Successful management of cutaneous lymphangitis carcinomatosa arising from cervical cancer with paclitaxel-cisplatin and bevacizumab combination therapy: A case report and review of the literature

Abstract

Background:
Globally, cervical cancer is the fourth most common cancer in women. Here, we report a case of cutaneous lymphangitis carcinomatosa arising from cervical cancer, an extremely rare and treatment-resistant condition.

Case presentation:
A 64-year-old Japanese woman presented with genital bleeding. She was diagnosed as having stage IB1 squamous cell cervical cancer and subsequently treated with radiotherapy. Approximately 2 years after the curative radiotherapy, she developed itching, skin rash, and small nodules on her left femoral and pubic area. Slight 18F-fluorodeoxyglucose uptake was detected at her left femoral skin on positron emission tomography with computed tomography. A histopathological examination was performed on a biopsy sample from an erythematous macule on her left femoral skin and vulva. Consequently, she was diagnosed as having cutaneous lymphangitis carcinomatosa arising from cervical cancer. Paclitaxel (135 mg/m2), cisplatin (50 mg/m2), and bevacizumab (15 mg/kg) combination therapy was administered every 21 days. Both itching and rash improved after three treatment cycles. After the completion of six cycles, skin erythema in the femoral and vulval area disappeared completely. Our patient experienced a 25-month symptom-free interval after the last chemotherapy session.

Conclusion:
Our findings suggest that combination chemotherapy plus bevacizumab is an effective therapeutic option in patients with cutaneous lymphangitis carcinomatosa arising from cervical cancer.

Full text

C A S E R E P O R T Open Access
Successful management of cutaneous
lymphangitis carcinomatosa arising from
cervical cancer with paclitaxel-cisplatin and
bevacizumab combination therapy: a case
report and review of the literature
Fumihiro Nakamura, Manabu Seino
*
, Yuriko Suzuki, Hirotsugu Sakaki, Takeshi Sudo, Tsuyoshi Ohta,
Seiji Tsutsumi and Satoru Nagase
Abstract
Background: Globally, cervical cancer is the fourth most common cancer in women. Here, we report a case of
cutaneous lymphangitis carcinomatosa arising from cervical cancer, an extremely rare and treatment-resistant
condition.
Case presentation: A 64-year-old Japanese woman presented with genital bleeding. She was diagnosed as
having stage IB1 squamous cell cervical cancer and subsequently treated with radiotherapy. Approximately 2
years after the curative radiotherapy, she developed itching, skin rash, and small nodules on her left femoral
and pubic area. Slight
18
F-fluorodeoxyglucose uptake was detected at her left femoral skin on positron
emission tomography with computed tomography. A histopathological examination was performed on a
biopsy sample from an erythematous macule on her left femoral skin and vulva. Consequently, she was
diagnosed as having cutaneous lymphangitis carcinomatosa arising from cervical cancer. Paclitaxel (135 mg/
m
2
), cisplatin (50 mg/m
2
), and bevacizumab (15 mg/kg) combination therapy was administered every 21 days.
Both itching and rash improved after three treatment cycles. After the completion of six cycles, skin erythema
in the femoral and vulval area disappeared completely. Our patient experienced a 25-month symptom-free
interval after the last chemotherapy session.
Conclusion: Our findings suggest that combination chemotherapy plus bevacizumab is an effective
therapeutic option in patients with cutaneous lymphangitis carcinomatosa arising from cervical cancer.
Keywords: Cervical cancer, Cutaneous lymphangitis carcinomatosa, Skin metastasis, Bevacizumab
Introduction
Cervical cancer is the fourth most common cancer in
women worldwide [1], resulting in approximately 275,
000 deaths per year [2]. The incidence and mortality
rates of cervical cancer in Japan were 16.1 and 4.4 per
100,000 people, respectively. The recurrence rate of cer-
vical cancer was 8–26%, and overall survival after recur-
rence ranged from 7 to 12 months [2].
The common sites of recurrence are local, lung, liver,
bone, and lymph node metastasis [3]. In contrast, cuta-
neous metastasis, especially cutaneous lymphangitis car-
cinomatosa arising from cervical cancer, is extremely
rare. It is caused by occlusion of the lymphatic channels
of the dermis by cancer cells [4]. Skin metastasis, includ-
ing cutaneous metastasis due to lymphangitis carcino-
matosa, is associated with a poor prognosis. The average
© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
* Correspondence: m-seino@med.id.yamagata-u.ac.jp
Department of Obstetrics and Gynecology, Yamagata University, School of
Medicine, 2-2-2 Iidanishi, Yamagata, Yamagata 990-9585, Japan
Nakamura et al. Journal of Medical Case Reports (2019) 13:328
https://doi.org/10.1186/s13256-019-2262-x
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

survival period after the appearance of skin metastasis is
as short as 3 to 8.5 months [5–8].
The treatment for recurrent cervical cancer de-
pends on the site of recurrence (local or distant re-
currence). Systemic chemotherapy is chosen for the
treatment of distant recurrence or local recurrence
within the irradiation field. In addition, bevacizumab
(BV) has been approved for targeted therapy in pa-
tients with recurrent or advanced cervical cancer on
the basis of the results of the Gynecologic Oncology
Group (GOG) 240 trial [9]. BV is a recombinant hu-
manized monoclonal antibody that inhibits vascular
endothelial growth factor (VEGF)-A [10]. VEGF-C, a
subfamily within the VEGF family, is expressed in
human cancers. VEGF-C promotes tumor angiogen-
esis and lymphangiogenesis in vivo,anddrivestumor
growth and metastasis [11,12]. BV has potential
antitumor effects against metastatic lesions in the
lymph system.
Here, we report a case of cutaneous lymphangitis
carcinomatosa arising from cervical cancer that was
successfully treated with paclitaxel-cisplatin and BV
(TP + BV) combination therapy. We believe that TP +
BV therapy can be effective against lymphangitis
carcinomatosa arising from cervical cancer.
Case presentation
Our patient was a 64-year-old Japanese woman,
gravida 2, para 2 (spontaneous deliveries), who pre-
sented with genital bleeding. She had asthma but
had not received any medication for it. She had no
previous history of obstetrics and gynecological is-
sues. She had obtained a diploma in cooking and
was a chef. She was from a family of three, and her
economic situation was like that of most Japanese
people. She was a tobacco smoker. Her family med-
ical history was unremarkable. She was diagnosed as
having cervical cancer, International Federation of
Gynecology and Obstetrics (FIGO) clinical stage IB1.
A histopathological examination was performed on a
cervical biopsy sample, resulting in a diagnosis of
squamous cell carcinoma. We explained that both
surgery and radiation therapy are radical treatments;
hence, she received radiation therapy with external
irradiation (48 Gy × 24 times) and remote afterload-
ing system (24 Gy × 4 times). Approximately 2 years
after curative radiation therapy, she complained of
itching, skin rash, and small papules and nodules on
her left femoral and vulval skin (Fig. 1); these were
edema and dermatitis flare-ups. A biopsy of an ery-
thematous macule on her left femoral and vulval
skin was performed. There were a few lymphocytes
around the vessels, and a subsequent histopatho-
logical examination revealed cytokeratin-positive
atypical cells invading the dermis; these were within
the thin-walled vessels and expressed D2-40, a
marker of lymphatic endothelium [13](Fig.2). The
atypical cells were similar to the cells in squamous
cell carcinoma. Positron emission tomography with
computed tomography (PET-CT) revealed slight
uptake of
18
F-fluorodeoxyglucose (
18
F-FDG) in her
left femoral skin with maximum standardized uptake
value (SUV
max
)of1.41(Fig.3). Apart from that, she
had no other lesion with abnormal
18
F-FDG uptake
on PET-CT. She was subsequently diagnosed as hav-
ing cutaneous lymphangitis carcinomatosa arising
from cervical cancer. At the time of diagnosis, her
muscle, circulatory, and respiratory functions were
normal. She had normal blood pressure (129/69
mmHg), heart rate (71 beats per minute), and body
temperature (36.9 °C) and did not have anemia
Fig. 1 A picture of the patient’sskin.aSkin erythema at the left
proximal femoral lesion (arrows). bSmall nodules on the
vulva (arrows)
Nakamura et al. Journal of Medical Case Reports (2019) 13:328 Page 2 of 6
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

(hemoglobin, 13.8 g/dL). Her liver and renal function
were normal (total bilirubin, 0.5 mg/dL; aspartate
aminotransferase, 19 U/L; alanine aminotransferase,
15 U/L; blood urea nitrogen, 13 mg/dL; and creatin-
ine, 0.52 mg/dL), and her electrolyte levels were nor-
mal (sodium, 143 mEq/ml; potassium, 3.9 mEq/ml;
and chloride, 109 mEq/ml). Moreover, her urine ana-
lysis results were normal (proteinuria, urinary glu-
cose, and ketone were not detected). Paclitaxel (135
mg/m
2
, for 24 hours)-cisplatin (50 mg/m
2
,for2
hours) and BV (15 mg/kg, for 1.5 hours) combination
therapy was administered every 21 days. An improve-
ment of both itching and rash was noted after three
cycles. After a total of six cycles were administered,
the femoral and vulval skin erythema completely dis-
appeared (Fig. 4). Our patient experienced a
symptom-free interval of 25 months after the last
TP + BV infusion.
Discussion
To the best of our knowledge, this is the first case
report on TP + BV therapy for skin metastasis from
cervical cancer. Skin metastasis occurs in 0.7–9% of
all patients with cancer [14]. Skin metastases have
the following distribution in women with primary
malignancies: breast (69%), large intestine (9%), mel-
anoma (5%), lung (4%), ovary (4%), sarcoma (2%),
pancreas (2%), and uterine cervix (2%) [14]. The
most common sites of skin metastases in patients
with cervical cancer are the abdominal wall, vulva,
anterior chest wall, and lower extremities [14]. Al-
though skin metastasis mainly presents as nodules or
Fig. 2 Histopathological analysis. aAtypical cells (arrows) similar to the cells in squamous cell carcinoma inside thin-walled vessels (hematoxylin
and eosin staining). bAtypical cells positive for cytokeratin. cThin-walled vessels positive for D2-40 (arrow)
Fig. 3 Uptake of
18
F-fluorodeoxyglucose on positron emission
tomography with computed tomography. Slight uptake of
18
F-
fluorodeoxyglucose by the left femoral skin on positron emission
tomography with computed tomography (arrows)
Nakamura et al. Journal of Medical Case Reports (2019) 13:328 Page 3 of 6
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

masses, these lesions may sometimes appear as
nodules or inflammatory disease [5,14]. The mor-
phologic patterns are nodules, plaques, and inflam-
matory telangiectatic lesions [6]. It is difficult to
distinguish lymphangitis carcinomatosa from derma-
titis. If the lesion is refractory dermatitis, a skin bi-
opsy should be performed.
Currently, no effective treatment has been estab-
lished for cutaneous metastasis due to lymphangitis
carcinomatosa of cervical cancer [15,16]. For recur-
rent cervical cancer, chemotherapy is one of the
options available in Japan [17]. The results of the
GOG 240 trial [9] suggested that TP + BV combin-
ation therapy can improve the prognosis of
recurrent cervical cancer. Furthermore, in another
study, the addition of BV to combination
chemotherapy in patients with recurrent cervical
cancer was associated with an improvement of 3.7
months in median overall survival [18]. There have
been several reports describing the use of various
regimens, including cisplatin-based chemotherapy
and radiotherapy, in patients with recurrent skin
metastasis from cervical cancer; however, most of
these patients experienced progression of disease
after chemotherapy (Table 1)[16,19–25]. In this re-
view, all skin metastases arose from squamous cell
carcinomas. Only two cases advanced to stage III–
IV, and eight cases were in stage I–II. Skin metasta-
sis could arise from stage I–II cervical carcinoma.
Skin metastasis from cervical cancer is possible even
in the early stage. In addition to the present report,
only one other case of complete response to chemo-
therapy has been reported, wherein the patient was
treated with radiotherapy followed by chemotherapy
[25]. Although palliative chemotherapy with pacli-
taxel resulted in complete clinical resolution in one
previous case [23], to the best of our knowledge,
this is the first report of complete response in a
patient with skin metastasis of cervical cancer
treated with combination chemotherapy plus BV.
In a mouse model of suture-induced corneal neo-
vascularization, BV decreased cell proliferation of
corneal lymphatic vessel cells through an anti-
angiogenic effect [26]. Although the evidence sup-
porting the anti-lymphangiogenic effects of BV in
cancer is limited [27], BV has an antitumor effect
in patients with breast cancer with lymph node me-
tastasis [28]. Regarding lymphangitis carcinomatosa
arising from other cancers, long survival has been
reported in two cases treated with chemotherapy in
combination with BV [29,30]: paclitaxel and
carboplatin (TC) in one patient with lung cancer
and 5-fluorouracil, leucovorin, and oxaliplatin
(mFOLFOX6) in a patient with colorectal cancer.
Thus, BV may be more effective in metastases
through lymph vessels, including lymphangitis
carcinomatosa.
Conclusion
In general, lymphangitis carcinomatosa is resistant to
various therapies and has a poor prognosis. In the
current case, TP + BV combination therapy was ex-
tremely effective against lymphangitis carcinomatosa.
Our findings indicate that a chemotherapy regimen
that includes bevacizumab should be considered an
effective therapeutic option in patients with cutane-
ous lymphangitis carcinomatosa arising from cervical
cancer.
Fig. 4 Images acquired after six courses of paclitaxel-cisplatin
and bevacizumab combination therapy. aVulva; b
femoral skin
Nakamura et al. Journal of Medical Case Reports (2019) 13:328 Page 4 of 6
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Acknowledgements
None.
Authors’contributions
All authors analyzed the patient data regarding the disease and conducted
patient care. FN collected patient data, described it in the case report with
literature review. FN, MS, and SN performed literature review and made
significant contributions to the writing of the manuscript. All authors read
and approved the final manuscript.
Funding
No funding available.
Availability of data and materials
All data generated or analyzed during this study are included in this
published article.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Written informed consent was obtained from the patient for the publication
of this case report and any accompanying images. A copy of the written
consent is available for review by the Editor-in-Chief of this journal.
Competing interests
Author, S Nagase, received lecture fees from Chugai Pharmaceutical Co., Ltd.
and AstraZeneca. The other authors declare that they have no competing
interests.
Received: 9 January 2019 Accepted: 22 September 2019
References
1. Rosen VM, Guerra I, McCormack M, Nogueira-Rodrigues A, Sasse A, Munk
VC, Shang A. Systematic review and network meta-analysis of bevacizumab
plus first-line topotecan-paclitaxel or cisplatin-paclitaxel versus non-
bevacizumab-containing therapies in persistent, recurrent, or metastatic
cervical cancer. Int J Gynecol Cancer. 2017;27:1237–46.
2. Elit L, Fyles AW, Devries MC, Oliver TK, Fung-Kee-Fung M, Gynecology
Cancer Disease Site Group. Follow-up for women after treatment for
cervical cancer: a systematic review. Gynecol Oncol. 2009;114:528–35.
https://doi.org/10.1016/ygyno.2009.
3. Cartson V, Delclos L, Fletcher GH. Distant metastases in squamous-cell
carcinoma of the uterine cervix. Radiology. 1967;88:961–6. https://doi.org/10.
1148/88.5.961.
4. Nashan D, Muller ML, Braun-Falco M, Reichenberger S, Szeimies RM,
Bruckner-Tuderman L. Cutaneous metastases of visceral tumours: a review. J
Cancer Res Clin Oncol. 2009;135:1–14.
5. Malfetano JH. Skin metastasis from cervical carcinoma a fatal event. Gynecol
Oncol. 1986;24:177–82.
6. Imachi M, Tsukamoto N, Kinoshita S, Nakano H. Skin metastasis from
carcinoma of the uterine cervix. Gynecol Oncol. 1993;48:349–54.
7. Yang HI, Lee MC, Kuo TT, Hong HS. Cellulitis-like cutaneous metastasis of
uterine cervical carcinoma. J Am Acad Dermatol. 2007;56:S26–8.
8. Pertzborn S, Buekers TE, Sood AK. Hematogenous skin metastases from
cervical cancer at primary presentation. Gynecol Oncol. 2000;76:416–7.
9. Penson RT, Huang HQ, Wenzel LB, Monk BJ, Stockman S, Long HJ 3rd, et al.
Bevacizumab for advanced cervical cancer: patient-reported outcomes of a
randomised, phase 3 trial (NRG Oncology-Gynecologic Oncology Group
protocol 240). Lancet Oncol. 2015;16:301–11. https://doi.org/10.1016/S1470-
2045(15)70004-5.
10. Shin T, Lindley C. Bevacizumab: an angiogenesis inhibitor for the treatment
of solid malignancies. Clin Ther. 2006;28:1779–802. https://doi.org/10.1016/j.
clinthera.2006.11.015.
11. Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L,
Alitalo K, Claffey K, Detmar M. Induction of tumor lymphangiogenesis by
VEGF-C promotes breast cancer metastasis. Nat Med. 2001;7:192–8. https://
doi.org/10.1038/84643.
12. Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, Banerji S,
Huarte J, Montesano R, Jackson DG, et al. Vascular endothelial growth
factor-C-mediated lymphangiogenesis promotes tumor metastasis. EMBO J.
2001;20:672–82. https://doi.org/10.1093/emboj/20.4.672.
13. Fukunaga M. Expression of D2-40 in lymphatic endothelium of normal
tissues and in vascular tumours. Histopathology. 2005;46:396–402.
Table 1 Literature for patients treated with chemotherapy against skin metastasis arising from squamous cervical carcinoma without
other metastasis
Author/Year Stage/Histology/Grade Site of skin metastasis Chemotherapy regime Cycles Best
response
This report/2019 IB1/SCC/Differentiated Thigh and vulva PTX-CDDP-BV 6 CR
Özcan et al.[19]/2017 IB2/SCC/N/A Vulva 1st line; PTX-CBDCA 2 PD
2nd line; GEM-BV N/A PD
IB1/SCC/N/A Umbilicus (incisional scar),
abdominal wall
1st line; PTX-CBDCA 1 N/A
2nd line; GEM-BV + RT 1 N/A
Benoulaid et al.[20]/2016 IIIB/SCC/Moderately
differentiated
Abdominal wall CBDCA 4 PD
Basu and Mukherjee [21]/2013 IIA/SCC/Moderately
differentiated
Thigh, inguinal region CDDP-PTX + palliative RT 6 PR
Behtash et al.[16]/2008 IIB/SCC/N/A Umbilicus PTX-CBDCA 6 PR
Behtash et al.[22]/2002 IIA/SCC/N/A Abdominal wall (drain
site)
Cisplatin-5FU + palliative RT 6 PR
Palaia et al.[23]/2002 IIB/SCC/Poorly differentiated Abdominal wall Palliative chemotherapy (PTX) 10 CR
Kagen et al.[24]/2001 IB/SCC/Poorly differentiated Thigh Ifosfamide N/A PD
Freeman et al.[25]/1982 IVB/SCC/N/A Abdominal wall RT + Bleomycin-MTX
-cyclophosphamide
N/A CR
5FU 5 fluorouracil, BV bevacizumab, CBDCA carboplatin, CDDP cisplatin, CR complete response, GEM gemcitabine, MTX methotrexate, N/A not assessed, PD
progressive disease, PR partial response, PTX paclitaxel, RT radiotherapy, SCC squamous cell carcinoma
Nakamura et al. Journal of Medical Case Reports (2019) 13:328 Page 5 of 6
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

14. Schwartz RA. Cutaneous metastatic disease. J Am Acad Dermatol. 1995;33:
161–84.
15. Agrawal A, Yau A, Magliocco A, Chu P. Cutaneous metastatic disease in
cervical cancer: a case report. J Obstet Gynaecol Can. 2010;32:467–72.
16. Behtash N, Mehrdad N, Shamshirsaz A, Hashemi R, Amouzegar Hashemi F.
Umblical metastasis in cervical cancer. Arch Gynecol Obstet. 2008;278:489–
91.
17. Ebina Y, Yaegashi N, Katabuchi H, Nagase S, Udagawa Y, Hachisuga T, et al.
Japan Society of Gynecologic Oncology guidelines 2011 for the treatment
of uterine cervical cancer. Int J Clin Oncol. 2015;20:240–8. https://doi.org/10.
1007/s10147-015-0806-7.
18. Tewari KS, Sill MW, Long HJ 3rd, Penson RT, Huang H, Ramondetta LM,
Landrum LM, Oaknin A, Reid TJ, Leitao MM, et al. Improved survival with
bevacizumab in advanced cervical cancer. N Engl J Med. 2014;370:734–43.
19. Özcan HÇ, Mustafa A, BozdağZ, Sucu S, Uğur MG, Balat Ö. Early vulvar and
umbilical incisional scar recurrence of cervical squamous cell carcinoma:
earlier than usually expected. Turk J Obstet Gynecol. 2017;14:141–4. https://
doi.org/10.4274/tjod.40225.
20. Benoulaid M, Elkacemi H, Bourhafour I, Khalil J, Elmajjaoui S, Khannoussi B,
et al. Skin metastases of cervical cancer: two case reports and review of the
literature. J Med Case Rep. 2016;10:265. https://doi.org/10.1186/s13256-016-
1042-0.
21. Basu B, Mukherjee S. Cutaneous metastasis in cancer of the uterine cervix: a
case report and review of the literature. J Turk Ger Gynecol Assoc. 2013;14:
174–7. https://doi.org/10.5152/jtgga.2013.62444. eCollection 2013
22. Behtash N, Ghaemmaghami F, Yarandi E, Ardalan FA, Khanafshar N.
Cutaneous metastasis from carcinoma of the cervix at the drain site.
Gynecol Oncol. 2002;85:209–11. https://doi.org/10.1006/gyno.2001.6559.
23. Palaia I, Angioli R, Cutillo G, Manci N, Panici PB. Skin relapse from cervical
cancer. Gynecol Oncol. 2002;87:155–6.
24. Kagen MH, Ruhl KK, Aghajanian C, Myskowski PI. Squamous cell carcinoma
of the cervix metastatic to the skin. J Am Acad Drmatol. 2001;45:133–5.
https://doi.org/10.1067/mid2001.1123489.
25. Freeman CR, Rozenfeld M, Schopflocher P. Cutaneous metastases from
carcinoma of the cervix. Arch Dermatol. 1982;118:40–1.
26. Tan JC, Mann S, Coronea MT. Successful treatment of conjunctival
lymphangiectasia with subconjunctival injection of bevacizumab. Cornea.
2016;35:1375–7. https://doi.org/10.1097/ICO.0000000000000899.
27. Stacker SA, Achen MG. The VEGF signaling pathway in cancer: the road
ahead. Chin J Cancer. 2013;32:297–302. https://doi.org/10.5732/cjc.012.
10319.
28. Min Kim H, Hasegawa J, Hirota M, Matsunami N, Mikata S, Shimizu J, et al. A
case of sigmoid colon cancer with Virchow's lymph node metastasis
successfully treated with chemotherapy. Gan To Kagaku Ryoho. 2012;39:
2249–51.
29. Sogabe S, Yuki S, Takagi T, Miyazaki T, Takano H, Kuwamoto Y, et al. A case
of sigmoid colon cancer with lymphangitis carcinomatosa successfully
treated with chemotherapies including molecular targeting drugs. Gan To
Kagaku Ryoho. 2010;37:535–8.
30. Suzuki E, Tanahashi M, Yukiue H, Yohii N, Shitara M, Fujino T, Niwa H. A
patient with lung adenocarcinoma, lymphangitis carcinomatosa, and
multiple bone metastases who achieved long-term survival after successful
treatment with carboplatin, paclitaxel, and bevacizumab. Gan To Kagaku
Ryoho. 2016;43:617–20.
Publisher’sNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Nakamura et al. Journal of Medical Case Reports (2019) 13:328 Page 6 of 6
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

1.
2.
3.
4.
5.
6.
Terms and Conditions
Springer Nature journal content, brought to you courtesy of Springer Nature Customer Service Center GmbH (“Springer Nature”).
Springer Nature supports a reasonable amount of sharing of research papers by authors, subscribers and authorised users (“Users”), for small-
scale personal, non-commercial use provided that all copyright, trade and service marks and other proprietary notices are maintained. By
accessing, sharing, receiving or otherwise using the Springer Nature journal content you agree to these terms of use (“Terms”). For these
purposes, Springer Nature considers academic use (by researchers and students) to be non-commercial.
These Terms are supplementary and will apply in addition to any applicable website terms and conditions, a relevant site licence or a personal
subscription. These Terms will prevail over any conflict or ambiguity with regards to the relevant terms, a site licence or a personal subscription
(to the extent of the conflict or ambiguity only). For Creative Commons-licensed articles, the terms of the Creative Commons license used will
apply.
We collect and use personal data to provide access to the Springer Nature journal content. We may also use these personal data internally within
ResearchGate and Springer Nature and as agreed share it, in an anonymised way, for purposes of tracking, analysis and reporting. We will not
otherwise disclose your personal data outside the ResearchGate or the Springer Nature group of companies unless we have your permission as
detailed in the Privacy Policy.
While Users may use the Springer Nature journal content for small scale, personal non-commercial use, it is important to note that Users may
not:
use such content for the purpose of providing other users with access on a regular or large scale basis or as a means to circumvent access
control;
use such content where to do so would be considered a criminal or statutory offence in any jurisdiction, or gives rise to civil liability, or is
otherwise unlawful;
falsely or misleadingly imply or suggest endorsement, approval , sponsorship, or association unless explicitly agreed to by Springer Nature in
writing;
use bots or other automated methods to access the content or redirect messages
override any security feature or exclusionary protocol; or
share the content in order to create substitute for Springer Nature products or services or a systematic database of Springer Nature journal
content.
In line with the restriction against commercial use, Springer Nature does not permit the creation of a product or service that creates revenue,
royalties, rent or income from our content or its inclusion as part of a paid for service or for other commercial gain. Springer Nature journal
content cannot be used for inter-library loans and librarians may not upload Springer Nature journal content on a large scale into their, or any
other, institutional repository.
These terms of use are reviewed regularly and may be amended at any time. Springer Nature is not obligated to publish any information or
content on this website and may remove it or features or functionality at our sole discretion, at any time with or without notice. Springer Nature
may revoke this licence to you at any time and remove access to any copies of the Springer Nature journal content which have been saved.
To the fullest extent permitted by law, Springer Nature makes no warranties, representations or guarantees to Users, either express or implied
with respect to the Springer nature journal content and all parties disclaim and waive any implied warranties or warranties imposed by law,
including merchantability or fitness for any particular purpose.
Please note that these rights do not automatically extend to content, data or other material published by Springer Nature that may be licensed
from third parties.
If you would like to use or distribute our Springer Nature journal content to a wider audience or on a regular basis or in any other manner not
expressly permitted by these Terms, please contact Springer Nature at
onlineservice@springernature.com