erythematous papules | 1 |
| Organs involved | |
| Skin | 3 |
| Lung | 1 |
| Bone | 1 |
| Lymph nodes | 1 |
| Brain | 1 |
| Treatment | |
| Patients treated | 3 |
| Alive | 2 |
| Outcome | |
| Overall survival | 2/3 = 67% |
TABLE 10. Differential Diagnosis of the “Blueberry Muffin Baby” (Cutaneous Blue Nodules)
Dermal extramedullary erythropoiesis
Congenital infection Rubella
Cytomegalovirus
Toxoplasmosis
Hemolytic disease of the newborn
Twin-twin transfusion syndrome
Hereditary spherocytosis
Blue rubber bleb nevus syndrome
Neoplastic infiltrations of the skin Leukemia
Neuroblastoma
Rhabdoid tumor
Rhabdomyosarcoma
Primitive neuroectodermal tumor
Choriocarcinoma
Adrenocortical carcinoma
Adapted from references 4, 5, and 7.
between appearance of skin lesions and diagnosis was often the same. Eventually, all patients had skin nodules. More than half (21/36, 58%) survived.
Rhabdoid Tumor
This highly malignant neoplasm is characterized clini- cally by rapid growth and early metastases and a high mortality rate in neonates and infants (5,19,20). Rhabdoid tumor may present in the skin, especially in the head and neck area, as a solitary primary tumor or as one or more metastatic skin nodules (5,19-22). Metastatic disease is present in more than half of fetuses and neo- nates at the time of diagnosis. Concomitant brain tumors are found in almost one-third with this malignancy (20). The histologic appearance of the tumor is similar to those occurring in the kidney and central nervous system (5,20).
Rhabdoid tumor ranked fourth in occurrence after leukemia, LCH, and neuroblastoma. The main primary sites were in the kidney, mediastinum, and chest. The appearance of skin metastases and time of diagnosis was the same in two-thirds of the neonates. Main loca- tions of skin metastases were the extremities, trunk, face, neck, and multiple sites. Almost all patients presented with blue cutaneous nodules. The main sites of metas- tases other than skin were liver, lungs, brain, lymph nodes, and adrenal glands. Rhabdoid tumor was asso- ciated with the lowest survival rate (1/24, 4%) of all malignancies.
Rhabdomyosarcoma
Rhabdomyosarcoma is a highly malignant neoplasm, accounting for most soft tissue sarcomas in infants; it is the second most common sarcoma found in newborns, after fibrosarcoma (4,5,20). Primary and metastatic rhabdomyosarcoma of the skin are unusual. The malig- nancy metastasizes to the skin, forming bluish cutaneous nodules (21-23). Alveolar rhabdomyosarcoma is the main histological type involving the skin. The sarcoma rarely presents with a leukemic-like picture characterized by the presence of small, dark malignant cells in peripheral blood smears and bone marrow. The tumor consists of small to medium-sized, darkly staining cells with rounded nuclei and scant cytoplasm arranged in an alveolar pattern. It is immunoreactive with vimentin, desmin, and muscle actin (4,5).
Rhabdomyosarcoma accounted for 6% of the malignancies metastasizing to the skin. Girls outnum- bered boys 3.3 to 1. Extremities were the leading primary site, and the neck and orbit and trunk were next. All patients were classified as Stage IV and diagnosed as alveolar rhabdomyosarcoma. Almost all neonates pre- sented with multiple skin metastases at the time of diagnosis. Rhabdomyosarcoma had the second lowest survival rate (2/13, 15%) after rhabdoid tumor (4%).
Primitive Neuroectodermal Tumor
Primitive neuroectodermal tumors consist of a group of small blue cell tumors occurring within the central ner- vous system and peripheral tissues (24-28). Peripheral PNET is rare in neonates, with only a few cases reported (24-28). PNETs comprise a group of highly malignant sarcomas, including Ewing sarcoma, showing various degrees of neuroectodermal and neural differentiation displaying epithelial and non-epithelial markers (e.g., desmin and S100 protein) (25). The malignancy is characterized by aggressive behavior and a poor prog- nosis, with most patients dying within 6 months of diagnosis (28).
There were five examples of PNET with skin metas- tases, making up 2% of the total. The tumor primary sites were one in the brain and four in peripheral loca- tions. All patients presented with blueberry muffin-like nodules, three noted at the same time of diagnosis. There was only one survivor at age 16 months, who had a tongue primary (24).
Choriocarcinoma
Choriocarcinoma is an aggressive malignant tumor of trophoblastic cells, most often arising from the placenta and characterized by the secretion of human chorionic gonadotropin (BhCG) (29). Metastatic spread to the fe- tus and infant is rare, with fewer than 20 cases reported (30,31). Presence of cutaneous skin lesions in these pa- tients is uncommon (29,31-33). The outlook is poor, with < 25% survivors, although more recently, early biopsy of a metastatic skin nodule and prompt diagnosis and treatment with chemotherapy has been shown to improve prognosis significantly (33).
The review included four of 208 (1.9%) examples of neonatal choriocarcinoma with cutaneous metastases. Skin nodules were noted at the same time as diagnosis in two infants and a few days to weeks later in the other two. Three of the four patients’ mothers survived after treat- ment of their metastatic pulmonary disease; one was lost to follow-up. There was a single neonatal survivor who received an early biopsy and diagnosis followed by chemotherapy (33).
Adrenocortical Carcinoma
Adrenocortical carcinoma is an uncommon malignancy occurring in fewer than 15 children per year in the United States (34). It is even rarer for ACC to occur in newborns, with only a few cases having been described (34-37). An abdominal mass is the major presenting finding. The incidence of metastases at diagnosis is significant,
occurring in one-third of newborns with ACC (34). Some patients present with the blueberry muffin appearance (35-37). Recurrence rates and mortality associated with ACC are high (3,34). For example, only half of ACC patients in a recent perinatal study survived (34).
ACC accounted for three of the 208 (1%) review neonates. Usually there was a delay between the dis- covery of skin nodules and diagnosis varying from 8 days to 5.5 months. All three patients presented with the appearance of multiple blue nodules. One who had widespread metastases, including the brain, was treated using adrenal surgical resection as the only form of therapy, and the child survived. The authors suggested that perhaps spontaneous remission had occurred (35).
CONCLUSION
Clinical conditions with cutaneous nodules occurring in the neonatal period often portend a poor prognosis and thus require prompt diagnosis. Skin biopsy should be an integral part of the initial examination because histology of the lesion will determine the course of diagnostic evaluation. Because some congenital skin conditions, non-neoplastic and neoplastic, resolve spontaneously, prompt recognition and diagnosis are required. Careful observation over a period of months or perhaps years for systemic involvement or disease recurrence should be a part of the treatment plan (6-8).
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