Cancer Risk in Klippel–Trenaunay Syndrome

Abstract

Background:

Klippel–Trenaunay syndrome (KTS) is an overgrowth syndrome defined by capillary/venous/lymphatic malformations (CVLM) with soft tissue and/or bone hypertrophy. Whether KTS predisposes to cancer is not clear.

Methods and Results:

We surveyed members of the K-T Support Group (KTSG) and reviewed PubMed for “Klippel Trenaunay Syndrome” or “CVLM” and “cancer.” Individuals with cancer were reviewed for confirmation of KTS, tumor type, location, and age at presentation. Of 223 KTSG respondents, 24 (10.8%) reported 26 malignancies or benign brain tumors (diagnosed from 6 months to 68 years of age, median 41 years), including 3 who were younger than 18 years (2 with Wilms tumor). Nine of twenty-six cancers were basal cell carcinomas (4% of respondents). From 475 articles, we identified 11 cancers or brain tumors in 10 individuals with KTS. Four of these were in children (Wilms tumor n = 2; rhabdomyosarcoma n = 1; serous borderline tumor n = 1). Tumors in adults included basal cell carcinoma (n = 1), squamous cell carcinoma of skin (n = 2), and angiosarcoma, Hodgkin disease, glioblastoma, malignant hemangiopericytoma in one patient each. Ulceration or lymphedema associated with VLM or capillary malformations were associated with some basal cell or squamous cell carcinomas and angiosarcomas.

Conclusions:

The risk of embryonal cancer other than Wilms tumor in children with KTS does not appear to be higher than in the general population. Wilms tumor incidence is under 5%, and routine surveillance is not indicated. In adults, particular attention should be paid to skin in the area of malformations. These conclusions may not apply to all overgrowth syndromes with vascular malformations.

Introduction

Several overgrowth syndromes are known to predispose affected individuals to embryonal cancers. Beckwith–Wiedemann syndrome (BWS) is the prototype, and screening of children younger than 8 years with BWS for neuroblastoma, other adrenal tumors, hepatoblastoma, and Wilms tumor often is recommended.¹ Other overgrowth syndromes such as the PTEN hamartoma tumor syndrome predispose to cancer beyond childhood.² Whether all overgrowth syndromes are cancer predisposition syndromes is less clear. This is an important issue, both because it is tied to surveillance guidelines and the potential implications for the pathogenesis of tumor development.

Klippel–Trenaunay syndrome (KTS) is an overgrowth syndrome defined by cutaneous capillary malformations (CMs), venous malformations (VMs), and/or lymphatic malformations (LMs), and limb overgrowth,³ and recently relabeled as capillary/venous/lymphatic malformation (CVLM) syndrome (ISSVA Classification of Vascular Anomalies ©2014 International Society for the Study of Vascular Anomalies Available at “issva.org/classification”). The prevalence of KTS is not known but has been estimated to be fewer than 200,000 people in the United States (National Organization for Rare Disorders [https://rarediseases.org/rare-diseases/klippel-trenaunay-syndrome]).

Although rare, KTS is the most common syndrome associated with vascular malformations. KTS occurs sporadically and while abnormal constitutional cytogenetics has been reported, none has been found consistently. KTS remains a clinical diagnosis. However, some patients who have undergone genetic testing have been found to have PIK3CA mutations in involved tissue, and experts consider KTS to be part of the PIK3CA-related overgrowth spectrum (PROS).⁴ A paradominant inheritance of a single gene defect has been proposed, through which heterozygous individuals would be phenotypically normal, and the trait would only be expressed when a “second hit” somatic mutation occurs in the normal allele early in embryogenesis in a mosaic manner.⁵

Nonetheless, there is no unifying single gene etiology for KTS. Thus, the risk of cancer, which in BWS and PTEN hamartoma tumor syndrome has been linked to specific mutations in tumor suppressor genes, may not apply to KTS. To address this issue as well as to determine if there are clinically identifiable risk factors for cancer, we surveyed members of the K-T Support Group (KTSG). In addition, we reviewed the literature for cancers and nonhemangioma benign tumors in individuals with KTS.

Materials and Methods

KTSG is an international self-help organization established in 1986 to support individuals with KTS and their families (http://k-t.org; M.F., Director). Its database is maintained by one of us (M.F.) and includes 2043 members who are self-reported to have KTS.

Survey and data collection

A survey was designed to obtain KT-specific information from KTSG members to validate diagnoses (location and extent of hemihypertrophy, CMs, VMs, or LMs); respondent information (patient or parent/significant other; patient age at time of survey), information about cancers or benign tumors (specific diagnosis, age at diagnosis, institution where diagnosis had been made, location, extent of disease, treatment), and patient country of origin. We also asked whether subjects were followed by a multidisciplinary vascular anomalies clinic or other specialists. After approval by the University of North Carolina Institutional Review Board, Survey Monkey was used to administer the survey. The need for individual consent was waived. Participant responses were deidentified before data analysis.

Literature review with search strategy and selection criteria

PubMed was reviewed from 1963 through May 1, 2018, for all listings with “Klippel Trenaunay Syndrome” or “CVLM.” Article titles and abstracts were screened for mention of “malignancy,” “cancer,” specific cancers, or benign tumors other than hemangiomas. Secondary searches were performed for “Klippel Trenaunay Syndrome Cancer” and “capillary venous lymphatic malformation CVLM Cancer.”

Relevant articles were reviewed for confirmation of KT diagnosis and excluded if a complete article in English was not available or if we could not otherwise determine that KTS criteria according to ISSVA were met. Cases of KTWS (Klippel–Trenaunay–Weber syndrome), an entity now referred to as Parkes-Weber syndrome and distinct from KTS or CVLM by the presence of arteriovenous malformations instead of venous or LMs, were excluded. Cases considered to be KTS were reviewed for individual patient characteristics (presence and location of hemihypertrophy and of cutaneous and internal vascular malformations; estimated size and extent of malformations), cancer type, location, and age at cancer diagnosis.

Results

Surveys

Of 2043 surveys sent to all members of the KTSG, 223 responses were received (response rate of 10.9%) from subjects (n = 156), parents (n = 63), spouses (n = 1), or doctors (n = 1 with permission from the family); 2 surveys did not specify who was responding. One hundred fifty-nine responses came from within the United States and 64 from international members (Argentina, Australia, Colombia, Canada, Germany, the Netherlands, South Africa, and the United Kingdom). The female:male ratio was 1.7:1.

Reported features of KTS included hemihypertrophy or asymmetry and VM or VLM in all respondents; four responses did not answer the question about CM. The median age of patients at time of response was 40 years (range 1–81 years old). In 19 respondents, the description of anomalies included the presence of “fatty deposits,” “lipomas,” “neuromas,” or an unusual distribution of CMs, suggesting the possibility of a diagnosis other than KTS (e.g., congenital lipomatous overgrowth, vascular malformations, epidermal nevi and scoliosis/skeletal/spinal anomalies [CLOVES] or complex phacomatoses); none of these patients reported cancers.

Thirty-one percent of respondents indicated that they had been followed by a multidisciplinary clinic; 18% of patients were seen by dermatologists, vascular interventional radiologists, hematologists, phlebologists, angiologists, or pain specialists outside the context of a multidisciplinary clinic; 22% each indicated that they primarily were followed by vascular surgeons or by primary health care providers. Twenty-two percent of patients either had no medical care related to their vascular anomalies or considered compression garment specialists to be their primary health care providers relating to the vascular malformations. Four percent of surveys did not answer this question.

Cancer in KTSG members

As shown in Table 1, 24/223 individuals with self-reported KTS (10.8%) were said to have developed 26 cancers or benign brain tumors. Only 3 occurred in children younger than 18 years, and only 2 of these were a Wilms tumor (2/223 patients or 0.89%). One of these patients was reported to have a CM covering 90% of his body, and to have had “calcifications” in one eye, raising the likelihood that this was not truly KTS. Only 14 respondents were <8 years old. Since Wilms tumor is not likely to occur after this age, it is unlikely that the remaining respondents are at ongoing risk of developing Wilms tumor.

Table 1.

Characteristics of Cancers in K-T Support Group Members

Diagnosis	Age (years) at cancer diagnosis/gender	Location	Comments
Wilms tumor	0.5/M	Left kidney
Wilms tumor	2/M	Kidney	CM included face; possible composite vascular anomalies syndrome
Ganglioglioma grade 2	14/F	Brain
Prolactinoma	19/M
Pituitary adenoma	62/F		CM of head, neck, face
Basal cell carcinoma	20/M	Nose	In CM
	28/F	Chest wall
	36/M	Face
	40/F	Nose
	50/F	Nose
	51/F	Back
	56/F	Nose
	45/M	N/A
Angiosarcoma	27/F	Left thigh	In area of CM, VLM
Squamous cell carcinoma	32/F	Oral cavity
Squamous cell carcinoma	48/M	Foot
Mucinous adenocarcinoma	53/F	N/A
stage 4
Leiomyosarcoma	64/M	Arm
Hodgkin lymphoma	19/F	N/A	Basal cell carcinoma, age 30–40 in CM
Hodgkin lymphoma	19/F	N/A	Secondary cancers “breast lung”
Non-Hodgkin lymphoma	45/M	Stage 3
Testicular	41/M	Left testis
Bladder cancer	68/M
Uterine cancer	29/F
Vaginal cancer	50/F

CM, capillary malformation; F, female; M, male; N/A, information not available; VLM, venolymphatic malformation.

The majority of cancers (8/24) were basal cell carcinomas of the skin. One of the basal cell carcinomas developed within a CM. A ninth basal cell carcinoma (listed separately) developed within a CM as a second malignancy in a patient with Hodgkin disease, who subsequently developed two other incompletely described malignancies over time. One squamous cell carcinoma developed in a patient's foot with a CM and underlying VM, and one patient had a cutaneous leiomyosarcoma. An angiosarcoma developed in a 27-year old in an area involved by a vascular malformation previously treated by sclerotherapy. None of the other cancers was known to be located within the KT-defining malformations, although the patient with bladder cancer did have pelvic malformations.

Although we attempted to capture the extent of vascular malformations and hemihypertrophy in our survey, most of our patients appear to have been severely affected. We did not see a clear relationship between the extent of KTS abnormalities and the development of cancer.

Literature review

A total of 1495 articles came up in PubMed by querying “Klippel Trenaunay Syndrome,” of which 1415 actually dealt with KTS. A secondary search for “Klippel Trenaunay Syndrome Cancer” identified 475 relevant articles, all of which had been captured in the original search. A search for “Capillary Venous Lymphatic Malformation CVLM Cancer” identified no additional cases.

As shown in Table 2, we identified 11 cancers and benign brain tumors in 10 patients reported in 11 of the 475 relevant articles, and in which patient descriptions were strongly suggestive of KTS. Only four patients were <18 years of age: We accepted a diagnosis of possible KTS in a 1-year-old girl with bilateral Wilms tumor⁶ and in a 4-year-old girl with left-sided Wilms tumor.⁷ Both had been excluded by a prior comprehensive review of Wilms tumor with hemihypertrophy⁸ because the CMs and the hemihypertrophy were contralateral and the description of the CMs raised diagnostic possibilities other than KTS. A 3-year-old boy who had an unusual ocular rhabdomyosarcoma had only equivocal evidence of a vascular malformation in the area of the cancer but was considered to have KTS by a dedicated vascular anomalies clinic.⁹ A 3-year-old girl had a serous borderline tumor of her fallopian tube.¹⁰

Table 2.

Characteristics of Cancers in Klippel–Trenaunay Syndrome Patients Based on a Review of the Literature

Diagnosis^Ref.	Age (years) at cancer diagnosis/gender	Location	KT characteristics			Comments
Diagnosis^Ref.	Age (years) at cancer diagnosis/gender	Location	HH	CM	VLM	Comments
Wilms^6–8	1/M	Kidney (bilateral)	LLE	+	+	Possible proteus
	1/M	Kidney (bilateral)	L head/neck	+	+	Possible proteus
	4/M	Kidney (L)				CM contralateral to HH
Rhabdomyosarcoma⁹	3/M	Orbit (R)	LUE	+	?	Cancer mimicked vascular malformation
Serous borderline tumor¹⁰	3/F	Fallopian tube (L)?	RLE	+	+	CM of face, neck, RUE
Basal cell carcinoma+	38/F	RLE	RLE
Squamous cell			RLE/
carcinoma¹¹				+	+
Squamous cell	48/F	RLE	RLE
Carcinoma¹²			RUE	+	+
Low-grade angiosarcoma¹³	72/M	Scrotum	RLE	?	+	Bilateral lymphedema
Hodgkin disease¹⁴	31/M	Mediastinum stage III or IV B	RLE	+	−
Glioblastoma multiforme¹⁵	61/M	Brain	LUE	+	+	CM on abdomen
			LLE
			L ear
Malignant hemangiopericytoma¹⁶	33/M	Sphenoid	LLE	+	+

?, Not clear from report; E, extremity; HH, hemihypertrophy; L, left; L, lower; R, right; U, upper.

Among older patients, two squamous cell carcinomas and one basal cell carcinoma of the skin were reported in two patients (i.e., one patient had both cancer types).^11,12 All of these skin cancers were located within CMs, one within an area of ulceration and the others within an area involved by a venolymphatic malformation. A low-grade angiosarcoma arose within an LM and an area of lymphedema.¹³ There were single patients with Hodgkin lymphoma,¹⁴ glioblastoma multiforme in a patient said to have KTWS but whose vascular anomalies were more in keeping with VLM,¹⁵ and malignant hemangiopericytoma of the brain.¹⁶

A number of other reports stated that patients had KTS without providing clinical descriptions in English that were detailed enough to allow independent confirmation. Other cases had features of KTS as well as of phacomatoses such as Sturge–Weber syndrome. These included one case of bilateral Wilms tumor (reported twice)^8,17; malignant angiosarcoma in a 1-year old whose “hemangioma” at the primary tumor site had been treated with radiation¹⁸; bilateral optic nerve and chiasmal gliomas in a 16-year-old girl¹⁹; choroidal melanoma in a 17-year-old boy²⁰; basal cell carcinoma arising within a CM²¹; esophageal carcinoma²²; meningioma²³; temporal lobe astrocytoma²⁴; malignant peripheral nerve sheath tumor (MPNST)²⁵; composite MPNST/angiosarcoma²⁶; and epithelioid angiosarcoma.²⁷ A 13-year-old girl was said to have systemic mastocytosis on the basis of an elevated tryptase level and anaphylaxis following general anesthesia.²⁸ Including all of these (excluded from Table 2) added 12 malignancies and/or brain tumors, which could possibly be linked to KTS variants. Combining KTSG survey results and literature involving likely and even less likely cases of KTS identified only 43 individuals with cancers.

From our review of the literature, we also identified five benign tumors in individuals with KTS: nephroblastomatosis, a precursor of Wilms tumor^8,29; leiomyoma of the diaphragm in a 6-year-old boy³⁰; bilateral congenital ocular nevus of Ota from which melanoma may develop and first diagnosed at age 25 years³¹; extradural spinal angiomyolipoma³²; and a retroperitoneal hamartoma.³³ As with the cancerous lesions or tumors of the central nervous system, a number of other reports were less clearly examples of KTS and therefore not listed in the table. These included several adrenal lesions (pseudocysts³⁴; adrenal adenomas³⁵); fibromatosis of the gums³⁶; focal nodular hyperplasia of the liver³⁷; osteoblastoma of the ribs in an 8-year-old girl³⁸; papillary cystadenoma of the epididymis in a 7-year-old boy³⁹; and nevi of Ota and Ito.⁴⁰ Bilaterality was noted in the nephroblastomatosis, nevi of Ota, and adrenal adenomas. KTSG survey results added no benign lesions in children.

Discussion and Conclusions

Cancers have been reported in individuals with KTS, but the relationship with the underlying syndrome has not been clear. Our report is among the first to comprehensively study lifelong tumor occurrence in this entity. Based on evaluation of self-reports from KTSG families and review of the literature, the risk of embryonal cancer other than Wilms tumor in children with KTS does not appear to be higher than in the general population. Wilms tumor incidence is almost certainly under 5%. These results are supported by those in a recent abstract from France and Canada.⁴¹

Other overgrowth syndromes are known to predispose to embryonal cancers, and an incidence of at least 5% of any single cancer type has been thought to justify surveillance.¹ Cancer risk in BWS and PTEN hamartoma tumor syndrome has been among the most critically examined. Both of these syndromes are associated with genetic mutations in tumor suppressor genes (imprinted 11p15 and PTEN at 10q23.3, respectively). In contrast, the pathogenesis of KTS is less clear at the genetic level. No individuals with KTS have been reported to have constitutional mutations in tumor suppressor genes or oncogenes, which might convey an increased risk of developing one or more cancer types.

On the contrary, KTS has been considered to be part of the group of syndromes, PROS, which may have somatic or mosaic occurrence of mutations. Other PROS syndromes, including the above-noted PTEN hamartoma tumor syndrome, are known to be tumor predisposition syndromes. A recent report identified four cases of Wilms tumor in children with CLOVES syndrome confirmed by somatic PIK3CA mutations.⁴² Moreover, isolated hemihypertrophy, without other features of known syndromes, also has been considered to be a reason for cancer surveillance during childhood.¹ Thus, it might have been anticipated that KTS would convey a risk of cancer on the basis of hemihypertrophy alone.

Our results are reassuring. The KTSG is the largest patient support organization for this rare disorder and includes 2043 affected individuals worldwide, of whom 1200 live in the United States. Among the 223 members of the KTSG, we identified only 24 patients with cancers and/or brain tumors. A comprehensive literature review identified another 10 reported in the literature with convincing evidence of KTS based on current diagnostic criteria. An additional 12 individuals with malignancies or brain tumors who had overgrowth syndromes, which may have been KTS variants, were found.

Thus, we identified at the most 46 patients with cancers credibly associated with KTS. Combining data from the KTSG survey and literature review, only six cancers were noted in children or adolescents younger than 18 years with likely KTS; a seventh child from the KTSG probably had a variant syndrome. Three patients with Wilms tumor and one with nephroblastomatosis (a Wilms tumor precursor) were identified among all reports, a number low enough to support a prior recommendation that screening for this cancer is unnecessary.⁴³ The above-noted preliminary report from France and Canada identified one more Wilms tumor patient in a child. No respondents to our survey were from France, although one individual with Hodgkin disease from the KTSG was a Canadian. Thus, we have reported unique patients.

We saw no obvious gender bias or laterality, and malignancies did not always occur on the same side as the hemi-hypertrophy or CM. All patients appeared to have had large areas involved by hemihypertrophy and CMs. However, we did not review the many cases of KTS reported in the literature without cancers, so that we cannot comment on whether the extent of overgrowth or vascular abnormalities is a risk factor. Most of our survey respondents and case reports appeared to have been severely affected.

It is notable that a number of skin cancers occurred within a CM. Because nonmelanomatous skin cancers are common in the general population, we cannot determine whether KTS is a risk factor per se. Nonetheless, their specific localization to areas involved by vascular malformations deserves attention. One elderly man developed a low-grade angiosarcoma in an area of lymphedema, although whether this was within an LM was not clear. Angiosarcoma arising within an area of chronic lymphedema is well-recognized following mastectomy or radiation⁴⁴ and may be a risk factor in the context of a vascular malformation.⁴⁵ Among all patients with either malignant or benign tumors, bilaterality was present in six.

There are a number of limitations to our review. The response rate from the KTSG was very low at <11%. However, it might be argued that this would lead to overestimation of cancer prevalence since patients with cancer might be assumed to have been more likely to respond to a survey asking about cancer occurrence. It is possible that some of the reports in the literature of patients with cancer included members of the KTSG, which also might have led to our overestimating cancer numbers, although results from our survey were similar to those of the literature review. Many publications were descriptive and did not provide numbers of individual cases of KTS, so that a denominator from which to estimate cancer prevalence is not available.

As with previous reports, confirmation of KTS was compromised by changing diagnostic criteria and variable adherence to these criteria, as well as by incomplete descriptions of diagnostic features. Even when photographs were provided, these often had poor resolution. With increased recognition of syndromes with similar phenotypes such as CLOVES syndrome and Parkes-Weber, it is probable that a number of the cases listed in the tables could reasonably be reclassified. Thus, we may have overestimated associations between cancer, other tumors, and KTS. However, as part of our survey, we took care to validate diagnoses of KTS by having respondents provide specific descriptors of their disorder. It is interesting in this regard that only 31% of patients had been evaluated and followed in dedicated vascular anomalies clinics.

We did not systematically include “overlap” syndromes, which express features both of KTS and of other phacomatoses. This might have led to an underestimation of risk, and one of our KTSG patients possibly had Sturge–Weber syndrome as well as KTS. However, we do not believe that most experts in vascular anomalies would consider patients with such findings to have KTS. Finally, in the absence of surveillance, it is possible that tumors (particularly benign tumors) would have been missed, with a resulting underestimation of risk.

We conclude that the risk of neoplasms in pediatric and adult patients with KTS is not clearly higher than in the general population, is almost certainly <5% for any single tumor type, and that routine surveillance is not indicated. The use of abdominal ultrasounds, measurements of serum alpha fetoprotein and urinary catecholamine metabolites in children, as has been recommended for screening of individuals with BWS or nonsyndromic hemihypertrophy, would not have detected the majority of neoplasms in this review. Evaluation of individual patients should be directed by history and physical examination, with particular attention to skin in the area of vascular malformations and to areas of lymphedema.

These conclusions may not apply to all phenotypes among PIK3CA-related overgrowth syndromes. Future genetic classification may help clarify risk. Consistent application of diagnostic criteria of vascular anomalies and prospective monitoring of well-characterized individuals included in institutional and family support group databases should better define risk factors for cancers, benign tumors, and other comorbidities. Nonvascular anomalist health care providers who only see occasional patients with vascular anomalies need ongoing education to understand diagnostic criteria and therapeutic options and should consider referring these patients to multidisciplinary clinics for evaluation and recommendations for care.

Footnotes

Acknowledgment

We thank the members of the KTSG who responded to the survey.

Author Disclosure Statement

No competing financial interests exist.

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