10. DELIMITACIÓN
10.4 RECOMENDACIONES
Institute of Pathology, Faculty of Medicine University of Ljubljana, Korytkova 2, SI-1000 Ljubljana, Slovenia
ABSTRACT►
Primary neuroendocrine carcinomas of the urinary bladder are extremely rare but aggressive tumors estimated to account for less than 1% of urinary bladder malignancies and have poor prog- nosis. Small cell carcinomas of urinary bladder usually coexist with urothelial carcinoma in elderly patients. We present a case of 69-years old woman with malignant cells in a bladder washing specimen initially interpreted as high grade urothelial carcinoma. Along with low grade papillary urothelial carcinoma a small cell carcinoma was diagnosed on transurethral resection biopsy specimen and neuroendocrine differentiation was confirmed by imunochistochemical staining for synaptophysin and chromogranin.
Key words
► neuroendocrine carcinoma, urinary bladder, cytology
IZVLEČEK ►
Primarni nevroendokrini karcinomi sečnega mehurja so izjemno redki, vendar agresivni tumorji s slabo prognozo. Po ocenah predstavljajo verjetno manj kot 1% vseh malignih tumorjev sečnega mehurja. Drobnocelični karcinomi se običajno pojavljajo skupaj z urotelijskimi karcinomi, zlasti pri starejših bolnikih. Predstavljamo primer 69-letne bolnice z malignimi celicami v izpirku seč- nega mehurja, ki smo jih ocenili kot urotelijski karcinom visokega gradusa. V vzorcih transuretralne resekcije sečnega mehurja je bil ugotovljen drobnocelični karcinom ob papilarnem urotelijskem karcinomu nizkega gradusa. Nevroendokrino diferenciacijo smo potrdili z imunocitokemičnimi barvanji na sinaptofizin in kromogranin.
Ključne
besede ► nevroendokrini karcinom, sečni mehur, citologija
Background
Neuroendocrine tumors can arise in diverse range of epithelium-containing organs. The primary neuro- endocrine carcinomas of the urinary bladder are ex- tremely rare and aggressive tumors accounting for less then 1% of urinary bladder malignancies and have poor prognosis. Neuroendocrine carcinomas of urinary bladder usually coexist with urothelial carci- noma in elderly patients. Most common neuroendo- crine tumors are small cell carcinomas, followed by carcinoids, while only a few large cell neuroendocrine carcinomas of bladder were reported (1). Only few reports on the cytologic characteristics of neuroendo- crine carcinoma of the bladder in urinary specimens have been published (2–4).
We present a case of 69-years old woman with ma- lignant cells in a bladder washing specimen initially interpreted as high grade urothelial carcinoma. A small cell carcinoma was diagnosed on transurethral resection biopsy specimen and neuroendocrine diffe- rentiation was confirmed by imunohistochemical staining for synaptophysin and chromogranin while
immunostaining for TTF-1 was negative excluding potential metastasis from the lung.
Case report
A 69-years old woman had a history of low grade papillary urothelial carcinoma of urinary bladder with initial invasion into lamina propria. Six years later she was diagnosed with another low grade papillary urothelial carcinoma. Besides urothelial carcinoma an area with small cell carcinoma was detected in one of the tissue fragments (Fig. 1). Neuroendocrine granules were confirmed with imunohistochemical staining for synaptophysin and chromogranin. Immu- nostaining for TTF-1 was negative excluding potential metastasis from the lung with great probability. The bladder washing was taken and submitted to our laboratory during the follow-up three months later. Clinical data stated only transurethral resection inquiring about possible tumor recurrence. The sample was poorly preserved with many inflammatory cells, degenerated cells and cell debris. Malignant cells
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were found, lying singly or in clusters of various shapes and sizes (Fig. 2). The medium sized cells showed some variation in cell size and shape and high nuclear-cytoplasmic ratio. They exibited enlarged hyperchromatic nuclei with irregular granular or smudged chromatin. Cytoplasm was scant and well delineated (Fig. 2, insert). Cytopathological diagnosis was high grade urothelial carcinoma. On the review some cell groups with nuclear molding were found (Fig. 3, arrow). Subsequent immunocytochemical staining for synaptophysin on previously Papanico- laou stained cytospins showed positive perinuclear staining (Fig. 4).
Figure 1. Overgrowth of invasive tumor, composed of uni-
form small to predominantly intermediate sized cells with scant cytoplasm, arranged in sheets and nests (H&E, x400).
Figure 2. Poorly preserved bladder washing sample with
many inflammatory cells and degenerated cells. Malignant cells are lying singly or in clusters of various shapes and sizes (Papanicolaou, x100). The medium sized cells with scant cytoplasm showed some variation in cell size and shape and high nuclear-cytoplasmic ratio, enlarged hyper- chromatic nuclei with irregular granular or smudged chro- matin (insert: Papanicolaou, x600).
Figure 3. Poorly preserved cell group with nuclear molding
(arrow) in bladder washing sample (Papanicolaou, x600).
Figure 4. Positive immunostaining for synaptophysin, retro-
spectively confirming neuroendocrine differentiation on bladder washing specimen (x600).
The patient underwent transurethral resection of the bladder mucosa one month later. All histology slides showed overgrowth of invasive tumor, composed of uniform small to predominantly intermediate sized cells with scanty cytoplasm arranged in sheets and nests. The cells had finely granular chromatin and inconspicuous nucleoli. The diagnosis was small cell carcinoma with extensive muscular invasion and mor- phology corresponding to previous biopsy.
Two years later a sample of bladder washing was sent for cytopathological evaluation with clinical data stating previous transurethral resection, followed by radio- and chemotherapy. On cystoscopy, an unhealed ulcer was found on the posterior left side of the bladder. However, the histological type of primary bladder cancer was not mentioned on the requisition form. The cytopathological examination of bladder washing showed few groups of malignant cells with
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enlarged, hyperchromatic nuclei with some variation in size and shape, irregular coarse chromatin distribu- tion and inconspicuous nucleoli. The cytoplasm of these cells was scant to moderate. Again, high grade urothelial carcinoma was diagnosed. However, majo- rity of urothelial groups in the specimen showed reactive atypia after radio- and chemotherapy. In the same year, the patient was diagnosed with brain metastases of carcinoma with neuroendocrine diffe- rentiation probably originating from urinary bladder.
Discussion
Primary neuroendocrine carcinoma of the urinary bladder is a rare entity and therefore represents a challenge in diagnosis and subsequent treatment. Histomorphological presentation and immunohisto- chemical profile are similar to the neuroendocrine tumors elsewhere in the body. In significant number of cases, the neuroendocrine carcinoma is coexisting with other histological types of urinary bladder carci- nomas, most frequently with urothelial carcinoma (1,2).
Cytomorphological characteristics of neuroendocrine urinary bladder carcinomas have been described mainly for the small cell type which shares simi- larities with the pulmonary counterpart that is well known in cytologic specimens. Urine or bladder wash- ing specimens typically show clusters and single small cells with scanty cytoplasm, moderate pleomorphism, nuclear molding and hyperchromasia (2–4). Some samples were described as containing mainly naked nuclei (4). Blood, necrotic debris and inflammation were found in the background.
In our case, the neuroendocrine differentiation of malignant cells in two different bladder washing specimens was not suspected. Malignant cells were of intermediate size with scant cytoplasm and other obvious cytomorphological signs of malignancy that are usually consistent with high grade urothelial car- cinoma. On the review only few groups of malignant cells with nuclear molding were found, however other
nuclear features including finely granular chromatin that is characteristic for small cell neuroendocrine carcinoma were not convincing.
Differential diagnosis of the urinary bladder neuro- endocrine carcinoma found either in cytological spe- cimen or tissue biopsy is primarily metastasis from another site (1–4). Secondly, high grade urothelial or undifferentiated carcinoma can share similar mor- phology. Primary or secondary lymphoma can also imitate small cell carcinoma however in cytological specimens an important diagnostic clue are single cells which predominate in lymphomas.
Immunocytochemical staining could confirm neuro- endocrine differentiation also on cytological urinary specimens.
Conclusion
Once in a while, malignant cells of small cell neuro- endocrine bladder carcinoma could be found in uri- nary cytology samples. With the typical cytomorpho- logy of small cell carcinoma an accurate cytopatho- logical diagnosis could be made. However with mixed cytomorphology the malignant cells could be inter- preted as high grade urothelial carcinoma.
References
1. Bertaccini A, Marchiori D, Cricca A, et al. Neuroendo- crine carcinoma of the urinary bladder: Case report and review of the literature. Anticancer Research 2008; 28: 1369–72.
2. Bui M, Khakbuss WE. Primary small cell neuroendo- crine carcinoma of the urinary bladder with coexisting high-grade urothelial carcinoma: a case report and a review of the literature. CytoJournal 2005; 2: 18. 3. Asc G, Gupta PK, Baloch ZW. Cytomorphology of
high-grade neuroendocrine carcinoma of the urinary tract. Diag Cytopathol 2000; 23: 92–6.
4. Ali SZ, Reuter VE, Zakowski MF. Small cell neuro- endocrine carcinoma of the urinary bladder. A clinico- pathologic study with emphasis on cytologic features. Cancer 1997; 79: 356–61.