Altered lymphatic drainage patterns in re- operative sentinel lymph node biopsy for ipsilateral breast tumor recurrence

Ayaka Sato
Takehiko Sakai
Takuji Iwase
Fumiko Kano
Kiyomi Kimura
Akiko Ogiya
Mitsuru Koizumi
Masahiko Tanabe
Rie Horii
Futoshi Akiyama
Takayuki Ueno
Shinji Ohno
Altered lymphatic drainage patterns in re- operative sentinel lymph node biopsy for ipsilateral breast tumor recurrence
10.1186/s13014-019-1367-0R E S E A R C H Open Access
Background: This study aimed to evaluate the impact of previous local treatment on lymphatic drainage patterns in ipsilateral breast tumor recurrence (IBTR) based on our data on re-operative sentinel lymph node biopsy (re-SLNB) for IBTR. Methods: Between April 2005 and December 2016, re-SLNB using lymphoscintigraphy with Tc-99 m phytate was performed in 136 patients with cN0 IBTR. Patients were categorized into two groups: the AX group included 55 patients with previous axillary lymph node dissection; the non-AX group included 69 patients with previous SLNB and 12 patients with no axillary surgery. The whole breast irradiation (RT) after initial surgery had performed in 17 patients in the AX group and 27 patients in the non-AX group. Results: Lymphatic drainage was visualized in 80% of the AX group and 95% of the non-AX group (P < 0.01). The visualization rate of lymphatic drainage was associated with the number of removed lymph nodes in prior surgery. In the non-AX group, lymphatic drainage was visualized in 96% of patients without RT and 93% with RT. Lymphatic drainage was observed at the ipsilateral axilla in 98% of patients without RT and in 64% with RT (P < 0.0001). Aberrant drainage was significantly more common in patients with RT than without RT (60% vs. 19%, P < 0.001); it was observed mostly to the contralateral axilla (52% vs. 2%, P < 0.0001). In the AX group, patients with previous RT showed decreased lymphatic drainage to the ipsilateral axilla compared to those without RT (29% vs. 63%, P < 0.05) and increased aberrant drainage to the contralateral axilla (64% vs. 5%, P < 0.0001). Conclusion: Lymphatic drainage patterns altered in re-SLNB in patients with IBTR and previous ALND and RT were associated with alterations in lymphatic drainage patterns.

Background

While sentinel lymph node biopsy (SLNB) is a wellestablished procedure for patients with clinically nodenegative primary breast cancer [1][2][3][4], established guidelines for the management of axillary lymph nodes in patients developing ipsilateral breast tumor recurrence (IBTR) are lacking.

It is known that a sentinel lymph node (SLN) is sometimes observed in extra-axillary regions of IBTR cases because lymphatic drainage patterns are altered by previous treatments, such as axillary surgery and irradiation of the breast [5][6][7][8]. Therefore, assessment of the ipsilateral axilla alone may not be sufficient for staging IBTR.

According to a report on SLNB for patients with primary breast cancer, the visualization rate of lymphatic drainage was 97%, and lymphatic drainage was mainly observed to the ipsilateral axilla (96%) [9]. In a small study, aberrant drainage was reported to the internal mammary chain (IMC) (22%), intramammary region (7%), subclavicular region (3%), supraclavicular region (0.5%), and interpectoral region (2%) [9]. In contrast, a meta-analysis of re-operative SLNB (re-SLNB) for IBTR revealed a success rate of 71% for lymphatic mapping, markedly lower than that of SLNB in patients with primary breast cancer [10]. Aberrant drainage was observed in 43% of these patients, a much higher frequency than in patients with primary breast cancer. Although it is well known that previous axillary lymph node dissection (ALND) decreases the identification rate of SLNs for IBTR and increases aberrant drainage [5][6][7]11], the impact of previous radiotherapy (RT) on re-SLNB remains largely unknown.

Because re-SLNB may provide useful information in determining adjuvant treatment for IBTR, we have performed re-SLNB for IBTR, using radioisotope techniques and preoperative lymphoscintigraphy to stage IBTR. The aim of this retrospective study was to evaluate lymphatic drainage patterns in re-operative SLNs (re-SLNs) in association with prior local therapy in patients with IBTR.

Methods

The institutional clinical database was used to identify patients who developed IBTR and underwent re-SLNB between April 2005 and December 2016. The ethical review committee of the institute approved this study protocol (No.2018(No. -1222. Informed consent was obtained from all individual participants included in the study. Patients who underwent re-SLNB without preoperative lymphoscintigraphy, those with synchronous or metachronous bilateral breast cancer, and those lacking detailed information on previous surgeries were excluded. None of the patients had clinically metastatic lymph nodes, as examined by preoperative ultrasound. Fine needle aspiration cytology was performed if node metastasis was suspected by ultrasound.

The day before surgery, total 55.5 MBq (1.5 mCi) Tc-99 m phytate was injected at two intradermal sites at the tumor and at two peritumoral sites. Static images were obtained 1 h after the injection from 3 projections (anterior, 30 degrees anterior-oblique, and 60 degrees anterior-oblique views). Hot spots on the lymphoscintigram were regarded as re-SLNs. SPECT/CT was also performed in a subset of patients. Patients were categorized into two groups according to their previous axillary surgeries: the non-AX group included patients with SLNB and no previous axillary surgery, and the AX group included those with ALND. Patients were further categorized based on the use of previous adjuvant RT.

A chi-squared test was applied to evaluate differences in lymphatic drainage patterns between the AX group and the non-AX group and between the RT group and the no RT group. The Mann-Whitney test was used to compare the number of removed nodes between different groups. The log-rank test was used to compare the disease-free interval (DFI), the interval from primary surgery to the diagnosis of IBTR, between the patients whose lymphatic drainage was visualized on lymphoscintigraphy and these whose lymphatic drainage was not visualized. GraphPad Prism v.5.04 (GraphPad Software, San Diego, CA, USA) was used for statistical analysis. A two-sided P value of < 0.05 was considered statistically significant.  shown in Table 1. Median age at IBTR was 55 years. The median DFI was 67 months. Median follow-up period from the day of surgery for IBTR was 141 months. Median age at primary surgery was 47 years. All patients had undergone breast-conserving surgery for their primary breast cancer. Sixty-nine and 55 patients had undergone SLNB and ALND, respectively, and 12 patients had no previous axillary surgery. Median number of lymph nodes removed at the primary surgery was 2 (1-6) in patients who had undergone SLNB and 20  in patients who had undergone ALND. RT after breast-conserving surgery was performed in 44 patients. The whole breast irradiation dose was 42.5-50Gy with or without a boost dose of 10-16Gy in tumor beds. RT was not performed when surgical margins were entirely free of cancer, as confirmed by a precise pathological examination according to our institutional treatment protocol [12].

Results

Characteristics of patients

Visualization of lymphatic drainage patterns on lymphoscintigraphy

Preoperative lymphoscintigraphy identified at least one SLN, defined as re-SLN, in 121 (89%) of the 136 patients ( Table 2). Lymphatic drainage was visualized at the ipsilateral axilla in 74%. Some patients showed multiple patterns of lymphatic drainage. Aberrant drainage was visualized in five regions: IMC, supraclavicular, intramammary, contralateral axilla, and contralateral IMC ( Table 2). A representative case of aberrant drainage is shown in Fig. 1. DFI was shorter in patients whose lymphatic drainage was visualized on lymphoscintigraphy compared with patients whose lymphatic drainage was not visualized (60 vs. 129 months, P < 0.05). No difference in visualization rate was observed according to hormone receptor status and HER2 status for both primary cancer and IBTR ( Table 3).

Impact of axillary surgery on lymphatic drainage patterns

Lymphatic drainage patterns were compared according to previous axillary surgeries. The visualization rate of lymphatic drainage was higher in the non-AX group (95%) than in the AX group (80%) (P < 0.01) ( Table 4). The visualization  rate was associated with the number of lymph nodes which had been removed in the prior surgery ( Table 5). The median number of removed lymph nodes in the prior surgery was fewer in patients whose lymphatic drainage was visualized on lymphoscintigraphy compared with patients whose lymphatic drainage was not visualized (8 vs. 16 nodes, P < 0.05). Lymphatic drainage was visualized in all 12 patients who had not undergone previous axillary surgery ( Table 5). The visualization rate was markedly low (71%) in patients in whom 20 or more lymph nodes had been removed in prior surgery (Table 5). Lymphatic drainage was visualized at the ipsilateral axilla in 87% of patients in the non-AX group and in 52% in the AX group (P < 0.001, Table 4). Aberrant drainage was visualized significantly more frequently in the AX (75%) than in the non-AX (33%) group (P < 0.0001, Table 4). Lymphatic drainage was visualized at the IMC in 16% of the non-AX group and 55% of the AX group (P < 0.001, Table 4). Although axillary dissection had been performed in the AX group, re-SLNs were visualized in the ipsilateral axilla in 52% of patients: at level I and II of the axillae in seven patients, in the Rotter space in ten patients, and at level III of the axilla in three patients. In three patients in the non-AX group, re-SLNs that were visualized by lymphoscintigraphy failed to be identified during surgery because of the poor responses of the gamma-ray detection probe.

Impact of adjuvant radiotherapy on lymphatic drainage patterns

In the non-AX group, lymphatic drainage was visualized in 96% of patients without RT and 93% of those with RT  Lymphatic drainage patterns were compared among the 136 patients according to previous axillary surgeries. The visualization rate of re-SLNs in the non-AX group was higher than in the AX group. Aberrant drainages were visualized more frequently in the AX group than in the non-AX group. Whereas re-SLNs were visualized at the ipsilateral axilla in about 87% of the non-AX group, drainage to the ipsilateral axilla was significantly decreased and an alternative aberrant drainage pattern to the internal mammary chain was significantly increased in the AX group a non-AX group: patients with previous SLNB and no previous axillary surgery b AX group: patients with previous axillary lymph node dissection c ns: no significant difference (Table 6a). Re-SLNs were visualized at the ipsilateral axilla in 98% of the patients without RT and in 64% of those with RT (P < 0.0001, Table 6a). Aberrant drainage was significantly more frequent in patients with RT (60%) than in those without RT (19%) (P < 0.001). Notably, more than half (52%) of patients with RT showed aberrant drainage to the contralateral axilla, whereas only 2% of those without RT did (P < 0.0001). No re-SLNs were visualized in the supraclavicular region in the non-AX group.

In the AX group, lymphatic drainage was visualized in 82% of patients with RT and 79% of those without RT (Table 6b). Aberrant drainage to the contralateral axilla was observed in nearly two-thirds (64%) of patients with RT but in 5% of those without RT (P < 0.0001, Table 6b).

Discussion

The present study revealed that the previous local treatment, not only axillary surgery but also RT, had impact on lymphatic drainage patterns in patients with IBTR. First, we confirmed the impact of previous axillary surgery on lymphatic drainage patterns. Next, we demonstrated that previous RT resulted in aberrant lymphatic drainage in 60% of patients in the non-AX group and in 93% in the AX group.

We found that the visualization rate of re-SLN was almost the same regardless of previous RT while it was reduced by axillary surgery (Tables 4, 6). In addition, RT reduced the ipsilateral axillary drainage from 98 to 64% and increased the aberrant drainage, especially to the contralateral axilla both in the AX group and in the non-AX groups. There were a few studies that examined the impact of RT on lymphatic drainage patterns and showed that RT had no effect on the identification rate of re-SLNs, in concordance with our study [5,13]. Interestingly, in a study with 22 patients with breast cancer who had previously undergone mantle field radiation for Hodgkin's lymphoma, the detection rate of SLNs was 86%, which was less than that in previously untreated patients with breast cancer (97%) [14]. The visualization rate of SLNs at the ipsilateral axilla was lower than that in patients with previously untreated breast cancer (86% vs. 92%), and SLNs were more often found outside the axilla (41% vs. 33%), especially at the IMC (32% vs. 21%) [14]. The discrepancy between our results and those of the patients receiving mantle field radiation could be attributed to the difference in the irradiated fields and doses. In the study of mantle field radiation, the lymphatic regions in the neck, bilateral axilla, and mediastinum received a radiation dose of 36-40 Gy [14]. The medial and upper outer quadrants of the breast were also exposed to radiation. In contrast, the whole breast irradiation dose was 42.5-50Gy in the present study, and some patients were also given a boost dose of 10-16Gy in tumor beds. Considering that lymphatic drainage had been damaged by irradiation and aberrant lymphatic drainage did not involve the irradiated area, it was understandable that lymphatic drainage to the IMC increased after patients received mantle field irradiation and that lymphatic drainage to the contralateral axilla increased in those with previous whole breast irradiation.

According to our results, in patients with IBTR with previous SLNB and non-RT, lymphatic drainage remains mostly in the ipsilateral axilla, and these patients will be suitable for re-SLNB. On the other hand, re-SLNs were visualized at the contralateral axilla in more than 20% of the whole population (Table 2). Although there are some reports showing the feasibility of the re-SLNB procedure [7,[15][16][17][18], the clinical significance of re-SLNB has not yet been confirmed. In addition, it is further complicated in cases with aberrant SLNs. Metastasis to the contralateral axilla is regarded as distant metastasis in primary breast cancer [19], but in patients with IBTR, the AX group: patients with previous axillary lymph node dissection Number of lymph nodes which had been removed in prior surgery was unknown in two patients of non-AX group and three patients of AX group The visualization rate was associated with the number of lymph nodes which had been removed in the prior surgery. Lymphatic drainage was visualized in all patients who had not undergone previous axillary surgery. The visualization rate was markedly low in patients in whom 20 or more lymph nodes had been removed in prior surgery contralateral axilla may be considered a regional lymph node if re-SLNs are identified in the contralateral axilla [20]. Although there are no guidelines for management of contralateral SLN and positive contralateral SLN, pathological results in contralateral SLN may be useful in deciding adjuvant treatment for IBTR [21]. Further studies to clarify the clinical significance of aberrant SLNs are required.

The major limitation of this study is the retrospective design with a small number of patients. In particular, the number of patients who had received previous RT was small and not enough to make any conclusion on the impact of RT on lymphatic drainage patterns. In addition, this study focuses only on lymphatic drainage patterns and does not examine the success rate of SLNB or pathological results of re-SLNs. Thus, the clinical significance of re-SLN examination is not clear. Another limitation is the lack of information on patient outcomes. It is important to examine the clinical outcomes of patients in association with treatment, including surgical procedures to determine the optimal treatment strategy. This is especially important in patients with aberrant lymphatic drainage.

Conclusion

In conclusion, lymphatic drainage patterns altered in re-SLNB in patients with IBTR and previous ALND and RT were associated with alterations in lymphatic drainage patterns. More studies focusing on the clinical usefulness of re-SLNB, including outcomes after re-SLNB, are warranted.

Lymphatic drainage patterns were compared among the patients according to the presence or absence of previous radiotherapy in the non-AX group and the AX group. RT had little impact on the visualization rate of re-SLNs in both groups (Table 6a, b). In the non-AX group, lymphatic drainage to ipsilateral axilla was significantly decreased and aberrant drainage to contralateral axilla was significantly increased in patients with RT (Table 6a). In the AX group, re-SLNs were visualized at contralateral axilla more commonly in patients with RT (

Between
April 2005 and December 2016, 277 patients were identified who developed IBTR and underwent re-SLNB. Of the 277 patients, 141 were excluded according to the exclusion criteria, with 136 patients remaining in the analysis. The characteristics of the 136 patients are

Fig. 1
1Lymphoscintigraphy and SPECT/CT images of aberrant lymphatic drainages. (A) Lymphatic drainages were visualized at the contralateral axilla (arrow a) and the ipsilateral internal mammary chain (IMC) (arrow b) in a case with left IBTR. SPECT/CT revealed hot spots at the right axillary region (B) and the left IMC (C)

Table 1
1Characteristics of patients with primary breast cancer and ipsilateral breast tumor recurrenceN = 136

Table 2
2Lymphatic drainage patterns in all 136 patients with IBTR a Lymphatic drainage was visualized in 121 of 136 patients. Lymphatic drainage to ipsilateral axilla was visualized in 74% of patients. Aberrant drainage was visualized in five regions: internal mammary chain (IMC), supraclavicular, intramammary, contralateral axilla, and contralateral IMC a IBTR ipsilateral breast tumor recurrenceN = 136

Table 3
3Visualization on lymphoscintigraphy according to hormone receptor and HER2 status of primary tumor and IBTRVisualization on lymphoscintigraphy
(N = 136)

Yes
No
P

a. Primary breast cancer

ER a

Positive
54
3
ns d

Negative
25
6

DCIS b
26
2

unknown
16
4

PgR c

Positive
46
5
ns

Negative
32
4

DCIS
26
2

Unknown
17
4

HER2

3+
8
0
ns

2+
5
0

1+, 0
40
6

DCIS
26
2

Unknown
42
7

b. Ipsilateral breast tumor recurrence

ER

Positive
64
10
ns

Negative
26
2

DCIS
29
2

Unknown
2
1

PgR

Positive
46
7
ns

Negative
44
5

DCIS
29
2

unknown
2
1

HER2

3+
10
0
ns

2+
0
0

1+, 0
78
12

DCIS
29
2

Unknown
4
1

The visualization on lymphoscintigraphy was not associated with hormone
receptor status and HER2 status of both primary cancer and IBTR

a

ER: estrogen receptor

b

DCIS: ductal carcinoma in situ

c

PgR: progesterone receptor

d

ns: no significant difference

Table 4
4Lymphatic drainage patterns according to previous axillary surgeryPrevious axillary surgery

non-AX group a AX group b

N = 81
N = 55
P value

Visualization on lymphoscintigraphy

Yes
77 (95.1%)
44 (80.0%) < 0.01

No
4 (4.9%)
11 (20.0%)

Lymphatic drainage patterns

Ipsilateral axilla
67 (87.0%)
23 (52.2%) < 0.001

Aberrant drainage
25 (32.5%)
33 (75.0%) < 0.0001

Internal mammary chain (IMC) 12 (15.6%)
24 (54.5%) < 0.001

Contralateral axilla
14 (18.2%)
11 (25.0%) ns c

Intramammary
6 (7.8%)
3 (6.8%)
ns

Supraclavicular
0 (0%)
2 (4.5%)
ns

Contralateral IMC
1 (1.3%)
0 (0%)
ns

Table 5
5The visualization rate on lymphoscintigraphy according to the number of lymph nodes removed in prior surgeryNumber of lymph nodes removed in prior surgery

Table 6
6Lymphatic drainage patterns according to previous radiotherapy a) non-AX group a Without RT c With RTN = 54
N = 27
P value

Visualization on lymphoscintigraphy

Yes
52 (96.3%)
25 (92.6%) ns d

No
2 (3.7%)
2 (7.4%)

Lymphatic drainage patterns

Ipsilateral axilla
51 (98.1%)
16 (64.0%) < 0.0001

Aberrant drainage
10 (19.2%)
15 (60.0%) < 0.001

Internal mammary chain (IMC) 7 (13.5%)
5 (20.0%)
ns

Contralateral axilla
1 (1.9%)
13 (52.0%) < 0.0001

Intramammary
4 (7.7%)
2 (8.0%)
ns

Supraclavicular
0 (0%)
0 (0%)
ns

Contralateral IMC
0 (0%)
1 (4.0%)
ns

b) AX group b

Without RT
With RT

N = 38
N = 17
P value

Visualization on lymphoscintigraphy

Yes
30 (78.9%)
14 (82.4%) ns

No
8 (21.1%)
3 (17.6%)

Lymphatic drainage patterns

Ipsilateral axilla
19 (63.3%)
4 (28.6%)
< 0.05

Aberrant drainage
20 (66.7%)
13 (92.9%) ns

Internal mammary chain (IMC) 17 (56.7%)
7 (50%)
ns

Contralateral axilla
2 (5.3%)
9 (64.3%)
< 0.0001

Intramammary
3 (10.0%)
0 (0%)
ns

Supraclavicular
1 (3.3%)
1 (7.1%)
ns

Table 6b )
6ba non-AX group: patients with previous SLNB and no previous axillary surgery b AX group: patients with previous axillary lymph node dissection c RT: previous radiotherapy after breast-conserving surgery d ns: no significant difference
AcknowledgementsWe thank all staffs working for the Breast Oncology Center of Cancer Institute Hospital of JFCR. We also express our gratitude to our data manager, Rie Gokan for her support.Authors' contributionsFundingThis study received no funding.Availability of data and materialsAll data generated or analyzed during this study are included in this published article.Ethics approval and consent to participateConsent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.
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Hospital-based HIV/HSV-2 seroprevalence among male patients with anal disease in Korea: cross sectional study

Jin-Sook Wang
Yeon Do
Hwang
Hye-Kyung Yu
Sung Soon Kim
Jong Kyun Lee
Mee-Kyung Kee
Hospital-based HIV/HSV-2 seroprevalence among male patients with anal disease in Korea: cross sectional study
R E S E A R C H A R T I C L E Open Access
Background: This study aimed

Background

When AIDS was first reported in 1981, it seemed to be a new disease that affected only homosexual men. However, it was discovered that the disease spread to the general population through drug users, hemophilia patients, children infected by their mothers, and sexual partners of individuals with HIV through blood or sexual contact [1]. Since 1985, when the first case of HIV infection was identified in Korea, the number of HIV infections has continued to increase, with the cumulative total reaching 9,406 in 2012. The ratio of males to females among reported HIV cases is approximately 11:1. Overall, 99% of HIV infections is caused by sexual contact, and the proportion of cases attributed to male-to-male sexual contact is about 40% [2]. Almost 70% of all newly identified cases is identified during hospital care [3]; thus, it was of interest to identify the type of medical procedures and treatment during which the highest number of new HIV diagnoses was made. According to Miles et al. and Wexner et al., 5.9-34% of the HIV-infected population has anal disorders, which are also the most frequent cause for surgery in this group [4,5]. Among men who have sex with men attending a sexually transmitted infection (STI) clinic, 30.8% had dysuria, pus, and urethral ulceration, and 37.1% had pus, bleeding, ulceration, and/or pain in the rectum [6]. A study of HIV infection and anal diseases in Korea found that most HIV infections detected at colorectal hospitals were in men, most of whom were homosexual [7]. Currently, there are more males than females HIV patients and the predominant route of transmission is homosexual contact in Korea.

Genital ulcers have been associated with increased risk factors for HIV infection, and genital herpes is usually caused by herpes simplex virus (HSV)-2 [8]. Our previous study had compared HSV-2 seroprevalence in HIVinfected males with that in the general male population in Korea, which was two or three times higher among HIV-infected males [9]. HSV-2 seroprevalence had a tendency to increase with age and HIV seroprevalence had a different characteristic by age in most countries including Korea [9][10][11].

Given these epidemiological characteristics of HIV infection in Korea, we aimed to estimate HIV seroprevalence and trends among men suffering from anal disease. We also aimed to identify the seroprevalence of these sexually transmitted viruses by measure of HSV-2 infection, a virus that is spread sexually.

Methods

Subjects

HIV seroprevalence in male patients who were treated for anal disease at Songdo (S) colorectal hospital from 2001 to 2011 was estimated for different age groups. S colorectal hospital is a representative large hospital specializing in the field of anal diseases in Seoul, Korea. HIV seroprevalence in male patients with anal disease was compared with that in those who presented for other reasons (including a health checkup) calculated for each year from 2007 to 2011. To understand HIV and/or HSV-2 seroprevalence, HSV-2 tests were conducted on 2,038 men who received treatment for anal diseases at S colorectal hospital. The HSV-2 samples randomly selected among 26,173 male patients with anal disease tested for HIV in 2009. Ethics approval was obtained from KCDC Institutional Review Board (IRB) Ethics Committee.

HIV and HSV-2 antibody tests

HIV screening was performed using Architect HIV AG/AB Combo Kit (Abbott Laboratories, Abbot Park, IL, USA) to determine the presence of HIV antibody and/or antigen. Patient samples that tested positive in HIV screening were subjected to an additional HIV western blot test (HIV BLOT 2.2 Western Blot Assay, MP Diagnostics, Asia Pacific Pte Ltd., Singapore) at an HIV confirmatory testing institute to confirm HIV infection. HSV-2 antibody tests were performed with the HerpeSelect 2 ELISA IgG Kit (Focus Diagnostics, Cypress, CA, USA). HSV-2 results were reported as an index value relative to the cut-off calibrator. An index value >1.10 was presumptive for the presence of IgG antibodies to HSV-2.

Statistical analysis

HIV seroprevalence was defined as the number of confirmed HIV cases per 10,000 HIV-tested people over a 1-year period. HSV-2 seroprevalence was defined as the proportion of HSV-2-positive people among the total number of people tested. Patients with any type of anal disease were grouped together as the anal disease patients, and patients who visited the hospital for a health checkup or for another intestinal disorder were categorized as the nonanal disease patients. Trend tests were conducted to determine how HIV seroprevalence varied from year to year in the anal and nonanal disease patients, using SAS version 9.3. χ 2 tests were used to compare HIV seroprevalence in patients with anal disease and nonanal disease, and HIV and HSV-2 seroprevalence in different age groups of patients with anal disease, with a 95% confidence level.

Results

Status of HIV tests and trends in HIV seroprevalence

S colorectal hospital administered HIV tests to 17,593-30,225 male patients with anal disease every year from 2001 to 2011. Approximately 50% of total HIV tests were performed in patients aged ≥50 years. Overall, 255 HIV-infected males were founded during the same period (data not shown). As shown in Figure 1, annual HIV seroprevalence among male patients with anal disease during the study period was 6.3-16.2 per 10,000. The trend revealed that HIV seroprevalence was highest in the group aged <20 years, followed by 20-29, 30-39, 40-49 and ≥50 years (P < 0.0001). Over 11 years, 1,254 teenagers (approximately 0.5% of the total) were treated for anal disorders and among these, 10 were diagnosed with HIV (data not shown). The trend in HIV seroprevalence over time did not show any specific pattern in any of the age groups: under 20 (P = 0.5982), 20-29 (P = 0.3675), 30-39 (P = 0.7476), 40-49 (P = 0.1336), 50-59 (P = 0.0815), and ≥60 (P = 0.3709) years.

As shown in Table 1, for the trend in HIV seroprevalence among male patients with anal or nonanal disease, 119 were found to be positive for HIV from 2007 to 2011. One hundred and sixteen male patients with anal disease were confirmed to have HIV (97% of total confirmed infections). HIV seroprevalence in patients with anal disease ranged from >10/10,000 in 2007 to 7.6/10,000 in 2011. Among patients with nonanal disease, three were found to have HIV with an estimated seroprevalence of 0.5/10,000 in 2008 and 0.9/10,000 in 2010.

HIV and/or HSV-2 seroprevalence among patients with anal disease As shown in Table 2, of the 2,038 male patients with anal disease, 1.8% were aged <20 years, 11.0% were 20-29 years, 20% were ≥30 years. Five men (25/10,000) were diagnosed with HIV, three of whom were in their 20s, and one each in the 30-39-and 40-49-year age groups. The total HSV-2 seroprevalence was 24.0%: 5.4% for men aged <20 years, 8.0% for those aged 20-29 years, and 11.7% for those aged 30-39 years, with the rate increasing with age (P < 0.0001). Infection with HIV and HSV-2 was found in only one patient (4/10,000) of the total number tested, who was in his 30s.

Discussion

In the present study, HIV seroprevalence among male patients with anal disease was between 6.3/10000 and 16.2/10000, which was nearly 30 times higher than that of male patients with nonanal disease at a colorectal hospital. This indicates a strong association between anal disease and HIV infection in male patients. Over the past 11 years (Figure 1), HIV seroprevalence in male patients with anal disease has decreased, although the status of HSV-2 seroprevalencehas remained at a level similar to that in the general male population.

According to the Joint United Nations Programme on HIV/AIDS (UNAIDS), HIV seroprevalence in Korea is at a low epidemic level of between 1/10,000 and 4/10,000 [12,13]. However, the number of HIV-infected individuals in Korea has continued to rise and isexpected to increase further, for two main reasons. First, the HIV epidemic pattern in Korea is similar to that observed in the early 1980s when HIV became a global pandemic. More specifically, the epidemic pattern of HIV in Korea closely follows the pattern of the early epidemiological stages of the virus when HIV was spread mainly through sexual contact, especially between men [14]. Second, in many of the recently identified cases, the infections were discovered long after onset. This means that the infected individuals may have unknowingly transmitted the virus to other people [3]. Moreover, an increasing number of HIV cases are detected during health checkups and treatment of   other conditions [13]. Therefore, the role of private health-care institutions has become important in both HIV treatment and diagnosis.

In a prior study that examined HIV seroprevalence during 2002 and 2007, based on data collected from colorectal hospitals across the country, HIV seroprevalence was between 2.2/10,000 and 3.9/10,000, which was about two or three times higher than that of all hospital patients [13,15]. This study analyzed the characteristics of HIV seroprevalence among patients in a colorectal hospital according to variables including sex, age and presence of anal disease. The results showed that most of the cases of HIV were in patients who also had anal disease. Overall, HIV seroprevalence in patients with anal disease was ≈ 10/10000. In Korea, HIV seroprevalence was highest among sexual partners of HIV-infected individuals (>1,000/10,000), followed by people who applied voluntarily for HIV testing because they wanted to know their status (>20/10,000), and people who underwent additional HIV tests when their doctor suspected HIV infection during treatment (>10/10,000) [11,16]. This study showed that male patients with anal disease were similar to those referred by their doctor and were assumed to be a high-risk group.

In addition, male patients in whom HIV infection was detected at the colorectal hospital tended to be younger than the general HIV-infected male population, and HIV seroprevalence increased significantly with younger age. For specific identification of high HIV seroprevalence in the group aged <20 years, we divided into groups aged <10 years, 10-14 years and 15-19 years. From 2001 to 2011, 1,061 male patients aged 15-19 years were treated and underwent HIV testing at the hospital. Ten HIV infections were found in the group aged 15-19 years.

In Korea, the HIV-infected young men aged 15-19 years accounted for 2.4% of the total number of HIV-infected men as of 2011. Sixty percent of these were infected through homosexual contacts, which is higher than the overall percentage infected through homosexual contact (43%) [17]. In the present study, male patients aged 15-19 years comprised 3.7% of the total number of male patients with HIV and anal disease. This produced a higher annual HIV seroprevalence than for any other group nationwide in Korea.

A survey of male sexual behavior in Korea showed that sexual activity began around age 16 years [18], and only 10-20% used condoms [19]. A survey of homosexual behavior in Korea showed that 60% of participants had a homosexual feeling before age 18 years [20]. It is expected that the group aged 15-19 years is a group at high risk for STI.

Approximately 70% of HIV-infected individuals in the present study contracted the virus through homosexual contact, according to the HIV database of KCDC. In Korea, HIV infection was detected in many people who visited HIV testing and consulting centers for homosexual people (HIV-positive rate of 5.5%) [21]. However, the proportion of homosexual men who tested for HIV over the past year in Korea was lower than that in other countries including Japan, China and the United States [22]. Moreover, nearly half of all homosexual men in Korea said that they had never tested for HIV [20]. Therefore, the present study shows that ensuring that colorectal surgeons can easily identify lesions associated with HIV infection in male patients with anal disease is important for preventing misdiagnosis or delayed diagnosis of HIV infection and stopping its spread.

HSV-2 can often cause acute infection or remain inactive until it is triggered by a decline in the immune system. HSV-2 is the cause of >90% of anorectal infections and frequently the source of proctitis in homosexual men [23]. In homosexual men living in San Francisco, the seroprevalence of HSV-2, HIV and HSV-2/HIV was 26.1%, 18.6% and 12.0%, respectively [24]. In male infected with HIV by sexual contacts in Korea in 2003, HSV-2 seroprevalence (23.9-69.2%) was higher than that in the general male population (6.8-26.0%) [9]. In the present study, 20% of HIV-infected individuals were found to have HSV-2. Moreover, HSV-2 seroprevalence in male patients with anal disease was similar to that in the general male population. The present study had the following limitations. First, there is limited scope to generalize the findings of the study, because the estimates of HIV seroprevalence were based on data obtained from a single colorectal hospital located in Seoul. However, the study did show the trends, status, and characteristics of HIV seroprevalence among male patients with anal disease. Second, although the estimated HSV-2 seroprevalence in male patients with anal disease was flawed because the results were based on data from a single hospital during a limited period, the estimate is important because it is believed to be the first such study in Korea. Finally, we don't have data on sexual behavior to find out the reason of high HIV seroprevalence among male patients with anal disease. And, HSV-2 seroprevalence was low in male patients with anal disease, which differed from other studies [25,26]. It will be necessary to establish the relationship between the study results and the epidemiological characteristics of the study subjects in Korea.

Conclusions

The HIV seroprevalence of male patients with anal disease was significantly higher than that in patients with other diseases. The high HIV seroprevalence in patients in a colorectal hospital suggests the need to develop effective prevention programs for sexually transmitted infections, with a focus on hospitals specializing in anal diseases.

Ethics statement

Figure 1
1Trends in HIV seroprevalence by age among male patients with anal diseases, 2001-2011. Annual HIV seroprevalence was 6.3 to 16.2 per 10,000 individuals.

a N (%): the number of individuals tested for HIV (the proportion of patients with anal disease or nonanal disease). b HIV+: the number of HIV-infected individuals.

Table 1
1Trend in HIV seroprevalence among male patients with anal disease or with nonanal disease, 2007 -2011HIV prevalence was defined as the number of confirmed HIV cases per 10,000 HIV-tested people over a 1-year period. Nonanal diseases: patients who presented at the hospital with a nonanal disease or for a health checkup.Year
With anal diseases
With nonanal diseases

N (%) a
HIV + b
HIV seroprevalence per 10,000
N (%) a
HIV + b
HIV seroprevalence per 10,000

2007
23,861 (58.0)
24
10.1
17,274 (42.0)
0
0

2008
22,581 (54.3)
30
13.3
18,986 (45.7)
1
0.5

2009
26,173 (53.2)
20
7.6
23,000 (46.8)
0
0

2010
27,552 (56.3)
19
6.9
21,378 (43.7)
2
0.9

2011
30,225 (56.4)
23
7.6
23,382 (43.6)
0
0

Table 2
2HIV seroprevalence and HSV-2 seroprevalence by age among male patients with anal disease, 2009 HIV seroprevalence was defined as the number of confirmed HIV cases per 10,000 of HIV-tested people. HSV-2 seroprevalence was defined as the proportion of HSV-2-positive people. The 2,038 HSV-2 samples randomly selected among 26,173 male patients with anal disease tested for HIV in 2009. HIV+: the number of HIV-infected individuals. HSV2: the number of HSV-2-infected individuals.Age
No. (%)
HIV + a
HIV seroprevalence per 10000
HSV-2 + b
HSV-2 seroprevalence (%)

Total
2,038 (100)
5
24.5
489
24.0

< 20
37 (1.8)
0
0
2
5.4

20-29
224 (11.0)
3
134
18
8.0

30-39
446 (21.9)
1
22
52
11.7

40-49
398 (19.5)
1
25
85
21.4

50-59
477 (23.4)
0
0
166
34.8

≥ 60
456 (22.4)
0
0
166
36.4

a

b

http://www.biomedcentral.com/1471-2334/14/34
Competing interestThe authors declare that they have no competing interests.Authors' contributions J-SW, DYH and SSK designed and conceived the idea for the study and M-KK supervised all aspects of its implementation. J-SW wrote the first draft of the manuscript. DYH and JKL contributed to the collection and interpretation of raw data. M-KK and H-KY completed all data analyses and SSK coordinated funding for the project. All authors read and approved the final version of the manuscript as submitted to BMC Infectious Diseases.
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Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution. Wang, BMC Infectious Diseases. 1434Hospital-based HIV/HSV-2 seroprevalence among male patients with anal disease in Korea: cross sectional study. Submit your manuscript at www.biomedcentral.com/submitCite this article as: Wang et al.: Hospital-based HIV/HSV-2 seroprevalence among male patients with anal disease in Korea: cross sectional study. BMC Infectious Diseases 2014 14:34. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit


Case reports in medical education: a platform for training medical students, residents, and fellows in scientific writing and critical thinking

Aleksandra G Florek
Robert P Dellavalle
Case reports in medical education: a platform for training medical students, residents, and fellows in scientific writing and critical thinking
10.1186/s13256-016-0851-5E D I T O R I A L
A case report is a detailed narrative that usually illustrates a diagnostic or therapeutic problem experienced by one or several patients. Case reports commonly serve as the first line of evidence for new interventions or they function as alarms that an issue exists with an already established therapy. Case reports are of minor importance in evidence-based medicine; however, they make meaningful contributions to both the knowledge and education of medical students, residents, and fellows. Case reports are written with the goal of sharing information for medical, scientific, or educational purposes. They often serve as medical or even undergraduate students' first experience with medical writing and they provide a solid foundation for manuscript preparation and publication. In the last few decades, there has been an exponential increase in medical student research, specifically in the number of manuscripts published by medical students. It is important to foster this academic spirit among students by encouraging them to become involved in research. This editorial will focus on the value and educational benefits of writing case reports for medical students, university students, residents, and fellows.

Introduction

The role of case reports is to provide descriptive information about a clinical patient scenario and to share this educational experience with the general medical and scientific community [1]. Furthermore, case reports foster an educational medium in disseminating new and rare diseases, thus increasing the knowledge of evaluation, diagnosis, treatment, and prognosis of diseases [2]. This editorial outlines why traditional case reports are not only valuable to the general medical community, but are also an integral part of medical education and clinical training. This editorial also hopes to inspire medical students, residents, and fellows of all disciplines to write and continue writing case reports.

From grand rounds to journals: importance of case presentation Case presentation has always been a time-honored and important tool of medical education and inpatient care, and has consisted of presenting challenging medical cases to an audience of medical students, residents, and attending physicians [3]. Grand rounds has a tradition in medicine dating back to the presentations of Sir William Osler, known by many as the father of modern medicine, at Johns Hopkins School of Medicine. Often, patients with disorders that are rare, difficult to treat, or challenging to diagnose are discussed during grand rounds. Grand rounds function as a teaching tool to increase medical knowledge and improve medical care. By participating in these events, medical students and residents enhance critical reasoning skills and learn new information as well as ways to avoid potential mistakes.

Similarly to grand rounds, case reports are a valuable tool for medical students and residents to recognize clinical questions as they arise in the daily clinical practice. Students are then permitted to formulate an answerable clinical question, and then to find current best evidence to answer this question by performing a thorough and effective literature search. During the search, students critically appraise the medical literature and choose the appropriate literature to support the case. By writing a case report or case series, students gain experience in literature search and medical writing. Also, students execute the steps of evidence-based medicine, which consists of formulating a clinical question, finding the best evidence, critically appraising the evidence, and applying the evidence to the patient. Even if the manuscript does not ultimately get published, the review of the literature required to support the case carries educational value. From evaluating a patient's medical history, to performing a physical examination, to considering various differential diagnosis, selecting a treatment plan, and considering various side effects and outcomes of treatments-all these components of case report write-ups provide an educational benefit to medical students, residents, and fellows.

Clinical learning during medical school and residency is to a large degree case-based [4]. Case presentations are often found in textbooks, conferences, daily team rounds, or departmental grand rounds. Case reports or presentations are an excellent tool for sharing educational experience. Some of the important educational objectives that case reports introduce include enhancing awareness of rare disorders to facilitate diagnosis, clarifying new aspects on the etiology of a disorder, clarifying misunderstood treatment response, and describing how to avoid future mistakes [5].

Preparation for an academic career

Furthermore, writing a case report can be an excellent preparation or exercise in a medical student's career, often preparing one for a scientific career [4]. Students will be able to add the publications to their curriculum vitae for residency and fellowship applications. They will also be able to present some of the cases at local, national, and regional medical conferences, enabling them to meet peers and faculty in the area of their interest, thus enhancing their networking skills.

Case reports as vehicles for documenting new knowledge: first-line of evidence of new or innovative treatment

By writing case reports, medical students can contribute to the first line of evidence for developing new therapies [6][7][8]. In one case, a woman with a long-standing history of psoriasis was treated with infliximab, a tumor necrosis alpha-antibody. By just after two weeks after the infliximab infusion, her psoriasis had significantly improved. This isolated case report began a new era of treatment for psoriasis [9]. Albrecht et al. analyzed case reports and case series from The Lancet, published from 1 January 1996 to 30 June 1997, and found that of the 103 reports published in this high-impact journal, 24 were followed by randomized controlled trials (RCTs) [6].

First and major source for detecting rare adverse events of treatment Case reports may serve as a source for detecting rare adverse events, at times leading to the removal of drugs from the market. Going back to the example of psoriasis, the phenomenon of psoriasis exacerbation with the use of interferon alpha was first described in a case report [10]. There are abundant examples of severe side effects of drugs that were detected after the drugs were approved by the US Food and Drug Administration. Furthermore, case reports help to identify side effects due to interaction between drugs, as well as side effects due to drugs being given to patients with renal failure.

First report of a rare condition

When encountering a rare pathology in the dermatologic clinic, one of the frequent procedures is to perform a search for similar cases in any of the search engines. A vigorous literature search in itself can be a valuable task assigned to a medical student.

Consensus-based clinical case reporting guidelines

In 2013, a group of researchers published a set of systematic reporting guidelines to guide authors in writing case reports. The group published a 13-item checklist that provides a framework to fulfill the need for precision, completeness, and transparency for published case reports [11]. Implementing these guidelines will help medical students or residents write case reports that met these these reporting standards, with the aim of focusing on individualized patient care.

Rapidity of publication

Compared to extensive studies such as RCTs, case reports offer the possibility of a quick publication, especially for busy clinicians or students who do not have the time or means of creating any prospective studies or RCTs [12]. Furthermore, there are many online openaccess journals that focus on publishing case reports and case series, and that offer rapid publication times.

Conclusion

Given the challenging and diverse nature of medicine, many medical students or residents will come across a perplexing patient case. By offering to write up such a case, medical students will learn how to perform a literature review, communicate with various physicians in charge with the care of the patient, structure a manuscript, gain consent from the patient, collect data from various sources in the clinic, and how to submit and revise the manuscript. All of these skills are worth crafting early in the career of a medical student. Additionally, reporting single cases and series of cases is an important aspect of clinical research, especially for medical students, who often have limited funds for research and eagerness to contribute to medical science.
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