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Pediatric Pathology
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Case 1B -
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Congenital Nonprogressive Hemangioma, Noninvoluting Clinical Variant (N.I.C.H.)
Paula E. North
Children's Hospital of Wisconsin
Milwaukee, WI
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Clinical History:
A 4 year old male child presented with a soft compressible nodule on the upper thigh with a reddish
hue. Increased vessel prominence was noted medial to the lesion, and Dopler ultrasound indicated high
flow. At surgery, a hypervascular mass restricted to the dermis and subcutis was completely excised.
Introduction:
This is an example of congenital nonprogressive hemangioma, a newly
recognized clinicopathological entity that differs from classical, postnatally developing infantile hemangioma in its presentation fully formed at birth, followed by a
static or rapidly involuting course, the latter much more rapid that that characteristic of infantile
hemangioma [1]. The noninvoluting and rapidly involuting clinical subtypes of congenital nonprogressive
hemangioma show considerable, perhaps indivisible, overlap, and are often referred to by clinicians as
"N.I.C.H." (noninvoluting congenital hemangioma) and "R.I.C.H" (rapidly involuting congenital
hemangioma), respectively
[2,
3].
Traditionally, these congenitally fully developed lesions have been
considered clinical variants of infantile hemangiomas that inexplicably completed their growth in utero rather that exhibiting the more typical postnatal growth pattern [4]. We
now recognize that these lesionsare histologically and immunophenotypically
distinct from classical infantile hemangioma, and thus are unlikely to be related to the latter in
pathogenesis
[1,
5,
6].
Pathologic and Clinical Features:
Lesions in this category typically display telangiectasias and a peripheral rim of pallor, and those
that will rapidly involute (R.I.C.H.) develop a central depression or ulcer before "melting away",
usually in 3-5 months. Occasional examples with limited progressive clinical growth do occur, but appear
to be exceptions to the rule. Many are first detected by prenatal ultrasound. Unlike infantile
hemangiomas, but like vascular malformations, congenital hemangiomas occur with equal frequency in males
and females. Doppler detects prominent arterial flow within the lesion in most cases. MRI findings are
similar to those of infantile hemangioma. Lesions most commonly affect skin and subcutis, but also occur
in viscera, notably as large solitary congenital lesions of the liver, and occasionally in the brain.
Deep intramuscular location has not been described.
The capillary lobules that comprise congenital nonprogressive hemangiomas, whether rapidly involuting
or noninvoluting in clinical type, are separated by abnormally dense fibrous tissue. This is in contrast
to infantile hemangiomas, in which the tumor lobules are separated by normal-appearing tissue elements.
Overlying skin is often atrophic, with loss of dermal adnexal appendages. Endothelial cells and
pericytes within the capillary lobules can be moderately plump, focally resembling those of proliferative
phase infantile hemangioma, but lack the increased endothelial mitotic activity and widespread
multi-lamination of basement membranes seen in infantile hemangioma. Foci of hemosiderin deposition,
lobular thrombosis, infarction, and calcification are commonly present, and sclerosis often extends into
the lobules either peripherally or globally. Foci of extramedullary hematopoiesis are also common, as
are thin-walled centri-lobular draining vessels that are stellate in contour. The interlobular vascular
network of feeding and draining vessels may be more prominent than the more cellular capillary lobules
themselves in some lesions, creating resemblance to vascular malformations. Grossly evident areas of
central depression and scarring in regressing lesions appear to correlate with a central core containing
large central draining channels and few capillary lobules. The residual lesion of R.I.C.H. following
regression is characterized by cutaneous and subcutaneous collapse with loss of dermal and adipose
tissue, often down to the level of the muscle fascia. Features more commonly seen in noninvoluting
variants than in rapidly involuting variants include hobnailed endothelium, large capillary lobules,
eosinophilic cytoplasmic inclusions, and arteriovenous fistulae
[2,
3,
7].
In both the R.I.C.H. and
N.I.C.H. variants of congenital nonprogressive hemangioma, the lesional endothelial cells are negative
for GLUT1 and other distinctive markers of infantile hemangioma [1].
Differential Diagnosis:
Congenital nonprogressive hemangiomas can be confused with either proliferative or involutive phase
infantile hemangioma. Unlike infantile hemangiomas, congenital nonprogressive hemangiomas have lobules
separated by typically fibrotic stroma, often containing, in addition to large draining veins and
lymphatic vessels, a prominent component of small arteries that course through the capillary lobules.
Intra-neural infiltration by lesional capillaries, typical of infantile hemangioma, is not seen in
congenital nonprogressive hemanioma. Also unlike infantile hemangioma, lobular sclerosis, foci of
hemosiderin deposition, extramedullary hematopoiesis, thrombosis, and central necrosis are common.
Endothelial mitotic figures are scant–to-absent (although the latter is also true of involutive phase
infantile hemangiomas). Widespread thickening and multilamination of basement membranes containing
apopototic dust (universally seen in involuting infantile hemangiomas) are not seen in congenital
nonprogressive hemangioma. Whenever there is any doubt, the endothelial cells of infantile hemangioma,
but not those of congenital nonprogressive hemangioma, are strongly positive for GLUT1 and other markers
uniquely shared with the capillaries of placental chorionic villi
[1,
8].
Clinical presentation is also
extremely helpful, since advanced congenital presence is the norm and postnatal growth is uncommon in
congenital nonprogressive hemangioma.
Perhaps the most clinically important differential diagnosis in the diagnosis of congenital
nonprogressive hemangioma is arteriovenous malformation. This reflects the shared congenital appearance
and high flow nature of these entities, although clinically significant arteriovenous shunting is either
absent or low-grade in congenital nonprogressive hemangioma. Both entities are negative for GLUT1 and
other infantile hemangioma/placental endothelial markers. Arteriovenous malformations often contain foci
of capillary proliferation, possibly related to local tissue ischemia, compounding the potential for
histological confusion. The zones of capillary proliferation in arteriovenous malformation are
mitotically active and are more infiltrative and "ragged" in appearance than the well-defined capillary
lobules of congenital hemangioma that display central draining vessels. Sequelae of direct arteriovenous
shunting consistently observed in arteriovenous malformations, such as venous mural arterialization and
marked intimal changes, are absent or focal in congenital nonprogressive hemangioma.
Congenital nonprogressive hemangiomas can also be confused with acquired reactive capillary
proliferations such as deeply seated lobular capillary hemangioma (a.k.a.,
"pyogenic granuloma"). These entities share with congenital nonprogressive hemangioma a number of
features including well-defined capillary lobules and stromal sclerosis. The high-flow character of the
intra-lobular stroma and supportive vasculature of congenital nonprogressive hemangioma is absent in
these reactive proliferations. Clinical history of congenital, rather than acquired presentation, is
also informative.
Final Diagnosis:
Congenital nonprogressive hemangioma, noninvoluting clinical variant (N.I.C.H.).
Case Discussion:
The preponderance of clinical, histological, and immunophenotypic evidence supports the conclusion
that both the rapidly involuting and noninvoluting clinical subtypes of congenital nonprogressive
hemangioma (R.I.C.H. and N.I.C.H) are biologically unrelated to classical infantile hemangioma
[1,
5,
6].
Endothelial cells of both are universally negative for Glut1 and other distinctive markers of infantile
hemangioma and placental villous capillaries
[1,
8].
Pathogenesis is unclear, but the degree of overlap
in clinical and histological features between "R.I.C.H." and "N.I.C.H." , and in particular between
"N.I.C.H." and rapidly involuting R.I.C.H. lesions that arrest short of full regression, suggests that
these lesions are part of the same disease spectrum, with the R.I.C.H. variant perhaps resulting from
early global auto-infarction due to thrombosis of central feeding and/or draining vessels
[5,
6].
Congenital nonprogressive hemangiomas share the early intrauterine development and equal sex predilection
of vascular malformations, and may represent a form of intra-uterine vascular injury or malformation with
history of past capillary proliferation and limited potential for continuing growth. Regardless, the
clinicopathological presentation is consistent and characteristic. Diagnosis can usually be made with
confidence clinically, although the differential diagnosis may include small vessel-rich arteriovenous
malformation, infantile hemangioma, or reactive capillary proliferations. Histologic confirmation is
thus often needed and can be supplemented by GLUT1 immunohistochemistry to fully rule-out infantile
hemangioma. Although lesions involving skin and subcutis have been best studied, histologically
equivalent visceral lesions do occur; current opinion favors classification of large solitary hepatic
congenital hemangiomas as visceral examples of R.I.C.H
[9,
10,
11].
Treatment options for congenital nonprogressive hemangiomas include surgery or embolization, although
lesions that demonstrate signs of impending rapid involution (R.I.C.H.) are usually best left to
spontaneously regress. Large lesions, especially the hepatic ones, may cause significant high output
heart failure, necessitating intense supportive care and occasionally early resection prior to
spontaneous regression. Large, non-resectable noninvoluting variants (N.I.C.H.) can be difficult to
manage clinically. Corticosteroids and propranolol, both mainstays of infantile hemangioma therapy, are
not effective.
Summary:
Congenital nonprogressive hemangioma is a clinically distinctive category of benign vascular lesions
that differ from the much more common, postnatally developing infantile hemangioma in that they present
fully formed at birth, then follow either a static or a rapidly involuting course that is much more rapid
than that characteristic of infantile hemangioma
[1,
2,
3,
4,
5,
6].
Also unlike infantile hemangioma, but
like vascular malformations, they occur equally in males and females. Large examples are often detected
by ultrasound in utero. Although most lesions involve skin and subcutis,
visceral examples are well-described. Clinically, lesions involving skin often display a peripheral rim
of pallor, and those destined to rapidly regress first develop a central depression or ulcer. Although
traditionally considered clinical variants of common infantile hemangiomas that completed their growth
phase in utero, recent studies have shown them to be both historically and
immunophenotypically distinct from classical infantile hemangioma, and thus unlikely to be related to the
latter in pathogenesis
[1,
5,
6].
Histological features of the rapidly involuting and non-involuting
clinical subtypes of congenital nonprogressive hemangioma, referred to by clinicians as "R.I.C.H." and
"N.I.C.H", respectively, show considerable, perhaps indivisible, overlap, and their etiological
relationship is not yet clear. Neither of these subtypes demonstrate endothelial positivity for GLUT1 or
any of the other distinctive microvascular markers of infantile hemangioma
[1,
8].
Characteristic histological features of congenital nonprogressive hemangioma, whether rapidly
involuting or noninvoluting in clinical type, include capillary lobules separated by often abnormally
dense fibrous tissue, little or no evident endothelial mitotic activity, thin-walled centri-lobular
draining vessels that are stellate in contour, and frequent foci of hemosiderin deposition and/or
extramedullary hematopoiesis, thrombosis, and calcification. Sclerosis often extends into the lobules
either peripherally or globally. The interlobular vascular network of feeding and draining in some
examples is more prominent than the more cellular capillary lobules themselves, creating resemblance to
vascular malformations.
Diagnosis of congenital nonprogressive hemangioma can often be made with confidence based on clinical
presentation alone, although the clinical differential diagnosis frequently includes infantile
hemangioma, arteriovenous malformation, or reactive capillary proliferation. Histological confirmation
is thus often needed, with GLUT1 immunohistochemistry allowing conclusive differentiation from infantile
hemangioma. The clinical subtype of the lesion (non-involuting versus rapidly involuting) will declare
itself clinically in the first few months of life and is not easily predicted by early histology.
References:
- North PE, Waner M, James CJ, et al. Congenital nonprogressive hemangioma: a distinct cli.nicopathological entity unlike infantile hemangioma. Arch Dermatol 2001;137:1607-1620.
- Enjolras O, Mulliken JB, Boon LM, et al. Noninvoluting congenital hemangioma: a rare cutaneous vascular anomaly. Plast Reconstr Surg 2001;107:1647-1654.
- Berenguer B, Mulliken JB, Enjolras O, et al. Rapidly involuting congenital hemangioma: clinical and histopathologic features. Pediatr Devel Pathol 2003;6:495-510.
- Boon LM, Enjolras O, Mulliken JB. Congenital hemangioma: evidence of accelerated involution. J Pediatr 1996;128:329-335.
- North PE, Waner M, Buckmiller L, James CA, Mihm MC. Vascular tumors of infancy and childhood: beyond capillary hemangioma. Cardiovasc Pathol 15:303-317, 2006.
- North PE. Vascular tumors and malformations of infancy and childhood. Pathology Case Review 13(6):213-235, 2008.
- North P and Kozakewich H. Vascular Malformations and Tumors in Children. Society for Pediatric Pathology Workshop (handout), pp. 20-22, 2005.
- North PE, Waner M, Mizeracki A, et al. A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol. 2001;137:559-570.
- DeAos I, James CA, North PE. Hepatic "hemangioma": Not a singular entity. Abstracts, 15th International Congress on Vascular Anomalies, Wellington, NZ, February 23, 2004, p.12.
- Paltiel HJ, Burrows PE, Kozakewich HPW, et al. Solitary infantile hemangioma: A distinct clinicopathological entity. Abstracts, 15th International Congress on Vascular Anomalies, Wellington, NZ, February 23, 2004, p.12.
- Mo JQ, Dimashkieh HH, Bove KE. GLUT1 endothelial reactivity distinguishes hepatic infantile hemangioma from congenital hepatic vascular malformation with associated capillary proliferation. Hum Pathol 2004;35:200-209
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