Keywords
multiple malignancies - metachronous - primary - synchronous
Introduction
Multiple primary malignancies (MPMs) are seen in 2.4 to 17% of all tumors.[1]
[2] MPMs can be further divided into synchronous and metachronous, based on the time
interval between the first and second tumor. In the synchronous group the diagnosis
of the second malignancy is made within 6 months of primary, while the metachronous
group is defined as occurrence of second diagnosis after 6 months of primary malignancy.
It is imperative for the surgeons to distinguish between MPMs and metastatic tumors,
as this has impact on both prognosis and subsequent therapeutic strategies.
Case Series
Case 1
A 40-year-old female diabetic patient presented with a lump in the right breast for
8 months. This was associated with pain that was continuous in nature. There was no
history of trauma, ulceration, nipple discharge, or retraction. She was amenorrheic
for the past 1 year and was on oral hypoglycemic drugs and injectable soluble insulin.
Laboratory investigations revealed mild anemia (Hb 10 g/dL) along with elevated glycosylated
hemoglobin (Hb; 12.5%). Kidney function tests were normal. Ultrasound (USG) of breast
revealed a lobular mass measuring 4.5 × 4 × 2.5 cm in the right upper quadrant along
with few echogenic areas of calcification. For the possibility of metastatic spread,
a positron emission tomography scan was done which confirmed the tumor in the right
breast along with an incidentally detected metabolically active lesion in the mid
pole of right kidney. Magnetic resonance imaging of abdomen showed a well-defined,
round, heterogeneous, encapsulated, hypodense mass measuring 4.2 × 3.9 × 4.3 cm in
the mid pole of right kidney. A possibility of oncocytoma or renal cell carcinoma
was given on imaging. Although, she had no urinary complaints or any palpable mass
per abdomen. Modified radical mastectomy along with axillary lymph node dissection
and right nephrectomy was done and sent for histopathological examination. Serial
sectioning of the breast showed an ill-circumscribed, gray white firm tumor measuring
5 × 3 × 2 cm, which on microscopic examination showed tumor cells arranged in tubules
and cords ([Fig. 1A]). The Nottingham score obtained was 6 (tubule formation 50–60%; moderate nuclear
pleomorphism; mitosis 8–10/10 high-power field [hpf]) ([Fig. 1B]). On immunohistochemistry (IHC), the tumor cells were estrogen receptor (ER) positive
and negative for progesterone receptor (PR), Her2neu ([Fig. 1C]). Cut surface of kidney showed a variegated tumor measuring 4.2 × 3.9 × 4 cm which
on histologic examination showed tumor cells arranged in sheet and focal alveolar
pattern separated by thin fibrovascular septa ([Fig. 1D]). Individual cells showed abundant clear to eosinophilic cytoplasm with round to
ovoid pleomorphic nuclei ([Fig. 1E]). IHC stain showed diffuse CD10 positivity in the tumor cells ([Fig. 1F]). Thus, a final diagnosis of synchronous invasive breast carcinoma and renal cell
carcinoma was given.
Fig. 1 Case 1: (A) Gross image of the breast showing a tumor with ill-circumscribed borders with firm
gray white cut surface. (B) Invasive breast cancer—Tumor cells arranged as tubules and cords in desmoplastic
stroma (hematoxylin and eosin [HE] 100 × ). (C) Immunohistochemistry (IHC): estrogen receptor (ER) positive (100 × ). (D) Cut surface of kidney showing a well-circumscribed tumor with a variegated cut surface.
(E) Clear cell renal cell carcinoma—Tumor cells arranged in sheet and focal alveolar
pattern, cells with abundant clear to eosinophilic cytoplasm (HE 40 × ). (F) IHC: CD10 positive (40 × ).
Case 2
A 36-year-old diabetic female patient presented with complaints of irregular menstrual
cycle sine 1 year and heavy uterine bleeding for the past 3 months. The menstrual
bleeding usually lasted for 10 to 12 days, soaking 8 pads/day. Patient also complained
of right breast mass for 2 to 3 months. She had a past history of left breast carcinoma
in 2016 for which she underwent modified radical mastectomy along with six cycles
of chemotherapy. On admission, she had moderate anemia (Hb < 7.8 g/dL). USG right
breast revealed an irregular hypoechoic lesion of 2.7 × 1.5 cm with irregular margins
and peripheral vascularity in the upper outer quadrant. Endometrial biopsy showed
a high-grade malignant spindle cell tumor, possibility of leiomyosarcoma and high-grade
endometrial stromal sarcoma was given. Intraoperatively, the uterus was enlarged to
14 to 16 weeks gravid uterus size and was soft and vascular. A fundal mass of 5 × 5 cm
with submucosal extension was observed. Total abdominal hysterectomy and bilateral
salpingo-oophorectomy along with modified radical mastectomy of right breast was done.
Serial sectioning of the uterine mass showed a polypoidal tumor measuring 11 × 7 × 6.5 cm
projecting into the endometrial cavity and infiltrating into myometrium ([Fig. 2A]). Microscopic examination of the uterine mass showed a highly cellular malignant
spindle cell tumor, arranged in sheet and fascicular growth pattern, composed of cells
with eosinophilic fibrillary cytoplasm, cigar-shaped nuclei with blunt ends showing
moderate to marked pleiomorphism along with many atypical mitotic figures ([Fig. 2B]). On IHC, the tumor cells showed positivity for smooth muscle actin and desmin and
were negative for ER, PR, epithelial membrane antigen, CD10, and p53 ([Fig. 2C] and inset). The breast tumor was well circumscribed, measured 4 × 3 × 2.5 cm with
a gray white cut surface and was arranged as solid nests and tubules ([Fig. 2D]). Nottingham score obtained was 7 (tubule formation 60%; moderate nuclear pleomorphism;
mitosis > 20/10 hpf) ([Fig. 2E]). Ki67 proliferative index was 50 to 60%. The tumor cells were positive for ER,
PR, Her2neu, and Ki67 was 70 to 80% ([Fig. 2F]). Thus, a final diagnosis of synchronous leiomyosarcoma of uterus and invasive breast
carcinoma was given.
Fig. 2 Case 2: (A) Gross image of the uterus showing a polypoidal tumor projecting into the endometrial
cavity and infiltrating into the myometrium. (B) Leiomyosarcoma—Malignant spindle cells arranged in sheet and fascicular growth pattern
(hematoxylin and eosin [HE] 40 × ). (C) Immunohistochemistry (IHC): smooth muscle actin (SMA) positive (100 × ) (inset showing
desmin positive [40 × ]). (D) Cut surface of breast showing a tumor with well-circumscribed borders. (E) Invasive breast cancer—Tumor cells arranged as solid nests (HE 100 × ). (F) IHC: Her2neu 3+ positive (100 × ).
Case 3
A 67-year-old male patient presented with complaints of constipation and hematuria
on and off for the past 8 to 9 months. He also complained of indigestion, loss of
weight, and decreased appetite in the last 3 to 4 months. Contrast-enhanced computed
tomography of abdomen showed an irregular polypoidal mass lesion of 4 × 4 cm involving
the right and posterior wall of bladder. Another lesion measuring around 4 × 4 × 1 cm
involving the distal wall of rectum with seen. Rectal biopsy and transurethral resection
of bladder tumor was done which confirmed presence of adenocarcinoma, rectum, and
low-grade papillary urothelial carcinoma, and urinary bladder, respectively. Radical
cystoprostatectomy along with low anterior resection was done. A polypoidal growth
of 4 × 4 cm was noted in the right and posterior bladder wall, adjacent to right ureteric
opening ([Fig. 3A]). Rest of the urinary bladder wall appeared normal. Histological examination showed
long branching papillae, with cells showing loss of nuclear polarity and moderately
pleomorphic nuclei ([Fig. 3B, C]). Although, no invasion into the muscular wall was noted. Grossly, an ulceroproliferative
circumferential hard growth measuring around 4 × 4 cm was observed proximal to the
anorectal junction ([Fig. 3D]). Rest of the bowel and viscera appeared unremarkable. The rectal tumor showed well-formed
glands, arranged in back-to-back manner ([Fig. 3E]). The malignant cells showed moderate nuclear pleomorphism along with conspicuous
nucleoli ([Fig. 3F]). Based on morphological features, diagnosis of synchronous low grade noninvasive
papillary urothelial carcinoma and moderately differentiated adenocarcinoma of rectum
was rendered.
Fig. 3 Case 3: (A) Gross image of the urinary bladder showing polypoidal growth involving the right
and posterior wall. (B) Noninvasive papillary urothelial carcinoma—Tumor cells arranged in long branching
papillae (hematoxylin and eosin [HE] 40 × ). (C) Urothelial cells showing loss of nuclear polarity and moderately pleomorphic nuclei
(HE 400 × ). (D) Low anterior resection specimen showing an ulceroproliferative circumferential growth
proximal to the anorectal junction. (E) Rectal adenocarcinoma—Glands arranged in back to back manner (HE 40 × ). (F) Tumor cells showing moderate pleomorphism with conspicuous nucleoli (HE 400 × ).
Discussion
Patients developing more than one malignancy in their lifetime are quite rare and
happen only in a subset of patients, where in course of detection and management of
the primary malignancy, another tumor is detected, mostly with the use of advanced
imaging modalities. Warren and Gates have defined the criteria for classifying a tumor
as “second primary malignancy.” Diagnostic criteria require each cancer to be proven
malignant by histopathological examination, and there should be at least 2 cm of normal
mucosa between the tumors, if they are in same location. They should also be separated
in time by at least 5 years and the possibility of metastasis should be excluded.[3] Zhai et al, in their retrospective analysis of 15,321 patients with malignant tumors,
found 167 patients (1.09%) with multiple primary malignant tumors, which included
144 double primaries and 23 triple primaries.[4]
Tumorigenesis involves successive “hits,” leading to a cascade of events, thus culminating
into neoplastic transformation of the cells. Genetic susceptibility, smoking, occupational
hazards, dietary intake, and aging are the known factors which are intricately linked
to each other, thus playing interacting roles in the development of various cancers
like breast, gallbladder, pancreatic, colon, and rectal cancers. Development of MPMs
is a multifactorial process, and the likely possible mechanisms involved are defective
immune surveillance systems, inherent faulty gene expression, tumor suppressor genes,
and many other possible etiologies. It has been observed that MPMs share a common
underlying oncogenic predisposition for the primary and the subsequent malignancies.
Indeed, time factor also plays an instrumental role, as supported by the fact that
elderly patients are more likely to develop MPMs.
Detection of successive malignancies is crucial for both clinicians and pathologists,
requiring vigilant examination of the organ system involved, for example, it is quite
reasonable for a urologist to expect the possibility of prostate cancer along with
concomitant bladder or renal malignancy. A gynecologist is always on a look out for
the possibility of cervical, endometrial, or ovarian malignancy after the diagnosis
of any one of the primaries. But, the detection of other primary cancers “outside”
the organ system with which the specialist doctor is primarily concerned is usually
masked during preoperative evaluation. MPMs are more commonly seen in gastrointestinal
tract followed by genitourinary system.[5] Among the gynecologic MPMs, breast cancers have been commonly associated with ovarian,
endometrial, or cervical cancer. Due to common mutations and pathogenic pathways,
there is always an increased probability of developing additional primary cancers.
It is well know that carriers of the BRCA-1 mutation are more likely to develop breast and ovarian cancer. Lu et al after performing
whole-exome sequencing on 11,416 patients, found out few addition genes, namely, MSH6 and ATM, that may increase the susceptibility to develop breast and ovarian cancer.[6]
CDKN2A mutations have also been detected in both cancers. Few of the pathogenic pathways
which have gained attention with respect to their association to MPMs are tumor-associated
macrophages (TAMs). They have a common association in breast, renal, and colorectal
carcinoma patients. In the published studies, it has been proven that TAMs facilitate
angiogenesis, by hampering antitumor immune responses, thus promoting tumor growth
and metastasis.[7] Dietary fat and obesity can enhance procreation of hormone-sensitive tumors, such
as endometrial, ovarian, prostatic, and breast malignancy as adipose tissue consists
of triglycerides and cholesterol and form elementary blocks for estrogen and testosterone.
Genetic syndromes like hereditary nonpolyposis colorectal cancer syndrome, confer
an increased risk of colon cancer as well as extracolonic tumors of uterus, ovaries,
stomach, biliary tree, urinary bladder, renal pelvis, and ureter. Calderwood et al
in their retrospective cohort of 3,57,597 colorectal cancer patients, observed 3,026
patients which subsequently developed urologic cancer on follow-up.[8] It has also been found that development of second cancers could be treatment-related
to the primary cancer. This has been observed in patients undergoing treatment with
highly selective RAF inhibitors (for melanomas), becoming prone to develop cutaneous
squamous tumors.[9]
MPMs are often misdiagnosed as recurrence or metastasis of the original malignancy,
which may result in inappropriate treatments, thus inevitably may lead to adverse
effects on the patient's prognosis. One of the frequent challenges encountered by
the oncologist is to find an anticancer treatment protocol that covers both malignancies
without chances of increased toxicity or any pharmacologic drug interaction or any
mishap that maybe incur deleterious impact on the overall outcome. Thus, there is
no universal protocol for the treatment of multiple malignancies. When multiple primary
malignant tumors are pathologically confirmed, each tumor should be evaluated and
staged as an independent tumor. In general, the pragmatic solution is to treat the
more aggressive tumor which would be more detrimental to the patient's survival or
quality of life. If patient is fit for surgery, resection for both tumors should be
prioritized and could be combined with chemo- or radiotherapy. Preoperative risk assessment,
postoperative monitoring, and long-term follow-up are indispensable and should be
strictly followed in such cases.
Conclusion
Strong clinical acumen and suspicion is required to identify malignancies with a synchronous
presentation and its differentiation from metastatic disease is pivotal as metastatic
disease indicates disease progression and a poor prognosis. A regular follow-up increases
the chances of early detection of synchronous or metachronous malignancies, thus improving
the overall survival. During follow-up, cancer patients should be informed about the
role of preventive medicine and should be encouraged of the various screening methods.
