Primary Multiple Metachronous Cervical Cancer: Difficulties in Differential Diagnosis - Juniper Publishers

Journal of Case Studies - Juniper Publishers

Abstract

This observation shows a combination of primary multiple tumors, where one of the tumor localizations is the cervix, the other is the mammary gland, the third is the lung.

For differential diagnosis in cases of primary multiple tumors, the most informative is CT of the lungs, PET-CT, ultrasound of the pelvic organs and abdominal cavity, histological examination, immunohistochemical examination. In case of difficulties in differential diagnosis, it is possible to perform extended genetic testing of frequent somatic mutations in the TP53, GATA3, EGFR, KRAS, NRAS, ESR, PIK3CA, AKT genes, which allows you to determine the source of metastasis, and in this regard, select the necessary antitumor therapy.

Despite the progression of cervical cancer (metastases to the supraclavicular lymph nodes), the patient was not denied specialized treatment for lung cancer. The multidisciplinary approach adopted in the clinic in the diagnosis and treatment of patients made it possible to detect a malignant lung tumor at the preclinical stage and perform a radical operation, which allows us to hope for a good long-term result. At the same time, the metastatic lesion was not confirmed, the data of pathomorphological examination and immunohistochemical studies established an independent primary nature of the tumor.

Keywords: Metachronous cervical cancer; Cervical cancer; Recurrence

Introduction

Cervical cancer (CC) is the second most common cancer among women under 65 years of age and is the most common cause of death from gynecological cancer worldwide. In terms of morbidity and mortality, cervical cancer ranks fourth among all cancers. In 2020, there were 604,127 new cases of cervical cancer and 341,831 deaths worldwide. In the structure of mortality from malignant neoplasms in women under 45 years of age, cervical cancer ranks 1st. Tumors with localization in the cervix, mammary gland, lungs and other organs are not casuistry, but represent an extremely complex and not fully resolved problem of oncology. In the available literature, we did not find a combination of primary multiple cancers of the breast, lung and cervix. The frequency of metachronous tumors in women reaches 4.5%. We present to your attention an extremely rare case - the presence of primary multiple metachronous cervical cancer.

Patient S., 60 years old, applied to the Novosibirsk Regional Clinical Oncological Center in 2014 with a diagnosis of breast cancer III st T2N1M0. - radical left-sided mastectomy with lymphadenectomy.

Histological examination No. 26854-69 dated August 27, 2014. Conclusion: infiltrating ductal cancer of the left breast, maligna II with growth in the vessels, secondary changes in two lymph nodes.

Immunohistochemical study dated 09/04/2014. - ER 8, PR 6, Her2neo 1+ Ki67 - 25%. Adjuvant radiation therapy was prescribed - a dose of 46-50Gy for 23-25 fractions 5 times a week for the operated mammary gland, supra-/subclavian, ipsilateral parasternal and part of the axillary zone (as a zone of special risk) ROD 2Gy, SOD 45-50Gy.

Polychemotherapy courses - according to the FAC scheme: Cyclophosphamide 800mg, Doxorubicin 80mg, 5 fluorouracil 800mg 4 courses, hormone therapy with Tamoxifen 20mg. The patient was registered with an oncologist and regularly underwent examinations.

In 2015, cervical cancer II st T2bN0M0 was diagnosed, cervical biopsy No. 30867-79 dated 10/14/2015. - squamous cell nonkeratinizing cancer.

Courses of chemoradiation therapy, remote beam therapy in a total dose of 45-50Gy, simultaneously with chemotherapy (3 cycles of cisplatin 50mg each week) followed by brachytherapy, EBRT - 2Gy per fraction, in the irradiation mode 5 times a week, were carried out. The total dose to the focus from combined radiation therapy was 75Gy, to the lymphatic outflow path - 58Gy.

In 2017, according to the results of a histological examination dated February 21, 2017. - Metastasis of squamous cell carcinoma of the cervix to the supraclavicular lymph nodes on the left, courses of polychemotherapy Paclitaxel 175 mg/m² IV 3 hours on the 1st day + Doxorubicin - 8 courses, completed in September 2017, palliative course of radiation therapy to the region of the supraclavicular lymph nodes on right. According to the control studies - stabilization of the process.

In February 2020, according to the results of bone scintigraphy - metastases in the bones of the spine Th8-Th10, reactive strontium therapy was prescribed, Fulvestrant 500mg 1 time in 28 days/m, continued growth of Th8-Th10, Palbociclib was added from 02.2020.

Ultrasound of the supraclavicular lymph nodes from 12/29/2020 - on the left: multiple (9) hypoechoic with clear and fuzzy contours ranging in size from 3 to 12mm (previously from 3 to 10mm) are located (Figure 1 & 2).

01/13/2021 - excisional biopsy of supraclavicular lymph nodes on the left.

01/20/2021 Histological examination of surgical material: No. 442-5/21: the histological picture and immunophenotype of tumor cells correspond to metastases of squamous cell carcinoma, taking into account the expression to p16 (Clone CINtec, Ventana) - carcinoma of the cervix.

MRI of the pelvis from 01/19/2021 - no pathology was detected.

Ultrasound of the abdominal organs from 01/29/2021 - echo signs of a liver cyst, a cyst of the left kidney, diffuse changes in the liver parenchyma, pancreas.

02/08/2021 - concilium - chemotherapy is indicated according to the scheme: Paclitaxel 175mg/m² IV drip + Cisplatin 75mg/m² IV drip on day 1 Cycle 1 time in 21 days, up to 6 courses with an assessment of the effect after 3 and a decision issue of radiation therapy 6 cycles of chemotherapy were performed (treatment was completed on 05/25/2021) MRI of the pelvis from 12/09/2021 - MRI signs: - abdominal infiltrate of the uterine bladder tissue with inhomogeneous contents and air with fistulas in the bladder and vagina, - post-radiation changes in the pelvis .

To clarify the process, PET-CT of the whole body was performed: - In the parenchyma of the right lung, nodular metabolically active seals in S2 - 1.2 * 0.8cm, in S6 - 0.9 * 0.8cm. Infiltration of the small pelvis.

According to PET-CT of the whole body dated 02.11.2021. - zone of tissue resorption in the region of the alveolar process of the upper jaw.

Consultation of the maxillofacial surgeon from 02.11.2021 - More evidence for osteonecrosis with bisphosphonates.

Due to difficulties in diagnosing the zone of tissue resorption in the region of the alveolar process of the upper jaw, an extended genetic testing of frequent somatic mutations in the genes TP53, GATA3, EGFR, KRAS, NRAS, ESR, PIK3CA, AKT was performed in the laboratory of pharmacogenomics of the Institute of Chemical Biology and Fundamental Medicine SB RAS: in block 26854-56, a mutation was found in the GATA3 gene (chromosome 10, position 8115971 in the assembly of the human genome No. 19) with a content of 30.4% with a coverage of 171 reads; in block 30867, a mutation was found in the TP53 gene (chromosome 17, position 757754) in the assembly of the human genome 19 with a content of 1.15% with a coverage of 783 reads, a mutation in the TP53 gene (chromosome 17, position 7577541 in the assembly of the human genome No. 19) was found in plasma with a content of 1.86% with a coverage of 22872, respectively.

Conclusion: tumor DNA corresponding to sample 30867 (cervical cancer) circulates in blood plasma Concilium at the Novosibirsk Regional Clinical Oncological Dispensary dated January 12, 2022 - given the progression of the disease, continued tumor growth is indicated for monochemotherapy: Karboplatin AUC 5 IV 1 hour on the 1st day every 3 weeks, up to 6 courses in total (with an assessment of the effect after 3 and 6 courses - CT of the chest + MRI of the small pelvis) MSCT of the chest on March 18, 2022 - no dynamics.

MRI of the pelvic organs on March 18, 2022 - no dynamics.

6 courses of monochemotherapy with Carboplatin AUC 5 IV 1 hour on the 1st day every 3 weeks were carried out, treatment was completed in May 2022.

Since August 2021, a vesico-vaginal fistula was diagnosed (Figure 3), which significantly reduced the quality of life of the patient.

Examined by a urologist in May 2022, cystoscopy was performed: - Formations: on the right side wall with a transition to the posterior multiple small bullous-solid formations - a biopsy was taken, urine was taken for atypical cells, cytological examination - no atypia. Histological examination - Moderately expressed active cystitis. Tumor growth was not detected in the preparation.

In July 2022, a set of examinations was carried out: pelvic ultrasound, abdominal ultrasound, CT of the lungs, skeletal bone scan, PET-CT, and stabilization of the process was established.

In this regard, on July 20, 2022, fistuloplasty was performed at the Avicenna clinic (Figure 4-6), the postoperative period was uneventful, without complications, and she was discharged on the fifth day. The patient notes a significant improvement in the quality of life.

In August 2022 according to the results of follow-up examinations on CT scan of the lungs, there are signs of metastatic lesions of the upper and lower lobe of the right lung, videoassisted thoracoscopic upper lobectomy on the right with atypical resection of the lower lobe is recommended (Figure 7 & 8).

At the Institute of Oncology and Neurosurgery of the Federal State Budgetary Institution “N.N. ak. E.N. Meshalkin” 30.08.2022 - videothoracoscopic upper lobectomy on the right with atypical resection of the lower lobe. Intraoperatively: in the root of S3 of the upper lobe of the right lung, a tumor of 2.5cm was determined, without pleura involvement. In the lower lobe on the right S6, S8, S9, 3 subpleural foci are determined. Performed upper lobectomy with atypical resection of the lower lobe.

According to the pathomorphological study dated 09/02/2022. No. 10147-10168 - taking into account the morphology of the formation - the presence of a pronounced exophytic component, the tumor stem, the solidary nature of the neoplasm, the most likely primary highly differentiated keratinizing squamous cell carcinoma S3 of the bronchus of the upper lobe of the right lung, pT1cN0M0.

A revision of the pathomorphological report was performed at the Tomsk National Research Medical Center dated 09/08/2022. No. 10147-10168, where the diagnosis was also confirmed - primary highly differentiated keratinizing squamous cell carcinoma S3 of the bronchus of the upper lobe of the right lung, pT1cN0M0.

According to the ultrasound of the small pelvis, ultrasound of the abdominal cavity dated December 14, 2022. - no negative dynamics, signs of post-radiation changes.

According to CT of the chest organs dated November 22, 2022. - condition after surgical treatment of the right lung. There are no new foci, lung metastases without dynamics, metastases of Th8- Th10 bodies - without dynamics.

According to colposcopy dated 12/17/2022. - no local recurrence, post-radiation changes (Figure 9).

Conclusion

This observation shows a combination of primary multiple tumors, where one of the tumor localizations is the cervix, the other is the mammary gland, the third is the lung. Figure 7 & 8 - CT scan of the lungs - in the root of S3 of the upper lobe of the right lung, a tumor of 2.5 cm is determined, without pleura involvement.

1. For differential diagnosis in cases of primary multiple tumors, the most informative is CT of the lungs, PET-CT, ultrasound of the pelvic organs and abdominal cavity, histological examination, immunohistochemical examination.

In case of difficulties in differential diagnosis, it is possible to perform extended genetic testing of frequent somatic mutations in the TP53, GATA3, EGFR, KRAS, NRAS, ESR, PIK3CA, AKT genes, which allows you to determine the source of metastasis, and in this regard, select the necessary antitumor therapy.

2. Despite the progression of cervical cancer (metastases to the supraclavicular lymph nodes), the patient was not denied specialized treatment for lung cancer. The multidisciplinary approach adopted in the clinic in the diagnosis and treatment of patients made it possible to detect a malignant lung tumor at the preclinical stage and perform a radical operation, which allows us to hope for a good long-term result. At the same time, the metastatic lesion was not confirmed, the data of pathomorphological examination and immunohistochemical studies established an independent primary nature of the tumor.

3. In the treatment of primary multiple tumors, a multidisciplinary approach is required with the involvement of a thoracic surgeon, an oncogynecologist, an oncomammologist, a molecular oncologist, and a pathologist. The final conclusions on this issue can be obtained by accumulating a sufficient number of observations.

Therefore, each case of a primary multiple metachronous lesions should be especially carefully studied and presented in international medical literature.

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Human Papillomavirus and Cervical Cancer - A Review - Juniper Publishers

 Tumor Medicine & Prevention - Juniper Publishers   

Abstract

Cervical cancer used to be the leading cause of cancer death for women. Human Papillomavirus (HPV) infection is responsible for more than 90% cervical cancer. About 6.6% of women in Indian population are estimated to harbor cervical HPV infection. HPV 16 and 18 are accounting most prevalent type in cervical adenocarcinomas. In HPV life cycle, high-level amplification of the viral genome move outer layers of the epithelium are released to re-initiate infection, persistent infection leads to precancerous lesion. The numbers of cervical cancer cases and deaths have decreased significantly over the period with efficient diagnostic technique like Pap smear test. Development of sensitive technique for early detection of HPV infection and vaccination further reduce the incidence of cervical cancer.

Keywords: Cervical cancer; Human Papillomavirus infection; Pap smear test

Abbrevations: HPV: Human Papillomavirus; LCR: Long Control Region; SCC: Squamous Cell Carcinoma; LSIL: Low Grade Squamous Intraepithelial Lesion; HSIL: High Grade Intraepithelial Lesion; TLR: Toll Like Receptors; NK: Natural Killer

Introduction

Globally cervical cancer is the fourth most common cancer in women. Cervical cancer occurs due to neoplastic transformation of cells in the cervix i.e. lower part of the uterus. The worldwide incidence of cervical cancer, 5,10,000 new cases diagnosed every year and approximately 2,88,000 deaths [1]. In India, 1,32,000 new cases diagnosed and 74,000 death every year. The incidence is more common in women above the age of 30 years. Cervical cancer is almost always caused by Human Papilloma Virus (HPV) infection [2]. HPV infection is responsible for more than 90% cervical cancer causes and the other less important factors include smoking, weak immune system, birth control pills, and unsafe sex (contraceptives) [3]. 90% of cervical cancer cases are squamous cell carcinomas and 10% are adenocarcinoma. About 6.6% of women in Indian population are estimated to harbor cervical HPV infection.

Human Papilloma Virus (HPV)

HPV are small (50 nm) double-stranded DNA viruses composed of a genome of 8kilobase pair, enclosed inside a nonenveloped capsid protein. The genome consists of three sets: (a) early genes (E1, E2, E4, E5, E6, E7) which regulate the vegetative and productive phase of viral life cycle: (b) late genes (L1, L2) which encode the capsid protein and (c) a non-coding regulatory region called Long Control Region (LCR) control the regulation of viral replication and transcription [4] (Figure 1).

Types

Approximately 200 different HPV types have been characterized, and the two most frequent high-risk HPV genotypes, HPV- 16 and HPV-18, according for 70% of cases. HPV6 and HPV11 are common causes of genital warts and precancerous lesions [5]. The HPVs can be broadly grouped into cutaneous types and mucosal types based on tissue tropism. The cutaneous types are found in the general population and cause common warts with individuals are immunosuppressed. The mucosal HPVs are further classified into high-risk and low-risk types, based on their respective degree of association with cervical cancer. The most common lowrisk types are HPV 6 and 11, detected most often in benign genital warts. HPV 16, 18, 31, and 45 are predominant types found in cervical Squamous Cell Carcinoma (SCC), accounting for more than 90% of cases, with HPV 16 alone accounting for about half the cases worldwide [6]. HPV 18 is the most prevalent type in cervical adenocarcinomas (55%), followed by HPV 16 (32%) and HPV 45 (10%). Epidemiological evidence suggests that infection with HPV is the greatest risk factor [7]. Its, role in the progression of the precursor lesions to cervical cancer is well established [8].

Mechanism of HPV infection

HPV infection normally does not integrate its DNA to host DNA. In high-risk HPV, DNA is often integrated into the human genome in cervical squamous cell carcinoma. It has been proposed that integration can be an early event associated with Low Grade Squamous Intraepithelial Lesion (LSIL) to High Grade Intraepithelial Lesion (HSIL) progression [9]. HPV can infect cells through damaged tissue. In the immune response, keratinocytes play an important role which can express Toll Like Receptors (TLR), participate in the innate immune response and recognize both endogenous and exogenous. In this process, TLRs are activated and can synthesize and release a variety of cytokines involved in immune regulation like IL-1, IL-6, IL-8, IL-10, TNF-α and IFN-β to activate Natural Killer (NK) cells [10]. The NK-activating receptors affect the cytolytic functionality. It elicits a proinflammatory expression profile which promotes innate immunity. The initial inflammatory response leads to infiltration of immune cells such as neutrophils, macrophages and lymphocytes.

HPVs are exclusively epitheliotropic, and their replication is intimately linked to the differentiation process of the host cells. Normal squamous epithelial cells grow as stratified epithelium, with those in the basal layers dividing as stem cells of transient amplifying cells. After division, one of the daughter cells migrates upward and begins to undergo terminal differentiation while the other remains in the basal layer as a slow-cycling, self-renewing population. Productive papillomavirus infection begins when infectious daughter cells of the basal layer, probably through micro-wounds. The viral genome is maintained in these cells as a stable episome at low copy number, and that generate productive wart. The early HPV genes E1 and E2 support viral DNA replication and its segregation such that the infected cells can be maintained in the lesion for a long period. As infected daughter cells migrate towards the epithelial surface, viral late gene products are produced to initiate the vegetative phase of the HPV life cycle, resulting in the high-level amplification of the viral genome. In the outer layers of the epithelium, viral DNA is packaged into capsids and progeny virions are released to re-initiate infection, persistent infection rather than clearance of the virus linked to the development of precancerous lesion followed for invasion and metastasis [11].

Diagnosis

The important methods to diagnose HPV infection are

• Pap smear test-It is a screening test first describe by Papanicolaou and Traut. Apart from premalignant and malignant changes, viral infections like HPV infection and Herpes can also be detected. Positive test requires further confirmatory tests like colposcopy, cervical biopsy, and DNA tests like PCR.

• Colposcopy and acetic acid test- Colposcopy is the examination of the cervix, vagina, and in some instances the vulva after the application of acetic acid solution.

• Biopsy- Colposcopy allows tissue sampling (biopsy) that is targeted to the abnormal areas.

• DNA test (PCR, Southern Blot Hybridization, In Situ Hybridization) - Initial methods of HPV detection used were direct probe hybridization such as dot blot and Southern blot.

Prevention

The two novel and highly efficacious prevention methods are prophylactic HPV vaccination to control the early peak of infections and sensitive HPV-based screening to detect and treat the secondary peak of precancerous [12,13].

Conclusion

This review has described the mechanism of HPV mediated carcinogenesis in human cells. A future challenge to this end is defining the research agenda for deciding on the optimal technology and intensity of screening to make cervical cancer a very rare disease while minimizing the possible harms.

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