NeoQuest June 2024: Cutaneous Nodules on a Term Newborn

A late preterm infant was born by uncomplicated spontaneous vaginal delivery. Fetal ultrasonography at 20 weeks’ gestation revealed swelling of the right forearm that persisted on repeat ultrasounds. Fetal ultrasonography at 35 weeks’ gestation also demonstrated an increased abdominal circumference. At birth, the infant was noted to have nodular lesions of the upper extremity (Figure 1A) and abdomen (Figure 1B). The remainder of the physical examination was unremarkable.

Figure 1. Nodular lesions of the (A) right upper extremity and (B) abdomen of the infant in the case vignette. Image adapted from: Velagala S, Heiden E, Lisse S, et al.  A unique presentation of nodular masses in infancy. Neoreviews. 2024.25(6): e370–e374.¹

The infant’s underlying diagnosis is most likely associated with which of the following?

1. Café au lait spots
2. Hypercalcemia
3. Positive S-100 staining
4. Spindle cell proliferation

Answer: D. Spindle cell proliferation

Explanation:

Soft tissue masses in neonates encompass a wide variety of diagnoses. Differentiation of these masses is imperative, as the evaluation and management vary based on the underlying diagnosis.

The masses seen in the infant in the case vignette are most consistent with infantile myofibromatosis (IM), also known as infantile fibromatosis or hemangiopericytoma.² This rare tumor is of mesenchymal origin, affecting approximately 1 per 150,000-400,000 live births.^1,3 Affected patients have rubbery, firm, skin-colored, or vascular-appearing lesions (resembling hemangiomas) known as fibromatoses.^1,2  These lesions are most commonly located in the skin, soft tissues, and muscle, and they contain proliferations of spindle cells (Figure 2) that are locally invasive (Option D).^1,2 Though these masses have a high rate of recurrence, they do not metastasize.² The fibromatoses in patients with IM can take one of three forms: solitary, multicentric, or generalized.^1-3 Solitary lesions are the most common and are usually located in the head and neck. Because these lesions do not tend to recur, they typically have a good prognosis.^2,4 Multicentric lesions tend to involve the skin, soft tissues, and infrequently, bone.^2,4 Multicentric lesions usually have a good prognosis and can spontaneously regress over time.² The generalized form is the most severe as a result of visceral involvement and can be fatal.²

Figure 2. Histopathology of a biopsied nodular lesion in a patient with IM that demonstrates clusters of primitive small blue cells (yellow stars) and spindle cells (blue star) in the dermis and subcutaneous tissue (H&E stain, 100X). Spindle cells have a characteristically long and slender appearance. Image adapted from: Velagala S, Heiden E, Lisse S, Wu H, Prior D, Chen G, Christison-Lagay E,Provini L, Antaya R, Spencer-Manzon M, Johnston L, A unique presentation of nodular masses in infancy. Neoreviews. 2024.25(6);e370–e374.¹

Café au lait spots (CALs) (Option A) are hyperpigmented areas of skin that can be found in healthy newborns, as well as in association with syndromes such as neurofibromatosis type 1 (NF1) (Figure 3).⁵ The presence of six or more CALs in a child less than one year of age should raise suspicion for NF1.⁵ NF1 is due to a germline mutation in the NF1 gene that encodes neurofibromin, a tumor suppressor gene.⁵ Early identification of NF1 is advantageous, as screening for optic gliomas and learning disabilities can begin as early as possible.⁵ Cutaneous neurofibromas seen in patients with NF1 do not develop until later in childhood or even adolescence, making this diagnosis unlikely for the infant in the vignette.

Figure 3. Multiple hyperpigmented café au lait macules of varying size on the abdomen of an infant. Image from: Liberman MR, Virmani P, Chotikanatis K, Glick SA. Birthmarks of medical significance. Neoreviews. 2015;16(1):e26-e35.⁸

Subcutaneous fat necrosis in the newborn (SCFN) consists of indurated nodules, with or without erythema, that are typically localized to bony prominences, including the upper back, buttocks, thighs, shoulders, and occiput.⁶ SCFN can occur following therapeutic hypothermia treatment for hypoxic-ischemic encephalopathy, which is not consistent with the infant in this case vignette.⁶ Therapeutic hypothermia induces hypoperfusion, leading to granulomatous inflammation and subsequent necrosis of fat tissue. Hypercalcemia is a complication of 80% of cases of SCFN (Option B) and is thought to be due to the release of 1,25-dihydroxyvitamin D (1,25(OH)₂ D), causing an increased uptake of calcium from the intestine.^6,7 In contrast to the infant in the case vignette, lesions in SCFN do not develop antenatally and are not present at birth; however, following development, the majority will slowly resolve by 6 months of age.⁶

Langerhans cell histiocytosis (LCH), previously known as histiocytosis X, is a rare disorder of histiocytes, an antigen-presenting cell of the innate immune system found in connective tissue.^8,9 Infants with LCH can present with single or multiple isolated skin lesions, including nodules (Figure 4A), or have disseminated multiorgan system involvement.^8,9 The associated lesions most often involve bone (80%), skin (33%), and the pituitary (25%).^8,9 Other, less common organs include the liver, spleen, lungs, and central nervous system (excluding the pituitary).⁸ Immunohistochemistry staining of tissue is positive for S-100 (Option C) and CD1a (Figure 4B and 4C) antigens.^8,9 There are several variants of LCH that range from benign to life-threatening disseminated forms.⁹ While the lesions that occur with LCH can be numerous and look similar to those seen in infantile myofibromatosis, LCH most commonly involves bone, whereas IM most commonly involves the skin.

Figure 4. An infant with Langerhans cell histiocytosis (LCH) with (A) a crusted nodule of the right foot. Biopsy of the nodule for immunohistochemical analysis revealed (B) S-100-positive and (C) and CD1a-positive cells, which are diagnostic features of LCH. Images from: Dokania G, Agrawal H, Niklinski W, Pyati S, Giordano L. Solitary foot nodule in a newborn. Neoreviews. 2016;17(12):e733-e757.⁹

Did you know?
Bone tumors from IM spontaneously regress with complete healing within the first few years of age.⁴

While café au lait spots can be seen in otherwise healthy neonates, what genetic conditions other than NF1 are associated with these skin lesions?

For a review of common neonatal pigmentary lesions, refer to: Habeshian KA, Kirkorian AY. Congenital pigmentary anomalies in the newborn. Neoreviews. 2021:22(10)e660-e670.⁵

NeoQuest June 2024 Authors:

Allison N. J. Lyle, MD, MA, University of Louisville School of Medicine
Lila S. Nolan, MD, Washington University School of Medicine in St. Louis

References:

1. Velagala S, Heiden E, Lisse S, et al. A unique presentation of nodular masses in infancy. Neoreviews. 2024;25(6);e370–e374
2. Fernandez KS. Solid tumors in the neonatal period. Neoreviews. 2014;15(2):e56-e68
3. Wu W, Chen J, Cao X, Yang M, Zhu J, Zhao G. Solitary infantile myofibromatosis in the bones of the upper extremities: two rare cases and a review of the literature. Oncology Letters. 2013;6(5);1406-1408
4. Eichenfield LF, Frieden IJ (Eds). Neonatal and Infant Dermatology (3^rd ed). Elsevier; 2015
5. Habeshian KA, Kirkorian AY. Congenital pigmentary anomalies in the newborn. Neoreviews. 2021:22(10);e660-e670
6. Vali P, Lakshminrushimha S. Case 2: Beware of lumps and bumps after cooling! Neoreviews. 2017.18(7);e441-444
7. Pavlek LR, Braswell E. Case 1: An infant with arm swelling and nodules. Neoreviews. 2019;20(2);e86-e89
8. Liberman MR, Virmani P, Chotikanatis K, Glick SA. Birthmarks of medical significance. Neoreviews. 2015;16(1);e26-e35
9. Dokania G, Agrawal H, Niklinski W, Pyati S, Giordano L. Solitary foot nodule in a newborn. Neoreviews. 2016;17(12);e733-e757