Abstract
We report on an unusual case of laterocervical bilateral metastatatic masses with unknown clinical, radiological or computer tomographicic detected primary site of origin. Cancer of an unknown primary site is a clinical syndrome, accounting for 2%-5% of patients with cancer. The peculiarities of our case are its evolution as fast-growing bilateral tumor masses with involvement of other neck structures and its unexpected origin from the lung, certified by complementary immunohistochemical tests following surgery, in the absence of any other clinical signs or any detectable lung tumor mass by radiological or computer tomographic tests.
Carcinoma of an unknown primary site is defined as a histological diagnosis of metastasis without any evidence of its emerging from a certified primary tumor. In 1882, Volkmann was the first to describe three cases of laterocervical lymph node metastasis in region II, while a primary malignant tumor could not be diagnosed (1). Since these malignant tumors were located in all three cases in regions typical for lateral cysts of the neck, Volkmann defined the disease as “deep branchiogenic carcinoma of the neck” (1). Up until the 1940s, several authors reported cervical lymph node metastasis of unknown primary site being caused by branchiogenic carcinomas of cysts of the neck. In 1944, Martin et al. was the first to clearly differentiate between branchiogenic carcinoma and the incidence of cervical metastasis from unknown primary site of origin (2, 3). Commes et al. described a cervical lymph node metastasis without diagnosis of a primary tumor and, for the first time, defined the malignant disease as “carcinoma of unknown primary” (CUP) (4). Later, the prerequisites for the diagnosis of a CUP syndrome were defined as follows: “biopsy and consecutive histological examination of a lymph node confirms malignant cell growth and makes a primary tumor at the location of the biopsy unlike, while physical examinations and those carried out with technical equipment do not detect any primary tumor” (5). The incidence of CUP in all patients with a malignant disease range between 3% and 15% (6). Histological examination of CUP metastasis most frequently shows adenocarcinoma (45%), followed by undifferentiated carcinoma (27%) and squamous cell carcinoma (15%). The remaining 13% of the cases include sarcoma, embryonic cell carcinoma and other rare malignant diseases (7). Previous studies of cervical CUP reported squamous cell carcinoma (65-76%) as the most frequent histopathological diagnosis, followed by undifferentiated carcinoma (13-14%), adenocarcinoma (13%) and lymphoepithelial (8%) carcinoma (8, 9). In approximately 10-40% of patients with cervical CUP, there is emergence of the occult primary tumor (9-12). Approximately 70% of all detected primary tumors are located in the head and neck region (e.g. the oral region, oropharynx, hypopharynx, nasopharynx and sinuses) if the middle and upper jugular lymph node regions of the neck are invaded by malignant squamous cells. Fewer than 20% of the emerging primaries are found within the lung or the thyroid gland (7, 11).
The management of patients with cervical CUP represents both a diagnostic and therapeutic challenge. The choice and timing of diagnostic procedures is still a matter of debate (9, 13, 14). Although there is no consensus regarding diagnostic procedures, it is generally accepted that the routine diagnostic workflow includes physical examinations, lymph node biopsy, diagnostic imaging with computer tomography, magnetic resonance imaging and 18-fluorodeoxyglucose positron emission tomography (FDG-PET) and further interdisciplinary consultations (8, 14). The impact of FDG-PET has not been completely established, but some promising reports have been published (14, 15). Unfortunately, the entire diagnostic workflow is usually finished without successful detection of a primary tumor. The choice of treatment is controversial and is often performed based on the histological differentiation of the tumor. Recommendations vary from surgery-alone in selected cases to ipsilateral radiotherapy and extensive prophylactic irradiation of all potential pharyngeal and laryngeal mucosal sites and both sides of the neck (12, 13, 16-18).
Case Report
A 43-year-old male, was admitted to the ENT Department for clinically-detected left laterocervical masses. The admission symptoms and signs were represented by the appearance of multiple cervical lymph node masses (47.4×20.4 mm involving the left parotid gland and submandibular area, round in shape, renitent, fixed on deep structures but mobile on superficial ones, with celsian signs of suprajacent skin: tumor, rubor, calor, without spontaneous and provoked pain), sicca cough, left upper limb paresthesia and edema, and 5 kg weight loss during the previous month. The patient had smoked 20 cigarettes/day for the previous 18 years. No other comorbidities were associated.
Clinical examination revealed, together with multiple cervical lymph node masses previously described, a left axillary lymph node mass (15 mm in diameter, round in shape, hard consistency, fixed on deep, but mobile on superficial structures, without celsian signs of suprajacent skin (Figure 1). Chest X-ray corresponded to a normal thoracic image. Cervical and thoracic contrast enhanced CT scan showed a non-homogenous mass of 4.74×2.04 cm, localized at the level of the left parotid gland and submandibular area, involving adjacent vascular structures. Cervical lymph node masses presented maximal axial diameter of 9.1 cm (Figure 2). Lung transparency was normal, no mediastinal lymph node enlargement was encountered. A hyperdense area appeared at the level of the T1 vertebral body (osteocondensant secondary dissemination aspect). Blood tests revealed: red blood cell sedimentation rate=88 mm/h, white blood cells=6200/mm3, granulocyces=78.4%, lymphocyte=17.2%, monocytes=4.4%, red blood cell=3,620,000/mm3, Platelets=245,000/mm3, hemoglobin=10.6 g/dl, hematocrit=33.6%. Possible sites of primary tumor were assessed by 00 nasal and rhinopharyngeal endoscopy, 700 hypopharingolaringoscopy, oesophagoscopy and suspended microlaryngoscopy. A slight edema of the left lateral hypopharyngeal wall and salivary stasis due to compression by the cervical lymph node masses were revealed. Several blind biopsies were performed from the rhinopharyngeal, oropharyngeal, hypopharyngeal and supraglottic areas, without successful identification of a primary tumor site.
The cervical lymph node masses grew rapidly and became bilateral in only two weeks after admittance. The axilary tumor increased and the upper limb edema become more evident. The patient was further assessed in Haematologic, Thoracic Surgery and Gastroentherology Departments. Enhancement MRI revealed multiple bilateral cervical bilateral lymph node masses (level Ia/Ib sublingual, submandibular; level IIa/IIb and III, jugulocarotid superior and middle) which were confluent and infiltrated the parotid glands, maseter, lateral pterygoid and sternocleidomastoid muscles and subcutaneous fatty tissue. The contrast showed lymph node involvement in infra, supraclavicular and axilar areas. The aspect was suggestive of Hodgkin's lymphoma. The next step in diagnosis was a left exploratory cervicotomy; a diffuse infiltrative tumor involving lateral and anterior cervical areas (parotid gland, maseter, lateral pterygoid and sternocleidomastoid muscles and subcutaneous fatty tissue) was assessed. The patient acquired respiratory insufficiency and dysphagia due to a marked hypopharyngeal edema and glottic space reduction revealed on 700 hypopharingolaryngoscopy. A tracheostoma and a nasogastric feeding tube insertion were performed.
Multiple cervical lymph node masses and a left axillary lymph node mass.
Biopsies were performed from the tumor mass localized medial to the sternocleidomastoid muscle and lateral of the internal jugular vein. Histopathological evaluation on routine hematoxilin and eosin stain revealed an extensive tumor area composed of groups of malignant epithelial cells with high-grade anaplasia separated by large bands of connective tissue and mixed with striated muscle tissue (Figure 3A) and lymph node remnant tissue at the periphery of the tumor mass. Tumor necrosis, vascular stasis and large hemorrhagic areas were also observed, together with several intravascular tumor emboli and perineural invasion. Few scattered cells from malignant epithelial areas seem to have squamous-like morphology but this appearance was not strong enough evidence to diagnose this tumor as a squamous cell carcinoma arising from the head and neck region. To clarify the diagnosis, a panel of immunohistochemical staining was performed, including vimentin, pankeratin (AE1/AE2 type), and specific monoclonal keratins 7, 18, 19, 20, leucocyte common antigen (LCA, CD 45) and thyroid transcription factor-1. All tumor cells had intensly-positive reaction for AE1/AE3 type keratin (Figure 3B) and negative imunostaining for vimentin, although we detected very rare vimentin-positive epithelial cells inside the tumor areas (Figure 3C), suggesting the presence of epithelial-to-mesenchymal transition. This could explain, partially, the high rate of this tumor development and its aggresive behaviour. Negative immunostaining was observed in tumor cells for CD45, this aspect being an exclusion criteria for the previously suspected Hodgkin's lymphoma diagnosis. Immunophenotyping regarding monoclonal keratins revealed intense positive reaction for keratin 7 and 18 (Figure 4A and 4B), weak, inconsistent positivity for CK19 (Figure 4C) and negative immunostaining for CK20 (Figure 4D). This immunophenotype, together with an intense nuclear-positive reaction for TTF1 in all tumor cells, strongly suggested the lung as the primary site of the tumor (Figure 4E). Most probably, in view of the already presented immunophenotype, the tumor originated from the terminal bronchioles of the lung, as an occult bronchioloalvelor carcinoma.
Enhancement magnetic resonance imaging – multiple bilateral cervical bilateral lymph node masses (level Ia/Ib sublingual, submandibular; level IIa/IIb and III, jugulocarotid superior and middle), confluent, infiltrate the parotid glands, maseter, lateral pterygoid and sternocleidomastoid muscles and subcutaneous fatty tissue. The contrast showed lymph node involvement in infra-, supraclavicular and axillar areas.
Discussion
Bronchioloalveolar carcinoma is a special type of lung cancer, characterized by lepidic growth along pre-existing airway structures, without detectable invasion or destruction of the underlying tissue, blood vessels, or lymphatics (19). Because of this special growth pattern, clinical, radiographic and computer tomographic signs can be absent, and, for these reasons, bronchioloalveolar carcinoma has also been called the masquerader. These data confirm the absence of clinical and radiological signs for our case. Three articles are available reporting metastases inside thyroid, ovary or pituitary, as a first clinical manifestation of a bronchioloalveolar carcinoma (20-22). One reported the presence of extrathoracic malignancies (most of them diagnosed as head and neck squamous cell carcinoma) followed, at a variable time from the first diagnosis, by detection of a solitary pulmonary nodule which was then classified as bronchioalveolar carcinoma (23). We speculate that most of these cases were underevaluated, in part, due to the silent development of bronchioloalveolar carcinoma in the lung and we consider that most of those extrathoracic primary tumours could represent metastasis from an undetected primary bronchioloalveolar carcinoma.
Histopathology of cervical metastasis (A) with tumor cells being positive for AE1/AE3 keratin (B), and negative for vimentin (C). Scattered cells were positive for vimentin, this aspect being suggestive of an epithelial to mesenchymal transition development.
Immunohistochemical intense positive reaction for keratin-7 (A), keratin 18 (B), scattered and low expression of keratin-19 (C), together with negative reaction for keratin-20 (D), thyreoglobulin and a high expression of thyroid transcription factor-1 in all tumor cells support a bronchioloalveolar carcinoma-origin of cervical metastasis.
The present article reports, to our knowledge, for the first time unusual first clinical evidence of lung cancer as metastatic masses, bilateral in the cervical lymph nodes, mimicking a head and neck squamous cell carcinoma and lacking radiological and computer tomographic evidence of lung cancer. For this case, the use of immunohistochemistry was mandatory and the results, including positive reaction for keratin AE1/AE3, keratin 7, 18 and especially TTF1, correlated with negative immunostaining for keratin-20 and vimentin, helped us to diagnose this case as a brochioloalveolar carcinoma metastatic to the bilateral cervical lymph nodes. Another particular feature of this case is the presence of the left axillary lymph node metastasis accompanied by lymphangitis carcinomatosis, aspects reported in fewer than 1% of patients with bronchioloalveolar cancer (24). At histological analysis, lymphangitis carcinomatosis is characterized by hematogenous dissemination of tumor microemboli and subsequent invasion of vessel wall, resulting in deposition of tumor in the interstitium surrounding the lymphatics. Lymphangitis carcinomatosis may result from retrograde spread of tumor from involved lymph nodes, an uncommon occurrence (25).
The prognosis of the patient is very poor because of the presence of cervical and axillary lymph node metastases, lymphangitis carcinomatosis, high-grade nuclear anaplasia of the tumor cells and bronchioloalveolar type carcinoma. Newly revised TNM-7 incorporates changes to the staging of non-small-cell lung carcinoma that were recommended by the International Association for the Study of Lung cancer, Lung Cancer Staging Project, but no evident improvements have been made in the evaluation of bronchioloalveolar carcinoma in this revision (25). The few cases (five in the literature) showing different sites of metastasis as the first clinical sign of a bronchioloalveolar carcinoma were not enough to include such an entity in the newly-revised TNM 7 staging of NSCLC.
Acknowledgements
This article was supported by Doctoral Grant NO: 970/31.01.2013 of Victor Babes University of Medicine and Pharmacy, Timisoara, Romania.
- Received January 6, 2013.
- Revision received April 4, 2013.
- Accepted April 5, 2013.
- Copyright © 2013 The Author(s). Published by the International Institute of Anticancer Research.
References
In this issue
Jump to section
Related Articles
Cited By...
- No citing articles found.