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Can Vet J. 2017 July; 58(7): 750–752.
PMCID: PMC5479671

Is melatonin of value in cancer treatment? Experience with a case of feline mammary carcinoma

A mature, spayed female domestic shorthaired (DSH) cat weighing 5.8 kg was presented to my clinic in January 2015 for evaluation of an upper left thoracic mammary mass, which was diagnosed as a poorly differentiated carcinoma. The cat had multiple recurrences and surgeries and supplementation with oral melatonin. She survived for 2 years following the initial visit. The details are as follows.

The subcutaneous mass was diffuse, 5 to 6 cm across, and had a ropey texture. All lymph nodes palpated normally and survey thoracic radiographs did not demonstrate any abnormalities. A complete blood (cell) count (CBC) showed a mild lymphopenia and blood biochemistry values were within normal limits. Mastectomy of the 2 upper left thoracic mammary glands was carried out under general anesthesia; post-operative recovery was unremarkable. Histopathology revealed a poorly differentiated high grade mammary adenocarcinoma with intravascular and intra-lymphatic invasion. Referral for additional oncology management including chemotherapy was declined. However the owners did elect to begin oral melatonin supplementation at 3 mg daily, administered in the morning.

In January of 2016 the cat was presented with a solitary grape-sized focal subcutaneous mass in the same general area but slightly more to the axilla. There were no other clinical or physical concerns. Pre-operative blood analysis revealed a moderate leukopenia due to a neutropenia and lymphopenia. A lumpectomy under general anesthesia was conducted and histopathology diagnosed a metastatic tubular carcinoma within an axillary lymph node. Recovery was without incident and the owners did not report any further abnormalities until September 2016, when a 3rd subcutaneous mass in the region had developed. This mass appeared more invasive, was diffuse, hard, not consistent in texture on palpation, and 6 to 8 cm in size. Pre-anesthetic serum biochemistry values continued to be within normal limits, but a leukopenia persisted. A mass removal was performed again. The owners had continued with the oral melatonin supplementation for the entire duration and did not report any other abnormal clinical signs. Histopathology was declined at the third surgical intervention.

Twenty-four months after presenting for the initial mass (January 2017), the patient was presented for the fourth time with an upper left thoracic/axillary subcutaneous mass. This mass was 8 cm across and irregular in shape, extending deep into the left axilla and feeling firm and lobular on palpation. The owners reported a transient period (24 h) of the cat being off food 2 to 3 wk before presentation, with 1 episode of vomition. The cat had maintained her weight to this point but she now weighed 5.3 kg. In addition to a mild leukopenia there was a mild increase in total serum protein. The mass was removed under general anesthesia and a drain was placed. A histopathological diagnosis of solid and tubular mammary carcinoma was made. The cat had survived over 730 d since the initial diagnosis.

Feline mammary tumors (FMT) are reported to be the third most common neoplasm in cats, after hemopoietic and skin (1) and there is an increased risk associated with being intact (2,3). Dorn et al (2) showed that neutering decreased the risk of developing FMT 7-fold. Similarly, a controlled retrospective study showed that ovariohysterectomy decreased the risk of FMT 2.7-fold (95% confidence interval; 1.4 to 5.3, P < 0.0010) compared to intact felines and that relative risk was reduced by 91% if the ovariohysterectomy was done by 6 mo of age and 86% if done by 1 y of age (3).

A breed associated risk may exist with DSH and Siamese cats being overrepresented (46). The majority of FMTs are classified as carcinomas with metastasis frequently reported (46). Feline mammary tumors are subtyped by both growth and histology. Tumors are graded I to IV using a tumor, node, metastasis (TNM) system depending on tumor size and evidence of lymph node involvement or metastasis (57). Various histological subtypes of FMTs including solid, tubular, papillary, tubulopapillary, complex, invasive micropapillary, squamous cell, cribiform, and mixed have been described (5,8,9). The grade of tumor can also be defined based on histology using modified versions of the World Health Organization (WHO) or Elston and Ellis grading systems (5,9) in which grade 1 (I) tumors are well-differentiated, grade 2 (II) are moderately differentiated and grade 3 (III) tumors are poorly differentiated. A recent review by Zapulli et al (7) confirmed a relationship between tumor size and survival time for felines with mammary neoplasms but suggests that standardization in histological classification and study methodology are required. For example, not all studies have reported significant findings for tumors < 3 cm which may be related to differences in accuracy and instrumentation (10). Further, while Castagnaro et al (8) demonstrated good predictive value for tumor grades I and III but not for grade II, Seixas et al (5) showed statistical significance between histological grade and overall survival using univariate analysis.

Some factors used to determine prognosis in human patients, such as hormone responsiveness (estrogen or progesterone receptor status) are not well-developed in veterinary medicine (11). However, some studies have shown that unlike humans, feline mammary carcinomas do not display a high degree of positive steroid receptors (3,4,11,12). The absence of estrogen responsiveness in most feline tumors (11) seems at odds with the demonstrated protective effect of ovariohysterectomy (3).

This case highlights a cat diagnosed with a poorly differentiated carcinoma; according to Seixas et al (5) only 3.1% of cats with grade III mammary lesions survive to 2 y after presentation. The initial tumor size of 5 cm is in the expected range for a grade III tumor (8). The fact that the lymph node mass diagnosed 1 y after the removal of the original tumor was a different histological type may not be that unusual as involved lymph nodes can display discordant results (42.9% of the time) compared to the primary tumor (11).

The primary recommendation for management of FMT is surgical removal (4,13). It is not clear whether radical mastectomy has any benefit over more conservative surgical removal in terms of survival (4,6). Cats with more aggressive disease as suggested by diagnosis with histological grade II and III tumors would appear to be candidates for adjunct therapy (6,13). However, studies have failed to consistently demonstrate that surgery plus chemotherapy confers any beneficial effect in terms of survival (4,6,14). Managing the side effects of chemotherapeutic agents in cats may be a substantial challenge (4,13). Other barriers to providing chemotherapy include financial means of the owner and patient personality and amenability to handling. Radiation therapy is not routinely recommended for FMT (4).

In this case, the patient received daily oral melatonin (3 mg/day) following removal of the original tumor. Melatonin is an indole amine hormone produced by pinealocytes and extra-pineal cells (15). Nocturnal secretions from the pineal gland provide a diurnal peak that mediates a number of biological effects including immunomodulatory, oncostatic, and anti-oxidant effects (15). Several studies have shown that women who do shiftwork or who regularly cross time zones (e.g., flight attendants) involving frequent changes in their sleep/wake cycle, are at increased risk of breast cancer. The “melatonin hypothesis” suggests that these disruptions in the normal circadian rhythm also disrupt the nocturnal emissions of melatonin (16) and that the loss of melatonin is related to increased risk of malignancy due to an inability to inhibit cyclooxygenase-2 activity which has been implicated in various malignancies including human and feline breast carcinomas (17,18).

This case illustrates a number of interesting points. The most remarkable is the duration of the patient’s survival. The prognosis for poorly differentiated carcinomas is very poor with some studies showing 100% of cats dying by 1 y after surgery (8) and other studies demonstrating only 3% surviving to 2 y after diagnosis (12). This patient’s primary mass also had micro blood vessel and lymphatic invasion. The observation that the subject received daily melatonin treatment suggests that further studies on the possible benefits of melatonin might be useful. While it is not possible to determine from this single case whether melatonin had any role, the paucity of randomized clinical trials of chemotherapeutic agents post-surgery and the high level of side-effects from treatment suggests melatonin might bear consideration for further clinical trials with and without other therapeutics. Further, as Hughes et al (12) discuss, the role of ovariohysterectomy in the incidence of feline carcinomas needs to be considered since most FMT are estrogen receptor negative. It has been suggested that FMT may be a suitable model for human carcinomas but any comparison to women requires that future studies look at the separate incidence and prognosis in all feline molecular subtypes. A final note needs to recognize the dedication of this patient’s owners, who played a major role in her long survival. CVJ

Acknowledgments

I thank Robert Lafrenie, PhD, of Health Sciences North Research Institute and Laurentian University, Sudbury, Ontario for his kind mentoring and review of the manuscript and the Irvine family for their permission to share the information about this case.

Footnotes

Use of this article is limited to a single copy for personal study. Anyone interested in obtaining reprints should contact the CVMA office (gro.vmca-amvc@nothguorbh) for additional copies or permission to use this material elsewhere.

References

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Articles from The Canadian Veterinary Journal are provided here courtesy of Canadian Veterinary Medical Association