Atypical Squamous Cells in the Urine Revealing Endometrioid Adenocarcinoma of the Endometrium with Squamous Cell Differentiation: A Case Report Yinong Wang, M.D., Ph.D.,1* Christopher N. Otis, M.D.,2 and Roxanne R. Florence, M.D.2
Urine cytology is mainly used to detect urothelial carcinoma (UC), especially for high-grade lesions including urothelial carcinoma in situ. Benign squamous cells are often seen in the urine specimens of women, they are either exfoliated from the trigone area of the bladder, the urethra, or the cervicovaginal region. However, abnormal squamous cells in the urine raise concerns of abnormalities of the urinary tract and cervicovaginal area which range from squamous metaplasia of the urothelium, a cervicovaginal squamous intraepithelial lesion, condyloma acuminatum of the bladder, UC with squamous differentiation, and squamous cell carcinoma. We present here a unique case of atypical squamous cells (ASCs) in the urine subsequently leading to the diagnosis of endometrioid adenocarcinoma of the endometrium with squamous differentiation. The presence of ASCs in voided urine is a rare finding that may indicate an underlying malignancy. Careful evaluation of squamous cells in the urine is an important part of our daily cytopathology practice. Diagn. Cytopathol. 2015;43:49–52. VC 2014 Wiley Periodicals, Inc.
1 Department of Pathology and Laboratory Medicine, University of Calgary, Calgary Laboratory Services, 3535 Research Road NW, Calgary, Alberta, Canada, T2L 2K8 2 Department of Pathology, Baystate Medical Center, Tufts Uiversity School of Medicine, 759 Chestnut Street, Springfield, Massachusetts *Correspondence to: Y. Wang, M.D., Ph.D, Department of Pathology and Laboratory Medicine, University of Calgary, Calgary Laboratory Services, DSC, 3535 Research Road NW, Calgary, Alberta, T2L 2K8, Canada. E-mail: [email protected] Received 5 June 2013; Revised 12 November 2013; Accepted 9 January 2014 DOI: 10.1002/dc.23118 Published online 17 February 2014 in Wiley Online Library (wileyonlinelibrary.com).
C 2014 WILEY PERIODICALS, INC. V
Key Words: urine; atypical squamous cells; endometrioid adenocarcinoma
Urine is one of the most common cytology specimens in our daily practices. The major indication for urinary cytology is hematuria to detect urothelial carcinoma (UC). Another indication is surveillance for recurrent UC. Diagnostic accuracy of UC increases with the grade of the tumor. Urine cytology has high sensitivity and specificity for diagnosis of urothelial carcinoma in situ (UCIS) and high-grade UC, but specificity for low grade urothelial papillary neoplasms is low as instrumentation, lithiasis, and inflammation can cause similar morphological features of low-grade UC. Despite many attempts to develop new tests with greater sensitivity and specificity such as fluorescence in situ hybridization (FISH, UroVysionTM) and fluorescent test using monoclonal antibodies (ImmunoCyt/uCytTM), cytology remains one of best methods to diagnose bladder lesions, most importantly for UCIS and high-grade UC.1,2 Squamous cells in the urine are commonly found in women because the trigone in the bladder in over 50% of adult women (and in some proportion of the male bladder) can be lined by squamous In addition, the distal urethra is partially lined by squamous epithelium.3 Occasionally, endometrial cells are present in the urine of women. Atypical squamous cells (ASCs) are rarely seen in urinary specimens, and there are few studies in the literature.4–6 However, the presence of ASCs in the urine raises the concern of abnormalities of the urinary tract and cervicovaginal region including squamous metaplasia of the urothelium, condyloma acuminatum, Diagnostic Cytopathology, Vol. 43, No 1
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Diagnostic Cytopathology DOI 10.1002/dc
WANG ET AL.
squamous intraepithelial lesion of the cervicovaginal region, UC with squamous differentiation, squamous cell carcinoma of urinary tract or gynecologic tract, and metastatic squamous cell carcinoma.4–8 Primary squamous cell carcinoma of the bladder is rare and strongly associated with Schistoma hematobium. Focal squamous differentiation is common in UC. We present here a unique case of ASCs in the urine subsequently leading to the diagnosis of endometrioid adenocarcinoma of the endometrium with squamous differentiation.
Case Report The patient was an 82-year-old former nurse who presented with hematuria. The patient stated that she had some vaginal bleeding for about a year, but had had some type of vaginal discharge of uncertain etiology for 4 years. She had never had any heavy vaginal bleeding. The patient had a past medical history of hypertension with renal artery stenosis. The patient saw her gynecologist and a voided urine specimen was sent to pathology for cytologic evaluation.
Cytopathological and Histopathological Findings On the ThinPrep preparation, the urine specimen was predominantly composed of acute inflammatory cells, red blood cells, and rare benign appearing urothelial cells. Abundant benign and rare ASCs were also noticed. The ASCs mostly appeared as keratinizing cells with hyperchromatic smudgy nuclei, high nuclear/cytoplasmic ratio, abnormal nuclear shapes, and densely orangeophilic cytoplasm. Some had more elongated fusiform nuclei (Figs. 1A and B). Based on these findings, the diagnosis of ASCs was rendered. A comment was also included: “The atypical squamous cells present may be derived from either the urinary tract or the cervical–vaginal area.” A cystoscopy was not performed. A cervical Pap test was then performed and was negative. Subsequently, the patient underwent an endocervical curettage that demonstrated unremarkable endocervical glandular mucosa and metaplastic squamous mucosa, with no dysplastic squamous epithelium identified, and a curettage of the endometrium which revealed endometrioid adenocarcinoma with squamous differentiation. One month later, a hysterectomy was performed and a 4.0 3 1.5 3 1.0 cm tumor was identified involving both anterior and posterior endometrium. In addition, leiomyomata and adenomyosis were present. Microscopically, the tumor consisted of well-formed glands admixed with solid sheets of malignant cells consistent with grade II (FIGO) endometrioid adenocarcinoma of the endometrium. The tumor invaded 50%–60% of the myometrial thickness. Squamous differentiation scattered in the superficial portion of the tumor forming morules or nests was noted 50
Diagnostic Cytopathology, Vol. 43, No 1
(Fig. 1C). There were atypical keratinizing squamous cells sloughing from the surface of the squamous differentiation (Fig. 1D). These ASCs were similar to the ASCs present in the urine (Figs. 1A and B). No cervical involvement or lymphovascular invasion was identified. The pathology staging was pT1c pN0 pMx according to AJCC 2010.
Discussion Clinical history is always important in the proper evaluation of any specimen, including urine. The most common symptoms of patients with bladder cancer are hematuria or cystitis-like symptoms (frequency, urgency, or pain), but these symptoms are nonspecific. From a clinical point of view, a careful and thorough history is paramount for the further evaluation of the patient. For example, for patients with hematuria, the initial evaluation is urine cytology. But for post-menopausal patients with spotting or bleeding, the initial evaluation includes pelvic examination, cervical Pap testing, and an endometrial biopsy. Our patient had some vaginal bleeding for about a year, but had had some type of vaginal discharge of uncertain etiology for 4 years. Interestingly, the first specimen sent in this patient was urine cytology and it showed ASCs that subsequently lead to a diagnosis of endometrioid adenocarcinoma of the endometrium with squamous differentiation. The presence of ASCs in urine cytology specimens is a rare finding (0.3%–0.9%) that may indicate an underlying malignancy.4,6 Owens et al. showed 25% of the patients with ASCs in the urine had squamous cell carcinoma or UC with squamous cell differentiation.4 In the same study, in 6% of the patients with ASCs in the urine, a diagnosis of high-grade cervical squamous cell carcinoma was made on the subsequent follow-up, while 69% remained benign on histologic and prolonged clinical follow-up. A recent study showed 28.6% of the patients with ASCs in their urine were diagnosed as combination of UC and squamous cell carcinoma, and in 38.1% of the patients with ASCs in the urine had squamous cell carcinoma originating from sites other than the urinary tract.6 In addition, a recent case report of dysplastic squamous cells in the urine revealed squamous cell carcinoma of the bladder, attesting again the value of urine cytology as an initial diagnostic test.7 To our knowledge, this is the first report in the literature of ASCs in the voided urine leading to a diagnosis of endometrioid adenocarcinoma of the endometrium with squamous differentiation. This report broadens the differential diagnosis of ASCs in the urine of women. Endometrioid carcinomas of the endometrium with squamous differentiation account for approximately 25% of endometrioid carcinomas of the endometrium. Morphologically, the
Diagnostic Cytopathology DOI 10.1002/dc
ATYPICAL SQUAMOUS CELLS IN THE URINE: A CASE REPORT
Fig. 1. Atypical squamous cells in the voided urine (A and B, ThinPrep, original magnification 4003). Squamous cell differentiation forming morules or nests in the superficial portion of the endometrioid adenocarcinoma (C, hematoxylin-eosin, original magnification 1003). Sloughing atypical squamous cells on the surface of the squamous differentiation (D, hematoxylin-eosin, original magnification 2003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
squamous component can have a variety of features such as rounded intraluminal aggregates (morules), infiltrating nests resembling conventional squamous cell carcinoma, micropapillae, individual cell keratinization, or overlapping appearances.9 In our case, the squamous differentiation had both a morule appearance and infiltrating nests, mainly located in the superficial portion of the tumor. In summary, careful evaluation of the squamous cells in urine cytology specimens is important. The presence of ASCs in voided urine is an uncommon finding that may be a sign of an underlying malignant process and war-
rants clinical follow-up. Endometrioid adenocarcinoma of the endometrium with squamous differentiation should be in the differential diagnosis of ASCs in the urine in female patients.
References 1. Cibas ES, Ducatman BS. Cytology: Diagnostic principles, and clinical correlates. 3rd ed. Philadelphia, PA: Saunders Elsevier; 2009. p 123–124. 2. Bernard T. Diagnosis of urothelial carcinoma from urine. Mod Pathol 2009;22:S53–S59. 3. Packham DA. The epithelial lining of the female trigone and urethra. Br J Urol 1971;43(2):201–205. Diagnostic Cytopathology, Vol. 43, No 1
51
Diagnostic Cytopathology DOI 10.1002/dc
WANG ET AL. 4. Owens CL, Ali SZ. Atypical squamous cells in exfoliative urinary cytology: Clinicopathologic correlates. Diagn Cytopathol 2005; 33(6):394–398. 5. Touijer AK, Dalbagni G. Role of voided urine cytology in diagnosing primary urethral carcinoma. Urology 2004;63(1):33–35. 6. Hattori M, Nishimura Y, Toyonaga M, et al. Cytological significance of abnormal squamous cells in urinary cytology. Diagn Cytopathol 2012;40(9):798–803.
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7. Rosa M. Clinical significance of dysplastic squamous cells in exfloliative urine cytology. Diagn Cytopathol 2010;38(6):468–469. 8. Demay RM. Practical principles of cytopathology. Revised 1st ed. American Society of Clinical Pathology; 2007. 9. Clement PB, Young RH. Endometrioid carcinoma of the uterine corpus: A review of its pathology with emphasis on recent advances and problematic aspects. Adv Anat Pathol 2002;9: 145–184.
Urine cytology is mainly used to detect urothelial carcinoma (UC), especially for high-grade lesions including urothelial carcinoma in situ. Benign squamous cells are often seen in the urine specimens of women, they are either exfoliated from the trigone area of the bladder, the urethra, or the cervicovaginal region. However, abnormal squamous cells in the urine raise concerns of abnormalities of the urinary tract and cervicovaginal area which range from squamous metaplasia of the urothelium, a cervicovaginal squamous intraepithelial lesion, condyloma acuminatum of the bladder, UC with squamous differentiation, and squamous cell carcinoma. We present here a unique case of atypical squamous cells (ASCs) in the urine subsequently leading to the diagnosis of endometrioid adenocarcinoma of the endometrium with squamous differentiation. The presence of ASCs in voided urine is a rare finding that may indicate an underlying malignancy. Careful evaluation of squamous cells in the urine is an important part of our daily cytopathology practice. Diagn. Cytopathol. 2015;43:49–52. VC 2014 Wiley Periodicals, Inc.
1 Department of Pathology and Laboratory Medicine, University of Calgary, Calgary Laboratory Services, 3535 Research Road NW, Calgary, Alberta, Canada, T2L 2K8 2 Department of Pathology, Baystate Medical Center, Tufts Uiversity School of Medicine, 759 Chestnut Street, Springfield, Massachusetts *Correspondence to: Y. Wang, M.D., Ph.D, Department of Pathology and Laboratory Medicine, University of Calgary, Calgary Laboratory Services, DSC, 3535 Research Road NW, Calgary, Alberta, T2L 2K8, Canada. E-mail: [email protected] Received 5 June 2013; Revised 12 November 2013; Accepted 9 January 2014 DOI: 10.1002/dc.23118 Published online 17 February 2014 in Wiley Online Library (wileyonlinelibrary.com).
C 2014 WILEY PERIODICALS, INC. V
Key Words: urine; atypical squamous cells; endometrioid adenocarcinoma
Urine is one of the most common cytology specimens in our daily practices. The major indication for urinary cytology is hematuria to detect urothelial carcinoma (UC). Another indication is surveillance for recurrent UC. Diagnostic accuracy of UC increases with the grade of the tumor. Urine cytology has high sensitivity and specificity for diagnosis of urothelial carcinoma in situ (UCIS) and high-grade UC, but specificity for low grade urothelial papillary neoplasms is low as instrumentation, lithiasis, and inflammation can cause similar morphological features of low-grade UC. Despite many attempts to develop new tests with greater sensitivity and specificity such as fluorescence in situ hybridization (FISH, UroVysionTM) and fluorescent test using monoclonal antibodies (ImmunoCyt/uCytTM), cytology remains one of best methods to diagnose bladder lesions, most importantly for UCIS and high-grade UC.1,2 Squamous cells in the urine are commonly found in women because the trigone in the bladder in over 50% of adult women (and in some proportion of the male bladder) can be lined by squamous In addition, the distal urethra is partially lined by squamous epithelium.3 Occasionally, endometrial cells are present in the urine of women. Atypical squamous cells (ASCs) are rarely seen in urinary specimens, and there are few studies in the literature.4–6 However, the presence of ASCs in the urine raises the concern of abnormalities of the urinary tract and cervicovaginal region including squamous metaplasia of the urothelium, condyloma acuminatum, Diagnostic Cytopathology, Vol. 43, No 1
49
Diagnostic Cytopathology DOI 10.1002/dc
WANG ET AL.
squamous intraepithelial lesion of the cervicovaginal region, UC with squamous differentiation, squamous cell carcinoma of urinary tract or gynecologic tract, and metastatic squamous cell carcinoma.4–8 Primary squamous cell carcinoma of the bladder is rare and strongly associated with Schistoma hematobium. Focal squamous differentiation is common in UC. We present here a unique case of ASCs in the urine subsequently leading to the diagnosis of endometrioid adenocarcinoma of the endometrium with squamous differentiation.
Case Report The patient was an 82-year-old former nurse who presented with hematuria. The patient stated that she had some vaginal bleeding for about a year, but had had some type of vaginal discharge of uncertain etiology for 4 years. She had never had any heavy vaginal bleeding. The patient had a past medical history of hypertension with renal artery stenosis. The patient saw her gynecologist and a voided urine specimen was sent to pathology for cytologic evaluation.
Cytopathological and Histopathological Findings On the ThinPrep preparation, the urine specimen was predominantly composed of acute inflammatory cells, red blood cells, and rare benign appearing urothelial cells. Abundant benign and rare ASCs were also noticed. The ASCs mostly appeared as keratinizing cells with hyperchromatic smudgy nuclei, high nuclear/cytoplasmic ratio, abnormal nuclear shapes, and densely orangeophilic cytoplasm. Some had more elongated fusiform nuclei (Figs. 1A and B). Based on these findings, the diagnosis of ASCs was rendered. A comment was also included: “The atypical squamous cells present may be derived from either the urinary tract or the cervical–vaginal area.” A cystoscopy was not performed. A cervical Pap test was then performed and was negative. Subsequently, the patient underwent an endocervical curettage that demonstrated unremarkable endocervical glandular mucosa and metaplastic squamous mucosa, with no dysplastic squamous epithelium identified, and a curettage of the endometrium which revealed endometrioid adenocarcinoma with squamous differentiation. One month later, a hysterectomy was performed and a 4.0 3 1.5 3 1.0 cm tumor was identified involving both anterior and posterior endometrium. In addition, leiomyomata and adenomyosis were present. Microscopically, the tumor consisted of well-formed glands admixed with solid sheets of malignant cells consistent with grade II (FIGO) endometrioid adenocarcinoma of the endometrium. The tumor invaded 50%–60% of the myometrial thickness. Squamous differentiation scattered in the superficial portion of the tumor forming morules or nests was noted 50
Diagnostic Cytopathology, Vol. 43, No 1
(Fig. 1C). There were atypical keratinizing squamous cells sloughing from the surface of the squamous differentiation (Fig. 1D). These ASCs were similar to the ASCs present in the urine (Figs. 1A and B). No cervical involvement or lymphovascular invasion was identified. The pathology staging was pT1c pN0 pMx according to AJCC 2010.
Discussion Clinical history is always important in the proper evaluation of any specimen, including urine. The most common symptoms of patients with bladder cancer are hematuria or cystitis-like symptoms (frequency, urgency, or pain), but these symptoms are nonspecific. From a clinical point of view, a careful and thorough history is paramount for the further evaluation of the patient. For example, for patients with hematuria, the initial evaluation is urine cytology. But for post-menopausal patients with spotting or bleeding, the initial evaluation includes pelvic examination, cervical Pap testing, and an endometrial biopsy. Our patient had some vaginal bleeding for about a year, but had had some type of vaginal discharge of uncertain etiology for 4 years. Interestingly, the first specimen sent in this patient was urine cytology and it showed ASCs that subsequently lead to a diagnosis of endometrioid adenocarcinoma of the endometrium with squamous differentiation. The presence of ASCs in urine cytology specimens is a rare finding (0.3%–0.9%) that may indicate an underlying malignancy.4,6 Owens et al. showed 25% of the patients with ASCs in the urine had squamous cell carcinoma or UC with squamous cell differentiation.4 In the same study, in 6% of the patients with ASCs in the urine, a diagnosis of high-grade cervical squamous cell carcinoma was made on the subsequent follow-up, while 69% remained benign on histologic and prolonged clinical follow-up. A recent study showed 28.6% of the patients with ASCs in their urine were diagnosed as combination of UC and squamous cell carcinoma, and in 38.1% of the patients with ASCs in the urine had squamous cell carcinoma originating from sites other than the urinary tract.6 In addition, a recent case report of dysplastic squamous cells in the urine revealed squamous cell carcinoma of the bladder, attesting again the value of urine cytology as an initial diagnostic test.7 To our knowledge, this is the first report in the literature of ASCs in the voided urine leading to a diagnosis of endometrioid adenocarcinoma of the endometrium with squamous differentiation. This report broadens the differential diagnosis of ASCs in the urine of women. Endometrioid carcinomas of the endometrium with squamous differentiation account for approximately 25% of endometrioid carcinomas of the endometrium. Morphologically, the
Diagnostic Cytopathology DOI 10.1002/dc
ATYPICAL SQUAMOUS CELLS IN THE URINE: A CASE REPORT
Fig. 1. Atypical squamous cells in the voided urine (A and B, ThinPrep, original magnification 4003). Squamous cell differentiation forming morules or nests in the superficial portion of the endometrioid adenocarcinoma (C, hematoxylin-eosin, original magnification 1003). Sloughing atypical squamous cells on the surface of the squamous differentiation (D, hematoxylin-eosin, original magnification 2003). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
squamous component can have a variety of features such as rounded intraluminal aggregates (morules), infiltrating nests resembling conventional squamous cell carcinoma, micropapillae, individual cell keratinization, or overlapping appearances.9 In our case, the squamous differentiation had both a morule appearance and infiltrating nests, mainly located in the superficial portion of the tumor. In summary, careful evaluation of the squamous cells in urine cytology specimens is important. The presence of ASCs in voided urine is an uncommon finding that may be a sign of an underlying malignant process and war-
rants clinical follow-up. Endometrioid adenocarcinoma of the endometrium with squamous differentiation should be in the differential diagnosis of ASCs in the urine in female patients.
References 1. Cibas ES, Ducatman BS. Cytology: Diagnostic principles, and clinical correlates. 3rd ed. Philadelphia, PA: Saunders Elsevier; 2009. p 123–124. 2. Bernard T. Diagnosis of urothelial carcinoma from urine. Mod Pathol 2009;22:S53–S59. 3. Packham DA. The epithelial lining of the female trigone and urethra. Br J Urol 1971;43(2):201–205. Diagnostic Cytopathology, Vol. 43, No 1
51
Diagnostic Cytopathology DOI 10.1002/dc
WANG ET AL. 4. Owens CL, Ali SZ. Atypical squamous cells in exfoliative urinary cytology: Clinicopathologic correlates. Diagn Cytopathol 2005; 33(6):394–398. 5. Touijer AK, Dalbagni G. Role of voided urine cytology in diagnosing primary urethral carcinoma. Urology 2004;63(1):33–35. 6. Hattori M, Nishimura Y, Toyonaga M, et al. Cytological significance of abnormal squamous cells in urinary cytology. Diagn Cytopathol 2012;40(9):798–803.
52
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7. Rosa M. Clinical significance of dysplastic squamous cells in exfloliative urine cytology. Diagn Cytopathol 2010;38(6):468–469. 8. Demay RM. Practical principles of cytopathology. Revised 1st ed. American Society of Clinical Pathology; 2007. 9. Clement PB, Young RH. Endometrioid carcinoma of the uterine corpus: A review of its pathology with emphasis on recent advances and problematic aspects. Adv Anat Pathol 2002;9: 145–184.
