Open Access

Radical esophagectomy for a 92-year-old woman with granulocyte colony-stimulating factor-producing esophageal squamous cell carcinoma: a case report

  • Mari Kitani1,
  • Yukinori Yamagata1, 2Email author,
  • Asami Tanabe1,
  • Kouichi Yagi1,
  • Susumu Aikou1,
  • Takashi Kiyokawa1,
  • Masato Nishida1,
  • Hiroharu Yamashita1,
  • Kazuhiko Mori1,
  • Sachiyo Nomura1 and
  • Yasuyuki Seto1
World Journal of Surgical Oncology201614:264

https://doi.org/10.1186/s12957-016-1023-1

Received: 3 August 2016

Accepted: 7 October 2016

Published: 13 October 2016

Abstract

Background

Granulocyte colony-stimulating factor (G-CSF)-producing esophageal squamous cell carcinoma (ESCC) has been considered to have a poor prognosis. We successfully treated a case of G-CSF-producing ESCC in a 92-year-old woman.

Case presentation

A 92-year-old woman was admitted to our hospital with the complaints of choking while swallowing and dysphagia. Esophagogastroduodenoscopy and contrast-enhanced computed tomography revealed a type 2 esophageal cancer located 26–35 cm from the dental arch, with no distant metastasis. The patient was diagnosed with G-CSF-producing ESCC based on remarkable leukocytosis and high G-CSF levels. The patient underwent radical subtotal esophagectomy. Subsequently, the level of neutrophils (from 23,500/μL to 5000/μL) and the level of G-CSF (from 131 to <19.5 pg/mL) decreased significantly. Immunohistochemistry analysis of the resected tissue specimen showed positive staining for G-CSF in the cytoplasm of the tumor cells. Although the patient developed aspiration pneumonitis, after antibiotic treatment, she promptly recovered and was discharged.

Conclusions

Herein, we describe a case of successfully treated G-CSF-producing ESCC in a 92-year-old woman. Precise detection and safely performed immediate radical operation are considered essential to achieve a good clinical course.

Keywords

Granulocyte colony-stimulating factorEsophageal squamous cell carcinomaGranulocyte colony-stimulating factor-producing esophageal squamous cell carcinoma

Background

In addition to the mass tumor effects, granulocyte colony-stimulating factor (G-CSF)-producing tumors display additional signs and symptoms of inflammation caused by G-CSF-producing malignant cells [1]. There have been a relatively high number of reports on G-CSF-producing lung carcinoma; however, reports on G-CSF-producing esophageal squamous cell carcinoma (ESCC) have been scarce.

With the aging of the population, the number of oldest old patients with cancer comorbidities has been increasing [2]. Therefore, effort should be made to determine the effectiveness of each treatment plan.

We report a very rare case of a 92-year-old woman who was promptly diagnosed with G-CSF-producing ESCC and successfully underwent surgical treatment.

Case presentation

A 92-year-old woman had a major complaint of choking when swallowing or dysphagia. The patient had been healthy and had no particular medical history besides cataract surgery. She had no history of oral medications, smoking, or alcohol. Another physician had previously attended to her was complaint of choking when swallowing. A narrowing of the lumen of the intrathoracic esophagus was detected by esophagogastroduodenoscopy, and the patient was referred to our hospital for detailed examination.

On admission, abnormal symptoms such as fever, anemia, or jaundice were not detected and the performance status was good (score 0 according to the Eastern Cooperative Oncology Group). Laboratory data on admission showed remarkable leukocytosis (leukocytes 23,500/μL, neutrophils 86.1 %, and no blast cells) and slight decrease in the serum albumin (3.5 g/dL) and C-reactive protein (CRP) levels (1.5 mg/dL). The levels of tumor markers, squamous cell carcinoma antigen (SCC-A), and p53 antibody were high (SCC-A, 3.4 ng/mL; p53, 22.2 U/mL). The respiratory functions and electrocardiograms were within normal ranges. However, the renal function was a slight concern.

Esophagogastroduodenoscopy revealed a type 2, circumferential cancer of the esophagus, approximately at 26–35 cm from the dental arch (Fig. 1), and the biopsy showed SCC. Contrast-enhanced computed tomography of the chest and abdomen demonstrated circumferential thickening of the wall and narrowing of the lumen of the middle and lower intrathoracic esophagus, and small lymph nodes were detected between the lower mediastinum and paracardiac area. Pleural effusion and ascites or distant metastases were not detected (Fig. 2).
Fig. 1

Esophagogastroduodenoscopy findings. Esophagogastroduodenoscopy revealed a type 2, circumferential esophageal cancer of the esophagus approximately at 26–35 cm from the dental arch

Fig. 2

Contrast-enhanced computed tomography findings. Contrast-enhanced computed tomography demonstrated circumferential thickening of the wall of the middle and lower intrathoracic esophagus

Based on these findings, the patient was diagnosed with T3N0M0, stage IIA (according to the Union for International Cancer Control TNM classification of malignant tumors, 7th edition) ESCC. Furthermore, the laboratory data suggested G-CSF-producing carcinoma with serum G-CSF levels of 131 pg/mL.

Despite her age, the patient had no comorbidities, and most importantly, she consented to a surgical operation. Therefore, we planned to perform esophagectomy. In Japan, the standard treatment for stage IIA esophageal carcinoma is subtotal esophagectomy with three-field lymph node dissection following preoperative chemotherapy [3]. However, considering the age disadvantage, multimodal management of disease with chemotherapy or radiotherapy was not performed.

In fact, the subtotal esophagectomy under the right thoracolaparotomy, right lower partial lobectomy, two-field lymph node dissection (instead of three-field), posterior mediastinal route gastric tube reconstruction, and intra-pleural anastomosis were successfully performed. The operation lasted 4 h and 15 min, and the blood loss was 50 mL. The tumor and the right lobe of the lung were attached; therefore, they were resected en bloc because the tumor was considered infiltrative.

Histopathological examination of the resected specimen revealed that the primary lesion sized 92 × 54 mm was a moderately differentiated squamous cell carcinoma with two lymph node metastases, and it was diagnosed as a stage III tumor (according to the Union for International Cancer Control TNM classification) (Fig. 3a, b). Immunohistochemistry of the resected tissue specimen stained positive for G-CSF in the cytoplasm of the tumor cells (Fig. 3c).
Fig. 3

Pathological findings. a Macroscopic examination of the primary lesion of the resected esophagus sized 92 × 54 mm. b Hematoxylin and eosin stains of the resected tissue specimen revealed moderately differentiated squamous cell carcinoma. c Immunohistochemistry of the resected tissue specimen showed positive staining for granulocyte colony-stimulating factor (G-CSF) in the cytoplasm of the tumor cells

After the operation, the patient developed aspiration pneumonitis; however, she promptly recovered with the administration of antibiotics. Three weeks after the operation, the leukocyte counts decreased to 5000/μL and the G-CSF levels to <19.5 pg/mL. Thereafter, the patient exhibited a good clinical course and she was discharged on the 29th postoperative day.

The patient had neutrophilia without any signs of infection or myeloblast genesis before the operation. After esophagectomy, the number of leukocytes and the level of G-CSF had decreased significantly and the presence of G-CSF was confirmed pathologically. Therefore, the patient was definitively confirmed to have a G-CSF-producing tumor.

There have not been any complaints or recurrence, and the patient has remained disease-free from 18 months after the operation until the present day.

Discussion

Robinson first described a G-CSF-producing tumor in 1974 [1], and the number of such cases has been increasing in the recent years. The primary sites of G-CSF cases have been reported as the lung, urinary tract, or the stomach [46]; however, reports of G-CSF-producing esophageal carcinoma have been scarce.

G-CSF is a hematopoietic factor produced by the endothelium, macrophages/monocytes, and fibroblasts. It stimulates the bone marrow to produce granulocytes from stem cells and release neutrophils into the bloodstream [7]. It is also produced by the malignant cancer cells. An excess amount of aberrant production causes an inflammatory response such as fever and positive CRP, a kind of leukemoid reaction (leukocytosis >50,000 leukocytes/μL), and paraneoplastic syndrome in clinical oncology. A recombinant form of G-CSF is currently used to prevent infections after chemotherapy or radiological therapy, which causes myelosuppression and neutropenia.

The diagnostic criteria for G-CSF-producing tumors include (1) a marked increase in the leukocyte counts, (2) elevated G-CSF activity, (3) a decrease in leukocyte counts following tumor resection, and (4) the verification of G-CSF production in the tumor [1]. Because all four criteria were fulfilled, we diagnosed the patient with G-CSF-producing ESCC.

Esophageal carcinoma is a disease with a poor prognosis [8]. Furthermore, the prognosis of G-CSF-producing ESCC is considered even poorer (Table 1) [918]. All of the cases have been found at rather advanced stage, in 12 cases (including our case), and 9 cases were poor prognosis. The reason might include (1) G-CSF per se having a capacity to expand tumor growth in an autocrine manner, (2) acute renal failure or hyperuricemia (so-called tumor lysis syndrome) by cytolysis of increased neutrophils after chemotherapy, (3) thrombosis by platelet aggregation by G-CSF [19]. The surviving three patients had undergone tumor resection. Furthermore, among the poor prognosis group, the survival period of excised cases was estimated to be longer than that of non-excised cases. From the above, in cases of the G-CSF-producing ESCC, if possible, the complete tumor resection is considered to be important. Since the prognosis of this disease is much poor, if possible, surgery as well, multimodal therapy that combines radiotherapy and/or chemotherapy is considered preferable.
Table 1

Summary of reported cases of G-CSF-producing esophageal squamous cell carcinoma

Case

Author

Age (years)

Gender

Leukocyte (μL)

Serum G-CSF (pg/mL)

Tumor location

Stage (TNM 7th)

Histologic grade (TNM 7th)

History of cancer

Treatment

Prognosis

1

Watanabe

81

Woman

22,100

1175

Mt

Unknown

Unknown

Lung (simultaneous)

BSC

12 days

Dead

2

Ichiishi

66

Man

33,900

Unknown

Lt

Unknown

G2-3

Stomach (simultaneous)

BSC

2 months

Dead

3

Matsumoto

66

Man

41,500

154

Lt

IV

G2

None

Resection + CRT

l6 months

Dead

4

Kato

54

Man

16,900

150

Lt

IV

G2

None

Chemotherapy

3 months

Deed

5

Komatsu

73

Man

45,710

231

AeLtG

IIB

G2

Stomach (simultaneous)

Resection

19 months

Alive

6

Nakata

56

Man

24,300

78

Lt

IIB

G2

None

Resection + CRT

10 months

Alive

7

Mimatsu

69

Man

19,600

113

Mt

IV

G3

None

Radiation

7 months

Dead

8

Tanabe

76

Man

24,260

134

LtAeG

Unknown

G2

None

Resection, CRT

10 months

Dead

9

Mayanagi

30

Man

19,020

53.7

Mt

IIIC

G1

Leukemia (metachronous)

Neoadjuvant CRT + resection

3 months

Recurrence

10

Shimakawa

73

Man

Unknown

41

Unknown

Unknown

G2

Unknown

Chemotherapy

2 months

Dead

11

Shimakawa

70

Man

16,700

254

Lt

IIIB

G2

None

NAC + resection

12 months

Dead

12

Our case

91

Woman

23,500

131

LtMt

IIIA

G2

None

Resection

18 months

Alive

Mt middle intrathoracic esophagus, Lt lower intrathoracic esophagus, Ae abdominal esophagus, G stomach, BSC best supporting care, CRT chemoradiotherapy, NAC neoadjuvant chemotherapy

According to Table 1, G-CSF-producing ESCC was male-dominated (83.3 %) and the average age of the 12 patients was 67 years old. These findings were considered to overlap with the population of normal ESCC. Association between leukocyte value, serum G-CSF value, tumor location, tumor stage, histologic grade, and prognosis was not clear. In addition, in one third in these 12 cases, a merger of other organs’ tumor was observed. It is suggested that the characteristic of G-CSF, which was mentioned above, might have influence on tumor growth [19].

In addition, with the aging of the population, the chances that we encounter the oldest old patients are increasing [8]. The appropriate evaluation of overall conditions and the selection of operative method are critical. The operative reports of the elderly are few, and among those cases, the cytoreductive (limited) operations were often chosen [2022] because of the increase of complications after the operation.

In the present case, the oldest old patient has been alive with a good condition after the operation. In order to improve the quality of life of the oldest old patients, the practical consideration for esophageal carcinoma should be the individualization of therapeutic protocols, tailoring the extent of resection and inclusion or exclusion of preoperative and postoperative procedures. A curative resection with relatively minimal invasion appears to be mandatory for better prognosis with minimal morbidity and mortality in elderly patients.

Conclusions

We described a case of successfully treated G-CSF-producing esophageal squamous cell carcinoma in a 92-year-old woman. We assessed the patient’s will and overall condition and chose the best operative method of radical subtotal esophagectomy and could achieve a good clinical course.

Abbreviations

CRP: 

C-reactive protein

ESCC: 

Esophageal squamous cell carcinoma

G-CSF: 

Granulocyte colony-stimulating factor

SCC-A: 

Squamous cell carcinoma antigen

Declarations

Acknowledgements

Not applicable.

Funding

None.

Availability of data and materials

All available data are presented in the case.

Authors’ contributions

All authors have been involved in the management of the patient and in the conception of the manuscript. MK, YY, and YS have been involved in the drafting of the manuscript or its critical revision for important intellectual content. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of the journal.

Ethics approval and consent to participate

We performed this case report in accordance with the Declaration of Helsinki and the Ethics Committee of The University of Tokyo Hospital.

New software

The authors declare that no new software has been used.

Open AccessThis 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.

Authors’ Affiliations

(1)
Department of Gastrointestinal Surgery, The University of Tokyo Hospital
(2)
Department of Surgery, Dokkyo Medical University Koshigaya Hospital

References

  1. Robinson WA. Granulocytosis in neoplasia. Ann NY Acad Sci. 1974;230:212–8.View ArticlePubMedGoogle Scholar
  2. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.View ArticlePubMedGoogle Scholar
  3. Yokota T, Ando N, Igaki H, Shinoda M, Kato K, Mizusawa J, Katayama H, Nakamura K, Fukuda H, Kitagawa Y. Prognostic factors in patients receiving neoadjuvant 5-fluorouracil plus cisplatin for advanced esophageal cancer (JCOG9907). Oncology. 2015;89(3):143–51.View ArticlePubMedGoogle Scholar
  4. Asano S, Urabe A, Okabe T, Sato N, Kondo Y. Demonstration of granulopoietic factor(s) in the plasma of nude mice transplanted with a human lung cancer and in the tumor tissue. Blood. 1977;49(5):845–52.PubMedGoogle Scholar
  5. Yasui H, Sato K, Takeyama Y, Ando A, Kato T, Hashimoto H, Fukui Y, Maeda M, Gonda H, Suzuki R. Granulocyte colony-stimulating factor-producing carcinoma of unknown primary site. Case Rep Oncol. 2014;7(3):780–8.View ArticlePubMedPubMed CentralGoogle Scholar
  6. Obara T, Ito Y, Kodama T, Fujimoto Y, Mizoguchi H, Oshimi K, Takahashi M, Hirayama A. A case of gastric carcinoma associated with excessive granulocytosis. Production of a colony-stimulating factor by the tumor. Cancer. 1985;56(4):782–8.View ArticlePubMedGoogle Scholar
  7. Metcalf D. The granulocyte-macrophage colony-stimulating factors. Science. 1985;229(4708):16–22.View ArticlePubMedGoogle Scholar
  8. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095–128.View ArticlePubMedGoogle Scholar
  9. Watanabe HA, Matsushita H, Matsui H, Komatsu T, Taguchi S, Sata H, Amano N. Esophageal carcinoma with high serum parathyroid hormone-related protein (PTHrP) level. J Gastroenterol. 1999;34(4):510–5.View ArticlePubMedGoogle Scholar
  10. Ichiishi E, Yoshikawa T, Kogawa T, Yoshida N, Kondo M. Possible paracrine growth of adenocarcinoma of the stomach induced by granulocyte colony stimulating factor produced by squamous cell carcinoma of the oesophagus. Gut. 2000;46(3):432–4.View ArticlePubMedPubMed CentralGoogle Scholar
  11. Matsumoto G, Ise H, Kimura Y, Inoue H, Suzuki N, Ohtani H, Ogawa H, Fukushima K, Matsuno S. Granulocyte-colony stimulating factor-producing esophageal carcinoma: serum level as a marker for monitoring the effects of treatment. Int J Clin Oncol. 2000;5(5):328–33.View ArticleGoogle Scholar
  12. Miyuki K, Hiroshi O, Noriko U, Hiroshi H. An autopsy case of esophageal squamous cell carcinoma associated with granulocyte colony-stimulating factor production. Jikeikai Med J. 2002;49(4):191–5.Google Scholar
  13. Komatsu D, Sakurai M, Nakafuji H, Koide N, Morishita H, Nakamura T. Granulocyte colony stimulating factor-producing collision tumor of the gastric cardia. J Gastroenterol. 2003;38(10):1013–5.View ArticlePubMedGoogle Scholar
  14. Nakata K, Ohtsuka T, Sato S, Tanaka M, Shimonishi T, Mori D, Nakafusa Y, Miyazaki K. Esophageal carcinoma with humoral hypercalcemia and leukocytosis successfully treated by a two-stage operation: report of a case. Esophagus. 2006;3(1):13–7.View ArticleGoogle Scholar
  15. Mimatsu K, Oida T, Kano H, Kawasaki A, Amano S. Aggressive progression of granulocyte colony-stimulating factor producing squamous cell carcinoma of the esophagus: case report and literature review. Esophagus. 2008;5(4):205–9.View ArticleGoogle Scholar
  16. Tanabe T, Kanda T, Ishihara N, Kosugi S-i, Matsuki A, Watanabe G, Sasamoto R, Hatakeyama K. An esophageal squamous cell carcinoma patient with high serum granulocyte-colony stimulating factor level: report of a case. Esophagus. 2009;6(4):253–8.View ArticleGoogle Scholar
  17. Mayanagi S, Niihara M, Goto H, Yokota T, Tabuse H, Yasui H, Ogawa H, Nishimura T, Kusafuka K, Tsubosa Y. Granulocyte colony-stimulating factor-producing esophageal squamous cell carcinoma following chemoradiotherapy and bone marrow transplantation for acute lymphoblastic leukemia. Esophagus. 2013;10(4):258–63.View ArticlePubMedPubMed CentralGoogle Scholar
  18. Shimakawa T, Asaka S, Usuda A, Yamaguchi K, Yoshimatsu K, Shiozawa S, Katsube T, Naritaka Y. Granulocyte-colony stimulating factor (G-CSF)-producing esophageal squamous cell carcinoma: a case report. Int Surg. 2014;99(3):280–5.View ArticlePubMedPubMed CentralGoogle Scholar
  19. Kawachi Y, Watanabe A, Uchida T, Yoshizawa K, Kurooka N, Setsu K. Acute arterial thrombosis due to platelet aggregation in a patient receiving granulocyte colony-stimulating factor. Br J Haematol. 1996;94(2):413–6.View ArticlePubMedGoogle Scholar
  20. Markar SR, Low DE. Physiology, not chronology, dictates outcomes after esophagectomy for esophageal cancer; outcomes in patients 80 years and older. Ann Surg Oncol. 2013;20(3):1020–6.View ArticlePubMedGoogle Scholar
  21. Internullo E, Moons J, Nafteux P, Coosemans W, Decker G, De Leyn P, Van Raemdonck D, Lerut T. Outcome after esophagectomy for cancer of the esophagus and GEJ in patients aged over 75 years. Eur J Cardiothorac Surg. 2008;33(6):1096–104.View ArticlePubMedGoogle Scholar
  22. Morita M, Egashira A, Yoshida R, Ikeda K, Ohgaki K, Shibahara K, Oki E, Sadanaga N, Kakeji Y, Maehara Y. Esophagectomy in patients 80 years of age older with carcinoma of the thoracic esophagus. J Gastroenterol. 2008;43(5):345–51.View ArticlePubMedGoogle Scholar

Copyright

© The Author(s). 2016

Advertisement