Some 3% to 6% of cancers present as metastatic lesions from an occult primary tumor,^4,14,19,47 making metastatic cancer with an unknown primary (CUP) the seventh most common malignancy.¹⁴ Lymph nodes (LNs) are the most common metastatic site and represent 31% to 46% of cases.^13,19,28,46 Cervical LN involvement without a primary is the most frequent^13,19 and is commonly reported in the “head and neck” literature. In contrast, metastatic cancer in thoracic LNs (peribronchial or/and hilar [N1] or mediastinal [N2])³⁶ is rare, even absent in some series of CUPs.¹³ It is more commonly reported as “case reports” (Tables 112-1 and 112-2). However, metastatic thoracic LNs were mentioned as early as 1970 and represented 1.5% of Holmes and Fouts’s CUP series.¹⁹

The majority of metastatic thoracic LNs with unknown primary are mediastinal LNs, most of them diagnosed by mediastinoscopy. The largest retrospective series on mediastinoscopy do not generally focus on this topic,^18,30 its frequency probably being underestimated. Three series mention that 11% to 16% of mediastinal LNs were metastases of an occult primary tumor.^8,10,50 Those patients were generally not operated, although most of them probably had resectable LNs. They represent small cohorts of 54,¹⁰ 45,⁸ and 23⁵⁰ patients, respectively. This last cohort consisted of as many patients as those collected from the literature in Table 112-2 (n = 22), among whom 6 were diagnosed by mediastinoscopy and only 2 were subsequently resected.^23,52 The 16 remaining patients underwent an exploratory thoracotomy for a suspected but never confirmed lung cancer. A mediastinal lymphadenectomy was performed after mediastinoscopy in only 1 of 8 patients treated by surgery,⁴² and suspicion of a lung tumor also motivated an exploratory thoracotomy in the other 7 cases. Thus, treatment of metastatic thoracic LNs is depending on the clinical presentation: either mediastinoscopy most often followed by a medical treatment when they present as T0N2 and either thoracotomy followed by surgery when they present as T0N1 or as suspicious tumors with resectable mediastinal LNs (N2).

Reviews of the literature^11,40 state that patients with metastases from a CUP have a median survival of approximately 6 months despite therapy, but some patients have more objective responses and better prognoses. Among these, those with extrathoracic LN metastases (axillary, cervical, and inguinal) have a better outcome with appropriate treatment. Patients with metastases to thoracic LNs only may have prolonged survival after treatment including surgery, as shown in Tables 112-1 and 112-2. Therefore awareness of this entity is of paramount importance.

Particular characteristics of patients with unknown primary malignancies metastatic to thoracic LNs are given in Tables 112-1 and 112-2 and are well described in a recent publication.⁴² About 25% were purely intrapulmonary (T0N1, Table 112-1) and 75% of patients presented with mediastinal N2 (Table 112-2). A specific profile may be defined as follows: right-sided (71% and 64% for N1 and N2 categories, respectively) and the age interval between 45 and 69 years for N1 patients and 44 and 78 years for N2 patients. Histology was either a squamous cell carcinoma or adenocarcinoma with no undifferentiated tumors for the N1 category. For the other category (N2), 75% of cases were based on an agressive histologic type, poorly or totally undifferentiated. Mediastinoscopy was used in almost one-quarter of N2 patients and never for N1 patients. No adjuvant treatment was given in 71% of N1 patients. The majority of N2 patients (73%) were treated with surgery, adjuvant treatment being given in 69% of them. The remaining patients (27%) underwent chemotherapy, radiotherapy, or both. No deaths or disease recurrences were observed in N1 patients, in contrast with N2 patients. The latter category had an excess of events (death or recurrence in 27% of cases). In case of mediastinal metastases, intrapulmonary “N1s” were observed in 20% of cases. The upper mediastinum was always concerned (aortopulmonary 5 and 6 LNs on the left and paratracheal 4R and 2R LNs on the right) except in one case (tracheal bifurcation, station 7). The N1 involvement (alone or associated with N2) was the main cause of lung resections; nine lobectomies and five pneumonectomies were performed. Mediastinal LN resection was generally performed by thoracotomy, but a video-assisted thoracoscopic surgery procedure was performed²³ and a sternotomy in three patients.^7,34,44 Resection of intrapulmonary LNs alone was performed in some cases.^37,42,53 It may be technically difficult, since this kind of surgery requires a careful dissection to avoid injuring pulmonary vessels as well as lung resection.

Thoracic LN metastases are generally observed when the primary malignancy is easily recognized. Mediastinal LN metastases of infradiaphragmatic malignancies are possible³² but rarely
appear as isolated secondary sites. However, LN metastases with a clear-cell carcinoma histology were reported in one patient.⁷ A renal cancer origin may be hypothesized in such a case and metastases explained by lymph reflux from the thoracic duct.^5,41 In fact, most metastatic thoracic LNs are due to small- or non-small-cell lung cancers, the lymphatic drainage of lungs passing through these LNs (N1 and N2 stations) being commonly involved.^36,43