Ann Thorac Surg 2003;75:244-249
© 2003 The Society of Thoracic Surgeons
Original article: general thoracic
Metastatic thoracic lymph node carcinoma with unknown primary site
Marc Riquet, MDa*,
Cécile Badoual, MDb,
Françoise le Pimpec Barthes, MDa,
Antoine Dujon, MDc,
Claire Danel, MDb
a Service de Chirurgie Thoracique, Hôpital Européen Georges Pompidou, 75015, Paris, France
b Service d’Anatomie Pathologique, Hôpital Européen Georges Pompidou, Paris, France
c Centre Médico Chirurgical du Cèdre, Boisguillaume, France
Accepted for publication July 26, 2002.
* Address reprint requests to Dr Riquet, Service de Chirurgie Thoracique, Hôpital Européen Georges Pompidou, 20-40 rue Leblanc, 75015 Paris, France.
e-mail: marc.riquet{at}hop.egp.ap-hop-paris.fr
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Abstract
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BACKGROUND: Metastatic cancer in thoracic lymph nodes without a primary site is rare. The purpose of this study is to draw attention to this probably underestimated entity, to speculate on its possible origins, and to suggest guidelines for its treatment.
METHODS: Eight heavy smokers with no past medical history of cancer were diagnosed at operation to have malignant cells in intrathoracic lymph nodes (N1 or N2) with no primary site in the lung. All patients underwent an exploratory thoracotomy with a presumed diagnosis of lung cancer except one who presented with a middle lobe mucosa-associated lymphoid tissue lymphoma. We reviewed the type of surgical resection, histologic and immunohistochemical analysis of resected specimens, treatments, survival, and long-term results.
RESULTS: Resections performed were pneumonectomy (n = 4), lobectomy (n = 3), and bilobectomy (n = 1). All patients underwent complete mediastinal lymph node dissection. Lung resection was performed for mucosa-associated lymphoid tissue lymphoma (n = 1) and for tumorlike lesions that appeared to be tuberculoma (n = 1) and intrapulmonary metastatic lymph nodes (n = 6). Malignant cells were located in intrapulmonary lymph nodes alone (n = 3) or also in mediastinal lymph nodes in three other cases. All these tumors were cytokeratin-positive, demonstrating their epithelial nature. Pulmonary origin was confirmed in two cases (thyroid transcription factor 1-positive and thyroglobulin-negative). No other origin could be demonstrated by immunochemistry. Three patients died within the first year. All other patients are still alive without recurrence (Kaplan-Meier 5-year survival rate, 62.5%).
CONCLUSIONS: Frequency of metastatic cancer in thoracic lymph nodes without a primary site is probably underestimated because the cancer is routinely diagnosed by mediastinoscopy and considered as metastatic disease not amenable to operation. The origin of the disease, either pulmonary, endogenous, or from extrathoracic sites, is often difficult to assess. Nevertheless, our data confirm those of the literature and demonstrate that survival can be increased by operation. This implies diagnosis of the entity and consideration that thoracic lymph node involvement can apparently be isolated and therefore resectable.
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Introduction
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Metastatic cancer from an undetermined primary site is known to occur in lymph nodes. Greager and colleagues [1] reported it as the most common metastatic site. However, metastatic cancer in thoracic lymph nodes (peribronchial, hilar, or mediastinal; N1 or N2) without a primary site is rare and has been seldom reported [2–6]. We report eight cases of metastatic intrathoracic lymph nodes (N1 or N2) without a primary site. The purpose of this report is to draw attention on a probably underestimated entity, to speculate on its possible origins, and to suggest guidelines for its treatment.
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Material and methods
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From January 1984 to April 2001, 2,348 patients underwent lung cancer operation in our department. In 8 patients malignant cells were detected in intrathoracic lymph nodes (N1 or N2) without a primary site in the lung. None of these patients had a history of previous cancer. All were men and were heavy smokers, with a mean age of 58 years (range, 49 to 73 years). Four patients presented without symptoms, 2 patients with chest pain, and 2 patients with cough. All patients underwent a thorough workup, which included chest roentgenography, fibrobronchoscopy, chest and brain computed tomography, and abdominal ultrasound scanning. Bone isotopic scanning was performed in 5 patients, and mediastinoscopy was performed in only one case for suspected malignant mediastinal lymphadenopathy.
A preoperative diagnosis of malignancy was obtained in only 2 patients: middle lobe mucosa-associated lymphoid tissue lymphoma in 1 patient (transbronchial biopsy) and squamous cell carcinoma in the other (mediastinoscopy). The remaining 6 patients underwent an exploratory thoracotomy with a presumed diagnosis of lung cancer because of a pulmonary mass in the right upper lobe (n = 1), right hilum (n = 3; Fig 1),
and left hilum (n = 2; Table 1). All patients underwent dissection of intrapulmonary (10, 11, and 12 on both sides) and mediastinal lymph nodes (2R, 4R, and 3 on the right, 4L, 5, and 6 on the left, and 7, 8, and 9 on both sides). Lymph nodes were classified according to Mountain and Dresler [7].
We reviewed the type of surgical resection, histologic and immunohistochemical analysis of resected specimens, treatment, survival, and long-term results. Histologic studies were conducted using paraffin-embedded specimens stained with hematoxylin and eosin and periodic acid–Schiff reaction with diastase digestion. For immunohistochemistry, staining was performed using an automated Ventana immunostainer (Ventana Medical Systems, Tucson, AZ) and a biotin-avidin method. Serial 5-µm paraffin sections were stained with various antibodies. Antibodies used are listed in Table 2:
EMA, CK7, CK20, AE1/AE3, thyroid transcription factor 1, thyroglobulin, calretinin, CD5, PS100, NCAM, NSE, synaptophysin, and prostate-specific antigen. This cytokeratin (CK7) is found in a wide variety of simple epithelia and carcinoma including those of lung. Its major utility is to exclude gastrointestinal adenocarcinoma, which are known to be positive with CK20. Thus, use of the CK7/CK20 carcinoma immunophenotype is a valuable diagnostic marker in the determination of primary site. These immunohistologic studies were performed to confirm the epithelial nature of the malignant cellular proliferation, to search for the primary site, and to eliminate possible endogenous lymph node cell origin [2]. Follow-up was obtained in all patients and ranged from 2 to 81 months (mean, 29.7 months).
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Results
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One patient underwent a right thoracotomy after mediastinoscopy, which resulted in the diagnosis of metastatic squamous cell carcinoma. He underwent a right pneumonectomy (because of a right hilar mass) and a mediastinal lymph node dissection. Recovery was uneventful, but he died 11 months later with brain metastases. The right hilar mass corresponded to enlarged hilar lymph nodes (N1), and although a primary tumor was carefully searched for, none was found in either bronchi or lung parenchyma. Another patient underwent a middle lobectomy for a mucosa-associated lymphoid tissue pulmonary lymphoma. A routine mediastinal lymph node dissection was performed. At histologic examination, an adenocarcinoma was discovered within mediastinal node 7 [7], but no carcinoma was found in the resected pulmonary lobe.
The other 6 patients underwent exploratory thoracotomy and lung resections because of lung opacities on computed tomographic scan (lobectomy, n = 2; bilobectomy, n = 1; pneumonectomy, n = 3) with radical mediastinal lymph node dissection. Lymph node involvement was classified as N1 (n = 3), N1 + N2 (n = 2), and N2 (n = 1). For these 6 patients, although a malignancy was carefully searched for, no intrapulmonary malignant cell proliferation was ever found. In these latter cases, the carcinoma was confined to lymph nodes, and the radiologic opacities observed before operation were a result of enlarged intrapulmonary lymph nodes (n = 4), lymphoma (n = 1), or a nonmalignant process such as tuberculoma (n = 1).
Results of histologic and immunohistochemical studies performed on metastatic lymph nodes are summarized in Table 2. All these tumors were cytokeratin-positive, showing their epithelial nature. Pulmonary origin was confirmed in only two cases (patients 6 and 8) with a positive thyroid transcription factor 1 and negative thyroglobulin. Three others were CK7-positive, and no tumor was labeled with CK20, prostate-specific antigen, CD5, or thyroglobulin.
Detail of treatments, adjuvant therapy, and long-term results of all patients are shown in Table 1. Five-year survival rate of the entire series calculated by the Kaplan-Meier method [8] was 62.5%. Three patients (N1, n = 1; N2, n = 2) died within the first year after operation. All other patients (N1, n = 2; N2, n = 2; N1+N2, n = 1) are still alive and faring well. In these 5 patients, no other cancer occurred during follow-up.
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Comment
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Approximately 3% of all cancers present with a metastatic lesion from an occult primary tumor [9, 10]. Overall, lymph nodes are the most common metastatic site [1, 11]. In the few studies reported in the surgical literature, most deal with lymph node metastases in the neck, and only a few described the mediastinal site [12, 13]. Metastatic cancer of mediastinal lymph nodes is rare. Holmes and Fouts [9] in a review reported only nine such cases from 686 metastatic cancers of unknown primary site. Mediastinal metastases of infradiaphragmatic malignancies are possible but appear rarely as isolated secondary sites [14].
Most metastatic cancers of mediastinal lymph nodes may be caused by lung cancer. Mediastinal lymph node metastasis is encountered in cases of small cell lung cancer. In such cases, it is a well-known feature of particular presentations such as may be observed in anti-HU paraneoplastic syndrome [15]. In non–small-cell lung cancer, mediastinal lymph node metastasis without a primary site is rare, and has only been described in case reports [2–4, 6].
However, mediastinal lymph node metastasis may also be diagnosed by mediastinoscopy [5, 16], and may represent as many as 45 of 342 patients as reported by Couraud and associates [16]. In our practice, we also managed by mediastinoscopy 325 patients presenting with isolated lymph node disease of the mediastinum: of these, 54 were metastases of a possible occult primary non–small-cell lung cancer [17]. Such a hypothesis was based on the fact that no patient suffered from a previous cancer and no cancer appeared during follow-up. A pulmonary origin was probable because all patients were heavy smokers, and the morphologic aspect of the tumor, although not specific, was compatible with that of a pulmonary origin. The above points were common with those of patients in the current series. Another fact supporting the pulmonary origin of the N1 or N2 location of malignant epithelial cells is that the lung lymphatic drainage passes through these lymph nodes and that they are the ones involved in lung cancer [7, 18]. The presence of intrapulmonary lymph node involvement in 6 of our 8 patients (75%) further supports this statement.
All patients in our series underwent an exploratory thoracotomy with a presumed diagnosis of lung cancer because of a pulmonary mass, one of them being a middle lobe mucosa-associated lymphoid tissue lymphoma. Therefore, they underwent only the standard prospective workup we routinely perform before operation, and mediastinoscopy was not included. In cases reported by Couraud and coworkers [16] and Faure and colleagues [17], mediastinoscopy had been performed for diagnosis purposes, and primary cancer, either intrathoracic or extrathoracic, was ruled out as we have discussed.
Nowadays, we think it would be advisable to look further for a primary. A multislice computed tomographic scan limited to the lung may prove mandatory. Positron emission tomographic scan, already a routine procedure in head and neck operation, although its value is not yet well established [19, 20], may be useful in permitting extrathoracic location screening. In such cases, however, mediastinoscopy would remain necessary to assess the histologic diagnosis.
With respect to mediastinal, hilar, or peribronchial lymph node metastases, histologic and immunohistochemical studies may help determine the nature of the primary tumor (lung, other organs, or endogenous lymph node cells). In the present series, we further searched for a primary site by immunohistochemical analysis. However, in only two cases could a pulmonary origin of the metastasis be confirmed. Tumor cells were thyroid transcription factor 1-positive in two cases of N1 involvement. Thyroid transcription factor 1 is a tissue-specific transcription factor expressed in normal lung and thyroid epithelial cells. Therefore, it is a very useful immunohistochemical marker in the diagnosis of tumors of lung origin [21, 22]. Complementary use of other immunohistochemical markers (prostate-specific antigen, CD5, thyroglobulin, calretinin, or vimentin) rule out the other possible primary sites.
The reasons for which metastatic cancers remain undiagnosed as to their primary origin are unknown; however, three main causes are commonly suggested [4]:
- The primary tumor is not large enough to be apparent by current means of clinical, radiologic, or pathologic examination This presupposes that the tumor never develops during follow-up, which was the case in our series.
- The primary tumor was removed and unrecognized in the past This presupposes previous operation, but none of our patients had undergone previous surgical resection of any kind.
- The primary tumor may have spontaneously regressed It is exceptional to see a non–small-cell lung cancer disappear and has been reported by Sperduto and coworkers [23], adding one case to two previous reports. The authors described an adrenal metastasis from a lung squamous cell carcinoma, but the mediastinal lymph nodes were not involved.
Finally, another hypothesis may be that there is no distant primary site: cancer may arise from endogenous cells present within the affected lymph nodes [2]. This remains to be confirmed and has never been demonstrated by recent immunohistochemical markers. Cancer may also arise from epithelial inclusions of lymph node themselves. The latter event is a common finding in high cervical lymph nodes [24]. Such benign glandular inclusions within intrapulmonary lymph nodes have only been described by Lin [25]. However, we also observed two cases of normal glandular inclusions in peribronchial lymph nodes (unpublished data, Fig 2). This endogenous origin is of paramount importance and requires further research.
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Fig 2. Benign glandular inclusions (arrowheads) in a peribronchial lymph node (arrows). Bronchial cartilage (*). (Hematoxylin and eosin, x40.)
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When metastatic lymph nodes are diagnosed by mediastinoscopy, operation is currently not performed. In our series, patients treated only medically did poorly [17]. However treatment by operation either combined with chemotherapy or radiation therapy may offer a chance of cure and may increase long-term survival. Our series supports this point of view not only for N1 patients but also in cases of N2 disease as suggested by rare published case reports (Table 3).
This is also supported by long-term survival currently reported after operation for extramediastinal lymph node metastasis without primary locations [1, 13, 26, 27]. Finally, the fact that carcinoma can arise from intranodal epithelial inclusions further supports the need for surgical removal.
Metastatic thoracic lymph node carcinoma without a primary site is considered a rare entity. However, its frequency is probably underestimated because it is routinely diagnosed by mediastinoscopy and considered as metastatic disease not amenable to operation. The origin of metastatic thoracic lymph node carcinoma, either pulmonary, endogenous, or extrathoracic, is often difficult to assess. Nevertheless, our data as well as those of others, although based on little data, demonstrate that the best results are obtained by operation. This implies diagnosis of the entity and consideration that thoracic lymph node involvement can apparently be isolated and therefore resectable.
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Abstract
Introduction
