Prospective clinicopathological study of breast cancer in Najaf

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Prospective clinicopathological study of breast cancer in Najaf

A thesis

Submitted to the Iraqi Board for Medical Specialization in partial fulfillment of the requirements for the degree of fellowship of Iraqi Board for Medical Specialization in General Surgery


Dr. Mais Sameer Shamsa


Supervised by

Ass. Prof. Dr. Ali M. Al-saiegh

M.B.Ch.B. D.S. F.I.C.M.S



To my dear father, mother & brother

who supported me all the times & made everything possible.


I would like to express my deep gratitude & thanks to my supervisor Dr.Ali M Al-saeigh for his care, to Dr.Asaad Al-janaby for his great help at the histological data & to Dr.Abdul-kareem Abdulla for his help at the statistics.








List of Tables


List of Figures


Abbreviations list






Patients & methods










Tables & Figures




List of Tables





Relation between age groups, tumour laterality &location among the studied group



Relation between age groups, family history & blood group



Relation between lymph node status, tumour ,tumour size, stage & grade



Relation between age groups, hormonal receptors & HER-2



Relation between tumour grade, hormonal receptors & HER-2



Relation between age groups & Nottingham Prognostic Index



Relation between LRR, DM with stage, grade ,hormonal receptors &HER-2



Relation between age groups & patients with LRR,DM or both



Time of development of LRR,DM or death



Clinico-pathological features of survivours & deceased


List of Figures





Distribution of LRR



Distribution of DM


Abbreviations List


Loco-regional recurrence


Distant metastases


Estrogen receptors


Progesterone receptors






Human epidermal growth factor-2receptor


Chest wall recurrence


Axillary recurrence


Chest x-ray


Nottingham prognostic index


Magnetic resonance imaging
















Background: Breast cancer accounts for 32% of all new cases of cancer among women& is the leading cause of death in those aged between 40-79 years. In Iraq, it is the commonest tumour affecting females accounting for more than 30% of registered female cancers with a sharp increase in young women.

Aim & design of study: A prospective study, aims to outline the clinico-pathological features & prognosis of patients with breast cancer in Najaf.

Patients & methods: A randomized 93 women living in Najaf in whom breast cancer was diagnosed, were studied & followed up at 6-monthly intervals from January 2005 –March 2008, with a mean follow up of 12.8 months.

Results: 57% of the studied patients were <=50 years. Lt-sided & laterally-located cancers were diagnosed in 59.1% &52.2% respectively. The great majority (77.8%) presented after 2-12 m from their complaints. 71% had T2 tumours & 75% had axillary lymph nodes metastases. 55.9% were diagnosed with stage III & 64.5% had poorly-differentiated cancers. 65.6 % were positive for ER &/or PR , & 41.9% were positive for HER-2. NPI was poor in 55.9% of the studied patients. 34 patients suffered recurrence of cancer during the study (13 LRR, 17 DM, 4 both). There was an association of grade III, stage III, negative hormonal receptors, & HER-2 positivity with the recurrence but it was statistically significant only for HER-2. Chest wall & liver were the most common sites for LRR & DM respectively. At the end of the study, 57% were disease-free & 16.1% were deceased.

Conclusion: The breast cancer among the studied patient characterized by younger age at the time of diagnosis & more frequently located on the Lt-side. The time till diagnosis was relatively prolonged. Also lymph node metastases, stage III, grade III, & poor NPI predominated. They had short disease-free interval, with more frequent unfavourable sites of distant metastases. There was a statistically significant association between HER-2 positivity & cancer recurrence.


Among women, the three most common cancers are those of: breast, bronchus, colo-rectal accounting for 55% of the new cases of malignancy in women with breast cancer being responsible for 32% of cancer burden. Breast cancer is the leading cause of death in women aged 40-79 years affecting 1 in every 8 women in USA(1 , 2) & 1 in every 9 women in Britain (3).It accounts for 26.8% in India(4) 18% in Kingdom of Saudia Arabia(5) & 30.3% in Kuwait.

Breast cancer is the commonest tumour in Iraqi female patients accounting for more than 30% of registered female cancers with a sharp increase in the rate of this tumour in the younger age group(7).

Women diagnosed with breast cancer in their twenties &thirties seem to have a poorer prognosis than those diagnosed in their middle age(8,9,10,11,12,13,14).They tend to have larger tumour size, more positive lymph nodes, more negative hormonal receptors, higher tumour grades than the older counterparts (8,15,16,17,18).

Breast cancer is the second most common malignancy in pregnancy after cervical cancer (19). Women with breast cancer in pregnancy tend to have larger tumours & are more likely to have positive lymph nodes, metastases &vascular invasion (20-28). Also studies have shown decreased ER-positive status(20,22,23,26,29,30,31,32,33) &increased HER-2 positivity(33,34) ,but the outlook is similar to that of non-pregnant women when adjusted for stage & age(22,23,24,35,36).

The majority of human breast cancers contain detectable amounts of either ER or PR or both, &the likelihood that a patient’s tumour is hormone positive increases with increasing age at diagnosis. The presence of both receptors in a tumour is associated with almost an 80% chance of favourable response to hormonal manipulation (37).­

The HER-2/neu receptor is part of the epidermal growth factor receptor family, which participates in epithelial cell growth &differentiation. (38, 39)

Over expression of HER-2 protein is observed in 20-40% of human breast cancers (40, 41, 42) & it appears to be inversely related to the expression of ER &PR even in hormone positive tumours.(43)

HER-2 positive patients are less likely to respond to second line hormonal therapy & had a significantly shortened duration of response &duration of survival. (44)

There is a 2-3 folds excess of breast cancer in the first degree relatives (mothers, sisters, & daughters) of the patient & the risk is much higher if the affected first degree relatives had premenopausal & bilateral cancers (45). Genetic factors are estimated to cause 5-10% of breast cancer cases, but they may account for 25% of cases in women younger than 30 years of age.BRCA-1 gene mutation accounts for 40% of all familial breast cancer cases &is associated with increased risk of ovarian cancer, colonic cancer. BRCA-2 gene mutation accounts for 30% of familial breast cancer (especially in males) &is associated with increased risk of ovarian, pancreatic, laryngeal cancers. BRCA-1 associated cancers are higher grade, more hormonal receptor negative in comparison with BRCA-2 associated cancers (46).
Recurrence of breast cancer can be loco-regional (LRR) or distant metastatic (DM).

The incidence of loco-regional recurrence (LRR) of breast cancer ranges from 4.6-27% according to various statistical reports. Local disease can be isolated but upto 50% of patients have associated systemic relapse (47, 48, 49). It should occur in <10% of cases within 10 years with adequate local & systemic therapies(49).LRR can be in the chest wall(CWR), axilla(AR),supra/infra-clavicular, & internal mammary lymph nodes(50).

Early LRR (<5 years) is associated with an overall poor survival. CWR has better prognosis than other varieties.

Metastatic breast cancer usually present as distant recurrence from a previously resected breast cancer, occurring in 35% of resected cancers within 10 years of surgery. A minority of patients initially present with metastases .Metastatic cancer is incurable but long-term & worthwhile short-term response can be achieved by appropriate treatment. Hormonally-sensitive patients, those with long disease-free interval (> 2 years after primary diagnosis), & patients with favourable metastatic sites (bone versus liver, lung &brain) survive longer. Median survival from symptomatic metastatic disease is 2-3 years (49).

The following factors are associated with recurrence of breast cancer(49,50,51,52,53):

  1. Young age.

  2. Involvement of > 4 lymph nodes.

  3. Larger tumours (>5 cm).

  4. Lymphovascular invasion.

  5. High grade.

  6. Involvement of the the overlying skin, or underlying muscle.

  7. Positive deep resection margin.

  8. Negative hormonal receptor status.

  9. Over expression of HER-2 receptors.

Nottingham Prognostic Index (NPI) is a pathological system that combines tumour grade, node status & tumour size .It has been validated as an accurate prognostic score.It‘s calculated by:

NPI=Grade score+ lymph node score+ [tumour size (cm)× 0.2]

Where grade I scores1, grade II 2 & grade III 3.

No involved lymph nodes scores 1, (1-3) scores 2, >3 scores 3.

The following table shows the 5-years survival of the groups of NPI ,where the survival for good, moderate & poor grades is close to stage I-III of the TNM system(54).

NPI score


5-year survival

2.0 -2.4












Patients & Methods:

During the period from January 2005 - March 2008, a randomized 93 cases of breast cancer in women living at Al-Najaf were studied &followed up for 2-38 months (mean 12.8 months).

  • The following data were enquired in history:

-Age: patients were classified into 2 age groups-(<=50), (>50)


-Blood group.

-History of breast cancer in the first &second degree relatives.

-complaint &duration, side involved, location of the tumour in the breast.

  • Physical examination done to stage the patients clinically.

  • Investigations performed include:

- Fine needle aspiration. - Breast ultrasound.

- CXR. - Abdominal ultrasound.

- Blood group.

- Skeletal X-rays (& MRI-spine): done only if there is suspicion

of metastases.

  • 91 patients underwent surgery: 84 Patey’s mastectomy, 6 simple mastectomy & 1 lumpectomy. The other 2 patients were subjected to neoadjuvent chemotherapy.

  • The following data were recorded from the histopathologic report:

- Size of the tumour - Histologic type of cancer.

- Lymph node status. - Staging. - ER/PR status. - HER-2 status (if available)

- Degree of differentiation.

Nottingham’s prognostic index was calculated from the following equation:

NPI= grade+lymph node score+ (0.2×tumour size).

Where grade I scored 1, grade II scored 2& grade III scored 3.

For the lymph nodes: no involved lymph nodes scored 1, 1-3 involved lymph nodes scored 2, > 3 scored 3.

  • Adjuvant therapy: 90 patients received post-operative chemotherapy (1 refused), & 26 patients received radiotherapy. Hormonal receptor positive patients were offered tamoxifen.

  • The patients were followed on 6-monthly bases by phone or by reviewing them at the oncology department.

  • Chi-square test was used for the statistics.


Mean age at diagnosis was 49.4 yrs. 57% of the studied group (53 patient) were <= 50 yrs.

59.1 %( 55 patients) presented with Lt-sided cancers, while 37.6% (35 patient) has Rt-sided ones, (P>0.05).

Laterally-located cancers were more frequent than central & medial cancers (51.6% versus 32.2% &14% respectively), (P>0.05)

Only 12 patients (12.9%) presented within 2 months of their symptoms, while the majority (72 patients, 77.8%) sought advice after 2-12 months from symptoms (P>0.05).There was no statistically significant difference between the two age groups in tumour laterality, location, & duration of complaint (P>0.05). ((Table 1))

3 patients were diagnosed with cancer during the first trimester of pregnancy (all aborted either deliberately or accidentally).

Blood group A&O predominated in the studied patients, accounting for 73% (68 patients), but they didn’t reach statistical significance (P>0.0 5). Additionally, these 2 groups were the most frequent among general population at Al-Najaf as recorded in the data of Al-Sadder Teaching Hospital laboratory. Blood groups were unavailable for 3 patients. 10 patients (10.8%) had a family history of breast cancer, 50% had blood group B, & 90% were <=50 years (P<0.05), as seen in ((Table 2)).

The tumour measured 2-5 cm & > 5 cm in 66 & 22 patients respectively (71% & 23.7% respectively), while only 5 cases (5.4%) had tumours < 2cm .No statistically significant age difference exists (P>0.05).

Axillary lymph nodes status were known for 84 patients with metastases being identified in 63 (75%) of them. Axillary nodal involvement was more frequent among those <=50yrs (78.4% versus 69.7%) but the difference was statistically insignificant (P>0.05).

Stage III disease has been diagnosed in 52 patients (55.9%). Stages II &IV were present in 33 &6 patients respectively (35.5% &9.7% respectively). Only 2 cases with stage I (2.2%) were diagnosed. Poorly-differentiated cancers(grade III) were three times more frequent than grade II, & five times more common than grade I , i.e. 60(64.5%) versus 21(22.6%) & 12(12.9%) . There was no statistically significant age difference regarding stage & grade.

((Table 3)) shows the relation between age, lymph nodes status, tumour stage &grade.

Hormonal receptor s&HER-2 status were not available for 3 & 11 patients respectively. However, 61 patients (65.6%) were positive for ER &/or PR; &39 patients (41.9%) were HER-2 positive. Positive hormonal receptor status was more common in those >50 yrs (70%) while HER-2 positivity was more common for those <=50 yrs (43.4%) ;but no statistically significant difference exist ,((Table 4)). Patients who had grade III tumours were more likely to be hormonal receptor negative & HER-2 positive as in ((Table 5)).

Upon calculating the NPI (which was possible in 84 patients), 52 patients (55.9%) had poor prognosis (score >5.4). Only 1 patient had excellent prognosis .However, the difference between prognostic groups& age was statistically insignificant (P>0.05) as seen in ((Table 6)).

All the pregnant ladies had involved axillary lymph nodes, & stage III. One patient had grade I cancer, the rest had grade III. Hormonal receptor status & HER-2 status were lacking for one patient, but the other two were positive for both.

Over the 38 months of the study, 34 patients (36.6%) developed recurrence; 50% of which were distant, the remaining were isolated loco-regional & combined loco-regional & distant recurrences as shown in ((Table 7)). There was no significant difference in the development of recurrence between the studied age groups ((Table 8)). Median disease-free intervals of those with LRR &DM were 10 & 8 months respectively. All LRR & 90.5% of DM were encountered in the first 18 months ((Table 9)).

All LRR patients had received radiotherapy (if they didn’t receive it post-operatively), otherwise chemotherapy was offered .For those with DM either chemotherapy or radiotherapy was offered (depending on the site of metastases).

Of the 34 cases with recurrence: 29(85.3%) had stage III disease,& 26(76.5%) had grade III cancer,while19(55.9%) were negative for hormonal receptors & 23(67.6%) positive for HER-2;However, only the latter was statistically significant(P value <0.05).There was no significant difference in hormonal receptor expression among the recurrent group though those with (LRR+DM) were more likely to be hormonally negative .Similarly, positive HER-2 status was more common among those with DM & (LRR+DM), ((Table 7)).

76.5% (26 patients) of those suffered recurrence had poor NPI.

Of the 17 LRR (13 isolated + 4 combined with DM): 14 in the chest wall, 2 in the axilla, 1 in the supra-clavicular region. ((Figure 1)).

Of the 21 DM (17 isolated+ 4 combined with LRR): 10 in the liver, 5 in the lung, 4 in the bones, 1 umbilical nodule, 1 with malignant ascites.((Figure 2)) .

At the end of the study, 15(16.1%) patients were deceased: 4 who presented as stage IV (2 in the bone, 2 visceral), 1 with LRR (supraclavicular, but death was due to radiation-pneumonitis), & 10 died due to their distant metastases (3 in the bone, 6 visceral, 1 in the brain). Most of the deaths (86.7%) occurred in the first 18 months after diagnosis, as seen in ((Table 9)).

53 patients (57%) were disease-free, while 12(12.9%) &13(14%) were living with their LRR, &DM respectively, as seen in ((Table 10)). All patients whose cancer was diagnosed during pregnancy were disease-free at the end of the study.


In contrast to what is commonly known about the rising incidence of breast cancer with age, our results showed that 57% of the patients were <= 50 years ,with a mean age at diagnosis of 49.4 years; while in USA & Western Europe the mean age at diagnosis is 63 years(2,3). Nagi et al (2001) in his study on 1320 Lebanese women showed that 50% were < 50 years, with a mean age at diagnosis of 50.8 years (55). Similarly, Ibrahim et al (1998) in his study on 292 Saudian women with breast cancer, found that 78% were <50 years (56) .Nissan et al(2004) found that Palestinian women tend to be younger at the time of diagnosis of breast cancer than their Jewish counterparts(57).

Lt-sided cancer was more common in our study (59.1%). It was also more common in the study of Ozlem Yavas et al (2007) being reported in 52.8% of patients (58) .Perez stated that Lt-sided cancer is more common possibly because this breast is usually larger than the Rt. one(59).In contrast, Saleh et al(2007) had more frequent cancers on the Rt-side(53.6% versus 42.2%)(6) .

Although blood groups A&O were predominant in our patients ,but they are also the most frequent among general population as recorded in the data of laboratory of Al-Sadder Teaching Hospital in Najaf. Conversely, Anderson & Haas (1984) stated that there may be an excess of blood group A among patients with breast cancer especially in familial cases (60). Similarly, Negib et al (1980) had found excess of group A in cases with rapidly progressive breast cancers (61).

Saxena et al (2005) studied the clinico-morpholological patterns of breast cancer in India, & found that approximately one-fifth of their cases had positive family history, particularly those <45 years (62).In comparison, 10.8% of our patients demonstrated positive family history of breast cancer.

In our study T1 accounted for only 5.4% of cases, while T2 constituted the majority (71%). Nagi et al (2001) recorded more frequent T1 (19%), but again T2 tumours were predominant (66.5%)(55). Nearly one third of the cases in Carr et al (2000) study wereT1, & 40% had T2 (63).

Axillary lymph nodes were involved in 75% of our patients, a result that is slightly higher than that of Nagi et al (2001) (55), but much different from Nissan et al (2004) who reported 44% axillary lymph node metastases in their study (57).

Stage III was the most common among the studied group accounting for 55.9% ,followed by stage II & IV (35.5% & 9.7%); while stage I was the least common (2.2%).Similarly, Ibrahim et al(1998) identified stage III as the most common stage among Saudian women constituting 44%of all cases(56). This was different from the results of Nagi et al(2001) in which stage II was the most common (59.9%),followed by stage III(20%)(55) ;similarly, stage II was predominant in the study of Nissan et al(2004),with stage III being next in frequency(57) .

Grade III predominated in our study forming 64.5%.Sundquist et al(2002) stated that grade III occured in38% of their patients but would rise to 64% if only the younger patients were considered(64). Al-Kuraya et al (2005) on comparing Saudi& Swiss breast cancers found that grade III accounted for 65% in the former but for only 32% in the latter (65).

65.6% of our patients expressed hormonal receptors, the percentage of which increased with age.Similarly, McGuire et al (1975) found that 50-85% of all breast cancers express hormonal receptors with direct correlation to the age (66), but Sundquist et al (2002) found higher percent of hormonal receptors among young women (64).

HER-2 was positive in 41.9% of our patients, being more common in those <=50 years. Lipton et al (2000) & Carr et al(2000) reported HER-2 over expression in 30% & 43% of their patients respectively(44,63).

Taucher et al (2003) found significant correlation between hormonal receptor negativity&HER-2 positivity with grade III tumours (67). In our study such association was found, but it didn’t reach statistical significance. Carr et al (2000) didn’t find a statistically significant association between tumour grade & hormonal receptor status with HER-2 positivity (63).

Galea et al (1992) on applicating NPI on the British population with breast cancer found that only 17% had poor prognosis (68).In comparison, 55.9% of our patients had poor prognosis.

Many researchers demonstrated that younger age women tend to have larger tumours, more positive lymph nodes, more negative hormonal receptors, higher tumour grades than the older counterparts (8,15,16,17,18).In our study even if differences were found, they didn’t reach statistical significance .

Demicheli et al (2004) reported that 31.4% of their 1173 patients developed recurrences within 4 years of treatment by mastectomy alone. Distant recurrences accounted for the majority (23.3% versus 8.1%) (69). In our study, LRR & DM accounted for 14% & 22.6% respectively.

Insa et al (1999) on analyzing 439 women with recurrent breast cancer with median disease-free interval of 33 months, found that larger tumour size & involvement of axillary lymph nodes at the time of diagnosis , negative hormonal receptor status , shorter disease-free interval , & site of metastases ( visceral versus bony) were significantly associated with shorter survival after first relapse(70). Similar results were reported by Solomayer et al (2000) (71).

Takeuchi et al(2005) found that recurrence of breast cancer mainly occurred within 30 months of surgery& that early recurrence was clearly associated with tumour size >2cm & negative hormonal receptor status(72).

Crowe et al (1999) on studying loco-regional recurrence after mastectomy concluded that patients with larger tumours, more extensive nodal involvement & shorter disease-free interval after mastectomy are more likely to have rapid appearance of distant metastases (73).

Carr et al (2000) demonstrated a shorter disease-free interval (22 versus 40 months) for HER-2 positive patients, & distant metastases were more common than local recurrence (63). Lipton et al (2002) found greater percentage of visceral metastases among HER-2 positive patients (59% versus39%) (44).

Emi et al (2002) stated that metastatic breast cancer with over expression of HER-2 tends to have a poor prognosis especially after first recurrence (74).

CWR was the most common site of LRR after mastectomy in 5 large American studies, followed by supra/infraclavicular region, axilla (in that order)(75-79). However, axilla was the second frequent site of LRR in our study but our sample is small & followed for relatively short duration of time.

Body (1995) stated that bone is the most common site of distant metastases from breast cancer, followed by lung, pleura, soft tissues & liver (80). Koenders et al (1992) & Insa et al (1999) reported that breast cancer patients with bone metastases have more favourable prognosis than those with visceral involvement (70, 81).In contrast, hepatic & pulmonary metastases predominated in our study.

Many researchers stressed that women with breast cancer in pregnancy tend to have larger tumours & are more likely to have positive lymph nodes, metastases &vascular invasion (20-28). Also studies have shown decreased ER-positive status(20,22,23,26,29,30,31,32,33) &increased HER-2 positivity(33,34). At the end of our study the 3 pregnant women were free of loco-regional or distant recurrence.

52% of the patients at Ibrahim et al study were disease-free 10 years after diagnosis & 39 % were deceased (56). However, their patients were followed for longer time than ours.


Breast cancer among the studied patients had unfavourable features:

  1. Young age at the time of diagnosis.

  2. Relative delay in the diagnosis.

  3. Frequent nodal metastases

  4. Predominance of stage III & grade III.

  5. Frequent poor NPI.

  6. Predominance of Lt-sided cancers.

  7. Short disease –free interval.

  8. Statistically significant association between HER-2 positivity & recurrence.

  9. Frequent distant metastases at unfavourable sites


  1. Extending the study both in size & duration of follow up.

  2. Increasing the efficacy of educational programmes about breast cancer to encourage more women attend at breast clinics.

  3. Making assessment of hormonal receptor &HER-2 status be a routine for patients with breast cancer.

  4. Making hormonal receptor status & HER-2 tests available at the general hospitals.

  5. Making Herceptin available for HER-2 positive patients with distant metastases.

  6. Stressing the importance of frequent (6-monthly) examination for those who have a positive family history of breast cancer especially among first degree relatives.

Age group



Tumour location*

Duration of complaint



































































Table (1) Relation between age groups, tumour laterality & location

One patient had no palpable disease (presented with nipple eczema).

Numbers in parentheses represent percentage.

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