An interesting presentation Carcinoma of Unknown Primary (CUP)

K.A.Sudharshanamurthy, K.M.Srinath, M.G.Mahesh, R.Sunil
Medicine 2 Unit JSSMC & Hospital Mysore

A 65 year old male patient, an agriculturist presented with chief complaints of Fever and generalized weakness of 1 month duration .He was a chronic smoker with no significant past history or family history. General physical examination and systemic examination were normal with no detectable clinical findings. Investigations were carried to evaluate cause of fever and all the investigations for the fever work up were normal except for chest radiograph which was suggestive of miliary mottling. HRCT Thorax was reported to be having features of ILD. During the course in the hospital, patient continued to have fever and developed mild cognitive dysfunction. Neurological examination revealed only an extensor plantar reflex on the left side with no motor deficits. CT Scan Head revealed a small, irregular, enhancing hyperdense lesion involving parietal cortex suggestive of neoplastic lesion. MRI Brain with GADO and MRS revealed features suggestive of primary neoplastic lesion- Glioma.

Patient was subjected to craniotomy and excision of the tumor. Patient developed severe hyponatremia in the postoperative period, which was successfully treated. Histopathology of the tumour revealed metastatic adenocarcinoma with a probable primary in the lung. Patient and his family were not willing for further evaluation.

Cancer of unknown primary site (CUP) is a common clinical entity, accounting for 2 percent of all cancer diagnoses in the Surveillance, Epidemiology and End Results (SEER) registries between 1973 and 1987. The designation Carcinoma of Unknown Primary site implies that the pathologist, although confident of the diagnosis of malignancy, is unable on light microscopy to distinguish between a carcinoma, sarcoma or a hematologic neoplasm. The use of immunohistochemistry, electron microscopy, and chromosomal analysis has given a scope of identifying most of the neoplasms of unknown primary site as carcinomas, sarcomas, or lymphomas. The decisions confronting the clinicians are multifold: firstly, which investigations are justified to determine the primary site and to what extent should patients be examined? Which therapeutic regimen have to be adapted and worse, the prognostication.

Cancers of unknown primary are categorized into four major subtypes by routine light microscopy criteria:
1. Adenocarcinoma well–moderately differentiated – 50%
2. Undifferentiated or poorly differentiated adenocarcinomas - 30%
3. Squamous cell carcinomas – 15% and
4. Undifferentiated neoplasms - 5%.

Early dissemination, clinical absence of primary tumor, unpredictability of metastatic pattern and aggressiveness constitute the fundamental characteristics of these tumors. Early dissemination is reflected in the clinical absence of symptoms related to a primary tumor. More than 50% of CUP patients present with multiple sites of involvement, while the rest have a single site, most commonly in liver, bone, lung or lymph nodes.

The initial work-up of patients presenting with a presumed CUP should not be exhaustive, and should instead be geared toward evaluation of likely primary sites. This initial evaluation should include, a thorough history and physical examination (including a pelvic examination in women and a prostate examination in men), complete blood count, urinalysis, blood chemistries, a chest radiograph, and computed tomography (CT) of the abdomen and pelvis. The use of immunohistochemistry, electron microscopy, and chromosomal analysis may permit the identification of most neoplasms of unknown primary site as carcinomas, sarcomas, or lymphomas.


Immunoperoxidase Markers Useful in CUP
Tumour Type Immunoperoxidase Marker
Carcinoma Cytokeratin, EMA
Lymphoma CLA,EMA
Sarcoma Vimentin, Desmin, Factor VIII Ag
Melanoma S-100,HMB-45,Vimentin-45,NSE
Neuro Endocrine Chromogranin,Synaptophysin,Cytokeratin,EMA,NSE
Germ Cell Cytokeratin,EMA,HCG,AFP
Prostate Cancer PSA, Cytokeratin,EMA
Thyroid Cancer Thyroglobulin,Cytokeratin, EMA,Calcitonin
Breast Cancer Cytokeratin,EMA,PR,ER
AFP-Alpha Feto Protein, CLA-Common Leucocyte Antigen, EMA-Epithelial
Membrane Antigen, ER-Estrogen Receptor, HCG-Human Chorionic Gonadotropin,
NSE-Neuron specific enolase, PSA-Prostate Specific Antigen, PR-Progesterone
Receptor

Prognostic Factors
Patients with CUP have a limited life expectancy with a median survival of ∼6–9 months. However, some subsets have a better prognosis and enjoy longer survival.
Retrospective analyses have identified clinical and pathologic features associated with a favorable response to treatment with empiric chemotherapy. These include:
• Tumor location in lymph nodes or soft tissue in comparison, patients with involvement of the liver or bones have relatively poor prognosis.
• Fewer sites of metastatic disease
• Female sex
• Poorly differentiated carcinoma histology
• Good performance status
• Normal serum lactate dehydrogenase (LDH) level
• Normal serum albumin
• Normal lymphocyte count
Recommendations for the treatment of patients with CUP are
• All patients with good performance status should be considered for a trial of empiric chemotherapy.
• The best regimen has not been defined in prospective randomized trials. At present, the combination of Paclitaxel and Carboplatin is a reasonable choice for first-line therapy.
• The value of adding a third agent (either etoposide or gemcitabine) is unclear, based upon data from existing phase II trials.
• Patients with poor performance status are much less likely to benefit from chemotherapy, and optimal management may include supportive measures only.

References:
1. Management of carcinoma of unknown primary site (CUP), any changes? Editorial Annals of Oncologv 12, 431-432. 2001
2. Cancer of unknown primary: biological and clinical characteristics
N. Pavlidis. Annals of Oncology 14 (Supplement 3): iii11–iii18, 2003
3. Muir C. Cancer of unknown primary site. Cancer 1995; 75: 353–356
4. Carcinoma of unknown primary site: treatment with 1-hour paclitaxel, carboplatin, and extended-schedule etoposide. Hainsworth JD; Erland JB; Kalman LA; Schreeder MT; Greco FA J Clin Oncol 1997 Jun;15(6):2385-93