1. PLANTEAMIENTO DEL PROBLEMA
1.2 PREGUNTA PROBLÉMICA
4.2.4 NUEVAS ALTERNATIVAS EDUCATIVAS
The biopsy material were numerous soft papillary grey white tissue fragments, measuring from 2×2 to 10×7 mm, which were all submitted for histological evaluation.
Histologically, the tumour was composed of numerous small, uniform cells with hyperchromatic, overlapping nuclei with inconspicuous nucleoli and scant cyto- plasm (Fig. 1B). In an invasive part nests and cords of small tumour cells penetrating lamina propria and muscularis propria were seen. Interestingly, the tu- mour was partially composed of papillary structures with fibrovascular cores surrounded by small neo-
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plastic cells (Fig. 1A). Numerous mitoses were pre- sent and focally also necrosis. Histology of the tu- mour was uniform across all slides examined and there was no conventional urothelial carcinoma present. In the bladder mucosa away from tumour, cystitis cystica and glandularis, intestinal type, was
demonstrated (Fig. 2).
Immunohistochemically, tumour cells were positive for synaptophysin (Cellmarque) (Fig. 3A), chromo- granin (Dako), Cam 5.2 (Becton-Dickinson) and TTF- 1 (Dako) (Fig. 3B), but negative for p63 (Novocastra).
Figure 1. Small cell neuroendocrine carcinoma composed of papillary structures surrounded by neoplastic cells (A,
100x) and higher magnification (B, 400x), hematoxylin and eosin.
Figure 2. Cystitis cystica and glandularis in the mucosa near the tumour, hematoxylin and eosin (100x).
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On the basis of histology, mostly its cytologic charac- teristics, and immunohistochemical analysis the tu- mour was diagnosed as pure small cell neuroendo- crine carcinoma. Because of TTF1-1 positivity and the absence of conventional urothelial carcinoma it was not clear whether it is a primary tumour or a metastasis.
The patient was admitted to the Institute of Oncology Ljubljana for further diagnostic procedures. The abdo- minal CT scan revealed three hypodense lesions in the liver, measuring from 5 to 22 mm, consistent with hemangioma. No enlarged lymph nodes or any tumour growth in genital organs were observed, but unfortunately it was not possible to evaluate the bladder thoroughly.
A thorax CT scan revealed a round, 7 mm large no- dule with smooth contours in the apical peripheral segment of upper right lobe, which did not however, seem typical for primary malignoma. Because of its peripheral location histological verification was not possible and the differential diagnoses encompassed a possible metastasis or hamartoma. Beside this no- dule, a 12×18 mm large lymph node was observed by the right interlobar artery, but no enlarged lymph nodes in the mediastinum or hilus were detected. Although the nodule and enlarged lymph node could not be biopsied because of their anatomical position, the radiologist concluded this not to be the primary tumour and that metastasis was also not very likely. Therefore, a pulmonary-oncologic-urologic council decided to treat the patient as having a primary small cell neuroendocrine carcinoma of the urinary bladder with muscle wall infiltration, pathologic T stage 2. The patient received neoadjuvant cisplatin based chemotherapy and after the completion of fourth cycle (seven months after the diagnosis) she underwent radical cystectomy with bilateral salpingo- oophorectomy, uterine and pelvic lymph node dis- section. The tissue was submitted for histological evaluation.
The resected bladder measured 60×20 mm in two greatest diameters. The bladder wall was soft and measured from 9 to 12 mm in thickness. The mucosa was focally hemorrhagic.
The histology revealed no residual tumour in the bladder. Only chronic cystitis with fibrosis and stro- mal giant cells – the usual post chemo- and radio- therapy histologic findings were present. The resected pelvic lymph nodes were also tumour free.
The resected uterus, ovaries and tubes were histolo- gically unremarkable with age related changes.
Discussion
Neuroendocrine tumours occur in various sites in the body, most commonly in the lungs and gastro- intestinal tract (7). Rarely, they also occur in the genitourinary system, with urinary bladder being the most common site. Nevertheless, with the incidence of 0.35% to 1.8% of all bladder carcinomas, a primary SCC of the bladder is a rare tumour (2,3,8). Several hypotheses regarding the origin of SCCB have been proposed. Firstly, the tumour was suppo- sed to originate from neuroendocrine cells normally present either in epithelia or in submucosa, which might increase in number in reactive or metaplastic settings (2,4,9,10). Interestingly, glandular metaplasia was found in our case in the mucosa around the tumour. According to another hypothesis, SCCB is thought to arise from a multipotent stem cell (4). Because of frequent coexistence of SCCB with other urothelial carcinomas as well as its expression of both epithelial and neuroendocrine markers, this option is very appealing since stem cells are capable of divergent differentiation. Indeed, Cheng with colleagues in their study of molecular genetic alte- rations in SCCB and coexisting urothelial carcino- mas demonstrated a nearly identical pattern of genetic changes in two tumour types (11) arguing, therefore, strongly in favour of this hypothesis. The authors further speculated that tumours, being of same genetic profile, probably differentiated after the carcinogenesis was initiated, yet at the same time allowing the possibility of urothelial carinoma pro- gressing to SCCB by un unknown mechanism (11). The age distribution of patients with neuroendocrine carcinoma of the bladder is similar to that of the primary transitional cell carcinoma with the highest incidence between 60 and 70 years (2–4,8,12), al- though our patient was younger, 53 years old. Men are affected more frequently than women (2–4,8,12). The most prominent risk factor, also present with our patient, is smoking (2,8). Clinically, the disease most often manifests itself with hematuria. Other symptoms include dysuria, local pain, urinary obstruc- tion, abdominal pain, urinary tract infection and weight loss (2,3,12). Although paraneoplastic syn- drome is rare, hypophosphatemia, hypercalcemia (possible due to bone metastases) and ectopic hor- mone secretion were reported (3,4,9).
Clinical data about cystoscopic view of the tumor are not regularly included in the studies but Blomjous with colleagues (4) observed that almost all tumours were solid broadly based masses, which is similar to
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the cystoscopic tumour description our urologists gave.
Histologically, SCCB is, like its lung counterpart, composed of rather uniform small cells with hyper- chromatic nuclei with stippled chromatin, inconspi- cuous nucleoli and scant cytoplasm. Mitoses can be numerous and necrosis is a frequent finding. Archi- tecturally, the cells grow in sheets or isles (1,2). In our case the tumour cells with cytological characte- ristics of neuroendocrine carcinoma formed papillae similar to the ones usually found in conventional transitional cell carcinoma and only in deeper inva- sive parts were the typical nests found. We would like to stress in this light the importance of recog- nition of cytologic characteristics of tumour cells, so the tumour could not be mistaken with poorly differentiated transitional cell carcinoma on conven- tional hematoxylin and eosin stain.
SCCB are immunohistochemically positive for epi- thelial (EMA, CK 7, Cam 5.2) and neuro-endocrine (neuron specific enolase, synaptophysin, chromo- granin, serotonin) markers (2,4). Once again the importance of morphology must be stressed since SCCB can be negative by neuroendocrine markers (1,4). In the light of extreme rarity of primary SCCB, the most important differential diagnosis, also bea- ring a huge impact on treatment and prognosis, is the possibility of a metastatic lung SCC. TTF-1, a marker commonly used in proving a possible pulmo- nary origin of tumours, has proved to be of a lesser value in these situations, since Agoff with coworwor- kers reported a 44% positivity in non-pulmonary SCC (13), and Jones in his study noted a 39% TTF- 1 positivity in SSCB (14), therefore the importance of clinicopathological correlation cannot be over- emphasised. Since the tumour cells in our case were TTF-1 positive, we stressed in the pathology report that primary lung carcinoma should be excluded. Subsequent CT scans revealed a small nodule in the lung, which was radiologically not typical for pri- mary carcinoma, but still this possibility could not be definitely excluded because of impossible histo- logical verification of the lesion. Nevertheless, the patient is thought to have a small cell neuroendo- crine carcinoma most probably of urothelial origin. The frequent coexistence of SCCB with other, more common epithelial bladder tumours, namely, transi- tional, squamous and adenocarcinoma (2–4,15) can be of help in differentiating primary bladder tumour from metastasis. In our case the tumour was com- posed of neuroendocrine component only.
At the time of diagnosis the majority of SCCB are advance-staged, implying their highly aggressive na-
ture, which is further outlined by low overall survival (1–4,8,12,15), extending as low as 8% in five-year period (8). While some authors claim mixed nature of tumours not to impact on prognosis (3), Ismaili et al observed a worse prognosis in pure SCCB com- pared to SCCB in combination with other type of bladder carcinoma (16). From the therapeutic, as well as prognostic, point of view, SCCB are, in analogy to SCC lung carcinoma, divided to two categories; namely localised and extensive disease. In this line, therapy of SCCB in past years was mostly derived from its lung counterpart and left to the discretion of an individual clinician. Ismaili ana- lysed several retrospective studies and one prospective and on their basis concluded that multimodal treat- ment seemed the best option in surgically resectable disease (less or equal to T1-4aN0M0) encompassing neoadjuvant chemotherapy followed by radical resection. According to this publication, sequential chemo-radiotherapy is the second treatment option and lastly, in cases where surgery was performed first, adjuvant chemotherapy or chemo-radiotherapy should be performed. In advanced disease chemo- therapy based on cisplatin is advised (2). Our patient received neoadjuvant cisplatin based chemotherapy and the response was excellent since in the resected bladder no residual tumour was identified. Of course, the patient had surgery only recently, therefore further follow-up is warranted to evaluate long-standing therapeutic effect.
In conclusion, we presented a case of primary small cell neuroendocrine carcinoma of the bladder with a papillary growth pattern. It was the cytology of malignant cells that incited the use of immunohisto- chemical methods which highlighted its true nature and prompted the use of neoadjuvant therapy prior to surgery. In addition to the correct histological diagnosis a close collaboration between the patholo- gist and the urologist is essential for optimal patient management and treatment.
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