Original article
Utility of 18F-FDG PET/CT in the diagnosis and staging of extramammary Paget’s disease Ying Tiana, Hu-Bing Wua, Dong-Li Lib, Hong-Sheng Lia, Wen-Lan Zhoua and Quan-Shi Wanga Purpose Extramammary Paget’s disease (EMPD) is rare, and limited data have been reported on the utilization of fluorine-18 fluorodeoxyglucose PET/computed tomography (18F-FDG PET/CT) in this disease. The aim of this study is to evaluate the role of 18F-FDG PET/CT in the diagnosis and staging of EMPD.
detected lymph node metastases in six patients, bone metastases in five patients, liver metastases in two patients, lung metastases in one patient, and an adrenal gland metastasis in one patient. Compared with conventional staging examinations, three of 10 patients were upstaged by PET/CT.
Materials and methods Whole-body 18F-FDG PET/CT images of 10 patients with newly diagnosed or recurrent EMPD were retrospectively analyzed. The lesion with increased 18F-FDG uptake was considered positive and was measured using the maximum standardized uptake value (SUVmax). The results of PET/CT were compared by conventional staging examinations.
Conclusion 18F-FDG PET/CT diagnosis of primary lesions in EMPD is mainly dependent on the thickness of the lesions, whereas it is more sensitive for the diagnosis of metastases. Nucl Med Commun 36:892–897 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Results All malignant lesions showed increased 18F-FDG uptake, except for some small lung metastases. Wholebody 18F-FDG PET/CT detected all primary lesions in four newly diagnosed patients and recurrences in the primary sites in two patients. Two thick lesions showed intense uptake of 18F-FDG (SUVmax: 14.9 and 7.5) whereas four thin lesions had only mild 18F-FDG uptake (mean SUVmax: 3.25 ± 0.24). A false-positive result was found in one patient with suspected primary recurrence. 18F-FDG PET/CT also
Introduction Extramammary Paget’s disease (EMPD) is a rare adenocarcinoma originating from apocrine gland-bearing skin, such as the perineum, vulva, the perianal area, scrotum, penis, and axilla. It is more common in Caucasians and women between the ages of 50 and 80 years. However, in Asian populations, men are more likely to be affected [1–4]. EMPD typically presents as nonspecific erythematous, erosive, eczematous, or circinate lesions of the skin. It often grows slowly, with a reported median delay of 2 years after symptoms first appear to the definitive diagnosis of the disease [5,6]. The diagnoses of the primary lesion and sentinel lymph node invasion primarily depend on biopsy and histopathological examination. Accurate staging and restaging are crucial in choosing the appropriate therapeutic regimens for patients with EMPD. Wide local excision is the standard treatment for the early-stage EMPD, whereas in locally advanced or metastatic EMPD, systemic chemotherapy is often used [7,8]. Although many reports are available on the value of fluorine-18 fluorodeoxyglucose PET/computed tomography (18F-FDG 0143-3636 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Nuclear Medicine Communications 2015, 36:892–897 Keywords: diagnosis, extramammary Paget’s disease, fluorine-18, fluorodeoxyglucose, PET/CT, staging a NanFang PET Center and bMedical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
Correspondence to Quan-Shi Wang, MD, PhD, NanFang PET Center, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, Guangdong Province, China Tel: + 86 20 87795061; fax: + 86 20 61642127; e-mail: [email protected] Received 22 March 2015 Revised 8 April 2015 Accepted 8 April 2015
PET/CT) in the diagnosis and staging of malignancies, few articles have evaluated the utility of PET/CT in the diagnosis and staging of EMPD [9–12]. In the present study, we retrospectively analyzed 10 patients with EMPD to assess the role of PET/CT in the diagnosis and staging of this rare disease.
Materials and methods Patients
This study was approved by the Institutional Review Board of our hospital. Because of the retrospective nature of the study, the requirement for informed consent was waived. From May 2006 to March 2014, a total of 10 patients with EMPD [seven men and three women, mean age 67 years (range: 58–80 years)] were enrolled in this study. The enrolled patients included four with newly diagnosed EMPD and six with suspected recurrence. Among these 10 patients, EMPD was initially diagnosed in the scrotum in five patients, in the penis in two patients, and in the perianal region, vulva, and axilla in one patient each, respectively. DOI: 10.1097/MNM.0000000000000340
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
No Upstage
No
No Excision Chemotherapy Photodynamic therapy + chemotherapy Excision
No No No
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
F-FDG, fluorine-18 fluorodeoxyglucose; LN, lymph nodes. 18
− , negative; + , positive; CT, computed tomography; EMPD, extramammary Paget’s disease;
+ + Female/80 Photodynamic therapy + radiotherapy Male/80 Excision + photodynamic therapy 9 10
Perianal region Penis
No Yes
− +
4.0/0.8 3.0/0.7
LN (multiple foci), bone (multiple foci), liver No LN (multiple foci), bone (multiple foci), left adrenal gland − Male/71 8
Scrotum
Yes
−
3.4/0.7 No No 7.5/1.3 + − − + Female/73 Male/62 Male/58 Male/68 4 5 6 7
Vulva Scrotum Scrotum Scrotum
No Yes Yes Yes
+ − − +
No
No No No Upstage
Upstage No No
LN (multiple foci), bone No LN, lung, liver, bone (multiple foci) No No LN, bone (multiple foci) LN 3.5/0.6 3.1/0.5 14.9/2.0 + + + + + + Yes No Yes Scrotum Penis Axilla
SUVmax/thickness (cm) Positive on PET/CT Positive on pathology at present Dermal invasion on initial diagnosis Initial location Sex/age
F-FDG PET/CT
A total of 11 F-FDG PET/CT scans were performed on 10 patients, including one scan for each of nine patients and two scans for one patient. While diagnosing the lesions at the primary site, seven positive lesions were detected using 18F-FDG PET/CT, including all primary lesions of the four newly diagnosed patients, recurrent lesions in two patients, and a false-positive lesion in one patient (Table 1). Among the six lesions diagnosed at the primary site, two thick lesions (2.0 and 1.3 cm in the thickness, respectively, as measured on the corresponding CT images) showed intense 18F-FDG uptake (SUVmax: 14.9 and 7.5, respectively) (Fig. 1b and c), whereas four thin lesions (all < 1.0 cm thick; mean thickness: 0.63 cm, range: 0.5–0.7 cm) showed only mild uptake of 18F-FDG (mean SUVmax: 3.25 ± 0.24) (Fig. 2a). In one patient with suspected recurrence, a positive lesion (SUVmax: 4.0, thickness: 0.8 cm) detected by PET/CT in the primary site was identified as a falsepositive finding secondary to an inflammatory fibroid polyp on the basis of histopathological examination.
Number
18
F-FDG PET/CT in EMPD patients
18
18
Diagnosis of EMPD with
Clinical information and findings of
Results
Table 1
SPSS, version 13.0 (SPSS Inc., Chicago, Illinois, USA) software was used for the statistical analysis. The mean SUVmax was expressed as mean ± SD. The independentsamples t-test was used for statistical comparison of the SUVmax of two groups of lymph node metastases. Differences were considered statistically significant at a level of P value less than 0.05 (two tailed).
Primary tumor
Statistical analysis
Male/61 Male/61 Female/59
F-FDG PET/CT examinations
Four examinations were carried out using a GE Discovery LS PET/CT scanner (GE Healthcare, Waukesha, Wisconsin, USA) and seven examinations were carried out using a Siemens Biograph mCTx scanner (Siemens Medical Solutions USA, Knoxville, Tennessee, USA). The patients were instructed to fast for at least 6 h before each scan. Approximately 60 min after the intravenous injection of 277 to 511 MBq (7.49 to 13.81 mCi, 5.5 MBq/kg) of 18 F-FDG, whole-body PET/CT was performed according to the guidelines for tumor imaging with 18F-FDG PET/CT 1.0 [13]. Lesions with increased 18F-FDG uptake were considered positive for tumor. The region of interest was drawn along the margin of the lesion for measurement of the maximum standardized uptake value (SUVmax).
Treatment before PET/CT
18
Metastases
The diagnosis of EMPD at the primary site was established by histopathological examination in seven patients. The diagnosis of metastasis was made by biopsy or multiple imaging modalities including CT, MRI, ultrasound, and radiologic follow-up. All patients received imaging and clinical follow-up for more than 6 months after diagnosis.
1 2 3
Change in stage after PET/CT
Diagnosis of EMPD with PET/CT Tian et al. 893
894 Nuclear Medicine Communications 2015, Vol 36 No 9
Fig. 1
(a)
(b)
(c)
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(d)
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(g) R
A 59-year-old woman with advanced EMPD. The patient had erythema, pruritus, erosion, and effusion in the left axilla for 6 years. Over the most recent 6 months, the erythema grew rapidly. The diagnosis of EMPD of the left axilla was confirmed by biopsy. Whole-body 18F-FDG PET/CT was performed for staging. MIP of PET (a) showed multiple lesions with intense uptake of 18F-FDG throughout the whole body. PET/CT showed the primary EMPD lesion with intense uptake of 18F-FDG (SUVmax: 14.9, thickness: 2.0 cm) in the left axilla (b, c; arrow) and multiple metastases in lymph nodes (d, arrow), lung (e, arrow), liver (f, arrow), and bone (g, arrow). CT, computed tomography; EMPD, extramammary Paget’s disease; 18F-FDG, fluorine-18 fluorodeoxyglucose; SUVmax, maximum standardized uptake value.
Of eight patients with newly diagnosed or recurrent EMPD, six were diagnosed with lymph node metastases. A total of 157 lymph node metastases (mean SUVmax: 6.06 ± 2.42) were detected by 18F-FDG PET/CT (Figs 1d, 2a and b). Among these, 20.4% (32/157) of lesions were smaller than 1.0 cm in diameter. The mean SUVmax of the less than 1.0 cm group was significantly lower compared with that in the more than or equal to 1.0 cm group (4.05 ± 1.17 vs. 6.58 ± 2.39, t = − 7.361, P = 0.000). The most commonly involved site of lymph node metastases in five patients with EMPD of the perineum was the inguinal region (5/5), followed by the external iliac arteries and abdominal aorta (4/5), mediastinum (2/5), and supraclavicular/infraclavicular fossa (1/5). 18
F-FDG PET/CT also detected 147 bone metastatic lesions in five patients (Figs 1g and 2b), eight liver metastatic lesions in two patients (Fig. 1f), 22 lung metastatic lesions in one patient (Fig. 1e), and an adrenal gland metastatic lesion in one patient (Fig. 2b). All distant metastases showed increased 18F-FDG uptake, except for some small lung metastases, which had no uptake on 18 F-FDG PET but were observed on the corresponding CT images. The mean SUVmax of lung metastases was 1.45 ± 1.25, whereas the uptake of 18F-FDG in the other distant metastases was high (mean SUVmax: 7.65 ± 1.88). In the present study, dermal invasion on initial diagnosis was identified by pathology in seven patients, and six of
these patients were found to have lymph node metastases and/or distant metastases. Staging of EMPD with
18
F-FDG PET/CT
Compared with conventional staging examinations, three of 10 patients were upstaged by 18F-FDG PET/CT. One patient could not undergo an operation because ‘unsuspected’ bone metastases in the seventh and 11th thoracic vertebrae were detected by PET/CT, and treatment was altered to four cycles of chemotherapy. One patient, who received photodynamic and chemotherapy, was advised to also undergo radiotherapy for lymph nodes metastases in the bilateral inguinal region and retroperitoneal area detected by PET/CT. Another patient received two PET/CT scans. He underwent wide local excision and left inguinal lymph node dissection because a recurrent lesion in the left scrotum and lymph node metastases in the left inguinal region were found by PET/CT (Fig. 2a). Four months later, the second PET/CT scan was performed for surveillance. PET/CT showed that the disease was not controlled and the tumor had spread to distant lymph nodes, the left adrenal gland, and bones. He then received standard chemotherapy (Fig. 2b). In one patient with EMPD of the axilla, although PET/CT detected ‘unsuspected’ metastases in the liver (Fig. 1f), her staging was not altered.
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Diagnosis of EMPD with PET/CT Tian et al. 895
Fig. 2
(a)
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R
R
A
B
C
R
R
R
D
E
F
(b)
A
R
R
R
B
C
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An 80-year-old man with recurrent EMPD of the penis. He complained of new-onset erythema in the left scrotum for more than 4 months after wide local excision and photodynamic therapy for his tumor. The first 18F-FDG PET/CT scan (a) showed a recurrent lesion with mild 18F-FDG uptake (a: A–C, arrow, SUVmax: 3.0, thickness: 0.7 cm) in the left scrotum and lymph nodes metastases with increased 18F-FDG uptake (a: D–F, arrow, SUVmax: 5.1) in the left inguinal region. The second 18F-FDG PET/CT scan (b) showed a large number of metastatic lesions with increased 18F-FDG uptake, including the lymph nodes metastases in the mediastinum (b: B–D, yellow arrow) and near the common iliac blood vessels (b: H–J, yellow arrow) and the distant metastases in the left adrenal gland (b: E–G, yellow arrow) and bones (b: B–D and H–J, blue arrow). CT, computed tomography; EMPD, extramammary Paget’s disease; 18F-FDG, fluorine-18 fluorodeoxyglucose; SUVmax, maximum standardized uptake value.
Discussion Although PET/CT has been used widely to diagnose patients with malignant tumor [14–18], the utility of PET/CT in EMPD has rarely been reported, except for two small case reports and two brief reports. The case reports by Niederkohr and Gambhir [11] and Treglia et al. [12] highlight the usefulness of 18F-FDG PET/CT for the detection and staging of EMPD. However, Aoyagi
et al. [9] suggested that 18F-FDG PET was less useful in detecting small or subclinical involvement. In three patients, PET failed to detect 5 to 7 mm nodal involvement, but succeeded in detecting nodes over 10 mm. Cho et al. [10] also reported that PET showed only mild uptake in the primary sites of EMPD in four patients and no uptake in three patients. Histologically, all four positive tumors on PET were found to be thicker than 2 cm.
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
896
Nuclear Medicine Communications 2015, Vol 36 No 9
Positive detection of 18F-FDG PET/CT depended on the lesion thickness, but not lesion size. Similar to the findings of Cho et al. [10], the present study showed that 18F-FDG PET/CT diagnosis of primary lesions in EMPD was mainly dependent on the thickness of the lesions. In four patients with thin lesions (mean thickness: 0.63 cm, range: 0.5–0.7 cm), the uptake of 18 F-FDG was mild (mean SUVmax: 3.25 ± 0.24), whereas in two patients with thick lesions (2.0 and 1.3 cm in the thickness), the uptake of 18F-FDG was intense (SUVmax: 14.9 and 7.5, respectively). Because of the low uptake of 18 F-FDG in the thin lesions, 18F-FDG PET/CT was limited in delineating the margin of the primary lesions that were potentially diagnosed as inflammation. In most cases with primary EMPD, the tumor usually remains confined to the epidermis, but it can slowly develop into an invasive tumor, spreading to the dermis, blood vessels, and lymphatics and producing potentially fatal metastases [19]. The prognosis for primary EMPD in situ is excellent, whereas invasive primary EMPD has a poor prognosis, particularly if metastases are present [3, 20]. Therefore, accurate staging is critical for selecting the appropriate treatment and predicting prognosis in patients with EMPD. For the detection of the lymph node and distant metastases, the present study showed that 18F-FDG PET/CT was a sensitive modality. In this study, in six patients diagnosed with lymph node and distant metastases, 18 F-FDG PET/CT showed increased uptake in all metastatic lesions, except for several small lung metastases. 18F-FDG PET/CT detected 20.4% (32/157) of lymph node metastatic lesions that were smaller than 1.0 cm in diameter. The high sensitivity of 18F-FDG PET/CT reported in this article might be because of the use of better equipment and significant improvement in the spatial resolution of PET in recent years [21,22]. Although the uptake of 18F-FDG was low in the lung metastases, they could be detected by the corresponding CT images. The uptake of 18F-FDG in the other distant metastases was very high (mean SUVmax: 7.65 ±1.88) and PET/CT was sensitive for their detection. Among six advanced-stage patients, 18F-FDG PET/CT detected more ‘unsuspected’ metastases in four patients and three patients were upstaged by PET/CT. Therefore, the present study indicated that 18F-FDG PET/CT could play a potential role in the staging of EMPD, especially in patients with advanced EMPD. It has been reported that dermal or deeper invasion, lymphovascular embolization, and negative expression of E-cadherin are important pathological predictors of EMPD metastatic potential [23]. This opinion was reinforced by the present study, in which six of seven patients with dermal invasion at initial diagnosis were found to have lymph node metastases and/or distant metastases. However, none of the three patients without
invasion of the dermis at initial diagnosis had metastatic disease. Because of its high sensitivity, 18F-FDG PET/CT may also play a role in surveillance of early metastases in EMPD patients with invasion of the dermis.
Conclusion This study showed that 18F-FDG PET/CT diagnosis of primary lesions in EMPD was mainly dependent on the thickness of the lesions, whereas it was more sensitive for the diagnosis of metastases. Therefore, 18F-FDG PET/CT is useful for the diagnosis and staging of EMPD, and also for patients with EMPD to select the appropriate treatment. Our study had several limitations including its retrospective nature and the small number of patients. Thus, future prospective studies with larger cohorts of patients are needed to confirm our findings.
Acknowledgements The authors wish to thank their colleagues at the Department of Dermatology and Department of Oncology of Nanfang hospital, who, in part, provided the follow-up data. This study was supported by grants from the National Natural Science Foundation of China (No. 81271641 and No. 81301215). Conflicts of interest
There are no conflicts of interest.
References 1
Chanda JJ. Extramammary Paget’s disease: prognosis and relationship to internal malignancy. J Am Acad Dermatol 1985; 13:1009–1014. 2 Zollo JD, Zeitouni NC. The Roswell Park Cancer Institute experience with extrammamary Paget’s disease. BR J Dermatol 2000; 142:59–65. 3 Hartman R, Chu J, Patel R, Meehan S, Stein JA. Extramammary Paget disease. Dermatol Online J 2011; 17:4. 4 Cheng PS, Lu CL, Cheng CL, Lai FJ. Significant male predisposition in extramammary Paget disease: a nationwide population-based study in Taiwan. Br J Dermatol 2014; 171:191–193. 5 Hatta N, Yamada M, Hirano T, Fujimoto A, Morita R. Extramammary Paget’s disease: treatment, prognostic factors and outcome in 76 patients. Br J Dermatol 2008; 158:313–318. 6 Isrow D, Oregel KZ, Cortes J, Gomez H, Milikowski C, Feun L, Silva O. Advanced extramammary Paget’s disease of the groin, penis, and scrotum. Clin Med Insights Oncol 2014; 8:87–90. 7 Lam C, Funaro D. Extramammary Paget’s disease: summary of current knowledge. Dermatol Clin 2010; 28:807–826. 8 Nomura H, Matoda M, Okamoto S, Kondo E, Omatsu K, Kato K, Takeshima N. Clinicopathologic features and treatment outcomes of primary extramammary Paget disease of the vulva. J Low Genit Tract Dis 2015; 19:145–148. 9 Aoyagi S, Sato-Matsumura KC, Shimizu H. Staging and assessment of lymph node involvement by 18F-fluorodeoxyglucose-positron emission tomography in invasive extramammary Paget’s disease. Dermatol Surg 2005; 31:595–598. 10 Cho SB, Yun M, Lee MG, Chung KY. Variable patterns of positron emission tomography in the assessment of patients with extramammary Paget’s disease. J Am Acad Dermatol 2005; 52:353–355. 11 Niederkohr RD, Gambhir SS. F-18 FDG PET/CT imaging of extramammary Paget disease of the perianal region. Clin Nucl Med 2006; 31: 561–563. 12 Treglia G, Giovannini E, Bertagna F, Giovanella L, Malaggese M. An unusual case of metastatic extramammary Paget’s disease of the vulva identified by 18F-FDG PET/CT. Rev Esp Med Nucl Imagen Mol 2013; 32:402–403.
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Diagnosis of EMPD with PET/CT Tian et al. 897
13
14
15
16
17 18
Delbeke D, Coleman RE, Guiberteau MJ, Brown ML, Royal HD, Siegel BA, et al. Procedure guideline for tumor imaging with 18F-FDG PET/CT 1.0. J Nucl Med 2006; 47:885–895. Chua ML, Ong SC, Wee JT, Ng DC, Gao F, Tan TW, et al. Comparison of 4 modalities for distant metastasis staging in endemic nasopharyngeal carcinoma. Head Neck 2009; 31:346–354. Wu HB, Wang QS, Wang MF, Li HS, Zhou WL, Ye XH, Wang QY. Utility of 18 F-FDG PET/CT for staging NK/T-cell lymphomas. Nucl Med Commun 2010; 31:195–200. Chiba K, Isoda M, Chiba M, Kanematsu T, Eguchi S. Significance of PET/CT in determining actual TNM staging for patients with various lung cancers. Int Surg 2010; 95:197–204. Prakash P, Cronin CG, Blake MA. Role of PET/CT in ovarian cancer. Am J Roentgenol 2010; 194:W464–W470. Kumar R, Halanaik D, Malhotra A. Clinical applications of positron emission tomography-computed tomography in oncology. Indian J Cancer 2010; 47:100–119.
19 20
21
22
23
Kanitakis J. Mammary and extramammary Paget’s disease. J Eur Acad Dermatol Venereol 2007; 2:581–590. Mochitomi Y, Sakamoto R, Gushi A, Hashiquchi T, Mera K, Matsushita S, et al. Extramammary Paget’s disease/carcinoma successfully treated with a combination chemotherapy: report of two cases. J Dermatol 2005; 32:632–637. Jakoby BW, Bercier Y, Conti M, Casey ME, Bendriem B, Townsend DW. Physical and clinical performance of the mCT time-of-flight PET/CT scanner. Phys Med Biol 2011; 56:2375–2389. Poon JK, Dahlbom ML, Moses WW, Balakrishnan K, Wang W, Cherry SR, Badawi RD. Optimal whole-body PET scanner configurations for different volumes of LSO scintillator: a simulation study. Phys Med Biol 2012; 57:4077–4094. Zhu Y, Ye DW, Yao XD, Zhang SL, Dai B, Zhang HL, et al. Clinicopathological characteristics, management and outcome of metastatic penoscrotal extramammary Paget’s disease. Br J Dermatol 2009; 161:577–582.
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Utility of 18F-FDG PET/CT in the diagnosis and staging of extramammary Paget’s disease Ying Tiana, Hu-Bing Wua, Dong-Li Lib, Hong-Sheng Lia, Wen-Lan Zhoua and Quan-Shi Wanga Purpose Extramammary Paget’s disease (EMPD) is rare, and limited data have been reported on the utilization of fluorine-18 fluorodeoxyglucose PET/computed tomography (18F-FDG PET/CT) in this disease. The aim of this study is to evaluate the role of 18F-FDG PET/CT in the diagnosis and staging of EMPD.
detected lymph node metastases in six patients, bone metastases in five patients, liver metastases in two patients, lung metastases in one patient, and an adrenal gland metastasis in one patient. Compared with conventional staging examinations, three of 10 patients were upstaged by PET/CT.
Materials and methods Whole-body 18F-FDG PET/CT images of 10 patients with newly diagnosed or recurrent EMPD were retrospectively analyzed. The lesion with increased 18F-FDG uptake was considered positive and was measured using the maximum standardized uptake value (SUVmax). The results of PET/CT were compared by conventional staging examinations.
Conclusion 18F-FDG PET/CT diagnosis of primary lesions in EMPD is mainly dependent on the thickness of the lesions, whereas it is more sensitive for the diagnosis of metastases. Nucl Med Commun 36:892–897 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Results All malignant lesions showed increased 18F-FDG uptake, except for some small lung metastases. Wholebody 18F-FDG PET/CT detected all primary lesions in four newly diagnosed patients and recurrences in the primary sites in two patients. Two thick lesions showed intense uptake of 18F-FDG (SUVmax: 14.9 and 7.5) whereas four thin lesions had only mild 18F-FDG uptake (mean SUVmax: 3.25 ± 0.24). A false-positive result was found in one patient with suspected primary recurrence. 18F-FDG PET/CT also
Introduction Extramammary Paget’s disease (EMPD) is a rare adenocarcinoma originating from apocrine gland-bearing skin, such as the perineum, vulva, the perianal area, scrotum, penis, and axilla. It is more common in Caucasians and women between the ages of 50 and 80 years. However, in Asian populations, men are more likely to be affected [1–4]. EMPD typically presents as nonspecific erythematous, erosive, eczematous, or circinate lesions of the skin. It often grows slowly, with a reported median delay of 2 years after symptoms first appear to the definitive diagnosis of the disease [5,6]. The diagnoses of the primary lesion and sentinel lymph node invasion primarily depend on biopsy and histopathological examination. Accurate staging and restaging are crucial in choosing the appropriate therapeutic regimens for patients with EMPD. Wide local excision is the standard treatment for the early-stage EMPD, whereas in locally advanced or metastatic EMPD, systemic chemotherapy is often used [7,8]. Although many reports are available on the value of fluorine-18 fluorodeoxyglucose PET/computed tomography (18F-FDG 0143-3636 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Nuclear Medicine Communications 2015, 36:892–897 Keywords: diagnosis, extramammary Paget’s disease, fluorine-18, fluorodeoxyglucose, PET/CT, staging a NanFang PET Center and bMedical Imaging Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
Correspondence to Quan-Shi Wang, MD, PhD, NanFang PET Center, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou 510515, Guangdong Province, China Tel: + 86 20 87795061; fax: + 86 20 61642127; e-mail: [email protected] Received 22 March 2015 Revised 8 April 2015 Accepted 8 April 2015
PET/CT) in the diagnosis and staging of malignancies, few articles have evaluated the utility of PET/CT in the diagnosis and staging of EMPD [9–12]. In the present study, we retrospectively analyzed 10 patients with EMPD to assess the role of PET/CT in the diagnosis and staging of this rare disease.
Materials and methods Patients
This study was approved by the Institutional Review Board of our hospital. Because of the retrospective nature of the study, the requirement for informed consent was waived. From May 2006 to March 2014, a total of 10 patients with EMPD [seven men and three women, mean age 67 years (range: 58–80 years)] were enrolled in this study. The enrolled patients included four with newly diagnosed EMPD and six with suspected recurrence. Among these 10 patients, EMPD was initially diagnosed in the scrotum in five patients, in the penis in two patients, and in the perianal region, vulva, and axilla in one patient each, respectively. DOI: 10.1097/MNM.0000000000000340
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
No Upstage
No
No Excision Chemotherapy Photodynamic therapy + chemotherapy Excision
No No No
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
F-FDG, fluorine-18 fluorodeoxyglucose; LN, lymph nodes. 18
− , negative; + , positive; CT, computed tomography; EMPD, extramammary Paget’s disease;
+ + Female/80 Photodynamic therapy + radiotherapy Male/80 Excision + photodynamic therapy 9 10
Perianal region Penis
No Yes
− +
4.0/0.8 3.0/0.7
LN (multiple foci), bone (multiple foci), liver No LN (multiple foci), bone (multiple foci), left adrenal gland − Male/71 8
Scrotum
Yes
−
3.4/0.7 No No 7.5/1.3 + − − + Female/73 Male/62 Male/58 Male/68 4 5 6 7
Vulva Scrotum Scrotum Scrotum
No Yes Yes Yes
+ − − +
No
No No No Upstage
Upstage No No
LN (multiple foci), bone No LN, lung, liver, bone (multiple foci) No No LN, bone (multiple foci) LN 3.5/0.6 3.1/0.5 14.9/2.0 + + + + + + Yes No Yes Scrotum Penis Axilla
SUVmax/thickness (cm) Positive on PET/CT Positive on pathology at present Dermal invasion on initial diagnosis Initial location Sex/age
F-FDG PET/CT
A total of 11 F-FDG PET/CT scans were performed on 10 patients, including one scan for each of nine patients and two scans for one patient. While diagnosing the lesions at the primary site, seven positive lesions were detected using 18F-FDG PET/CT, including all primary lesions of the four newly diagnosed patients, recurrent lesions in two patients, and a false-positive lesion in one patient (Table 1). Among the six lesions diagnosed at the primary site, two thick lesions (2.0 and 1.3 cm in the thickness, respectively, as measured on the corresponding CT images) showed intense 18F-FDG uptake (SUVmax: 14.9 and 7.5, respectively) (Fig. 1b and c), whereas four thin lesions (all < 1.0 cm thick; mean thickness: 0.63 cm, range: 0.5–0.7 cm) showed only mild uptake of 18F-FDG (mean SUVmax: 3.25 ± 0.24) (Fig. 2a). In one patient with suspected recurrence, a positive lesion (SUVmax: 4.0, thickness: 0.8 cm) detected by PET/CT in the primary site was identified as a falsepositive finding secondary to an inflammatory fibroid polyp on the basis of histopathological examination.
Number
18
F-FDG PET/CT in EMPD patients
18
18
Diagnosis of EMPD with
Clinical information and findings of
Results
Table 1
SPSS, version 13.0 (SPSS Inc., Chicago, Illinois, USA) software was used for the statistical analysis. The mean SUVmax was expressed as mean ± SD. The independentsamples t-test was used for statistical comparison of the SUVmax of two groups of lymph node metastases. Differences were considered statistically significant at a level of P value less than 0.05 (two tailed).
Primary tumor
Statistical analysis
Male/61 Male/61 Female/59
F-FDG PET/CT examinations
Four examinations were carried out using a GE Discovery LS PET/CT scanner (GE Healthcare, Waukesha, Wisconsin, USA) and seven examinations were carried out using a Siemens Biograph mCTx scanner (Siemens Medical Solutions USA, Knoxville, Tennessee, USA). The patients were instructed to fast for at least 6 h before each scan. Approximately 60 min after the intravenous injection of 277 to 511 MBq (7.49 to 13.81 mCi, 5.5 MBq/kg) of 18 F-FDG, whole-body PET/CT was performed according to the guidelines for tumor imaging with 18F-FDG PET/CT 1.0 [13]. Lesions with increased 18F-FDG uptake were considered positive for tumor. The region of interest was drawn along the margin of the lesion for measurement of the maximum standardized uptake value (SUVmax).
Treatment before PET/CT
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Metastases
The diagnosis of EMPD at the primary site was established by histopathological examination in seven patients. The diagnosis of metastasis was made by biopsy or multiple imaging modalities including CT, MRI, ultrasound, and radiologic follow-up. All patients received imaging and clinical follow-up for more than 6 months after diagnosis.
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Change in stage after PET/CT
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894 Nuclear Medicine Communications 2015, Vol 36 No 9
Fig. 1
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A 59-year-old woman with advanced EMPD. The patient had erythema, pruritus, erosion, and effusion in the left axilla for 6 years. Over the most recent 6 months, the erythema grew rapidly. The diagnosis of EMPD of the left axilla was confirmed by biopsy. Whole-body 18F-FDG PET/CT was performed for staging. MIP of PET (a) showed multiple lesions with intense uptake of 18F-FDG throughout the whole body. PET/CT showed the primary EMPD lesion with intense uptake of 18F-FDG (SUVmax: 14.9, thickness: 2.0 cm) in the left axilla (b, c; arrow) and multiple metastases in lymph nodes (d, arrow), lung (e, arrow), liver (f, arrow), and bone (g, arrow). CT, computed tomography; EMPD, extramammary Paget’s disease; 18F-FDG, fluorine-18 fluorodeoxyglucose; SUVmax, maximum standardized uptake value.
Of eight patients with newly diagnosed or recurrent EMPD, six were diagnosed with lymph node metastases. A total of 157 lymph node metastases (mean SUVmax: 6.06 ± 2.42) were detected by 18F-FDG PET/CT (Figs 1d, 2a and b). Among these, 20.4% (32/157) of lesions were smaller than 1.0 cm in diameter. The mean SUVmax of the less than 1.0 cm group was significantly lower compared with that in the more than or equal to 1.0 cm group (4.05 ± 1.17 vs. 6.58 ± 2.39, t = − 7.361, P = 0.000). The most commonly involved site of lymph node metastases in five patients with EMPD of the perineum was the inguinal region (5/5), followed by the external iliac arteries and abdominal aorta (4/5), mediastinum (2/5), and supraclavicular/infraclavicular fossa (1/5). 18
F-FDG PET/CT also detected 147 bone metastatic lesions in five patients (Figs 1g and 2b), eight liver metastatic lesions in two patients (Fig. 1f), 22 lung metastatic lesions in one patient (Fig. 1e), and an adrenal gland metastatic lesion in one patient (Fig. 2b). All distant metastases showed increased 18F-FDG uptake, except for some small lung metastases, which had no uptake on 18 F-FDG PET but were observed on the corresponding CT images. The mean SUVmax of lung metastases was 1.45 ± 1.25, whereas the uptake of 18F-FDG in the other distant metastases was high (mean SUVmax: 7.65 ± 1.88). In the present study, dermal invasion on initial diagnosis was identified by pathology in seven patients, and six of
these patients were found to have lymph node metastases and/or distant metastases. Staging of EMPD with
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F-FDG PET/CT
Compared with conventional staging examinations, three of 10 patients were upstaged by 18F-FDG PET/CT. One patient could not undergo an operation because ‘unsuspected’ bone metastases in the seventh and 11th thoracic vertebrae were detected by PET/CT, and treatment was altered to four cycles of chemotherapy. One patient, who received photodynamic and chemotherapy, was advised to also undergo radiotherapy for lymph nodes metastases in the bilateral inguinal region and retroperitoneal area detected by PET/CT. Another patient received two PET/CT scans. He underwent wide local excision and left inguinal lymph node dissection because a recurrent lesion in the left scrotum and lymph node metastases in the left inguinal region were found by PET/CT (Fig. 2a). Four months later, the second PET/CT scan was performed for surveillance. PET/CT showed that the disease was not controlled and the tumor had spread to distant lymph nodes, the left adrenal gland, and bones. He then received standard chemotherapy (Fig. 2b). In one patient with EMPD of the axilla, although PET/CT detected ‘unsuspected’ metastases in the liver (Fig. 1f), her staging was not altered.
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Diagnosis of EMPD with PET/CT Tian et al. 895
Fig. 2
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An 80-year-old man with recurrent EMPD of the penis. He complained of new-onset erythema in the left scrotum for more than 4 months after wide local excision and photodynamic therapy for his tumor. The first 18F-FDG PET/CT scan (a) showed a recurrent lesion with mild 18F-FDG uptake (a: A–C, arrow, SUVmax: 3.0, thickness: 0.7 cm) in the left scrotum and lymph nodes metastases with increased 18F-FDG uptake (a: D–F, arrow, SUVmax: 5.1) in the left inguinal region. The second 18F-FDG PET/CT scan (b) showed a large number of metastatic lesions with increased 18F-FDG uptake, including the lymph nodes metastases in the mediastinum (b: B–D, yellow arrow) and near the common iliac blood vessels (b: H–J, yellow arrow) and the distant metastases in the left adrenal gland (b: E–G, yellow arrow) and bones (b: B–D and H–J, blue arrow). CT, computed tomography; EMPD, extramammary Paget’s disease; 18F-FDG, fluorine-18 fluorodeoxyglucose; SUVmax, maximum standardized uptake value.
Discussion Although PET/CT has been used widely to diagnose patients with malignant tumor [14–18], the utility of PET/CT in EMPD has rarely been reported, except for two small case reports and two brief reports. The case reports by Niederkohr and Gambhir [11] and Treglia et al. [12] highlight the usefulness of 18F-FDG PET/CT for the detection and staging of EMPD. However, Aoyagi
et al. [9] suggested that 18F-FDG PET was less useful in detecting small or subclinical involvement. In three patients, PET failed to detect 5 to 7 mm nodal involvement, but succeeded in detecting nodes over 10 mm. Cho et al. [10] also reported that PET showed only mild uptake in the primary sites of EMPD in four patients and no uptake in three patients. Histologically, all four positive tumors on PET were found to be thicker than 2 cm.
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Nuclear Medicine Communications 2015, Vol 36 No 9
Positive detection of 18F-FDG PET/CT depended on the lesion thickness, but not lesion size. Similar to the findings of Cho et al. [10], the present study showed that 18F-FDG PET/CT diagnosis of primary lesions in EMPD was mainly dependent on the thickness of the lesions. In four patients with thin lesions (mean thickness: 0.63 cm, range: 0.5–0.7 cm), the uptake of 18 F-FDG was mild (mean SUVmax: 3.25 ± 0.24), whereas in two patients with thick lesions (2.0 and 1.3 cm in the thickness), the uptake of 18F-FDG was intense (SUVmax: 14.9 and 7.5, respectively). Because of the low uptake of 18 F-FDG in the thin lesions, 18F-FDG PET/CT was limited in delineating the margin of the primary lesions that were potentially diagnosed as inflammation. In most cases with primary EMPD, the tumor usually remains confined to the epidermis, but it can slowly develop into an invasive tumor, spreading to the dermis, blood vessels, and lymphatics and producing potentially fatal metastases [19]. The prognosis for primary EMPD in situ is excellent, whereas invasive primary EMPD has a poor prognosis, particularly if metastases are present [3, 20]. Therefore, accurate staging is critical for selecting the appropriate treatment and predicting prognosis in patients with EMPD. For the detection of the lymph node and distant metastases, the present study showed that 18F-FDG PET/CT was a sensitive modality. In this study, in six patients diagnosed with lymph node and distant metastases, 18 F-FDG PET/CT showed increased uptake in all metastatic lesions, except for several small lung metastases. 18F-FDG PET/CT detected 20.4% (32/157) of lymph node metastatic lesions that were smaller than 1.0 cm in diameter. The high sensitivity of 18F-FDG PET/CT reported in this article might be because of the use of better equipment and significant improvement in the spatial resolution of PET in recent years [21,22]. Although the uptake of 18F-FDG was low in the lung metastases, they could be detected by the corresponding CT images. The uptake of 18F-FDG in the other distant metastases was very high (mean SUVmax: 7.65 ±1.88) and PET/CT was sensitive for their detection. Among six advanced-stage patients, 18F-FDG PET/CT detected more ‘unsuspected’ metastases in four patients and three patients were upstaged by PET/CT. Therefore, the present study indicated that 18F-FDG PET/CT could play a potential role in the staging of EMPD, especially in patients with advanced EMPD. It has been reported that dermal or deeper invasion, lymphovascular embolization, and negative expression of E-cadherin are important pathological predictors of EMPD metastatic potential [23]. This opinion was reinforced by the present study, in which six of seven patients with dermal invasion at initial diagnosis were found to have lymph node metastases and/or distant metastases. However, none of the three patients without
invasion of the dermis at initial diagnosis had metastatic disease. Because of its high sensitivity, 18F-FDG PET/CT may also play a role in surveillance of early metastases in EMPD patients with invasion of the dermis.
Conclusion This study showed that 18F-FDG PET/CT diagnosis of primary lesions in EMPD was mainly dependent on the thickness of the lesions, whereas it was more sensitive for the diagnosis of metastases. Therefore, 18F-FDG PET/CT is useful for the diagnosis and staging of EMPD, and also for patients with EMPD to select the appropriate treatment. Our study had several limitations including its retrospective nature and the small number of patients. Thus, future prospective studies with larger cohorts of patients are needed to confirm our findings.
Acknowledgements The authors wish to thank their colleagues at the Department of Dermatology and Department of Oncology of Nanfang hospital, who, in part, provided the follow-up data. This study was supported by grants from the National Natural Science Foundation of China (No. 81271641 and No. 81301215). Conflicts of interest
There are no conflicts of interest.
References 1
Chanda JJ. Extramammary Paget’s disease: prognosis and relationship to internal malignancy. J Am Acad Dermatol 1985; 13:1009–1014. 2 Zollo JD, Zeitouni NC. The Roswell Park Cancer Institute experience with extrammamary Paget’s disease. BR J Dermatol 2000; 142:59–65. 3 Hartman R, Chu J, Patel R, Meehan S, Stein JA. Extramammary Paget disease. Dermatol Online J 2011; 17:4. 4 Cheng PS, Lu CL, Cheng CL, Lai FJ. Significant male predisposition in extramammary Paget disease: a nationwide population-based study in Taiwan. Br J Dermatol 2014; 171:191–193. 5 Hatta N, Yamada M, Hirano T, Fujimoto A, Morita R. Extramammary Paget’s disease: treatment, prognostic factors and outcome in 76 patients. Br J Dermatol 2008; 158:313–318. 6 Isrow D, Oregel KZ, Cortes J, Gomez H, Milikowski C, Feun L, Silva O. Advanced extramammary Paget’s disease of the groin, penis, and scrotum. Clin Med Insights Oncol 2014; 8:87–90. 7 Lam C, Funaro D. Extramammary Paget’s disease: summary of current knowledge. Dermatol Clin 2010; 28:807–826. 8 Nomura H, Matoda M, Okamoto S, Kondo E, Omatsu K, Kato K, Takeshima N. Clinicopathologic features and treatment outcomes of primary extramammary Paget disease of the vulva. J Low Genit Tract Dis 2015; 19:145–148. 9 Aoyagi S, Sato-Matsumura KC, Shimizu H. Staging and assessment of lymph node involvement by 18F-fluorodeoxyglucose-positron emission tomography in invasive extramammary Paget’s disease. Dermatol Surg 2005; 31:595–598. 10 Cho SB, Yun M, Lee MG, Chung KY. Variable patterns of positron emission tomography in the assessment of patients with extramammary Paget’s disease. J Am Acad Dermatol 2005; 52:353–355. 11 Niederkohr RD, Gambhir SS. F-18 FDG PET/CT imaging of extramammary Paget disease of the perianal region. Clin Nucl Med 2006; 31: 561–563. 12 Treglia G, Giovannini E, Bertagna F, Giovanella L, Malaggese M. An unusual case of metastatic extramammary Paget’s disease of the vulva identified by 18F-FDG PET/CT. Rev Esp Med Nucl Imagen Mol 2013; 32:402–403.
Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.
Diagnosis of EMPD with PET/CT Tian et al. 897
13
14
15
16
17 18
Delbeke D, Coleman RE, Guiberteau MJ, Brown ML, Royal HD, Siegel BA, et al. Procedure guideline for tumor imaging with 18F-FDG PET/CT 1.0. J Nucl Med 2006; 47:885–895. Chua ML, Ong SC, Wee JT, Ng DC, Gao F, Tan TW, et al. Comparison of 4 modalities for distant metastasis staging in endemic nasopharyngeal carcinoma. Head Neck 2009; 31:346–354. Wu HB, Wang QS, Wang MF, Li HS, Zhou WL, Ye XH, Wang QY. Utility of 18 F-FDG PET/CT for staging NK/T-cell lymphomas. Nucl Med Commun 2010; 31:195–200. Chiba K, Isoda M, Chiba M, Kanematsu T, Eguchi S. Significance of PET/CT in determining actual TNM staging for patients with various lung cancers. Int Surg 2010; 95:197–204. Prakash P, Cronin CG, Blake MA. Role of PET/CT in ovarian cancer. Am J Roentgenol 2010; 194:W464–W470. Kumar R, Halanaik D, Malhotra A. Clinical applications of positron emission tomography-computed tomography in oncology. Indian J Cancer 2010; 47:100–119.
19 20
21
22
23
Kanitakis J. Mammary and extramammary Paget’s disease. J Eur Acad Dermatol Venereol 2007; 2:581–590. Mochitomi Y, Sakamoto R, Gushi A, Hashiquchi T, Mera K, Matsushita S, et al. Extramammary Paget’s disease/carcinoma successfully treated with a combination chemotherapy: report of two cases. J Dermatol 2005; 32:632–637. Jakoby BW, Bercier Y, Conti M, Casey ME, Bendriem B, Townsend DW. Physical and clinical performance of the mCT time-of-flight PET/CT scanner. Phys Med Biol 2011; 56:2375–2389. Poon JK, Dahlbom ML, Moses WW, Balakrishnan K, Wang W, Cherry SR, Badawi RD. Optimal whole-body PET scanner configurations for different volumes of LSO scintillator: a simulation study. Phys Med Biol 2012; 57:4077–4094. Zhu Y, Ye DW, Yao XD, Zhang SL, Dai B, Zhang HL, et al. Clinicopathological characteristics, management and outcome of metastatic penoscrotal extramammary Paget’s disease. Br J Dermatol 2009; 161:577–582.
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