This carcinoma must be distinguished from nasopharyngeal carcinomas. Indeed many studies often lump these tumors with the latter diagnosis. It is a distinct clinical-pathologic entity and is not related to Epstein-Barr Virus infection like the latter tumor. The nasal cavity is the most common location followed by the ethmoid and maxillary sinuses.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/
Other Diagnostic Testing
Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION SEX (M:F) 3:1
DISEASE ASSOCIATIONS CHARACTERIZATION
Malignancies arising in oncocytic schneiderian papillomas: a report of 2 cases and review of the literature.
Maitra A, Baskin LB, Lee EL.
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Arch Pathol Lab Med 2001 Oct;125(10):1365-7 Abstract quote
Oncocytic schneiderian papillomas (OSPs) are uncommon benign neoplasms that arise from the sinonasal schneiderian epithelium. Malignancies arising in OSPs are rare, and, to our knowledge, only 14 such instances have been reported in the medical literature.
We report 2 additional cases--a small cell carcinoma and a sinonasal undifferentiated carcinoma arising in OSPs and presenting synchronously with the benign neoplasm. The potential for malignant transformation in OSPs is small, but warrants that these papillomas be completely excised to exclude a coexisting carcinoma.
PATHOGENESIS CHARACTERIZATION Lack of EBV association
Am J Surg Pathol 2001;25:156-163
If stringent histologic criteria are applied to the diagnosis of SNUC, then the tumor is not associated with EBV
Sinonasal undifferentiated carcinoma: CT and MR imaging of an uncommon neoplasm of the nasal cavity.
Phillips CD, Futterer SF, Lipper MH, Levine PA.
Department of Radiology, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Radiology 1997 Feb;202(2):477-80 Abstract quote
PURPOSE: To determine the computed tomographic (CT) and magnetic resonance (MR) imaging appearance of sinonasal undifferentiated carcinoma.
MATERIALS AND METHODS: Findings from 11 patients with histopathologically proved sinonasal undifferentiated carcinoma were retrospectively reviewed. All 11 patients had undergone CT, and six of them had undergone MR imaging.
RESULTS: The tumors usually were large (larger than 4 cm in maximum dimension in eight patients), had poorly defined margins, and arose within the ethmoid sinuses and superior nasal cavity. The aggressive nature of the tumor was demonstrated by bone destruction (n = 10) and by invasion of adjacent structures, including paranasal sinuses (n = 10), anterior fossa (n = 7), orbits (n = 4), pterygopalatine fossa (n = 2), parapharyngeal space (n = 1), and cavernous sinus (n = 1). On contrast material-enhanced CT scans, all tumors were enhanced to varying degrees. They tended to be noncalcified (n = 10) and often caused sinus obstruction (n = 10). MR signal intensity of the lesions was isointense to muscle on T1-weighted images in all six patients and iso- to hyperintense on T2-weighted images in five patients. Heterogeneous enhancement of tumors was seen on gadolinium-enhanced images.
CONCLUSION: Sinonasal undifferentiated carcinoma cannot be distinguished from other tumors of this region (with the possible exception of melanoma) on the basis of imaging features.
CLINICAL VARIANTS/GROSS DISEASE CHARACTERIZATION
A clinicopathological study of sinonasal neuroendocrine carcinoma and sinonasal undifferentiated carcinoma.
Smith SR, Som P, Fahmy A, Lawson W, Sacks S, Brandwein M.
Department of Otolaryngology, Mount Sinai School of Medicine, New York, New York, USA.
Laryngoscope 2000 Oct;110(10 Pt 1):1617-22 Abstract quote
OBJECTIVE: Sinonasal undifferentiated carcinoma (SNUC) and sinonasal neuroendocrine carcinoma (SNEC) are relatively newly recognized, rare entities requiring further clinicopathological analysis to advance our understanding and determine prognostic distinctions between them.
STUDY DESIGN: Retrospective chart review.
METHODS: Cases were retrieved from the Copath system. One patient was seen in consultation from an outside institution. Histological and immunohistochemical findings, patient demographics, treatment regimens, and outcomes were analyzed and compared.
RESULTS: Ten patients (7 men, 3 women) ranging in age from 17 to 58 years (mean age, 44.7 y) were included. Four patients were classified with SNEC, six as having SNUC. The predominant site was the superior nasal cavity or ethmoids (seven cases), followed by the maxilla (four cases). Disease in four patients was clinically staged as N1 (three with SNUC, one with SNEC), and in six patients as NO (three with SNEC, three with SNUC). Of the nine patients who were treated initially with surgical resection, seven received postoperative radiation therapy alone, one received postoperative radiation and chemotherapy, and one had only limited postoperative chemotherapy. One patient was treated with radiation therapy and chemotherapy alone, without surgical resection. Follow-up was obtained ranging from 6 to 108 months (mean period, 26.4 mo). Three patients died of disease 10, 14, and 41 months, respectively, after diagnosis. Three patients had persistent disease at 6, 9, and 21 months, respectively, two of them with distant metastases. Four patients were disease free after 6, 18, 31, and 108 months, respectively.
CONCLUSIONS: SNUC and SNEC are both aggressive tumors, usually presenting in middle age as a nasal mass. Both tumors have the capacity to metastasize locally and distantly, and both can result in poor outcomes. This small series precludes a demographic or prognostic distinction between the two groups.
HISTOLOGICAL TYPES CHARACTERIZATION General
By definition, tumors with glandular or squamous differentiation, syncytial growth with numerous interspersed lymphocytes, intercellular fibrils, or Homer Wright rosettes are excluded
Flexner-Wintersteiner rosettes not seen
Small to medium-sized cells with large, ovoid nuclei, generally high nuclear-to-cytoplasmic ratios, and correspondingly small amounts of eosinophilic cytoplasm
Distinct cell borders present
Extensive coagulative necrosis, often with areas of central ``comedonecrosis'' in larger cell nests
Nuclear chromatin was usually homogeneous and coarse
A single prominent nucleolus was typically present
Nuclei were typically rather uniform within a given example
Arranged in sheets, nests, wide trabeculae, or ribbons, and many showed a vaguely organoid growth pattern
Mitotic activity was invariably brisk, often with many more than 10 mitotic figures per 10 high-power fields
Vascular invasion was usually extensive
Severe dysplasia or carcinoma in situ was documented in the overlying mucosa in two cases
Dense lymphoid or lymphoplasmacytic infiltrate was invariably absent.
- Sinonasal Undifferentiated Carcinoma: Clinical and Pathologic Features and a Discussion on Classification, Cellular Differentiation, and Differential Diagnosis.
Ejaz A, Wenig BM.
From the Department of Pathology and Laboratory Medicine, Continuum Hospitals of New York (Beth Israel Medical Center and Saint Luke's-Roosevelt Hospitals), New York, New York.
Adv Anat Pathol. 2005 May;12(3):134-143. Abstract quote
Sinonasal undifferentiated carcinoma (SNUC) is an uncommon, highly aggressive, and clinicopathologically distinctive carcinoma of uncertain histogenesis. SNUC typically presents as a rapidly enlarging tumor mass involving multiple (sinonasal tract) sites, often with evidence of extension beyond the anatomic confines of the sinonasal tract.
The light microscopic features include the presence of a hypercellular proliferation with varied growth patterns, including trabecular, sheet-like, ribbon, lobular, and organoid patterns. The tumor cells are medium to large sized and round to oval and have pleomorphic and hyperchromatic nuclei, inconspicuous to prominent nucleoli, varying amount of eosinophilic cytoplasm, high nuclear-to-cytoplasmic ratio, marked increase in mitotic activity frequently with atypical mitoses, tumor necrosis, and apoptosis. Adjunct analyses (eg, immunohistochemistry, electron microscopy, and molecular biologic studies) are often required in the diagnosis of SNUC and in differentiating it from other undifferentiated malignant neoplasms.
The treatment of SNUC includes aggressive multimodality therapy, including surgical resection and adjuvant therapy (ie, radiotherapy, chemotherapy). The prognosis associated with SNUC is poor, and death due to disease often occurs within short periods following the diagnosis.
We believe that the histologic definition of SNUC can be expanded to include tumors with limited differentiated foci (ie, squamous cell differentiation) predicated on the caveats that the clinical parameters (ie, rapidly enlarging and destructive sinonasal lesions) and the majority of the histologic findings (ie, undifferentiated pleomorphic cell population) match those features that have heretofore defined SNUC. The presence of squamous cell differentiation would correlate to origin in the Schneiderian epithelium, thereby conferring an ectodermal derivation to these tumors.
Irrespective of its cell of origin and perhaps even in the face of differentiated foci in limited parts of the tumor, given its rather unique clinicopathologic characteristics, this tumor should be identified and classified as SNUC, thereby differentiating it from the other specific types of sinonasal carcinomas and nonepithelial malignant tumors.
CHARACTERIZATION Special stains Immunoperoxidase
Am J Surg Pathol 2001;25:156-163
All 25 tumors were negative for EBER-1 by ISH
Negative in one case
1+ in nine
2+ in six
3+ in five
4+ in one
Negative in nine
1+ in five
2+ in two
3+ in none
4+ in six
Strongly positive in 3 of 22 (14%)
Variably intense focal staining for EMA was present in 4 of 22 (18%)
NSE faintly stained 4 of 22 (18%)
Chromogranin, synaptophysin, PLAP, CEA, and LMP-1 were negative (0 of 22)
Sinonasal undifferentiated carcinoma, nasopharyngeal-type undifferentiated carcinoma, and keratinizing and nonkeratinizing squamous cell carcinoma express different cytokeratin patterns.
Franchi A, Moroni M, Massi D, Paglierani M, Santucci M.
Am J Surg Pathol 2002 Dec;26(12):1597-604 Abstract quote
Sinonasal undifferentiated carcinoma (SNUC) is a highly aggressive malignant neoplasm that is often difficult to distinguish from other poorly differentiated carcinomas arising in the sinonasal tract.
To search for a differential cytokeratin (CK) expression that could be useful for diagnostic purposes, we compared the expression of a large panel of CKs in a series of 6 SNUCs, 10 poorly differentiated squamous cell carcinomas (SCCs), 10 nonkeratinizing squamous cell carcinomas (NKSCCs), and 5 nasopharyngeal-type undifferentiated carcinomas (NPTCs). SCC, NKSCC, and NPTC frequently showed immunoreactivity for CK5/CK6, CK8, CK13, and CK19. In addition, SCC and NKSCC expressed CK14, which was not detected in NPTC, and SCC expressed CK7 (60% of cases) and CK4 (30% of cases), which were absent in NKSCC and NPTC. Three NKSCCs were associated with a Schneiderian papilloma, and the results of the immunostaining were similar in the two components, with the exception of CK4 and CK7, which were expressed by the papilloma and not by the carcinoma.
In contrast to other carcinomas, SNUC was characterized by the exclusive expression of CKs of simple epithelia, such as CK8 (100% of cases), CK7 (50% of cases), and CK19 (50% of cases). Thus, there are significant differences in the pattern of CK expression between SNUC, SCC, NKSCC, and NPTC, which could be of diagnostic aid. Moreover, these findings support the hypothesis that SNUC is a separate entity from SCC and NPTC of the sinonasal tract.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES Nasopharyngeal carcinoma Sinonasal Undifferentiated Carcinoma and Nasopharyngeal-Type Undifferentiated Carcinoma
Two Clinically, Biologically, and Histopathologically Distinct Entities
Yung-Ming Jeng, M.D.; Ming-Tse Sung, M.D.; Chia-Lang Fang, M.D., M.S.; Hsuan-Ying Huang, M.D.; Tsui-Lien Mao, M.D., M.S.; Wei Cheng, M.D., M.S.; Cheng-Hsiang Hsiao, M.D.
From the Department of Pathology (Y.-M.J., T.-L.M., W.C., C.-H.H.), National Taiwan University Hospital, Taipei, the Department of Pathology (M.-T.S., H.-Y.H.), Chang-Gung Memorial Hospital, Koahsiung, and the Department of Pathology (C.-L.F.), Taipei Medical University-affiliated Taipei Wan Fang Hospital, Taipei, Taiwan.
Am J Surg Pathol 2002;26:371-376 Abstract quote
Sinonasal undifferentiated carcinoma (SNUC) is a rare aggressive neoplasm arising in the nasal cavity and paranasal sinuses. Primary sinonasal nasopharyngeal-type undifferentiated carcinoma (PSNPC) is an even rarer tumor that has not been adequately reported. Both tumors have been reported to be associated with EpsteinBarr virus (EBV).
We studied the clinicopathologic features and EBV status of 36 SNUC and 13 PSNPC patients from Taiwan, an EBV endemic area.
The median age of SNUC patients was 53 years (range 2076 years), with a male/female ratio of approximately 2:1. Five patients had histories of previous nasopharyngeal carcinoma treated with irradiation 626 years earlier. The most common locations were nasal cavity and ethmoid sinus. Orbital and intracranial invasion and distant metastasis were frequent findings. The median survival was 10 months. All 36 tumors were negative for EBER-1 by in situ hybridization.
The median age of PSNPC patients was 58 years (range 3675 years), with a male/female ratio of approximately 2:1. The most common location is nasal cavity. Eight patients achieved disease-free survival. Eight tumors had the morphology of lymphoepithelioma, whereas significant inflammatory infiltrate was not detected in the other five tumors. All 13 tumors were positive for EBER-1 by in situ hybridization.
Because of the difference in the relation with EBV, prognosis, and response to radiotherapy, SNUC and PSNPC should be considered as two entirely different entities. The most important criteria for PSNPC are vesicular nuclei, syncytial pattern, spindle cells, and absence of necrosis.
Olfactory neuroblastoma Homer-Wright rosettes or neurofibrillary stroma
No nuclear pleomorphism, prominent mitoses, or vascular invasion
Keratin and EMA negative
Synaptophysin and S-100 positive
PROGNOSIS AND TREATMENT CHARACTERIZATION Prognostic Factors Failure to eradicate local disease with extension into the critical adjacent tissues (e.g., brain, orbit) was the cause of death in most patients Survival
Otolaryngol Head Neck Surg 1993;108:697–700.
Am J Surg Pathol 2001;25:156-163
Am J Otolaryngol 1996:17;167–71.
Median 18 months
Follow-up data for the original series of cases suggested that the prognosis for patients with localized disease might be better
One study documents three cases with extended survival with two of these patients received autologous bone marrow transplantation, and one of the transplant recipients subsequently underwent a second radical procedure to remove recurrent disease
Both patients survived 9 years after diagnosis but ultimately died of disease, emphasizing that 5-year disease-free survivals cannot be equated with cure
One patient remains free of disease 10 years after tumor resection
Sinonasal undifferentiated carcinoma: a 10-year experience.
Righi PD, Francis F, Aron BS, Weitzner S, Wilson KM, Gluckman J.
Department of Otolaryngology-Head and Neck Surgery, Indiana University Medical Center, Indianapolis 46202, USA.
Am J Otolaryngol 1996 May-Jun;17(3):167-71 Abstract quote
PURPOSE: Sinonasal undifferentiated carcinoma (SNUC) is a rare and aggressive malignancy of the paranasal sinuses and nasal cavity. Of the few reported series, most indicate a dismal prognosis. In this report, the clinical presentation, histopathologic criteria used for diagnosis, mode of treatment, and outcome are evaluated in seven patients with SNUC.
MATERIALS AND METHODS: Seven patients with SNUC treated at the University of Cincinnati between 1983 and 1993 were analyzed retrospectively.
RESULTS: Most of the patients presented with extensive local disease, and two patients also had cervical metastases. All except one were treated using a multimodality approach. Four of the seven patients died of disease (DOD), with a mean survival of only 11.5 months following treatment. Inability to eradicate local disease was responsible for treatment failure in all cases. Three patients have achieved short-term control of disease following combined therapy, but one is at high risk for recurrence.
CONCLUSION: SNUC was associated with an overall poor prognosis in our series despite aggressive treatment. Control of local disease was the central therapeutic consideration. Intensive multimodality therapy is recommended for all patients with SNUC.
METASTASES Disseminated metastases common VASCULAR ENDOTHELIAL GROWTH FACTOR
- Prognostic significance of microvessel density and vascular endothelial growth factor expression in sinonasal carcinomas.
Valente G, Mamo C, Bena A, Prudente E, Cavaliere C, Kerim S, Nicotra G, Comino A, Palestro G, Isidoro C, Beatrice F.
Pathology Section, Department of Medical Sciences, Amedeo Avogadro University Medical School, Novara, Italy.
Hum Pathol. 2006 Apr;37(4):391-400. Epub 2006 Feb 8. Abstract quote
The prognostic significance of microvessel density and proliferative activity of the neoplastic cells, evaluated respectively by CD31 and Ki-67 positivity, and immunohistochemical expression of vascular endothelial growth factor (VEGF) was retrospectively investigated in 105 cases of sinonasal carcinoma (80 surgical specimens and 25 biopsies).
The most represented histologic types were intestinal-type adenocarcinoma found in 36 patients (34.3%), squamous cell carcinoma (SCC) in 34 (32.4%), mucinous adenocarcinoma (mainly made up of signet-ring cell patterns) in 15 (14.3%), and adenoid cystic carcinoma in 7 (6.7%). Microvessel density values (in vessels per square millimeter), VEGF, and Ki-67 were not dependent on histologic type but were rather correlated to the histologic grading in SCC. Clinical data were available for 92 (87.6%) of 105 patients, with minimum follow-up of 48 months. Most of the patients (81.5%) were at an advanced stage (T3-T4) at diagnosis. The values of all markers were correlated to tumor stage (P = .03).
Multivariate analysis showed that both microvessel density and proliferative activity of the neoplastic cells were independent prognostic parameters (mortality hazard ratio, 1.33 and 1.60, respectively). Although VEGF expression was not correlated to prognosis on the whole series (P = .06), it was a powerful prognostic marker when the analysis was restricted to the group of SCCs (hazard ratio, 3.02; 90% confidence interval, 1.58-5.80).
These results show that tumor neoangiogenesis, expressed by microvessel density, together with proliferative activity, is a pathologic marker with a strong prognostic impact in sinonasal carcinomas. Therefore, it may be a useful tool in this field so as to carry out therapeutic protocol planning, which may be further enhanced by the adoption of the more recent antiangiogenic molecules.
A combination therapy of continuous superselective intraarterial carboplatin infusion and radiation therapy for locally advanced head and neck carcinoma. Phase I study.
Fuwa N, Ito Y, Matsumoto A, Kamata M, Kodaira T, Furutani K, Sasaoka M, Kimura Y, Morita K.
Department of Radiation Oncology, Aichi Cancer Center Hospital, Chikusaku, Nagoya, Japan.
Cancer 2000 Nov 15;89(10):2099-105 Abstract quote
ACKGROUND: To improve the treatment result for locally advanced head and neck carcinoma, the authors used a combination of radiotherapy with superselective continuous intraarterial therapy using carboplatin. The dose limiting toxicity (DLT), maximum tolerated dose (MTD), and treatment effectiveness were tested in Phase I and II protocols.
PATIENTS AND METHODS. Thirty-five patients were entered into the study from August 1992 to May 1997. The target arteries were the lingual artery in 18 cases, facial artery in 5 cases, maxillary artery in 11 cases, and external carotid artery initially changing to lingual artery in 1 case. Escalating daily carboplatin doses were tested, starting from 10 mg/m(2) (total dose, 360 or 400 mg/m(2)) to 15 mg/m(2) (total dose, 405 or 450 mg/m(2)) and then 20 mg/m(2) (total dose, 460 or 500 mg/m(2)). Radiotherapy was administered using a 6-megavolt linear accelerator to a total dose of 50-60 grays. Interstitial radiotherapy boost also was used for carcinoma of the tongue.
RESULTS: Excluding 3 patients who discontinued treatment, the treatment results of 32 patients were complete response in 21 cases, partial response in 10 cases, and no change in 1 case. Neutropenia was the DLT, and the MTD was 500 mg/m(2). The local control rate was 64%.
CONCLUSIONS: Superselective continuous intraarterial carboplatin and concurrent radiation therapy can be delivered safely with good efficacy for locally advanced carcinomas of the tongue and base of the tongue. Surgical treatment of these diseases usually incurs severe functional loss. This current approach may be a breakthrough in these cancers. Copyright 2000 American Cancer Society.
High-dose intra-arterial cisplatin and concurrent hyperfractionated radiation therapy in patients with locally advanced primary squamous cell carcinoma of the head and neck: report of a phase II study.
Regine WF, Valentino J, John W, Storey G, Sloan D, Kenady D, Patel P, Pulmano C, Arnold SM, Mohiuddin M.
Department of Radiation Medicine, University of Kentucky, 800 Rose Street, Lexington, Kentucky 40536-0293, USA.
Head Neck 2000 Sep;22(6):543-9 Abstract quote
BACKGROUND: This phase II study evaluates the tolerability and efficacy of concurrent hyperfractionated radiation therapy (HFX-RT) and high-dose intra-arterial (IA) cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).
METHODS: Between December 1995 and November 1997, 20 patients with locally advanced T4/T3 SCCHN were treated with HFX-RT (76.8-79.2 Gy at 1.2 Gy bid over 6-7 weeks) and high-dose IA cisplatin (150 mg/m(2) given at the start of RT boost treatment [start of week 6]). Seventeen patients (85%) had T4 disease, and 14 (70%) had N2/ N3 disease.
RESULTS: Grade 3-5 acute toxicity was limited to one grade 4 (5%) and 14 grade 3 (70%) mucosal events. No grade 3/4 hematologic toxicity was observed. Median weight loss during therapy was 9% (range, 2%-16%). Eighteen patients had complete response (90%) at the primary site; 14 were confirmed pathologically. Among 17 patients with positive neck disease, 16 (94%) achieved complete response in the neck, including 12 of 13 patients with N2/N3 disease who underwent planned neck dissection. Active follow-up ranges from 12 to 32 months (median, 20 months) with 11 patients alive without disease, 5 dead of disease, and 4 dead of intercurrent disease. Eighteen patients (90%) remained disease free at the primary site, and the locoregional control rate is 80%.
CONCLUSIONS: High-dose IA cisplatin and concurrent HFX-RT as used in this study is feasible and warrants further investigation. The high complete response rate and low grade 4 toxicity in this highly unfavorable subset of patients appears better than previously reported chemoradiation regimens for more favorable patients.
High-dose intra-arterial cisplatin therapy followed by radiation therapy for advanced squamous cell carcinoma of the head and neck.
Wilson WR, Siegel RS, Harisiadis LA, Davis DO, Nguyen HH, Bank WO.
Division of Hematology and Oncology, George Washington University Medical Center, 2150 Pennsylvania Ave, NW, Suite 3-428, Washington, DC 20037, USA.
Arch Otolaryngol Head Neck Surg 2001 Jul;127(7):809-12 Abstract quote
OBJECTIVE: To assess the effectiveness of a protocol consisting of 4 cycles of high-dose intra-arterial cisplatin infusions followed by radiation therapy for improving chemotherapy response rates, organ preservation, and survival in patients with advanced-stage untreated and previously treated squamous cell carcinoma of the head and neck.
DESIGN AND SETTING: A prospective study of sequentially enrolled patients treated in an academic medical center. The Kaplan-Meier method was used for survival analysis.
PATIENTS: Fifty-eight nonpregnant adults, 18 years of age or older, with measurable untreated or recurrent advanced biopsy-proven squamous cell carcinoma of the head and neck.
MAIN OUTCOME MEASURES: Response rate to targeted intra-arterial cisplatin infusions, organ preservation, and survival.
RESULTS: Fifty-eight patients (44 men and 14 women) were followed up for at least 2 years (median duration of follow-up, 27 months). Twenty-nine (67%) of the 43 previously untreated patients had a complete response to intra-arterial cisplatin therapy. Of the untreated patients, 28 are alive and disease free after a median follow-up time of 30 months. Five of the patients with recurrent disease had a complete response to intra-arterial cisplatin therapy. There were 4 survivors after a median follow-up time of 17.5 months. Of note, there were no deaths or serious complications related to the treatment in either group.
CONCLUSIONS: High-dose intra-arterial cisplatin therapy provides a high complete and partial response rate (91%). The combination of high-dose intra-arterial cisplatin and radiation therapy is effective in improving survival and organ preservation rates in patients with previously untreated, advanced squamous cell carcinoma of the head and neck. This treatment protocol is much less effective for recurrent disease.
Am J Surg Pathol 2001;25:156-163
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