IJSXXX10.1177/1066896915594882International Journal of Surgical PathologyAcosta et al

Case Report

Primary Ureteral Thyroid Transcription Factor 1–Positive Small Cell Neuroendocrine Carcinoma: Case Report and Review of the Literature

International Journal of Surgical Pathology 2015, Vol. 23(6) 472­–477 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896915594882 ijs.sagepub.com

Andrés Martin Acosta, MD1, Farid Saei Hamedani, MD1, Joshua James Meeks, MD, PhD2,3, and Shoujin Wu, MD3

Abstract Upper urinary tract neoplasms comprise only 5% of urinary malignancies overall, the overwhelming majority showing an urothelial histology. Nonurothelial lesions represent 1.9% of upper tract neoplasms, and small cell carcinomas (SmCCs) only account for a minute fraction of them, with few cases reported in the literature to date. In the genitourinary tract, these lesions are most frequently found in the urinary bladder, where they tend to show a mixed histology with a characteristic small cell neuroendocrine component that is positive for chromogranin A, synaptophysin, and CD56 immunostains. Urinary SmCCs are almost invariably aggressive, with a propensity to infiltrate surrounding tissues and vascular structures. Unfortunately, clinical stage at presentation is often advanced, with early dissemination to lymph nodes or distant organs in a significant proportion of patients. For the most part, prognosis is dismal and can be predicted by the pathologic stage at diagnosis. Recently, new chemotherapeutic regimens have shown some potential benefit for the treatment of urinary SmCC, albeit not achieving curative results. Here we present the case of a 71-year-old male patient with a history of treated bladder urothelial carcinoma that presented with subacute flank pain and was diagnosed with a primary pure SmCC of the ureter. Besides the usual neuroendocrine immunomarkers, this tumor showed intense positivity for TTF-1 (thyroid transcription factor-1), a phenomenon that has been described for extrapulmonary SmCC of other locations. Keywords small cell carcinoma, neuroendocrine tumor, ureter, ureteral, upper urinary tract, TTF-1, genitourinary neoplasms

Introduction Urothelial carcinoma is the fourth most frequently diagnosed malignancy in the United States, with a projected incidence of 70 530 new cases and 14 680 deaths in 2010.1 Most of these tumors are located in the lower urinary tract, with bladder as the primary location and urothelial as the major histologic type. Upper urinary tract tumors are relatively infrequent and account for no more than 5% of urinary neoplasms, with an estimated annual incidence of 1.2 cases/100 000 inhabitants in Europe.2,3 The overwhelming majority of these malignancies show an urothelial histology, with nontransitional variants representing only 1.9% of upper urinary tract cancers.4 Primary urinary tract small cell carcinoma (SmCC) is very rare and usually arises in the urinary bladder, where it represents 0.5% to 1% of all malignant tumors.5,6 Only a few primary ureteral SmCCs have been reported in the literature worldwide since the first one was published in 1986, and these cases include

both “pure” ureteral SmCC as well as tumors with a mixed histology.7,8 In fact, monophasic urinary SmCCs are very infrequent in general, since at least 50% are admixed with urothelial carcinoma, adenocarcinoma, squamous cell carcinoma, or sarcomatoid elements.9,10 Although the extreme rarity with which ureteral SmCCs are encountered precludes an adequate calculation of their real incidence; based on an MD Anderson series, they can be estimated to 1

University of Illinois at Chicago Hospital and Health Sciences System, Chicago, IL, USA 2 Feinberg School of Medicine, Northwestern University, Chicago, IL, USA 3 Jesse Brown VAMC, Chicago, IL, USA Corresponding Author: Andrés Martin Acosta, Department of Pathology, University of Illinois at Chicago Hospital and Health Sciences System, 840 S Wood St, Suite 130 CSN, Chicago, IL 60612, USA. Email: [email protected]

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Acosta et al

Figure 1.  (A) Groups of round to oval cells with nuclear molding are seen surrounded by smaller loosely cohesive groups and single cells (magnification 200×). (B) At higher magnification the cells show high nucleocytoplasmic ratio, coarse or speckled chromation, and inapparent nucleoli (Romanowsky stain, magnification 400×).

represent roughly 0.1% of the already infrequent upper urinary tract cancers.4,11 Here we report a 71-year-old patient with a history of recurrent urothelial carcinoma, presenting with a primary pure SmCC of the right ureter.

Case Report A 71-year-old patient presented to the emergency department with right flank pain of several weeks’ duration and recent-onset oliguria. He had a surgical history of recurrent urothelial carcinoma of the bladder treated with repeated transurethral resections and adjuvant intravesical BCG for non-muscle-invasive carcinoma. His clinical history was significant for chronic kidney disease (baseline serum creatinine of 1.23 mg/dL), diabetes mellitus, hypertension, and congestive heart failure. The bladder cancer had been diagnosed and treated 10 years before the current presentation, and follow-up studies suggested no evidence of disease. Other than flank tenderness and the absence of a palpable urinary bladder, the rest of the physical examination was unremarkable. An emergency laboratory workup evidenced a serum creatinine of 2.6 mg/dL (corresponding to an estimated glomerular filtration rate of 26 mL/min), mild hyperkalemia, and the absence of major acid–base imbalances. A computed tomography without contrast enchancement showed moderate right hydronephrosis, and ureteral dilatation proximal to the point of crossing of the right Iliac vessels, but no detectable calculus. Cystoscopy and retrograde pyelograms were performed, in which a ureteral stent was placed. The bladder was without cystoscopic evidence of recurrence. A magnetic resonance imaging study demonstrated diffuse thickening of the right ureteral wall proximal to the ureterovesical junction. Once his renal function had improved, an ureteroscopy was performed, revealing the presence of an occlusive fleshy nodular mass, which was thoroughly biopsied and submitted for pathologic examination together with ureteral urine samples. Urine cytology was positive for cells with unequivocal

malignant characteristics and cytomorphologic features suggestive of a neuroendocrine phenotype. A grade 3 neuroendocrine neoplasm with features of SmCC was diagnosed on the biopsy of the tumor. After ruling out the presence of lesions in any other organ by imaging survey, the patient was started on carboplatin plus etoposide systemic chemotherapy.12 Despite a good initial response to the chemotherapeutic regimen, the tumor recurred 4 months later, at which time salvage nephroureterectomy was undertaken. The patient expired approximately 6 months after resection from metastatic disease.

Cytologic, Histopathologic, and Immunohistochemical Findings The Romanowsky-stained cytology specimen from the upper right urinary tract revealed 3-dimensional groups of loosely cohesive medium-sized round to oval cells with a moderate amount of cytoplasm, and high nucleocytoplasmic ratio (Figure 1). The largest aggregates of neoplastic cells showed marked nuclear molding and revealed the presence of moderate nuclear pleomorphism. Individual cells showed medium-sized round to oval hyperchromatic nuclei, with chromatin varying in appearance from coarse to speckled, and either inapparent or characteristically small and inconspicuous nucleoli. The biopsy of the right ureteral lesion showed marked crush artifact, sheets of molded medium-sized nuclei, and abundant necrotic debris. Mitotic count was high, consistent with a Ki-67 nuclear staining estimated at 80%. Besides, the tumor cells were markedly positive for chromogranin A, synaptophysin, and neuronal specific enolase (NSE) immunostains. Macroscopic inspection of the surgical specimen showed a 17.5 cm in length × 1.5 cm in average diameter right ureter, with a focal dilatation located 6.3 cm away from the renal pelvis, and 7 cm away from the bladder resection margin. When the ureter was opened, a 4.3 cm × 1.4 cm × 1.1 cm firm round nodular mass was revealed,

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International Journal of Surgical Pathology 23(6)

Figure 2.  SmCC replacing the submucosa and invading into the muscular wall of the ureter, causing a subtotal occlusion of the lumen (Lum) (magnification 8.5×). Inset. A different section shows the SmCC invading through the muscular wall into the periureteral fat (arrows) (hematoxylin–eosin, magnification 40×).

within the ureteral wall which corresponded to the focal dilatation observed externally. This tumor had a homogeneous white to gray cut surface, without any evidence of calcification, hemorrhage, or internal cystic structures. On microscopic examination at low magnification, the mucosa and submucosa were completely effaced by a nonencapsulated infiltrating tumor, which invaded through the muscular wall and focally into the periureteral adipose tissue (Figure 2). Scattered areas of residual benign urothelium were found overlying the luminal surface of the tumor. At higher magnification, the lesion was noted to be composed of medium-sized cells with high nucleocytoplasmic ratio, and round to oval moderately pleomorphic hyperchromatic nuclei. Chromatin varied from coarse to speckled, and nucleoli were either indistinct or entirely absent. Architecturally, cells were arranged into tightly packed islands and sheets, separated by dense fibrous septa. Tumor necrosis, defined elsewhere as microscopic foci of coagulative necrosis with homogeneous clusters and sheets of degenerating or dead cells, was readily found throughout the lesion (Figure 3).13,14 Moreover, larger areas of necrosis were also found, and calculated to comprise 10% of the total tumoral volume. Intracapillary tumor growth was also focally demonstrated at the edges of the neoplasm. The lesion was highly proliferative, with 21 mitotic figures per 10 high power fields, and a Ki-67 labeling index was 80% (Figure 3), in accordance with the biopsy. An external iliac lymph node submitted with the main specimen was shown to harbor a focus of metastatic SmCC measuring 2 mm in greatest dimension. The malignant cells in the ureteral lesion were positive for synaptophysin (Figure 4), chromogranin A, CD56, and the pan-keratin cocktail AE1/AE3. However, they were completely negative for both cytokeratin 7 and cytokeratin 20, which argued against a pulmonary

Figure 3.  At high magnification the tumor is composed of sheets of small to medium-sized cells with high nucleocytoplasmic ratio and coarse or speckled chromatin. Both mitoses (arrows) and areas of tumor necrosis (star) are present throughout the tumor (magnification 200×). Inset. Immunostain for Ki-67 shows a highly proliferative lesion (nuclear labeling index ≈80%) (hematoxylin–eosin, magnification 200×).

Figure 4.  Synaptophysin immunostain is strongly positive in the cytoplasm of the tumor cells (magnification 200×).

origin of the lesion or the presence of a malignant urothelial component.15-17 Interestingly, the nuclei were strongly positive for TTF-1 (thyroid transcription factor-1; Figure 5), as it has been demonstrated in 44% of extrapulmonary SmCCs in general, and in 40% of bladder SmCC in particular.18,19 Besides, the possibility of a primary lung SmCC metastatic to the ureter had been ruled out by computed tomography and positron emission tomography studies. Our final diagnosis was that of a pT3 pN1 primary ureteral SmCC, with no clinical or radiological evidence of metastasis in other organs.

Discussion Since SmCCs arising outside respiratory or digestive organs are infrequent, a thorough imaging survey should be performed before making a diagnosis of primary ureteral

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Acosta et al

Figure 5.  Thyroid transcription factor-1 immunostain highlights the nuclei of the tumor cells (magnification 200×).

SmCC.20 In fact, at least one case of pulmonary SmCC metastatic to the ureter can be found in the literature.21 Moreover, the histogenesis of these neoplasms poses a dilemma, since the ureters are normally devoid of neuroendocrine cells. To this regard, a thorough immunohistochemical and histochemical search for normal neuroendocrine cells in the genitourinary tract of a female pig could confirm their presence in both the lower genital tract and the urinary bladder, but not in the ureters.22 Therefore, several theories have been formulated to explain the histopathogenesis of these lesions. Some authors believe that ureteral SmCCs are actually stem cell tumors that differentiate toward a neuroendocrine lineage.23,24 In support of this concept, positivity for cancer stem cell markers has been demonstrated in the neuroendocrine component of mixed tumors arising in organs that normally lack neuroendocrine cells.25 Another possibility is that upper urinary tract SmCCs might actually derive from migrating neural crest cells that became entrapped in this location during embryogenesis.26 Finally, it has been theorized that neuroendocrine malignancies arising in organs that are normally devoid of neuroendocrine cells might originate from the transdifferentiation or metaplastic transformation of tumors with an originally different histology.27 With regard to this matter, knock-down of Notch1 mRNA induced a cholangiocarcinoma cell line to express chromogranin A and Ascl-1 (Achaete-scute homolog 1, an inducer of neuroendocrine differentiation) mRNA, suggesting that phenotypic transdifferentiation is attainable in vitro.28 While it is not clear to which degree this finding can be extrapolated to in vivo models or to ureteral neuroendocrine malignancies, the fact that many SmCCs of the upper urinary tract display a mixed histology and immunohistochemical profile can be interpreted as empirical support for the theory of tumoral transdifferentiation.8,9,23,29-32 Histopathologic features of ureteral SmCC are similar to those of small cell neuroendocrine tumors from other locations, with individual cells usually showing scant to

moderate amounts of cytoplasm, fine speckled chromatin, and high nucleocytoplasmic ratio. To the best of our knowledge, only one neuroendocrine tumor of the ureter with large cell histology has been reported to date.33 The architecture of SmCC is typically characterized by diffuse sheets, islands, and solid tumor nests with an organoid pattern. Reactive stromal desmoplasia is not uncommon, and mixed tumors with squamous or transitional elements are frequently encountered.23,29-32 Necrosis, lymphovascular invasion, and direct infiltration of adjacent structures have all been described in the literature.23,34,35 Ureteral SmCCs almost invariably show histologic features of aggressiveness, with elevated mitotic counts and high proliferation indexes, as measured by Ki-67 nuclear labeling.8,35 Ureteral SmCCs almost invariably stain for chromogranin A, synaptophysin, NSE, pan-keratin (AE1/AE3), and CD56, with a few published cases also staining for cytokeratin 20, cytokeratin 7, and epithelial membrane antigen (EMA).8,11,33,34 Uroplakin III has been reported as negative, making it a useful additional stain for differentiating between ureteral SmCC and urothelial carcinoma, with the caveat that this marker is positive in 57% to 81% of urothelial malignancies.33,36,37 However, it should be noted that the variant of urothelial carcinoma that more closely resembles the architectural features of SmCC (nested variant) is usually uroplakin III negative.36 Furthermore, this case demonstrates that primary ureteral SmCC, like its bladder counterpart, can be TTF-1 positive, adding to the bulk of evidence indicating this stain is more probably a general small cell neuroendocrine tumor marker rather than a specific one for pulmonary malignancies.18 Although electron microscopy is rarely resorted to, it can demonstrate the characteristic 100 to 200 nm in diameter membrane bound electron dense cytoplasmic granules.33 Median age at presentation is 66.5 years, with a male to female ratio of 2:1, and an initial presentation characterized by hematuria (72%), abdominal pain (54%), and/or urinary infections (10%). Paraneoplastic syndromes constitute an exceedingly rare phenomenon in the context of a primary ureteral SmCC.38 Although some studies have reported relative survival for extrapulmonary SmCC to be better than that for primary lung lesions, overall prognosis is still dismal.39,40 Existing data show that median survival for upper urinary tract SmCCs is 8 to 15 months, with a high rate of metastasis (32% to 53.8%) and frequent relapses after initial treatment.8,12 Studies have demonstrated that surgery alone conveys a median survival of 12 months, while the administration of adjuvant chemotherapy might extend it up to 24 months, albeit lacking statistical significance.8,12 The highest benefit has been obtained with platinum-based regimens, which seems to confer a modest survival benefit when compared to other drugs.12,41 A combined neoadjuvant scheme alternating ifosfamide/doxorubicin with

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International Journal of Surgical Pathology 23(6)

etoposide/cysplatin has also yielded promising results for the treatment of neuroendocrine tumors of the urinary tract, particularly in patients with resectable disease at presentation.42 But for practical purposes, the most important predictor of survival seems to be the pathological stage at diagnosis, giving the pathologist a crucial role in the management of these infrequent urinary tumors.12 Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

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Primary Ureteral Thyroid Transcription Factor 1-Positive Small Cell Neuroendocrine Carcinoma: Case Report and Review of the Literature.

Upper urinary tract neoplasms comprise only 5% of urinary malignancies overall, the overwhelming majority showing an urothelial histology. Nonurotheli...
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