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RESEARCH LETTER

Second Primary Malignancies After Initial Cutaneous
Angiosarcoma: A SEER Population-Based Study

Vignesh Ramachandran, MD1, Asad Loya, MD2, Kevin Phan, MD3,4

1 Department of Dermatology, New York University, New York, NY
2 Department of Ophthalmology, Baylor College of Medicine, Houston, TX
3 Department of Dermatology, Liverpool Hospital, Sydney, Australia
4 University of New South Wales, Sydney, Australia

Conic and colleagues1 provide an important
epidemiologic study of cutaneous
angiosarcomas (CAS) using the National
Cancer Institute’s Surveillance,
Epidemiology, and End Results (SEER)
database. They describe incidence rates

and survival outcomes based on age,
disease extent, and treatment. However, an
important epidemiologic consideration after
initial CAS is the risk of second primary
malignancies (SPMs). SPMs may have
implications on surveillance post-CAS
diagnosis and prognosis.

ABSTRACT

Introduction: The epidemiology of second primary malignancies is an under-investigated domain
within dermatology. This notion is particularly true for more uncommon cutaneous oncologic diseases.
While general epidemiological characteristics and survival data of patients with cutaneous
angiosarcoma have been reported before, there is no investigation of the incidence and types of
second primary malignancies (SPMs) that these patients face, which has relevance to screening and
surveillance.
Methods: The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER)
database was utilized in this study. Initial cases of CAS were extracted and analyzed using
standardized incidence ratios (SIR) and excess absolute risks (EAR) for SPMs relative to a control
population, which was matched by sex, race (white/unknown, black, other), age group (5-year
interval), and calendar year (5-year interval). EAR was calculated per 10,000 persons. P-value <0.05
was deemed statistically significant.
Results: Compared to a matched cohort from the general population, patients with CAS
demonstrated increased incidence of new malignancies (SIR 1.54; 95% CI, 1.05-2.17; EAR 107.02).
Specifically, there was increased risk of soft tissue malignancies, and non-epithelial skin malignancies
other than melanoma/basal cell/squamous cell.
Discussion: SPMs may be linked to many etiologies, including genetic susceptibility, treatment-
related sequelae, lifestyle/environmental factors, or shared risk factors. Indefinite treatments may
induce SPMs. Recently, immunotherapy/immune-modulating drugs have been used to treat CAS4;
this therapy may increase the risk of SPMs via immunosuppression. Shared etiology (i.e. blood vessel
or soft tissue-derived neoplasms) may also explain SPMs observed. Importantly, CAS is associated
with high recurrence even after complete resection.

INTRODUCTION

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To address this question, we used the
SEER 18 dataset, which pools cancer
incidence and survival data from 34.6% of
the U.S. population.2 Initial cases of CAS
(2000-2016) were extracted using the
International Classification of Diseases for
Oncology 3rd edition (ICD-O-3) histology
code 9120/3 (“Hemangiosarcoma”). Skin
sites were isolated using ICD-O-3
topographical code C44.0-C44.9 (all skin
sites). Standardized incidence ratios (SIR)
and excess absolute risks (EAR) were
computed for SPMs relative to a control
population, which was matched by sex, race
(white/unknown, black, other), age group (5-
year interval), and calendar year (5-year
interval). EAR was calculated per 10,000
persons. P-value <0.05 was deemed
statistically significant.

Overall, 358 CAS cases were extracted.
Of these, 8.9% (32/358) developed SPMs.
Mean follow-up period was 39.4 (+/- 40.8)
months and mean age at diagnosis of first
neoplasm was 74.6 (+/- 13.0) years. At
study end, 31.8% of the cohort remained
alive. Compared to a matched cohort from
the general population, patients with CAS
demonstrated increased incidence of new
malignancies (SIR 1.54; 95% CI, 1.05-2.17;
EAR 107.02) (Table 1).

Specifically, there was increased risk of soft
tissue malignancies, and non-epithelial skin
malignancies other than melanoma/basal
cell/squamous cell. Of the soft tissue SPMs,
75% (3/4) were blood vessel neoplasms (2
angiosarcomas, 1 malignant epithelioid
hemangioendothelioma) and 25% (1/4) was
sarcoma (sarcoma, NOS). Of the non-

epithelial skin malignancies other than
melanoma/basal cell/squamous cell SPMs,
100% (8/8) were angiosarcomas.

The mechanisms underlying the association
of CAS with SPMs remain unclear. It is
known that underlying risk factors for CAS
include radiation therapy as well as
exposure to arsenic, polyvinyl chloride and
viral hepatitis.3 However, these are also
common risk factors for various other
cancers. Of note, in our study the risk was
highest for non-epithelial skin cancers as
highest risk of SPMs in patients with initial
CAS. We postulate this risk may also be
partly attributed to treatment-related
sequelae, such as chemotherapy and
radiation. For CAS, there is no clear
treatment regimen; surgical resection
appears to be the mainstay, and some
patients receive adjuvant radiation therapy
or chemotherapy.4 These indefinite
treatments may induce SPMs.

Recently, immunotherapy/immune-
modulating drugs have been used to treat
CAS;4 this therapy may increase the risk of
SPMs via immunosuppression. Furthermore,
the literature reveals that particular
mutations and pathophysiologic pathways
may be implicated in angiosarcomas (e.g.
KDR, TP53, and PIK3CA. PIK3CA).5 It is
plausible that these pathways may be
implicated in SPMs in patients with initial
CAS as they serve as a genetic
predisposition that may become unmasked,
especially when the SPM is of vascular
etiology. Future studies would benefit from
collaboration with translational researchers
to elucidate the genetic sequencing and
molecular characterization of malignant
tissue in these patients via bio-banking. This
may lead to more targeted therapy options

METHODS

RESULTS

DISCUSSION

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for the management of this challenging
malignancy as well. The Angiosarcoma
Project, for instance, is an example of such
an effort.5 Our analysis of CAS within the
SEER database is constrained by several
limitations. We were unable to study the
tumor site, tumor characteristics, type of
treatment received, and socioeconomic
factors. Additionally, lifestyle/modifiable risk
factors cannot be assessed through SEER,
which also limited our analysis. Data entry
errors and physician-dependent factors (e.g.
surgical technique) are also unable to be
accounted for.

In conclusion, patients who have been
diagnosed with CAS should be continuously
monitored post initial diagnosis and
treatment not only for recurrence but also for
SPMs.

Conflict of Interest Disclosures: None

Funding: None

Corresponding Author:
Vignesh Ramachandran, MD
Department of Dermatology, New York University
Ambulatory Care Center, 11th Floor, Room 11-84
240 East 38th Street, New York, NY 10016
Phone: 212-263-5313
Fax: 212-263-8752
Email: Vignesh.Ramachandran@nyulangone.org

References:

1. Conic RRZ, Damiani G, Frigerio A, Tsai S,
Bragazzi NL, Chu TW, Mesinkovska NA,
Koyfman SA, Joshi NP, Budd GT, Vidimos A,
Gastman BR. Incidence and Outcomes of
Cutaneous Angiosarcoma: a SEER
Population Based Study. J Am Acad
Dermatol. 2019 Jul 13. pii: S0190-
9622(19)32382-5.

2. Surveillance, Epidemiology, and End Results
(SEER) Program (www.seer.cancer.gov)
SEER*Stat Database: Incidence - SEER 18
Regs Research Data + Hurricane Katrina
Impacted Louisiana Cases, Nov 2018 Sub
(2000-2016) <Katrina/Rita Population
Adjustment> - Linked To County Attributes -
Total U.S., 1969-2017 Counties, National
Cancer Institute, DCCPS, Surveillance
Research Program, released April 2019,
based on the November 2018 submission.

3. Huang NC, Wann SR, Chang HT, Lin SL,
Wang JS, Guo HR. Arsenic, vinyl chloride,
viral hepatitis, and hepatic angiosarcoma: a
hospital-based study and review of literature
in Taiwan. BMC Gastroenterol. 2011;11:142.

4. Ishida Y, Otsuka A, Kabashima K.
Cutaneous angiosarcoma: update on biology
and latest treatment. Curr Opin Oncol.
2018;30(2):107–112.

5. Painter CA, Jain E, Tomson BN, Dunphy M,
Stoddard RE, Thomas BS, Damon AL, Shah
S, Kim D, Gómez Tejeda Zañudo J, Hornick
JL, Chen YL, Merriam P, Raut CP, Demetri
GD, Van Tine BA, Lander ES, Golub TR,
Wagle N. The Angiosarcoma Project:
enabling genomic and clinical discoveries in
a rare cancer through patient-partnered
research. Nat Med. 2020 Feb;26(2):181-187.

CONCLUSION

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Table 1. Second primary malignancy occurrence following cutaneous angiosarcoma diagnosis by specific sites.

Observed Expected O/E CI

Lower

Upper

Excess Risk

All Sites 32 20.85 1.54* 1.05 2.17 107.02

Oral Cavity and Pharynx 1 0.49 2.04 0.05 11.34 4.88

Digestive System 3 4.36 0.69 0.14 2.01 -13.02

Respiratory System 3 3.42 0.88 0.18 2.56 -4.03

Bones and Joints 0 0.02 0 0 191.08 -0.19

Soft Tissue including Heart 4 0.13 30.58* 8.33 78.3 37.12

Skin excluding Basal and

Squamous

9 1.24 7.26* 3.32 13.78 74.45

Melanoma of the Skin 1 1.1 0.91 0.02 5.09 -0.91

Other Non-Epithelial Skin 8 0.14 55.28* 23.87 108.93 75.37

Breast 2 1.4 1.43 0.17 5.16 5.75

Female Genital System 0 0.53 0 0 6.95 -5.1

Male Genital System 4 3.71 1.08 0.29 2.76 2.77

Urinary System 2 2.39 0.84 0.1 3.02 -3.74

Eye and Orbit 0 0.03 0 0 109.1 -0.32

Brain and Other Nervous

System

0 0.2 0 0 18.04 -1.96

Endocrine System 0 0.19 0 0 18.95 -1.87

All Lymphatic and 2 2.05 0.98 0.12 3.53 -0.45

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Hematopoietic Diseases

Lymphoma 1 1.02 0.98 0.02 5.49 -0.15

Myeloma 1 0.33 3.03 0.08 16.87 6.43

Leukemia 0 0.7 0 0 5.26 -6.73

Mesothelioma 0 0.09 0 0 43.33 -0.82

Kaposi Sarcoma 0 0.01 0 0 246.1 -0.14

Miscellaneous 2 0.57 3.48 0.42 12.57 13.67

Excess risk is per 10,000,
Confidence intervals are 95%
* P < 0.05