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[Electron microscopy of needle biopsies from cancer patients with unknown primary tumors].

The aim of the present study was to evaluate the diagnostic value of electron microscopy (EM) performed on Surecut biopsies from patients without known primary tumour. The material consisted of 108 consecutive biopsies, obtained over a period of two years, from patients with tumour(s) in the liver or lymph nodes (on the neck, in the axilla or retroperitoneum). From each patient fine needle aspirations and Surecut biopsies for light microscopy and electron microscopy were taken. Only biopsies in which material for both electron microscopy and light microscopy was sufficient were included (60%). Immunohistochemical reactions were performed on paraffin sections when indicated. Final diagnoses were confirmed on surgically removed specimens and/or autopsies. Electron microscopy was necessary for obtaining the final histological diagnosis in 15% of the cases. It is therefore recommended to obtain additional ultrasound guided biopsies for EM from cancer patients with tumours in the liver or lymph nodes in cases where the primary origin of the tumour is unknown.

Biopsy, Needle↗

Massive deep venous thrombosis and venous gangrene in a 29-year-old case: metastatic epidermoid carcinoma with an unknown primary.

Cancer-associated venous thromboembolism is a severe form of paraneoplastic syndrome. It rarely leads to venous gangrene. We report a case who presented with multiple deep venous thrombosis and venous gangrene of the lower extremity. During the follow-up period, the patient developed bilateral cervical and right supraclavicular lymphadenopathies. The fine needle aspiration of the lymph nodes revealed metastatic epidermoid carcinoma of an unknown primary. Thrombotic manifestations may complicate the clinicopathological course of malignancies.

Adult↗

Metastatic thyroid cancer occurring as an unknown primary lesion: the role of F-18 FDG positron emission tomography.

Thyroid cancer can appear as metastatic disease of an unknown primary origin, and fluorine-18 fluorodeoxyglucose (F-18 FDG) positron emission tomographic (PET) studies are helpful in the workup evaluation of these patients. The authors describe two patients who had metastatic disease from an unknown primary lesion. F-18 FDG PET studies played an important role in localizing the primary malignant site in the thyroid gland. The utility of F-18 FDG imaging in decreasing the number of procedures, cost, and inconvenience to patients is shown clearly in both cases.

Aged↗

[A study of cervical metastases from unknown primary tumor].

Cervical metastases of cancer of an unknown primary tumour (CMUPT) are infrequent but they represent botha diagnostic and therapeutic challenge for ENT physicians. We present a retrospective study over 22 patients with CMUPT diagnosed in our hospital during 13 years (3.4% of the patients with head and neck cancer). The sensitivity of the fine-needle aspiration technique was 94.7%. 54% were N2a, 36% N3 and 9% N2b. 73% were squamous cell carcinoma and 27% were undifferentiated carcinoma. We established our protocol on diagnosis and management: panendoscopy with biopsies of nasopharynx, vallecula and pyriform sinus and ipsilateral tonsillectomy. The primary source was identified in 23% of the series. All squamous cell carcinoma were treated with radical neck surgery plus radiotherapy and the undifferentiated carcinoma with chemotherapy and radiotherapy. The overall survival was 64% at 3 years. The N-stage affected the survival rate.

Adult↗

Value of neck dissection in patients with squamous cell carcinoma of unknown primary.

Lymph node metastases of cancer of an unknown primary (CUP syndrome) are responsible for 3-5% of the malignant diseases in the head and neck area. More than 70% of these patients show lymph node metastases of an unknown squamous cell carcinoma. The survival depends immediately on number and location of lymph node metastases. For a curative approach modified radical neck dissection combined with postoperative radiation therapy with or without chemotherapy should be considered in N1-N3 lymph node status. A radical neck dissection with postoperative radiation therapy should only be approved in cases of infiltration of the internal jugular vein, the accessory nerve and/or the sternocleidomastoid muscle. The different prognosis of patients with upper cervical and lower cervical lymph nodes should influence the indication and the extent of a neck dissection in the contralateral N0 neck.

Carcinoma, Squamous Cell↗

[Immunohistochemical diagnosis in cancer metastasis of unknown primary tumor].

Immunohistochemical studies on metastatic carcinomas of unknown primary site are cost-effective and often allow a specific identification of the tumour origin, especially if the metastases are adenocarcinomas by light microscopy. Commercially available site-specific markers include prostate-specific antigen, thyroglobulin, thyroid transcription factor-1, uroplakin III, GCDFP-15, oestrogen and progesterone receptors, alpha-fetoprotein, the A103 monoclonal antibody against MART-1, cytokeratins 7 and 20, cytokeratins of basal cell type, p63, carcinoembryonic antigen, CA125, EMA, vimentin, HepPar-1, WT-1 and S100 protein. However, immunostaining with most of these markers does not show an absolute specificity for a certain primary site. For this reason, histopathologists interpretating staining results with these markers should take the available clinical data and the histological features of the metastatic carcinoma into consideration. These data are necessary to estimate the relative a priori probability of possible carcinomas. Based on Bayes' theorem, the a priori probability can then be used to calculate the diagnostically relevant predictive values for immunostaining results with the chosen markers.

Biomarkers, Tumor↗

FDG PET in patients with cancer of an unknown primary.

BACKGROUND: This prospective study was undertaken to address the capacity of positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) to determine the primary tumour site of carcinomas with unknown primary site. PATIENTS AND METHODS: Twenty-five patients with metastases from adenocarcinoma or undifferentiated carcinoma of unknown primary site (CUP) were included prospectively. For all patients, extensive imaging was unsuccessful in localizing the primary site. Patients received 370 MBq of 18F-FDG intravenously, and whole-body images were acquired 60 min after injection. All hot spots that could not be attributed to a metastatic site were considered as the primary tumour. The evaluation of FDG PET data was based on clinical and radiological outcome or surgery if indicated. RESULTS: Twenty-four patients were eligible for analysis. All known metastases were visualized. In six patients, FDG PET showed a primary tumour site which was confirmed by follow-up or surgery. In five patients, the primary tumour site was suggested by FDG PET but not confirmed by clinical outcome. No primary tumour was found in the other patients, with a mean follow-up of 15 months. CONCLUSION: In our series, FDG PET allowed the identification of primary tumour site in one quarter of patients with CUP (6/24). We conclude that FDG PET has a place in the initial staging of these patients.

Adenocarcinoma↗

[A case of the cancer of an unknown primary site with elevated titer of serum CEA which was followed by the right sleeve upper lobectomy and mediastinal lymph node dissection].

A 63-year-old man was admitted because of right pneumothorax. As serum CEA revealed high titer, we underwent further evaluation, but we were not unable to find any lesion except mediastinal and hilar lymph node swelling. Though we performed sleeve resection of right upper lobe and mediastinal lymph node dissection, we were not unable to find primary lesion. But serum CEA was reduced markedly after surgery and we are not able to find the apparent primary site after that.

Adenocarcinoma↗

Detection of primary breast cancer presenting as metastatic carcinoma of unknown primary origin by 111In-pentetreotide scan.

Women with isolated metastatic carcinoma or adenocarcinoma involving axillary lymph nodes are a well-recognized group of unknown primary carcinoma (UPC) patients with a favorable prognosis. This group of patients are generally treated based on the assumption that they have occult breast cancer. However, to facilitate patient access to the whole spectrum of therapies available for patients with breast cancer, including strategies involving the use of high-dose chemotherapy, a precise diagnosis is increasingly important. In this clinical case we report the detection of a primary breast cancer by 111In-pentetreotide scanning in a woman who presented with metastatic carcinoma in axillary nodes, no palpable breast lesion, a nondiagnostic mammogram, and negative breast ultrasonography. Previous outcomes analysis of patients with UPC have emphasized the value of identifying women with breast cancer. This report suggests that the 111In-pentetreotide scan can contribute specific, clinically useful information in the evaluation of women presenting with metastatic carcinoma in axillary nodes and an occult primary and deserves prospective study in women with UPC presenting with isolated axillary metastases.

Algorithms↗

Adenocarcinoma of unknown primary: retrospective analysis of chemosensitivity of 313 freshly explanted tumors in a tumor cloning system.

Cancer of unknown primary origin is the eighth most common form of malignancy and accounts for up to 10% of all neoplasms diagnosed. It is a set of heterogenous tumors with widely varying sensitivity to systemic chemotherapy. Over the past years progress has been made in identifying subsets of patients that can be effectively treated with chemotherapy and may achieve long-term survival even with metastatic disease. However, the large majority of cancers of unknown origin still is resistant to chemotherapy. In an attempt to identify conventional and investigational new agents with possible activity against cancers of unknown primary, we have retrospectively analyzed the results of chemosensitivity testing in a soft agar cloning system in vitro and have compared these data with published clinical trials. Between 1978 and 1993, a total of 19584 tumor specimens were studied using a variety of investigational or established antitumor agents. Of these, 615 (3.1%) were tumors of unknown origin and confirmed on pathology review. The largest histologic subgroup was adenocarcinoma (332, 54%). Sufficient numbers of cells for in vitro testing were obtained from 313 tumor specimens (94.3%). Of 278 agents tested in adenocarcinoma of unknown origin, borderline activity (< 20% in vitro response) was noted for 5-FU, doxorubicin, bleomycin, mitoxantrone, mitomycin-C, cisplatin, and etoposide. In vitro response rates of > or = 20% were observed for actinomycin-D, BCNU, melphalan, methotrexate, taxol, and vinblastine. In addition, several investigational agents including fludarabine, amira235, bisantrene, Dupont840, echinomycin, tiazofurin, LY104208 (vinzolidine), intoplicine, and topotecan had activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗

Role of 18F-FDG PET-CT imaging for the detection of an unknown primary tumour: preliminary results in 21 patients.

PURPOSE: Metastatic cancer of unknown primary origin is a syndrome characterised by a poor prognosis, with a typical survival rate from diagnosis of no longer than 1 year. Only 20-27% of primary tumours are identified by conventional radiological imaging. By contrast, it has been reported that 18F-fluorodeoxyglucose positron emission tomography (FDG PET) allows the identification of 24-40% of otherwise unrecognised primary tumours. To our knowledge, the studies on this topic have been conducted using 18F-FDG PET imaging alone. The aim of this study was to evaluate the potential additional diagnostic role of fused 18F-FDG PET-CT imaging for the detection of metastatic occult primary tumours. METHODS: The study population consisted of 21 consecutive patients with biopsy-proven metastatic disease and negative conventional diagnostic procedures. Each patient underwent a PET scan, carried out according to a standard procedure (6 h of fasting, i.v. injection of 370 MBq of 18F-FDG and image acquisition with a dedicated PET-CT scanner for 4 min per bed position). RESULTS: 18F-FDG PET-CT detected the occult primary tumour in 12 patients (57% of cases), providing a detection rate higher than that reported with any other imaging modality, including conventional 18F-FDG PET. CONCLUSION: The favourable results of this study need to be confirmed in larger patient populations with long-term follow-up.

Adenocarcinoma↗

Cancer to the inguinal nodes from an unknown primary site.

Three cases of metastatic cancer to inguinal lymph nodes from unknown primaries are presented. All three patients had exhaustive workups which produced no primary lesions. There were two cases of metastatic squamous cell carcinoma and one of melanoma. A review of the literature shows that it is unusual to have metastatic disease without detectable primary lesions to the inguinal lymph nodes. Furthermore, and more importantly, these cases open discussion of recent concepts of tumor biology. Based on these newer concepts, suggestions are made concerning the examination and treatment of these unusual lesions.

Aged↗

Severe non-haematological toxicity after treatment with gemcitabine.

The authors report that 4 out of a series of 56 patients (7.1%) treated with gemcitabine developed an unexplained non-cardiogenic pulmonary distress syndrome most likely related to gemcitabine. One further patient developed ventricular arrhythmia immediately after gemcitabine exposure, leading to cardiac arrest. Between 1995 and 1998 56 patients with locally advanced or metastatic carcinoma were treated with gemcitabine. The patients suffered from breast cancer (n = 17), pancreatic cancer (n = 17), lung cancer (n = 12), cancer of unknown primary (n = 5), ovarian cancer (n = 2), oral cavity cancer (n = 2) and cancer of the bladder (n = 1). Their median age was 55 years, and there were 33 female and 23 male patients. Fifteen patients had been pretreated with radiation therapy: 2 had received radiation therapy involving the mediastinum as treatment for non-small-cell lung cancer and cancer of unknown origin respectively, 11 patients had had prior neoadjuvant or adjuvant radiation therapy of the chest wall for breast cancer and 2 patients had received radiation therapy for head/neck cancer. All patients received gemcitabine on days 1, 8 and 15 and this was repeated on day 29 at a dose of 1000 mg/m(2) as a 30-min infusion in 250 ml isotonic NaCl. In 4 patients gemcitabine treatment was combined with cisplatinum, in 7 patients with a somatostatin analogue and in 1 patient with epirubicin. All other patients received gemcitabine as a single agent. We assume that the pulmonary or cardiac toxicity of 5 patients was related to gemcitabine. In 3 patients re-exposure resulted in repeated toxicity. One patient did not receive gemcitabine again because of the life-threatening nature of the primary response. Two patients had received prior radiation to the mediastinum with 62 Gy and 50 Gy respectively, 3 years and 1 year before gemcitabine application. In our experience pulmonary toxicity after gemcitabine treatment is more common than initially anticipated. Gemcitabine should be used with caution in patients who have received prior radiation to the mediastinum.

Adult↗

Diagnostic strategies in cervical carcinoma of an unknown primary (CUP).

In patients with cervical cancer of an unknown primary (CUP), no established concept exists for the necessary diagnostic procedures. In order to find the primary tumor, extensive diagnostic steps are generally recommended; however, they are often not performed consistently. In the current study, we consistently used a diagnostic algorithm and analyzed its consequences on patients' prognoses. We retrospectively studied 57 patients who were found to have a cervical metastasis of the upper- or midneck and an unknown primary tumor after routine examination of the head and neck region. Patients were analyzed for the value of applied diagnostic measures, tumor classification, survival rates and frequencies of subsequent lymph node or distant metastases after the initial treatment. Our results showed that a diagnostic algorithm (lymph node biopsy, rigid panendoscopy with systematic biopsies of suspect regions as well as blind biopsies of endoscopically inconspicuous regions, including the tongue base and nasopharynx and bilateral tonsillectomy) led to the detection of 14 occult oropharyngeal and 5 nasopharyngeal primary tumors in the patients. These tumors were primarily diagnosed as CUP. Oropharyngeal tumors either grew submucosally or were so small that only microscopic evaluation of the entire tonsil uncovered the tumor. Imaging procedures (X-ray, ultrasound, CT, MRT and FDG-PET) as well as gynecological, urological and gastroenterological consultations did not reveal the primary tumors in any of the cases. The 3-year survival rate for the patients with occult oropharyngeal primary tumors was 100% after treatment, while the patients in which our diagnostic schedule did not reveal a primary tumor showed a survival rate of 58%. The prognosis of all of the patients with cervical carcinoma metastasis was dependent on the initial nodal stage. Metachronous metastasis after completion of the initial treatment was prognostically infaust, while secondary detection of the primary tumor was worthwhile during follow-up as long as further treatment options were offered. The prognosis of patients with cervical carcinoma metastases of the upper- and midneck is much more favorable than that of patients with a CUP syndrome of other localizations. Identification of an occult pharyngeal tumor is prognostically relevant, since it opens up the possibility of specific locoregional treatment. In patients with cervical CUP, blind but systematic pharyngeal biopsies, including bilateral tonsillectomy, should be performed.

Adult↗

Long-term intravenous hydroxyurea infusions in patients with advanced cancer. A phase I trial.

BACKGROUND: Hydroxyurea is an S-phase specific drug. Constant exposure of tumor cells with a low S-phase fraction to the agent may result in improved cell kill. Because of its short half-life, a continuous intravenous infusion may result in better tumor exposure than intake by mouth. The goal of this trial was to find the longest tolerable duration of a continued intravenous infusion of hydroxyurea (HU) given at escalating doses. METHODS: Eligible patients had histologically confirmed cancer without effective alternate therapy, normal blood counts, liver and kidney function. After giving informed consent, the infusion began via a permanent indwelling catheter utilizing a portable pump. Dose levels (in g/m2/d) were 0.5 for level I, 1.0 for level II, 1.66 for level III, and 2.5 for level IV. RESULTS: Fourteen patients were entered. Five were men. Median age was 56 years of age (range: 32-67), median performance status 1 (range: 0-2). Diagnoses were as follows: colorectal cancer, seven; unknown primary site, three; breast cancer, two; melanoma, one; and adenoid-cystic carcinoma, one. Nine patients were pretreated with chemotherapy. Three patients were entered per dose level, except on level I, were five were entered. The mean duration of infusion was 12 weeks on level I, 5 weeks on II, 3 on III, 1 on IV. Toxicity included leukopenia below 2.0 K/mm3 in one patient each on levels III and IV, thrombocytopenia below 100 K/mm3 in one patient each on levels II and IV, and stomatitis in three patients (one on level II and two on IV). This toxicity was dose limiting. One patient on level III, with an unknown primary, had an objective response. HU levels were measured by a modification of the Fabricius-Rajewsky method. Mean plasma levels in micrograms per milliliter (SEM) were as follows: level I, 3.6 (0.23); level II, 5.1 (0.57); level III, 10.1 (1.55); and level IV, 16.7 (one point). Fetal hemoglobin rose two-fold and five-fold in two patients on level I after 9 and 16 weeks on therapy, respectively. CONCLUSIONS: HU as a continuous intravenous infusion is well tolerated; the maximum duration of therapy is related inversely with the dose given. No major antitumor activity was seen. The greatest interest in the drug rests in its future use as a modulator and radiation potentiator. The increase in hemoglobin F was of interest and may be important in the treatment of sickle cell disease.

Adult↗