Wednesday, February 13, 2013

Metastatic squamous neck cancer with occult primary:

Metastatic squamous neck cancer with occult primary: 


The diagnosis of an occult primary tumor is made only if no primary tumor is detected after careful search, and it does not appear during therapy. Patients with cervical lymph node metastases histologically related to a previously treated primary tumor as well as patients with lymphomas and adenocarcinoma are excluded. If the 
biopsy is an undifferentiated carcinoma (in particular, a lymphoepithelioma), the most probable primary site is in Waldeyer's ring; for example, the nasopharynx, base of tongue, or tonsil. Most epidermoid carcinomas metastatic to lymph nodes of the upper half of the neck will originate from a head and neck primary site. Squamous carcinomas metastatic to the lower neck may represent a primary site in the head and neck, esophagus, lung, or genitourinary tract. A search for primaries in these areas must be undertaken before 
assuming that the primary is occult. Primary tumors cryptically arising in the nasopharynx may be secondary to Epstein-Barr Virus (EBV) infection, and EBV genomic material may be detectable in cervical nodal tissue after DNA amplification using the polymerase chain reaction. Such a finding should lead to an in-depth search for 
a primary in the nasopharynx.[1] The extent of investigation and type of treatment must be individualized depending on the age of the patient, site, and extent of the metastatic lymph node involvement, histology, and patient's wishes. When a patient qualifies as having squamous carcinoma of the neck with occult primary, check for other obvious metastatic disease, such as lung, liver, or bone, since this would affect the locoregional approach to therapy.[2] \Three-year disease-free survival rates following surgery and/or radiation therapy for unknown squamous primaries range from 40%-50% in N1 patients to 38% and 26% for N2 and N3 disease, respectively. Patients who later develop primary lesions have poor survival rates compared to those patients whose primaries remain occult, for example 30% versus 60%. A patient with neck metastases from an undetectable primary should not be abandoned but given the benefit of definitive treatment. significant number of patients do achieve cure by both surgical and radiotherapeutic approaches. In some patients, long-term repeat 
examinations will eventually disclose the primary tumor, and at a treatable stage. 


This section helps lead the clinician and pathologist through a differential diagnosis for an unknown primary presenting with cervical node metastases. The therapeutic section, however, relates only to squamous carcinoma and assumes that the primary physician has worked with the pathologist as described below to eliminate 
other possibilities that would require alternative therapies. The pathologist plays a central role in evaluating an occult primary tumor. A thorough evaluation of an adequate specimen through histologic or immunohistochemical techniques, and, when appropriate, electron microscopy (EM) provides guidance for the clinical evaluation that ensues. A critical interaction should exist between the pathologist, oncologist, and primary physician. 

The complexity of the pathologic evaluation tends to be inversely related to the degree of differentiation of the tumor. For instance, for well or moderately differentiated tumors, the pathologic diagnosis of an epithelial cancer is often readily apparent, in contrast to lymphoma, sarcoma, melanoma, or a germ cell tumor. 
Commonly used stains such as mucicarmine or diastase-sensitive Periodic Acid Schiff (PAS) can be important in confirming the diagnosis of certain tumors of gastrointestinal or renal origin. If the clinician is faced with a male patient less than 50 years of age with a poorly differentiated tumor, serum levels of bHCG and AFP 
should be obtained and specimens should be evaluated with immunohistochemical stains for bHCG and AFP. Certain of these tumors respond to platinum-based combination chemotherapy in a manner similar to extragonadal germ cell malignancies, and this group of patients should be so treated unless other alternative diagnoses are made.

Special studies can help in differentiating more poorly differentiated tumors. Often, a generic distinction is important between a poorly differentiated tumor of epithelial, hematopoietic, neuroendocrine, or neuroectodermal origin (i.e., melanoma). Immunohistochemical: Immunohistochemical studies can be important in making these broad distinctions, in particular, studies that evaluate staining for keratins, leukocyte common antigen (LCA), and 
S-100, a neuroectodermal antigen expressed in melanomas. Polymerase chain reaction: In patients with suspected nasopharyngeal carcinoma, DNA amplification of Epstein-Barr virus (EBV) genomes can be used for diagnosis with tissue provided by fine-needle aspiration biopsy. The presence of EBV in metastases from an occult primary tumor suggests the development of overt nasopharyngeal carcinoma.

Acinar spaces and microacini are seen with adenocarcinomas. Electron dense secretory granules are seen in tumors of neuroectodermal origin. Premelanosomes can be found in most amelanotic melanomas. But these features are generally associated with differentiation along a particular line. Often poorly differentiated tumors do not display such characteristics, and EM evaluation would be of little value. Electron microscopy may aid in distinguishing a primary diagnosis not obtained by light microscopy approximately 10% of the time.[4-6] 



The American Joint Committee on Cancer (AJCC) has designated staging 
by TNM classification.[1] 

TNM definitions

There is no tumor classification (T) for occult primary cancer metastatic to neck lymph nodes. 
Regional lymph nodes (N) The following regional node classification is applicable to all squamous carcinomas of the upper aerodigestive tract: 

NODES: Regional lymph nodes cannot be assessed N0: No regional lymph node metastasis N1: Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension N2: Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension, or in multiple ipsilateral lymph nodes, none 
more than 6 cm in greatest dimension, or in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension N2a: Metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension N2b: Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest 
dimension N2c: Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension N3: Metastasis in a lymph node more than 6 cm in greatest dimension 

In clinical evaluation, the actual size of the nodal mass should be measured and allowance should be made for intervening soft tissues. Most masses over 3 cm in diameter are not single nodes but are confluent nodes or tumor in soft tissues of the neck. There are 3 stages of clinically positive nodes: N1, N2, and N3. The use of 
subgroups a, b, and c is not required but recommended.Midline nodes are regarded as homolateral nodes. 

Distant metastasis (M) MX: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis There is no generally accepted Roman numeral staging system for this disease. 


Untreated metastatic squamous neck cancer with occult primary means that a patient is newly diagnosed and has had no prior treatment except supportive care. 



Patients with neck nodes from a presumed unknown primary tumor should be evaluated as follows: 1. Surgical biopsy or excision to establish a histologic diagnosis, but only after an aerodigestive tract primary has been carefully ruled out as in the following procedures: 

2. Direct nasopharyngoscopy, laryngoscopy, bronchoscopy, and esophagoscopy, with biopsy of any suspicious area.If no suspicious lesions are found, random biopsies of the nasopharynx, base of tongue, tonsil, and pyriform sinus on the side of the lesion should be performed. If the tonsil is not present, biopsy of the tonsillar fossa should be performed. Sinus x-rays are probably indicated; if abnormality is found, it should be biopsied as well. 

3. Selected other studies if indicated.In the detection of head and neck tumors and in the distinction of lymph nodes from blood vessels, magnetic resonance imaging (MRI) offers an advantage over CT scans and should be considered in the initial evaluation of the patient with metastatic squamous cell cancer in cervical lymph nodes.

Patients should be managed with either a full course of radiation therapy or adequate neck dissection, when possible. In cases of massive homolateral adenopathy that is fixed or bilateral nodes, radiation therapy should be administered first. The radiation fields should also include the nasopharynx, base of tongue, and pyriform sinuses. If radiation therapy is the primary mode of treatment and the neck mass persists upon completion of radiation therapy, cervical lymph node dissection should be performed. Patients with metastatic carcinoma in the supraclavicular region are best managed with a full course of radiation therapy followed by surgical dissection if palpable tumor persists. Careful continued follow-up of these patients is of utmost importance. Depending on the likely site of origin and histology, chemotherapy appropriate to the most treatable site may be indicated. 

Accumulating evidence has demonstrated a high incidence (>30%-40%) of hypothyroidism in patients who received external-beam irradiation to the entire thyroid gland or the pituitary gland. Thyroid function 
testing of patients should be considered prior to therapy and as part of post-treatment follow- up.

Treatment options: 
1. Radical neck dissection. 
2. Radiation therapy.[5,6] 
3. Combined surgery and radiation therapy.

Under clinical evaluation: 
1. Chemotherapy followed by radiation therapy. 
2. Simultaneous chemotherapy and hyperfractionated radiation 
3. Clinical trials for advanced tumors should be considered.
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