(UroToday.com) The 2024 European Society for Medical Oncology (ESMO) Annual Congress held in Barcelona, Spain between September 13th and 16th, 2024 was host to a session focusing on rare genitourinary cancers. Professor Syed Hussain provided an overview of the histologic subtypes (i.e., variants) of bladder cancer.
Dr. Hussain began with a case presentation of a 51-year-old male who presented with hematuria. Baseline CT demonstrated a 57 mm T3b urachal adenocarcinoma and neuroendocrine small cell tumour with a rounded 9 mm right external iliac node.
MRI showed a VI-RADS 5 tumor. The solid component was intra-luminal; however, the urachal component appeared to be cystic in nature.
He received 4 cycles of etoposide + platinum-based chemotherapy. Post-chemotherapy scans demonstrated a minor increase in the size of the urachal tumor, which now appeared to be in close proximity to the adjacent sigmoid colon.
On biopsy, this tumor was found to have both adenocarcinoma and neuroendocrine components. There was evidence of synaptophysin expression in the neuroendocrine component, but none in the adenocarcinoma.
He subsequently underwent a urachal excision with a partial cystectomy, which confirmed the presence of both neuroendocrine and adenocarcinoma components.
The patient presented post-operatively with hematuria, right groin pain, and nausea, with subsequent CT demonstrating evidence of extensive pelvic recurrence. Multiple pelvic nodal recurrences and anterior abdominal wall deposits were appreciated. The patient passed away within 9 months of diagnosis at the age of 52.
Squamous differentiation is characterized by a transition from conventional morphology to squamous morphology, as evidenced by either intercellular bridges or keratinization. This is the most common form of divergent differentiation in most series (30–40% of cases). Although there is a tendency for more locally advanced disease to demonstrate squamous histology, stage-by-stage, it has not been found to be associated with worse cancer-specific survival.
A basal-squamous molecular subtype of urothelial carcinoma is now recognized by its genomic expression signature. If direct involvement by HPV-associated squamous cell carcinoma of uterine, cervical, or anal origin is a consideration, studies to detect HPV (such as chromogenic in situ hybridization or molecular testing) can be helpful in establishing the diagnosis. Of note, p16 expression is frequent in urothelial carcinoma, making it of limited utility in this context.
Glandular differentiation is often considered the second most common form of divergent differentiation, following squamous tumors (18% of tumors). True glandular differentiation should be distinguished from the occurrence of gland-like luminal spaces in otherwise conventional urothelial carcinoma. The divergent glandular differentiation is often of intestinal type, akin to colorectal adenocarcinoma. Immunohistochemistry is of little value in establishing a primary bladder origin for an intestinal-type adenocarcinoma. The presence of a conventional urothelial carcinoma component can help establish the primary bladder origin.
Similar to tumors with squamous differentiation, there is some evidence that tumors with glandular differentiation often present at advanced stages. However, glandular differentiation does not influence prognosis once stage is adjusted for.
A definitive distinction between the two types of neoplasm is not possible using morphological or immunohistochemical approaches (both can be positive for CDX2 and/or CK20). Although an absence of nuclear staining for β-catenin has been suggested as favoring bladder primary adenocarcinoma, the differential is best resolved on clinical grounds and by imaging studies.
In urothelial carcinoma with trophoblastic differentiation, a component of trophoblastic cells (including syncytiotrophoblastic and cytotrophoblastic cells) is present. Serum elevation of β-hCG is usually observed. However, a considerable proportion of patients with metastatic urothelial carcinoma without apparent trophoblastic histology also have β-hCG elevation, which has been used by some as a marker for monitoring response to therapy.
As for urothelial carcinomas with Mullerian differentiation, these tumors displays papillary, tubulocystic, and/or solid growth patterns. The cells are flat, cuboidal, and hobnail, with clear, glycogen-rich, or eosinophilic cytoplasms. Cytological atypia is moderate to severe, with variable mitotic activity and necrosis. Tumors with relatively bland cytological features resembling nephrogenic adenoma have been described
An associated urothelial carcinoma component or adjacent endometriotic foci may rarely be present. The cells are usually positive for CK7, CA125, PAX8, AMACR, HNF1β, p53, and Napsin. A CK20 staining is variable. They are negative for GATA3, p63, 34βE12, PSA, ER, PR, and WT1. PAX8 positivity and urothelial marker negativity differentiate clear cell adenocarcinoma from the clear cell (glycogen-rich) pattern of urothelial carcinoma.
The histological and immunohistochemical overlap with nephrogenic adenoma can be difficult to distinguish. Mitotic activity, invasive growth with involvement of the muscularis propria, hyperchromasia, and p53 staining are key distinguishing features.
Micropapillary urothelial carcinoma is defined by the presence of small clusters of tumor cells without fibrovascular cores, often surrounded by lacunae resembling vascular invasion. The presence of multiple clusters within the same lacuna is typical. The tumor cells have peripherally oriented nuclei and occasional cytoplasmic vacuoles distorting the nuclear contour (ring forms).
Lymphovascular invasion is common, and CIS is present in more than half of all micropapillary carcinomas.
Overexpression and/or amplification of ERBB2 is more frequent in micropapillary carcinoma and could offer a target for therapy. Micropapillary urothelial carcinoma is an aggressive subtype. Radical cystectomy could be a consideration in patients with non-muscle-invasive bladder cancer with a substantial micropapillary component.
The nested subtype of urothelial carcinoma has a bland histological appearance. It is characterized by a proliferation of small round to ovoid nests of urothelial cells with limited cytological atypia, mimicking von Brunn nests. Clues to this diagnosis include the confluence of multiple nests and the irregular infiltrative base of the lesion that usually involves the muscularis propria. Increased cytological atypia in the deeper aspect of the tumor can be encountered. Identification of TERT promoter mutations can help in difficult TURBT cases. Nested carcinoma is often pure, but it can be mixed with other urothelial carcinoma subtypes and shares the immunophenotype of conventional urothelial carcinoma.
With regards to the tubular or microcystic subtypes, these two subtypes are thought to be closely related to their nested counterpart, in which cytologically bland cells line small tubular or microcystic distended structures. In the nested subtype, deep irregular infiltration, including the involvement of the muscularis propria, is a clue to the malignant nature of this proliferation and helps distinguish it from cystitis cystica. Urothelial markers, such as GATA3 or p63, are typically positive.
Plasmacytoid urothelial carcinoma is an aggressive subtype, characterized by single infiltrating cells, with or without cytoplasmic lumina or vacuoles. At times, they may also resemble signet-ring carcinoma cells, but notably lack the extracellular mucin found in signet-ring adenocarcinomas.
The discohesive tumor cells can spread extensively along tissue planes and peritoneal surfaces.
Plasmacytoid carcinoma is characterized by somatic mutations of CDH1 (leading to frequent loss of E-cadherin expression), akin to lobular breast carcinoma and signet ring gastric cancer. The plasma cell marker CD138 may be positive, which can be misleading as it is also expressed in epithelial neoplasms. Plasmacytoid carcinoma typically labels for urothelial markers such as p63 or GATA3. Expression of the latter is shared with metastatic lobular breast carcinoma, which presents a differential diagnostic challenge. Markers such as ER, PR, and mammaglobin are of utility in such cases.
The sarcomatoid urothelial carcinoma subtype is characterized by the presence of areas of neoplasm that are indistinguishable from sarcoma. Conventional urothelial, squamous, glandular, or small cell neuroendocrine carcinoma components are frequently admixed. Morphological features vary from the bland spindle cell pattern to those of an undifferentiated pleomorphic sarcoma. Heterologous components include osteosarcoma, chondrosarcoma, rhabdomyosarcoma, and angiosarcoma. The presence of one or more heterologous components has been suggested to impart an adverse behavior.
The survival of patients with sarcomatoid urothelial carcinoma is particularly poor, with a reported 5-year cancer-specific survival of 28% and a median overall survival of 14 months. Immunohistochemical expression of markers of urothelial differentiation such as p63, GATA3, and high-molecular-weight cytokeratin is supportive of the diagnosis. Benign myofibroblastic proliferations, such as postoperative spindle cell nodules and inflammatory mvofibroblastic tumors, can mimic sarcomatoid carcinoma given their frequent expression of cytokeratin and the occasional brisk mitotic activity. The lack of expression of urothelial markers (e.g. p63 and GATA3) and positivity for ALK (present in as many as two thirds of inflammatory myofibroblastic tumors) can be helpful.
Lipid-rich urothelial carcinoma contains lipoblast-like cells with one or more cytoplasmic vacuoles indenting their nuclei. The lipid nature of the vacuolar content has been confirmed by electron microscopy and histochemical staining. The lipid-rich subtype is usually admixed
with conventional urothelial carcinoma and other subtypes. Epithelial immunohistochemical markers are frequently positive. A poor 5-year survival outcome (42%) was found in the largest reported multi-institutional series.
Lymphoepithelioma-like urothelial carcinoma (LELC) is a rare subtype composed of sheets and clusters of undifferentiated cells with poorly defined cytoplasmic borders imparting a typical syncytial appearance. LELC of the bladder has morphological similarities to nasopharyngeal lymphoepithelioma and occasionally oropharyngeal carcinoma but differs from both by its lack of any association with EBV or HPV.
Tumors with pure or predominant (> 50%) LELC features have been suggested by some (but not all) authors to be associated with better overall survival than those in which LELC is admixed with conventional and other subtypes. A recent study showed that LELC tumors are enriched for basal-squamous molecular subtype markers and for PD-L1 expression. These findings are consistent with the known sensitivity of LELC tumors to chemotherapy and support the potential of immune checkpoint inhibitors, as a therapeutic option.
Clear cell (glycogen-rich) urothelial carcinoma is characterized by an accumulation of glycogen within tumor cells, resulting in a clear cell appearance. The immunohistochemical profile is similar to that of conventional urothelial carcinoma and can help distinguish this subtype from metastasis of a clear cell renal cell carcinoma origin. Clear cell (glycogen-rich) urothelial carcinoma should be distinguished from urothelial carcinoma with Mullerian differentiation, clear cell type which is generally considered to have more aggressive behavior.
Giant cell urothelial carcinoma is a very rare subtype that is often accompanied by conventional urothelial carcinoma. Like its lung counterpart, bizarre pleomorphic giant tumour cells are typical of this subtype and should be distinguished from trophoblastic and osteoclast-like giant cells. Immunohistochemical positivity for epithelial and urothelial markers is present in at least some of the bizarre tumour cells. The behavior of this rare subtype is highly aggressive.
Overall, the presence of variant histology is an adverse prognostic factor that may be under-reported by non-expert GU pathologists. They are seen in up to 15% of tumors. In a series of 589 TUR specimens, variant histology was missed in 44% of referrals into a central multidisciplinary tumor review process. The most commonly missed variants were squamous (32%), small cell (16%), glandular (13%), micropapillary (12%), nested (8%), sarcomatoid (6%), lymphoepithelial (3%), and plasmacytoid (1%) differentiation types. Muscle invasion may be present in up to 69% of cases.1
Micropapillary disease accounts for 1–2% of tumors and are characterized by early lymphovascular invasion and metastases. In a review of 100 cases from the MD Anderson Cancer Center, 67% of CIS, T1, and T1 cases progressed to muscle invasion at a median of 8 months, despite intravesical treatment. The study investigators concluded that ‘intravesical therapy appears to be ineffective in this disease.2
Adenocarcinoma can be either primary urachal (10–30%) or non-urachal with secondary local invasion and/or metastatic spread.
There are some differences between urachal and non-urachal adenocarcinoma. The urachus isan embryological remnant of the urogenital sinus and allantois. Tumors are located at the dome in the urachus. There is normal bladder urothelium overlying the tumor. These are mostly muscle-invasive lesions. They have a congenital etiology and present in younger patients (median: 49–56 years), with equal distribution among males and females.
Conversely, non-urachal adenocarcinoma originates from the trigone and/or side wall. They have an abnormal epithelium with muscle invasion. They present in older patients (median: 61 years) and predominantly in males (3:1 ratio). They arise secondary to acquired exposures, with evidence of glandular metaplasia from chronic infection and inflammation from stones/urinary tract infections.
The phase II ABACUS-2 trial is evaluating neoadjuvant atezolizumab in invasive non-conventional urothelial carcinoma. One key takeaway from this trial, the results of which were presented at ESMO 2023, is the change in the assigned baseline histopathologic subtypes included. Following a central pathology review, the histologic subtypes were ‘reassigned’ to the more accurate histologic subtype. This highlights the importance of central pathology review in these cases.
Pathologic responses were observed more frequently in patients with sarcomatoid variant histology (62%) and least frequently in patients with squamous pathology (8%).
The UK AURORA phase II trial is a single arm open label clinical trial of atezolizumab in immunotherapy naïve patients with urinary tract squamous cell carcinoma. To date, accrual has been slow with only 20 patients recruited.
An analysis of the UNITE study demonstrated that outcomes with enfortumab vedotin vary by histologic subtype. As demonstrated in the table below, the response varies from up to 70% in patients with urothelial predominant disease with variant squamous histology down to 33% in patients with squamous variant predominant histology.
Dr. Hussain concluded as follows:
- The diagnosis and management of variant histology bladder tumors remains a challenge.
- This is an area of unmet need as we encounter poor prognosis and survival in these cases presenting with advanced disease. Unfortunately today this remains an
- "orphan disease".
- Exclusion of many of these patients in clinical trials has led to little progress in treatment for these patients with predominant variant histology.
- The importance of central pathology review was highlighted by the phase II ABACUS-2 trial of neoadjuvant atezolizumab
- Poor and slow recruitment in ongoing trials addressing the management of these patients with predominant variant histology tumors highlights the need for international efforts to design and deliver clinical trials
Presented by: Professor Syed A. Hussain, MBBS, MSc, MD, FRCP, Professor and Consultant in Medical Oncology, University of Sheffield, Sheffield, UK
Written by: Rashid Sayyid, MD, MSc – Robotic Urologic Oncology Fellow at The University of Southern California, @rksayyid on Twitter during the 2024 European Society of Medical Oncology (ESMO) Annual Congress held in Barcelona, Spain between September 13th and 17th
References:- Shah RB, Montgomery JS, Montie JE, Kunju LP. Variant (divergent) histologic differentiation in urothelial carcinoma is under-recognized in community practice: impact of mandatory central pathology review at a large referral hospital. Urol Oncol. 2013; 31(8):1650-5.
- Kamat AM, Dinney CPN, Gee JR, et al. Micropapillary bladder cancer: a review of the University of Texas M. D. Anderson Cancer Center experience with 100 consecutive patients. Cancer. 2007; 110(1):62–7.