Ann Thorac Cardiovasc Surg 2016; 22: 116–121
Case Report
Online September 2, 2015 doi: 10.5761/atcs.cr.15-00154
Lung Cancer Detected 5 Years after Resection of Cancer of Unknown Primary in a Mediastinal Lymph Node: A Case Report and Review of Relevant Cases from the Literature Hidenori Kawasaki, MD, PhD,1 Kazunari Arakaki, MD, PhD,2 Naohiro Taira, MD,1 Tomonori Furugen, MD,1 Takaharu Ichi, MD,1 Tomofumi Yohena, MD, PhD,1 and Tsutomu Kawabata, MD, PhD1
We report the rare and interesting case of a primary lung cancer detected 5 years after cancer of unknown primary (CUP) of a mediastinal lymph node (LN) was resected. A 40-year-old male was diagnosed with adenocarcinoma of unknown primary in a mediastinal lymph node after resection of the mediastinal tumor. Five years after resection of the CUP in mediastinal LN, a small, abnormal nodular shadow in left upper lobe was detected by chest CT. This pulmonary tumor was diagnosed as a lung adenocarcinoma. The pathological and immunohistological findings of the resected pulmonary tumor resembled those of the LN resected 5 years before. We speculated that the pulmonary lesion represented primary lung cancer that enlarged later than the metastatic mediastinal LN. This case illustrates the importance of careful observation and long-term follow-up in patients treated for CUP of a thoracic LN. Keywords: cancer of unknown primary site, lung cancer
Introduction Cancer of unknown primary (CUP) site is not an unusual phenomenon. It has been reported that patients with CUP make up 3%–5% of all cancer patients.1–3) However, CUP of the thoracic lymph nodes (LNs) is comparatively rare, representing 1%–1.5% of all CUP cases.1,4,5) It is typically difficult to detect the primary lesion even when a systemic, Department of Surgery, National Hospital Organization Okinawa National Hospital, Okinawa, Japan 2Department of Pathology, University Hospital, University of the Rykyus, Okinawa, Japan 1
Received: May 17, 2015; Accepted: August 11, 2015 Corresponding author: Hidenori Kawasaki, MD, PhD. Department of Surgery, National Hospital Organization Okinawa National Hospital, 3-20-14 Ganeko, Ginowan, Okinawa 901-2214, Japan Email: [email protected] ©2015 The Editorial Committee of Annals of Thoracic and Cardiovascular Surgery. All rights reserved.
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detailed evaluation is performed, and the primary site rarely becomes manifest during the long-term clinical course. Here, we report a rare and interesting case in which primary lung cancer was detected 5 years after resection of CUP of a mediastinal LN.
Case Report A 40-year-old male was referred to our hospital for evaluation of an abnormal shadow in the left pulmonary hilum on a chest X-ray taken in November 2004. The patient’s past and family histories were unremarkable. He had smoked 20 cigarettes per day since the age of 15 years. Physical examination revealed no abnormalities and no lymphadenopathy. Routine laboratory tests were within the normal range except for a slight elevation of carcinoembryonic antigen (CEA) to 5.9 ng/ml. Chest X-ray showed a slightly high-intensity shadow in the left pulmonary hilum. Chest CT revealed a well-circumscribed tumor, Ann Thorac Cardiovasc Surg Vol. 22, No. 2 (2016)
Lung Cancer Detected 5 Years after Resection of Cancer of Unknown Primary (A)
(B)
(C)
(D)
Fig. 1 C hest CT revealed a well-circumscribed tumor, 2.7 cm in diameter, located on the left side of the aortic arch (A). Pathological examination of the lymph node resected in 2005 revealed large cells with nuclear atypia growing in glandular structures within the lymphatic structure (B). Immunohistochemical studies of the lymph node showed to be positive for TTF-1 (C) and CAM5.2 (D).
2.7 cm in diameter, located on the left side of the aortic arch. The tumor was well defined and homogenous, and it was enhanced on contrast CT (Fig. 1A). These features were suggestive of an anterior mediastinal solid tumor such as a thymoma. There were no abnormal findings in the lung fields or other organs, and there was no lymphadenopathy in other regions. In January 2005, thoracoscopic resection of the mediastinal tumor with the thymus was performed. The resected specimen weighed 81 g. The dimensions of the resected specimen were as follows: thymic right lobe, 9 × 4 cm; left lobe, 11 × 7 cm. A tumor located on the left side of the upper thymic pole measured 2.7 × 2.5 × 2.0 cm in size. The cut surface of the tumor revealed a well-encapsulated, homogenous solid tumor with a dark reddish color. Pathology revealed large cells with nuclear atypia growing in a glandular structure within the lymphatic structure; the pathologic diagnosis was adenocarcinoma of the lymph node (Fig. 1B). Immunohistochemical studies showed the tumor to be positive for TTF-1 (Fig. 1C) and CAM5.2 Ann Thorac Cardiovasc Surg Vol. 22, No. 2 (2016)
(Fig. 1D) but negative for cytokeratin 5/6 and CD56. These findings suggested the presence of metastatic adenocarcinoma of the lymph node originating from another organ such as the lung. At this time, we performed systemic evaluation, including gastrointestinal endoscopy, in an effort to detect the primary lesion. However, we were unable to detect a primary lesion, so the patient was diagnosed with CUP of the mediastinal LN. Postoperative chemotherapy was recommended but declined by the patient. The patient was followed at an outpatient clinic at 3- to 6-month intervals. Starting in 2006, his serum CEA gradually rose again. We added annual 18F-fluorodeoxy-glucose (FDG)-positron emission tomography/computed tomography (PET/CT) for systemic evaluation from 2007 onward, but there was no abnormal FDG accumulation. In May 2010, a small, abnormal nodular shadow in the left upper lung lobe was detected by chest CT. The nodular shadow measured 1.2 cm in diameter and had an irregular shape and spicula; it was suggestive of lung cancer (Fig. 2A). FDG-PET/CT showed abnormal accumulation in the 117
Kawasaki H, et al. (A)
(B)
(C)
(D)
Fig. 2 C hest CT revealed a small, nodular shadow 1.2 cm in diameter with an irregular shape and spicula in the left upper lobe (A). Pathological examination of the pulmonary tumor resected in 2010 revealed lepidic growth on the alveolar epithelial wall; some areas exhibited a solid glandular structure, and both structures showed a shift to continuity (B). Immunohistochemical studies of the left lung showed to be positive for TTF-1 (C) and CAM5.2 (D).
nodular shadow within the left upper lobe (SUVmax = 8.3) and in the left pulmonary hilar LN (SUVmax = 6.1). In August 2010, we performed wedge resection of the left upper lobe; adenocarcinoma was diagnosed by rapid frozen section pathological examination, so we proceeded to perform an upper lobectomy of the left lung and lymph node dissection. Pathological examination of the tumor showed lepidic growth of the alveolar epithelial wall; some areas showed a solid glandular structure, and both structures exhibited a shift to continuity (Fig. 2B). Immunohistochemical studies showed the tumor to be positive for TTF-1 (Fig. 2C) and CAM5.2 (Fig. 2D) but negative for cytokeratin 5/6 and CD56. Pleural involvement and metastatic involvement in the subaortic, subcarinal and pulmonary hilar lymph nodes were found. Thus, patient was diagnosed with adenocarcinoma, pT2aN2M0 Stage IIIA. These pathological and immunohistological findings resembled those of the lymph node resected in 2005. As a result, we speculated that the
118
left lung tumor represented a primary lung carcinoma that had enlarged later than the metastatic LN. The patient’s postoperative course was uneventful. His serum CEA level decreased to 3.7 ng/ml in 2 months after the operation, and he received postoperative chemotherapy. However, 1 year after the left upper lobectomy, in April 2011, the patient’s serum CEA level elevated again. The tumor had recurred at the right paratracheal and subcarinal LNs, so he had received chemoradiotherapy. We evaluated mutation of EGFR gene and EML4-ALK fusion gene in a pulmonary tumor resected in 2010, but neither study was positive. As of July 2015, the patient was alive with relapsed disease and was undergoing continuous chemotherapy.
Discussion There are several possible explanations for the development of CUP in the LNs. First, the primary lesion may not
Ann Thorac Cardiovasc Surg Vol. 22, No. 2 (2016)
Ann Thorac Cardiovasc Surg Vol. 22, No. 2 (2016)
Matsuge
Sakuraba
Chen
Suzuki
Hara
Nishikawa
Baba
Baba
Higuchi
Present case
2
3
4
5
6
7
8
9
10
11
40
63
72
68
66
76
41
68
63
64
61
Age (y)
Male
Male
Male
Male
Male
Male
Male
Male
Male
Male
Male
Sex
AD
LA
SQ
AD
AD
SQ
AD
SQ
SQ
LCNEC
AD
Pathology
Yes
Yes
Yes
Yes
Yes
Yes
ND
ND
ND
Yes
ND
CEA
CEA
SCC
CEA
None
CEA, Cyfra
None
CEA
None
CEA
SCC, SLX
Lt. Med
Rt. Med
Lt. Med
Lt. Med
Rt. Med & Hil
Rt. Med
Rt. Hil
Rt. Med
Rt. Hil
Rt. Med
Rt. Med
LND
LND
BX
EX
None
LND
LND
LND
LND
LND
LB & LND
None
None
CT & RT
None
CT
None
CT
RT
None
CT
CT
64
112
12
84
77
30
84
14
34
2
18
Lt. UL
Rt. UL
Lt. UL
Lt. UL
Rt. UL
Rt. UL
Rt. LL
Rt. UL
Rt. UL
Rt. UL
Rt. UL
LB
LB
None
PR
LB
LB
LB
PN
PN
None
PN
CT
None
CT
None
None
None
None
None
None
CT
None
59
30
29
36
11
6
24
6
13
28
18
Alive with recurrence
Alive without recurrence
Alive with recurrence
Died of another disease
Alive without recurrence
Alive without recurrence
Alive without recurrence
Died of recurrence
Alive without recurrence
Died of recurrence
Died of another disease
Outcome
CUP: cancer of unknown primary; LN: lymph node; TM: tumor marker; PL: pulmonary lesion; AD: adenocarcinoma; SQ: squamous cell carcinoma; LCNEC: large cell neuroendocrine carcinoma; LA: large cell carcinoma; ND: no data; SCC: squamous cell carcinoma antigen; SLX: Sialyl Lewis X antigen; CEA: carcinoembryonic antigen; Cyfra: Cytokeratin subunit 19 fragment; Med: mediastinum; Hil: hilum; LB: lobectomy; LND: lymph node dissection; EX: extirpation; BX: biopsy; CT: chemotherapy; RT: radiation therapy; Rt. UL: right upper lobe; Rt. LL: right lower lobe; Lt. UL: left upper lobe; PN: pneumonectomy; PR: partial resection
Kita
Author
1
Case
Time from Time History Location Surgical Adjuvant treatment Surgical Adjuvant Elevated Location elapsed after of of LN treatment treatment of CUP to treatment treatment TM(s) of PL treatment of smoking with CUP of CUP of CUP detection of of PL of PL PL (mo) PL (mo)
Table 1 Characteristics of patients diagnosed with lung cancer after treatment of CUP of the thoracic LNs
Lung Cancer Detected 5 Years after Resection of Cancer of Unknown Primary
119
Kawasaki H, et al.
be detectable because of insufficient size or because it grew too slowly to be detected on clinical, radiologic, or pathologic examinations; the primary lesion may also be hidden by an enlarged metastatic LN.4,5) The second possibility is that the host defense mechanism has destroyed the primary tumors, termed spontaneous regression. However, spontaneous regression of primary lesions other than metastatic LNs is rare, especially in lung cancer.6) Another possible theory is that the cancer may arise from epithelial inclusions in the LN. Benign epithelial inclusions have occasionally been reported to exist in the LNs7,8) and rarely in the pulmonary LNs.5) We speculate that, in our case, the primary lesion in the left upper lobe was too small to detect when CUP of the mediastinal LN was detected and that it progressed so slowly that it took 5 years to become detectable. This fits into the first theory described above. We hypothesize that the lung cancer in the left upper lobe was the primary lesion because of the following reasons: (1) no primary lesions developed in organs other than the lung over a period of more than 10 years, (2) the CUP of the LN was located in the lymphatic pathway of the left upper lobe, and (3) pathological and immunohistochemical examination showed similar findings in the lung and mediastinal LN tumors (i.e., both specimens were positive for TTF-1 and CAM5.2 but negative for cytokeratin 5/6 and CD56). Various imaging procedures have been developed to detect the primary site in cases of CUP. The development of FDG-PET/CT has contributed to human cancer detection and staging, and its usefulness has been well established. The use of FDG-PET/CT has improved the diagnosis of CUP.2,3,9) In our case, based on the pathological and immunohistological findings of the LN CUP, we estimated that there was a high possibility of lymph node metastasis from lung cancer. One year after resection of the CUP, serum CEA was again elevated. Accordingly, we proceeded to conduct an extensive work-up that included PET, but it took 4 years to detect the pulmonary lesion. This indicates the limitations of PET/CT with regard to detecting extremely small foci. In our review of the Japanese literature, there were only ten case reports that described the detection of lung cancer after resection of CUP of the intrathoracic LNs.10–18) The patient characteristics of all eleven cases (including our case) is shown in Table 1. All of these patients were men; their average age was 62.4 years (range, 41–76 years). Five patients had adenocarcinomas, four had squamous cell carcinomas, one had a large cell neuroendocrine carcinoma, and one had a large cell carcinoma. In eight 120
patients, certain tumor markers exceeded the normal range. The CUPs were located in the LNs of the mediastinum in eight cases, the pulmonary hilum in two cases, and both sites in one case. Adjuvant treatment after CUP resection consisted of chemotherapy in four cases, radiation therapy in one case, chemoradiation therapy in one case, and no additional treatment in four cases. The period between diagnosis of CUP in the LN and detection of the pulmonary lesion averaged 48.3 months (range, 2–112 months). The pulmonary lesion was treated with surgery in nine cases and chemotherapy in two cases. The outcomes after pulmonary lesion treatment were as follows: five patients were alive without recurrence at an average of 16.8 months (range, 6–30 months), two patients were alive with recurrence at an average of 44 months (29 and 59 months), two patients had died of their disease after an average of 17 months (6 and 28 months), and two patients had died of other diseases after an average of 27 months (18 and 36 months). In general, when all CUPs are considered, the prognosis has been reported to be poor, with a 5-year survival of 2%–6% and a median survival time of 2–7 months.1–3) However, patients with CUP in the mediastinal LNs have been reported to have a relatively good prognosis when compared with patients diagnosed with primary lung cancer and mediastinal lymph node involvement;4,5,19,20) the median survival time of the former has been reported as 28 months19) and 30.7 months,20) representing a relatively good outcome.
Conclusion We have presented a rare case in which lung carcinoma was detected 5 years after the resection of CUP in the mediastinal LN. This case illustrates the importance of careful observation and long-term follow-up in patients treated for CUP in the intrathoracic LNs even when initial PET/CT results are negative.
Consent Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Disclosure Statement The authors declare that they have no competing interests. Ann Thorac Cardiovasc Surg Vol. 22, No. 2 (2016)
Lung Cancer Detected 5 Years after Resection of Cancer of Unknown Primary
References 1) Holmes FF, Fouts TL. Metastatic cancer of unknown primary site. Cancer 1970; 26: 816-20. 2) Pavlidis N, Briasoulis E, Hainsworth J, et al. Diagnostic and therapeutic management of cancer of an unknown primary. Eur J Cancer 2003; 39: 1990-2005. 3) Fizazi K, Greco FA, Pavlidis N, et al. Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2011; 22 Suppl 6: vi64-8. 4) Kohdono S, Ishida T, Fukuyama Y, et al. Lymph node cancer of the mediastinal or hilar region with an unknown primary site. J Surg Oncol 1995; 58: 196-200. 5) Riquet M, Badoual C, le Pimpec BF, et al. Metastatic thoracic lymph node carcinoma with unknown primary site. Ann Thorac Surg 2003; 75: 244-9. 6) Cafferata MA, Chiaramondia M, Monetti F, et al. Complete spontaneous remission of non-small-cell lung cancer: a case report. Lung Cancer 2004; 45: 263-6. 7) Rosai J, ed. Ackerman’s surgical pathology. Lymph node inclusions, 8th ed. St. Louis: Mosby, 1996. 8) Fellegara G, Carcangiu ML, Rosai J. Benign epithelial inclusions in axillary lymph nodes: report of 18 cases and review of the literature. Am J Surg Pathol 2011; 35: 1123-33. 9) Kwee TC, Kwee RM. Combined FDG-PET/CT for the detection of unknown primary tumors: systematic review and meta-analysis. Eur Radiol 2009; 19: 731-44. 10) Kita Y, Kondo D. Occult lung cancer with sarcoidosis; a case report. The primary lesion appeared on chest X-ray taken 18 months after resection of mediastinal lymph node metastases. Jpn J Chest Surg 1996; 10: 488-93. (in Japanese with English abstract) 11) Matsuge S, Hosokawa Y, Sato K, et al. An occult intrapulmonary large cell neuroendocrine carcinoma presenting mediastinal lymph adenopathy as an initial manifestation. Jpn J Chest Dis 1999; 58: 668-72. (in Japanese with English abstract)
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12) Sakuraba M, Mae M, Oonuki T, et al. Mediastinal and hilar lymph node of cancer unknown origin: 3 case reports. J Jpn Respir Soc 1999; 37: 72-7. (in Japanese with English abstract) 13) Chen F, Tatsumi A, Nii E, et al. Four cases of cancer of unknown primary site that manifested as mediastinal metastatic lesions. J Jpn Respir Soc 1999; 37: 1003-7. (in Japanese with English abstract) 14) Suzuki Y, Ogawa N, Ishiwa N, et al. Resection of a primary lung lesion after resection of a malignant hilar lymph node of unknown origin. Jpn J Lung Cancer 2002; 42: 283-7. (in Japanese with English abstract) 15) Hara H, Suzuki M, Takagi T, et al. A case of mediastinal lymph node metastases followed by appearance of primary multiple lung cancer. Jpn J Lung Cancer 2008; 48: 130-4. (in Japanese with English abstract) 16) Nishikawa T, Ninomiya T, Fujiwara T, et al. A case of lung cancer after chemotherapy of hilar and mediastinum lymphnode cancer on unknown origin. J Jpn Surg Assoc 2010; 71: 2000-4. (in Japanese with English abstract) 17) Baba T, Uramoto H, Yamada S, et al. Three cases of mediastinal lymph node carcinoma with an unknown primary site. Jpn J Chest Surg 2011; 25: 175-81. (in Japanese with English abstract) 18) Higuchi T, Nagata A, Hamada T, et al. A case of primary lung cancer developing 9 years after surgery for metastatic mediastinal lymph node carcinoma. Jpn J Chest Surg 2015; 29: 220-5. (in Japanese with English abstract) 19) Hayasi K. A case report of a long-surviving patient with mediastinal lymph node carcinoma from an unknown primary site, with a review of 31 cases reported in Japan. Jpn J Chest Surg 2007; 21: 624-9. (in Japanese with English abstract) 20) Morio A, Miyamoto H, Izumi H, et al. A case report of adenocarcinoma of unknown origin metastatic to the mediastinal lymph nodes with a review of 21 cases reported in Japan. Jpn J Lung Cancer 2001; 41: 73-8. (in Japanese with English abstract)
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Case Report
Online September 2, 2015 doi: 10.5761/atcs.cr.15-00154
Lung Cancer Detected 5 Years after Resection of Cancer of Unknown Primary in a Mediastinal Lymph Node: A Case Report and Review of Relevant Cases from the Literature Hidenori Kawasaki, MD, PhD,1 Kazunari Arakaki, MD, PhD,2 Naohiro Taira, MD,1 Tomonori Furugen, MD,1 Takaharu Ichi, MD,1 Tomofumi Yohena, MD, PhD,1 and Tsutomu Kawabata, MD, PhD1
We report the rare and interesting case of a primary lung cancer detected 5 years after cancer of unknown primary (CUP) of a mediastinal lymph node (LN) was resected. A 40-year-old male was diagnosed with adenocarcinoma of unknown primary in a mediastinal lymph node after resection of the mediastinal tumor. Five years after resection of the CUP in mediastinal LN, a small, abnormal nodular shadow in left upper lobe was detected by chest CT. This pulmonary tumor was diagnosed as a lung adenocarcinoma. The pathological and immunohistological findings of the resected pulmonary tumor resembled those of the LN resected 5 years before. We speculated that the pulmonary lesion represented primary lung cancer that enlarged later than the metastatic mediastinal LN. This case illustrates the importance of careful observation and long-term follow-up in patients treated for CUP of a thoracic LN. Keywords: cancer of unknown primary site, lung cancer
Introduction Cancer of unknown primary (CUP) site is not an unusual phenomenon. It has been reported that patients with CUP make up 3%–5% of all cancer patients.1–3) However, CUP of the thoracic lymph nodes (LNs) is comparatively rare, representing 1%–1.5% of all CUP cases.1,4,5) It is typically difficult to detect the primary lesion even when a systemic, Department of Surgery, National Hospital Organization Okinawa National Hospital, Okinawa, Japan 2Department of Pathology, University Hospital, University of the Rykyus, Okinawa, Japan 1
Received: May 17, 2015; Accepted: August 11, 2015 Corresponding author: Hidenori Kawasaki, MD, PhD. Department of Surgery, National Hospital Organization Okinawa National Hospital, 3-20-14 Ganeko, Ginowan, Okinawa 901-2214, Japan Email: [email protected] ©2015 The Editorial Committee of Annals of Thoracic and Cardiovascular Surgery. All rights reserved.
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detailed evaluation is performed, and the primary site rarely becomes manifest during the long-term clinical course. Here, we report a rare and interesting case in which primary lung cancer was detected 5 years after resection of CUP of a mediastinal LN.
Case Report A 40-year-old male was referred to our hospital for evaluation of an abnormal shadow in the left pulmonary hilum on a chest X-ray taken in November 2004. The patient’s past and family histories were unremarkable. He had smoked 20 cigarettes per day since the age of 15 years. Physical examination revealed no abnormalities and no lymphadenopathy. Routine laboratory tests were within the normal range except for a slight elevation of carcinoembryonic antigen (CEA) to 5.9 ng/ml. Chest X-ray showed a slightly high-intensity shadow in the left pulmonary hilum. Chest CT revealed a well-circumscribed tumor, Ann Thorac Cardiovasc Surg Vol. 22, No. 2 (2016)
Lung Cancer Detected 5 Years after Resection of Cancer of Unknown Primary (A)
(B)
(C)
(D)
Fig. 1 C hest CT revealed a well-circumscribed tumor, 2.7 cm in diameter, located on the left side of the aortic arch (A). Pathological examination of the lymph node resected in 2005 revealed large cells with nuclear atypia growing in glandular structures within the lymphatic structure (B). Immunohistochemical studies of the lymph node showed to be positive for TTF-1 (C) and CAM5.2 (D).
2.7 cm in diameter, located on the left side of the aortic arch. The tumor was well defined and homogenous, and it was enhanced on contrast CT (Fig. 1A). These features were suggestive of an anterior mediastinal solid tumor such as a thymoma. There were no abnormal findings in the lung fields or other organs, and there was no lymphadenopathy in other regions. In January 2005, thoracoscopic resection of the mediastinal tumor with the thymus was performed. The resected specimen weighed 81 g. The dimensions of the resected specimen were as follows: thymic right lobe, 9 × 4 cm; left lobe, 11 × 7 cm. A tumor located on the left side of the upper thymic pole measured 2.7 × 2.5 × 2.0 cm in size. The cut surface of the tumor revealed a well-encapsulated, homogenous solid tumor with a dark reddish color. Pathology revealed large cells with nuclear atypia growing in a glandular structure within the lymphatic structure; the pathologic diagnosis was adenocarcinoma of the lymph node (Fig. 1B). Immunohistochemical studies showed the tumor to be positive for TTF-1 (Fig. 1C) and CAM5.2 Ann Thorac Cardiovasc Surg Vol. 22, No. 2 (2016)
(Fig. 1D) but negative for cytokeratin 5/6 and CD56. These findings suggested the presence of metastatic adenocarcinoma of the lymph node originating from another organ such as the lung. At this time, we performed systemic evaluation, including gastrointestinal endoscopy, in an effort to detect the primary lesion. However, we were unable to detect a primary lesion, so the patient was diagnosed with CUP of the mediastinal LN. Postoperative chemotherapy was recommended but declined by the patient. The patient was followed at an outpatient clinic at 3- to 6-month intervals. Starting in 2006, his serum CEA gradually rose again. We added annual 18F-fluorodeoxy-glucose (FDG)-positron emission tomography/computed tomography (PET/CT) for systemic evaluation from 2007 onward, but there was no abnormal FDG accumulation. In May 2010, a small, abnormal nodular shadow in the left upper lung lobe was detected by chest CT. The nodular shadow measured 1.2 cm in diameter and had an irregular shape and spicula; it was suggestive of lung cancer (Fig. 2A). FDG-PET/CT showed abnormal accumulation in the 117
Kawasaki H, et al. (A)
(B)
(C)
(D)
Fig. 2 C hest CT revealed a small, nodular shadow 1.2 cm in diameter with an irregular shape and spicula in the left upper lobe (A). Pathological examination of the pulmonary tumor resected in 2010 revealed lepidic growth on the alveolar epithelial wall; some areas exhibited a solid glandular structure, and both structures showed a shift to continuity (B). Immunohistochemical studies of the left lung showed to be positive for TTF-1 (C) and CAM5.2 (D).
nodular shadow within the left upper lobe (SUVmax = 8.3) and in the left pulmonary hilar LN (SUVmax = 6.1). In August 2010, we performed wedge resection of the left upper lobe; adenocarcinoma was diagnosed by rapid frozen section pathological examination, so we proceeded to perform an upper lobectomy of the left lung and lymph node dissection. Pathological examination of the tumor showed lepidic growth of the alveolar epithelial wall; some areas showed a solid glandular structure, and both structures exhibited a shift to continuity (Fig. 2B). Immunohistochemical studies showed the tumor to be positive for TTF-1 (Fig. 2C) and CAM5.2 (Fig. 2D) but negative for cytokeratin 5/6 and CD56. Pleural involvement and metastatic involvement in the subaortic, subcarinal and pulmonary hilar lymph nodes were found. Thus, patient was diagnosed with adenocarcinoma, pT2aN2M0 Stage IIIA. These pathological and immunohistological findings resembled those of the lymph node resected in 2005. As a result, we speculated that the
118
left lung tumor represented a primary lung carcinoma that had enlarged later than the metastatic LN. The patient’s postoperative course was uneventful. His serum CEA level decreased to 3.7 ng/ml in 2 months after the operation, and he received postoperative chemotherapy. However, 1 year after the left upper lobectomy, in April 2011, the patient’s serum CEA level elevated again. The tumor had recurred at the right paratracheal and subcarinal LNs, so he had received chemoradiotherapy. We evaluated mutation of EGFR gene and EML4-ALK fusion gene in a pulmonary tumor resected in 2010, but neither study was positive. As of July 2015, the patient was alive with relapsed disease and was undergoing continuous chemotherapy.
Discussion There are several possible explanations for the development of CUP in the LNs. First, the primary lesion may not
Ann Thorac Cardiovasc Surg Vol. 22, No. 2 (2016)
Ann Thorac Cardiovasc Surg Vol. 22, No. 2 (2016)
Matsuge
Sakuraba
Chen
Suzuki
Hara
Nishikawa
Baba
Baba
Higuchi
Present case
2
3
4
5
6
7
8
9
10
11
40
63
72
68
66
76
41
68
63
64
61
Age (y)
Male
Male
Male
Male
Male
Male
Male
Male
Male
Male
Male
Sex
AD
LA
SQ
AD
AD
SQ
AD
SQ
SQ
LCNEC
AD
Pathology
Yes
Yes
Yes
Yes
Yes
Yes
ND
ND
ND
Yes
ND
CEA
CEA
SCC
CEA
None
CEA, Cyfra
None
CEA
None
CEA
SCC, SLX
Lt. Med
Rt. Med
Lt. Med
Lt. Med
Rt. Med & Hil
Rt. Med
Rt. Hil
Rt. Med
Rt. Hil
Rt. Med
Rt. Med
LND
LND
BX
EX
None
LND
LND
LND
LND
LND
LB & LND
None
None
CT & RT
None
CT
None
CT
RT
None
CT
CT
64
112
12
84
77
30
84
14
34
2
18
Lt. UL
Rt. UL
Lt. UL
Lt. UL
Rt. UL
Rt. UL
Rt. LL
Rt. UL
Rt. UL
Rt. UL
Rt. UL
LB
LB
None
PR
LB
LB
LB
PN
PN
None
PN
CT
None
CT
None
None
None
None
None
None
CT
None
59
30
29
36
11
6
24
6
13
28
18
Alive with recurrence
Alive without recurrence
Alive with recurrence
Died of another disease
Alive without recurrence
Alive without recurrence
Alive without recurrence
Died of recurrence
Alive without recurrence
Died of recurrence
Died of another disease
Outcome
CUP: cancer of unknown primary; LN: lymph node; TM: tumor marker; PL: pulmonary lesion; AD: adenocarcinoma; SQ: squamous cell carcinoma; LCNEC: large cell neuroendocrine carcinoma; LA: large cell carcinoma; ND: no data; SCC: squamous cell carcinoma antigen; SLX: Sialyl Lewis X antigen; CEA: carcinoembryonic antigen; Cyfra: Cytokeratin subunit 19 fragment; Med: mediastinum; Hil: hilum; LB: lobectomy; LND: lymph node dissection; EX: extirpation; BX: biopsy; CT: chemotherapy; RT: radiation therapy; Rt. UL: right upper lobe; Rt. LL: right lower lobe; Lt. UL: left upper lobe; PN: pneumonectomy; PR: partial resection
Kita
Author
1
Case
Time from Time History Location Surgical Adjuvant treatment Surgical Adjuvant Elevated Location elapsed after of of LN treatment treatment of CUP to treatment treatment TM(s) of PL treatment of smoking with CUP of CUP of CUP detection of of PL of PL PL (mo) PL (mo)
Table 1 Characteristics of patients diagnosed with lung cancer after treatment of CUP of the thoracic LNs
Lung Cancer Detected 5 Years after Resection of Cancer of Unknown Primary
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Kawasaki H, et al.
be detectable because of insufficient size or because it grew too slowly to be detected on clinical, radiologic, or pathologic examinations; the primary lesion may also be hidden by an enlarged metastatic LN.4,5) The second possibility is that the host defense mechanism has destroyed the primary tumors, termed spontaneous regression. However, spontaneous regression of primary lesions other than metastatic LNs is rare, especially in lung cancer.6) Another possible theory is that the cancer may arise from epithelial inclusions in the LN. Benign epithelial inclusions have occasionally been reported to exist in the LNs7,8) and rarely in the pulmonary LNs.5) We speculate that, in our case, the primary lesion in the left upper lobe was too small to detect when CUP of the mediastinal LN was detected and that it progressed so slowly that it took 5 years to become detectable. This fits into the first theory described above. We hypothesize that the lung cancer in the left upper lobe was the primary lesion because of the following reasons: (1) no primary lesions developed in organs other than the lung over a period of more than 10 years, (2) the CUP of the LN was located in the lymphatic pathway of the left upper lobe, and (3) pathological and immunohistochemical examination showed similar findings in the lung and mediastinal LN tumors (i.e., both specimens were positive for TTF-1 and CAM5.2 but negative for cytokeratin 5/6 and CD56). Various imaging procedures have been developed to detect the primary site in cases of CUP. The development of FDG-PET/CT has contributed to human cancer detection and staging, and its usefulness has been well established. The use of FDG-PET/CT has improved the diagnosis of CUP.2,3,9) In our case, based on the pathological and immunohistological findings of the LN CUP, we estimated that there was a high possibility of lymph node metastasis from lung cancer. One year after resection of the CUP, serum CEA was again elevated. Accordingly, we proceeded to conduct an extensive work-up that included PET, but it took 4 years to detect the pulmonary lesion. This indicates the limitations of PET/CT with regard to detecting extremely small foci. In our review of the Japanese literature, there were only ten case reports that described the detection of lung cancer after resection of CUP of the intrathoracic LNs.10–18) The patient characteristics of all eleven cases (including our case) is shown in Table 1. All of these patients were men; their average age was 62.4 years (range, 41–76 years). Five patients had adenocarcinomas, four had squamous cell carcinomas, one had a large cell neuroendocrine carcinoma, and one had a large cell carcinoma. In eight 120
patients, certain tumor markers exceeded the normal range. The CUPs were located in the LNs of the mediastinum in eight cases, the pulmonary hilum in two cases, and both sites in one case. Adjuvant treatment after CUP resection consisted of chemotherapy in four cases, radiation therapy in one case, chemoradiation therapy in one case, and no additional treatment in four cases. The period between diagnosis of CUP in the LN and detection of the pulmonary lesion averaged 48.3 months (range, 2–112 months). The pulmonary lesion was treated with surgery in nine cases and chemotherapy in two cases. The outcomes after pulmonary lesion treatment were as follows: five patients were alive without recurrence at an average of 16.8 months (range, 6–30 months), two patients were alive with recurrence at an average of 44 months (29 and 59 months), two patients had died of their disease after an average of 17 months (6 and 28 months), and two patients had died of other diseases after an average of 27 months (18 and 36 months). In general, when all CUPs are considered, the prognosis has been reported to be poor, with a 5-year survival of 2%–6% and a median survival time of 2–7 months.1–3) However, patients with CUP in the mediastinal LNs have been reported to have a relatively good prognosis when compared with patients diagnosed with primary lung cancer and mediastinal lymph node involvement;4,5,19,20) the median survival time of the former has been reported as 28 months19) and 30.7 months,20) representing a relatively good outcome.
Conclusion We have presented a rare case in which lung carcinoma was detected 5 years after the resection of CUP in the mediastinal LN. This case illustrates the importance of careful observation and long-term follow-up in patients treated for CUP in the intrathoracic LNs even when initial PET/CT results are negative.
Consent Written informed consent was obtained from the patient for publication of this case report and accompanying images.
Disclosure Statement The authors declare that they have no competing interests. Ann Thorac Cardiovasc Surg Vol. 22, No. 2 (2016)
Lung Cancer Detected 5 Years after Resection of Cancer of Unknown Primary
References 1) Holmes FF, Fouts TL. Metastatic cancer of unknown primary site. Cancer 1970; 26: 816-20. 2) Pavlidis N, Briasoulis E, Hainsworth J, et al. Diagnostic and therapeutic management of cancer of an unknown primary. Eur J Cancer 2003; 39: 1990-2005. 3) Fizazi K, Greco FA, Pavlidis N, et al. Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2011; 22 Suppl 6: vi64-8. 4) Kohdono S, Ishida T, Fukuyama Y, et al. Lymph node cancer of the mediastinal or hilar region with an unknown primary site. J Surg Oncol 1995; 58: 196-200. 5) Riquet M, Badoual C, le Pimpec BF, et al. Metastatic thoracic lymph node carcinoma with unknown primary site. Ann Thorac Surg 2003; 75: 244-9. 6) Cafferata MA, Chiaramondia M, Monetti F, et al. Complete spontaneous remission of non-small-cell lung cancer: a case report. Lung Cancer 2004; 45: 263-6. 7) Rosai J, ed. Ackerman’s surgical pathology. Lymph node inclusions, 8th ed. St. Louis: Mosby, 1996. 8) Fellegara G, Carcangiu ML, Rosai J. Benign epithelial inclusions in axillary lymph nodes: report of 18 cases and review of the literature. Am J Surg Pathol 2011; 35: 1123-33. 9) Kwee TC, Kwee RM. Combined FDG-PET/CT for the detection of unknown primary tumors: systematic review and meta-analysis. Eur Radiol 2009; 19: 731-44. 10) Kita Y, Kondo D. Occult lung cancer with sarcoidosis; a case report. The primary lesion appeared on chest X-ray taken 18 months after resection of mediastinal lymph node metastases. Jpn J Chest Surg 1996; 10: 488-93. (in Japanese with English abstract) 11) Matsuge S, Hosokawa Y, Sato K, et al. An occult intrapulmonary large cell neuroendocrine carcinoma presenting mediastinal lymph adenopathy as an initial manifestation. Jpn J Chest Dis 1999; 58: 668-72. (in Japanese with English abstract)
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