Martin Mihm, Jr. MD; Linda Rozell-Shannon, M.S.
To the naked eye, some birthmarks look as though someone had permanently stained the skin with wine, thus the term “port-wine stain.” It has been documented (Mulliken, 1988) that from the early eighteenth century until World War II, more port wine was consumed in England than any other wine. Because of the wine’s popularity, English novelists and medical writers of that time period used the term “port-wine stain” to describe a crimson colored vascular birthmark. To this day, the term “port-wine stain” is used to describe a specific type of vascular birthmark. The Latin term for this type of birthmark is naevus flammeus. Folklore hints at a superstition that the mother had a craving for port wine and that is why the infant is “stained”.
Aside from folklore, the port-wine stain has also been the subject of great confusion with another type of vascular birthmark that was once called a “capillary hemangioma” and now is more accurately known as a “hemangioma.” Unlike the port-wine stain, the hemangioma is a tumor of infants that fades or involutes over a period of years. Over time and as diagnostic skills have improved, the port-wine stain became known as a “capillary malformation” and has recently been revised to a more accurate classification of “venular/capillary malformation” through the use of histologic and immunophenotypic criteria. Prior to the use of modern immunophenotypic screening and histologic profiling, physicians relied on clinical presentation to diagnose and classify vascular birthmark types. Some biology was also used to segregate the hemangioma from the malformation, with a port-wine stain being a type of malformation. This type of biologic classification (Mulliken and Young 1988) that differentiated a cellular-hyerplasia (hemangiomas) from a cellular hypertrophy (malformations) was the beginning of establishing a more scientific basis for understanding and classifying vascular birthmarks. With this in mind, the objective of this paper is to educate its readers regarding the role of histopathology and immunophenotypic staining in understanding the diagnosis and classification of port-wine stains, as well as the role nerve innervation plays in the progression and treatment of these vascular birthmarks. The understanding of the histology and innervation of these lesions is critical in ascribing the proper laser settings to insure the best “clearance” of the port wine stain. Additionally, this paper summarizes a new mathematical approach that is being used to determine the optimal laser wavelength for treating port wine stains.
Histopathology of port-wine stains as used to diagnose and differentiate these lesions from other common vascular tumors
Port-wine stains are congenital birthmarks characterized histologically by ecstatic vessels of capillary or venular type within the papillary and reticular dermis. In some cases they extend into the superficial subcutaneous tissues. They are non-proliferative lesions that do not involute and are therefore better known as a type of vascular malformation, rather than a hemangioma.
In the past, port-wine stains have been lumped together with very common vascular birthmarks known as salmon patches, stork bites or angel kisses. However, port-wine stains are different from these common vascular birthmarks in a number of important aspects. Salmon patches are common in newborns; occur as pink macules, most commonly on the nape of the neck, eyelids and glabella and often fade or disappear with time. The color of these macular stains may deepen with exercise or emotional upset. These lesions thus may represent focal areas of physiologic vascular dysfunction. On the other hand, port-wine stains are relatively rare macular lesions (occurring in about 0.3% of newborns) and generally appear on the skin of the head and neck within the distribution of the trigeminal nerve. They persist throughout life and may become raised, nodular, or darken with age. Port-wine stains may also be associated with ipsilateral leptomenigeal and choroids venous malformations (Sturge-Weber Syndrome). Port-wine like stains may sometimes directly overlie deeper malformations of large vessel type in other regions of the body, as in association with Klippel-Trenaunay Syndrome and Parkes-Weber Syndrome. These latter lesions are histologically distinct, however, from true port-wine stains. The establishment of this molecular biological basis for stain classifications is probably the most significant effort toward understanding these lesions in decades.
Immunophenotypic criteria of port-wine stains
Biopsies of port-wine stains from infants and young children may not reveal the characteristic vessel ectasia, which does not begin to become prominent until about 10 years of age (Finley 1984). From that time onward, capillary and venule-size vessels in the upper dermis become progressively dilated and filled with erythrocytes. These vessels are lined by flat, inactive-appearing endothelia, without evidence of mitotic activity. While there is some controversy as to whether dermal vessels are actually increased in number in port-wine stains compared with normal skin (Barsky 1980; Smoller and Rosen, 1986) there is no evidence that the number of vessels in these lesions changes with aging. What we do know is that ectasia begins superficially within the lesion and progressively involves deeper vessels, eventually extending into the reticular dermis and focally into the subcutaneous tissue. Immunoreactions for vWf, collagenous basement membrane proteins, and fibronectin have not shown differences between port-wine stains and normal skin (Finley 1982). However, immunoreaction for S-100, a protein found in Schwann cells, reveals a significant decrease in perivascular nerve density in port-wine stains, suggesting that inadequate innervation may be responsible for the progressive vascular dilation that is characteristic of the lesion (Smoller and Rosen 1986).
This progression may also explain the nodular clinical appearance that develops mostly in older patients, and is called “cobbling”.
The Sick Dermatome Theory
In 1986 Smoller and Rosen postulated that an altered or even absent neural modulation of the vascular plexus was responsible for the progressive ectasia that occurs with the advancing age of the port-wine stain. An analysis of biopsy specimens from both normal skin and port-wine stained skin showed no difference in vessel number. There was, however, a marked increase in the perivascular nerve density in port-wine stained biopsy specimens. Rydy (1990) demonstrated a decrease in both sympathetic and sensory innervation of the papillary plexus. Because sensory fibers elaborate several neuropeptides, including substance P, which is known to stimulate smooth muscle growth and calcitonin gene-related peptide (which stimulates endothelial cell growth), they postulated an absence of trophic effects as a possible cause (Nilsson 1985; Haegerstrand 1990). In light of all of these findings, the “sick dermatome” theory was postulated (Waner and Suen 1999) to explain the etiology of port-wine stains. Waner/Suen theorized that a port-wine stain is a manifestation of a “sick dermatome” in which there is an absolute or relative deficiency of vascular autonomic and sensory vascular innervation as the underlying pathology. Lesions with an absolute deficiency will progress more rapidly and early hypertrophy with cobblestone formation is likely, whereas a relative deficient of autonomic innervations will give rise to a slower progression.
Classification and Treatment Parameters
Within the papillary vascular plexus, video microscopy has revealed three patterns of vascular ectasia (Motly 1996); type 1, ectasia of the vertical loops of the papillary plexus; type 2, ectasia of the deeper, horizontal vessels in the papillary plexus; and type 3, mixed pattern with varying degrees of vertical and horizontal vascular ectasia. Recognition of these patterns is important in that they impact on the response to laser treatment. Given that laser light has a limited depth of penetration, type 1 lesions are more apt to respond well to treatment and type 3 lesions are likely to respond poorly (Waner/Suen 1999).
Because there is so much variability in the appearance of port-wine stains, it becomes essential to classify these lesions. Earlier attempts at classification relied on color and used paint color charts. These were found to be unreliable because it was difficult to match flesh tones with the colors used to paint the interior of a building. Therefore, this was not an appropriate way of classifying port-wine stains. Further, the color of a lesion is determined by the degree of oxygenation of the hemoglobin, which is dependent on the degree of perfusion of the vascular bed, which in turn depends on a number of factors such as ambient temperature, the level of circulating catecholamines and local metabolites. We now classify port-wine stains in accordance with their degree of vascular ectasia because this is the true cause of the variation in clinical appearance. This classification recognizes four grades of ectasia, Grades I to IV. Grade I represents the smallest vessels and Grade IV the largest. When using this classification, one should always bear in mind that there is a progression between the grades and that the division between grade are, to a large extent, arbitrary. The main purpose of this new classification is to assign a grade for ease in communication and determination of the appropriate laser treatment settings.
Grade I lesions are the earliest lesions and thus have the smallest vessels (50-80 um in diameter). Using x6 magnification and transillumination, individual vessels can only just be discerned and appear like grains of sand. Clinically, these lesions are light or dark pink macules. Grade II lesions are more advanced (vessel diameter = 80-120 um). Individual vessels are clearly visible to the naked eye, especially in less dense areas. They are thus clearly distinguishable macules. Grade III lesions are more ecstatic (120-150 um). By this stage, the space between the vessels has been replaced by the dilated vessels. Individual vessels may still be visible on the edges of the lesion or in a less dense lesion, but by and large individual vessels are no longer visible. The lesion is usually thick, purple, and palpable. Eventually, dilated vessels will coalesce to form nodules, otherwise known as cobblestones.
Treatment Enhanced By New Mathematical Model
Various mathematical models have been developed to predict optimal laser parameters to achieve high-efficacy laser treatment of port-wine stains.
A recent study was done using a numerical method to use the diffusion approximation to model photothermal effects in a heterogeneous medium to study the laser treatment of PWS. The thermal field within the specific vessels was calculated with spatial resolution of sub micrometer for small vessels and of a few micrometers for large vessels with temporal resolution of microseconds. The model used allowed the study of coagulation patterns within specific blood vessels and was able to explain histopathologic observations reported for laser treatments of PWS. These included partial coagulation in vessels of 200 um and up in diameter and the sparing of small vessels (10 um). It also indicated that partial coagulation might lead to insufficient vessel destruction, which could result in vessel repair over time. This is also significant in that it may explain the very controversial theory that some port wine stains reappear. The prediction of the sparing of small vessels is the premise for the effective laser treatment of PWS in which dilated vessels (50-150 um) are damaged and capillaries remain intact to continue to supply blood to the treated region. The model was combined with histopathology and supports the theory that the diffusion approximation is valid for modeling photothermal interactions in the laser treatment of PWS with FPDL (flashlamp-pumped dye laser) at the 585 and the 595 nm wavelengths.
Current clinical diagnosis combined with histologic and immunophenotypic criteria has become key to the pathological diagnosis and proper classification of vascular birthmarks. The new classification and port-wine stain grading criteria, combined with the more in-depth understanding of the “sick dermatome” theory have assisted us in our study of these hyper vascular birthmarks. The combination of good clinical evaluation supported by histologic and immunophenotypic criteria, and this new scientific understanding, will assist the treating physician in prescribing the use of laser therapy to oblate the appearance of the port-wine stain. Additionally, the recent application of mathematical modeling to understand vessel depth and laser wavelength settings and absorption rates will insure optimal use of the laser to treat the port-wine stain most effectively.
As we continue to learn more and more about such vascular birthmarks as port-wine stains, we realize that they are truly multi-disciplinary and as such, require physicians and scientists from multiple disciplines to work closely together to understand the histopathology and progression of these lesions in order to prescribe the most effective treatment. This is a new beginning for the fields of math, science and medicine to work together to diagnose, classify and prescribe treatment for a very complicated and often problematic birth defect…the port-wine stain.
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Shafirstein, Gal PhD., Baumler, Wolfgang PhD., Lapidoth, Moshe MD, Ferguson, Scott BS, North, Paula E., Phd MD, Waner, Milton MD. A New Mathematical Approach to the Diffusion Approximation Theory for Selective Photothermolysis Modeling and Its Implication in Laser Treatment of Port Wine Stains. Lasers in Surgery and Medicine. 2004 Wiley-Liss, Inc.
July 18, 2004