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Grand Rounds

Case Presentation
Carcinoma of Unknown Primary

By Janet Robbins Hosenpud, M.D.; Assistant Professor of Medicine

G.A. is a 28-year-old Hispanic man who presented to a health care provider in the summer of 1994 with complaints of chest tightness unrelated to exertion or breathing. A CXR revealed hilar and mediastinal adenopathy, and a CT scan essentially confirmed these findings, plus demonstrated a paraspinal mass in the T3 to T5 region. Mediastinoscopy showed reactive hyperplasia of the nodes, as well as features of sarcoid. He was started on Prednisone, which was slowly tapered during the next three months. Over the next several months he noted slowly progressive mid-thoracic back pain. Finally, in November of 1994 he presented to his health care provider with lower extremity parasthesia and rapidly progressing lower extremity weakness. He was transferred to Froedtert Hospital for further care, and was admitted to the neurosurgery service.
On admission, he was noted to be completely paraplegic, unable to move or feel from the level of umbilicus. An MR of the spine revealed a thoracic paraspinal mass and evidence of cord compression. An angiogram revealed the mass to be hypervascular. A fine needle aspirate of the mass showed clusters of small round cells consistant with a "neoplasm." The mass was angiographically embolized and 24 hours later the patient was taken to the operating room where he underwent excision of the posterior mediastinal mass, partial T3 and T4 corpectomies, anterior spinal cord decompression, a T2 to T3 anterior fusion, and a T2 to T10 posterior fixation. The pathology of the mass was consistant with a epithelial malignancy. PAS stains showed little or no glycogen in the tumor cells. Immunoperoxidase stains revealed: leukocyte common antigen negative, chromografin negative, low molecular weight cytokeritin positive, factor VIII negative, MMB 45 negative, neurofilament negative. Electron microscopy showed the cells to be poorly differentiated with rare junctional complexes, there were no glycogen aggregates or lipid-glycogen aggregates typical of Ewings sarcoma, no cytoplasmic inclusions consistant with dense-core neurosecretory granules were seen.
Between December 1994 and February 1995 the patient received 4 cycles of chemotherapy consisting of Ifosfamide, cis-Platinum, and Etoposide. During this time he was followed closely be the rehabilitation service, and experienced progressive improvement in his lower extremity strength, and progressive normalization of sensation. He went from being wheelchair-bound, to walking into the clinic with his children. CT scans of the thoracic spine have shown no abnormalities other than post-operative changes, which have been stable.
It is estimated that carcinoma of unknown primary occurs in 3 to 15% of all patients referred to medical oncologists. Despite advances in immunocytochemistry and the use of monoclonal antibodies to help with our assessment, these neoplasms continue to bedevil oncologists. In fact, the "unknown primary carcinoma" (UPC) is a distinct entity in the medical oncology literature. While traditional teaching in medical schools is that an exhaustive search for a primary site in these patients is not warranted, a recent review of these cases and their treatment argues that limited searches may benefit some patients. (1) This review 879 patients referred to MD Anderson revealed that of the patients whose primary site COULD be found, (20% of the total), there was improved survival (11 months vs. 15 months). The group with known primary tumors had a 10% better survival each year. The improvement in outcome of the "known" UPCs was mainly the result of finding treatable cancers such as lymphoma, breast cancer, ovarian cancer and germ cell malignancies. Almost a third of the "unknown primary cancers" were able to be identified simply by a complete pathology review. The identification of a group of unsuspected lymphomas was a major reason why these patients had a relatively better outcome.
In a previous review by the same group (2), a sub-set of patients with a favorable prognosis were confirmed: those with axillary node involvement, and those with neuroendocrine cancer. Patients with poorer outcomes were males with non-neuroendocrine hepatic metastasis, and supraclavicular lymph node metastasis. Not suprisingly, it appeared that patients presenting with multiple metastatic lesions had a poorer outcome. These reports seem to confirm a survival advantage to patients with the gamut of more treatable cancers such as breast cancer, small cell carcinoma, lymphoma and ovarian cancer compared to the patients with the list of less responsive cancers such as pancreas, lung, or melanoma. Using the CT scan to definitively find the pancreatic cancer does not make it more responsive to treatment.
The younger, non-smoking patient with predominantly retroperitoneal and/or "midline" tumor involvement is in yet another group that are felt to have a particularly good outcome. In a review of UPC patients that seemed to be heavily weighted toward this population, Hainsworthe et all found a 63% response to cis-platinum based chemotherapy, and actuarial survival at 10 years was a relatively impressive 16%. (3) It appears, then, that a certain number of these patients will respond to and definitely benefit from both a recognition of their disease and systemic treatment. The guidelines in these patients seems to be first, do the simple tests that will simply find the most treatable malignancies (mammogram, chest x-ray, a complete physical exam including pelvic and rectal exams). Second, the pathology review is indispensable. Third, watch for the young man with predominantly midline disease, he has a chance for a long life.

Warmly, lillian
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